The utility of inflammatory biomarkers in predicting overall survival and recurrence in skull base chordoma.

OBJECTIVE: Numerous studies have investigated the impact of inflammatory factors in cancer, yet few attempts have been made to investigate these markers in skull base chordoma (SBC). Inflammatory values including neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI) can serve as prognostic markers in various cancers. This study aimed to determine whether these inflammatory factors influence overall survival (OS) or progression-free survival (PFS) in patients with primary SBC. METHODS: The electronic medical records of patients with primary SBC who underwent resection from 2001 to 2020 were retrospectively reviewed for the associations of sex, age at diagnosis, preoperative steroid use, tumor volume, extent of resection, adjuvant radiation after surgery, tumor metastasis, Ki-67 index, percent homozygous deletion of 9p23 and percent 1p36 loss, and potential prognostic inflammatory markers of NLR, PLR, LMR, SII, and SIRI with the primary outcome measures of OS and PFS. Maximum log-rank statistical tests were used to determine inflammatory marker thresholds for grouping prior to Kaplan-Meier and Cox proportional hazards analysis for OS and PFS of the elucidated groups. RESULTS: The cohort included 115 primary SBC patients. The mean ± SD tumor volume was 23.0 ± 28.0 cm3, 73% of patients received gross-total resection, 40% received postoperative radiation, 25% had local recurrence, and 6% had subsequent metastatic disease (mean follow-up 47.2 months). Univariable Cox analysis revealed that NLR (p < 0.01), PLR (p = 0.04), LMR (p = 0.04), SII (p < 0.01), and SIRI (p < 0.01) were independently associated with PFS. Additionally, NLR (p = 0.05) and SII (p = 0.03) were significant in multivariable Cox analysis of PFS. However, both univariable and multivariable Cox analysis revealed no correlations with OS. CONCLUSIONS: The routine assessment of inflammatory biomarkers such as NLR and SIRI could have prognostic value in postresection SBC patients.

The role of surgical management for prolactin-secreting tumors in the era of dopaminergic agonists: An international multicenter report.

OBJECTIVE: First-line prolactin-secreting tumor (PST) management typically involves treatment with dopamine agonists and the role of surgery remains to be further explored. We examined the international experience of 12 neurosurgical centers to assess the patient characteristics, safety profile, and effectiveness of surgery for PST management. METHODS: Patients surgically treated for PST from January 2017 through December 2020 were evaluated for surgical characteristics, outcomes, and safety. RESULTS: Among 272 patients identified (65.1% female), the mean age was 38.0 ± 14.3 years. Overall, 54.4% of PST were macroadenomas. Minor complications were seen in 39.3% of patients and major complications were in 4.4%. The most common major complications were epistaxis and worsened vision. Most minor complications involved electrolyte/sodium dysregulation. At 3-6 months, local control on imaging was achieved in 94.8% of cases and residual/recurrent tumor was seen in 19.3%. Reoperations were required for 2.9% of cases. On multivariate analysis, previous surgery was significantly predictive of intraoperative complications (6.14 OR, p < 0.01) and major complications (14.12 OR, p < 0.01). Previous pharmacotherapy (0.27 OR, p = 0.02) and cavernous sinus invasion (0.19 OR, p = 0.03) were significantly protective against early endocrinological cure. Knosp classification was highly predictive of residual tumor or PST recurrence on 6-month follow-up imaging (4.60 OR, p < 0.01). There was noted institutional variation in clinical factors and outcomes. CONCLUSION: Our results evaluate a modern, multicenter, global series of PST. These data can serve as a benchmark to compare with DA therapy and other surgical series. Further study and longer term outcomes could provide insight into how patients benefit from surgical treatment.

Crooke Cell Adenoma Confers Poorer Endocrinological Outcomes Compared with Corticotroph Adenoma: Results of a Multicenter, International Analysis.

BACKGROUND: Crooke cell adenomas (CCAs) are a rare, aggressive subset of secretory pituitary corticotroph adenomas (sCTAs) found in 5%-10% of patients with Cushing disease. Multiple studies support worse outcomes in CCAs but are limited by small sample size and single-institution databases. We compared outcomes in CCA and sCTA using a multicenter, international retrospective database of high-volume skull base centers. METHODS: Patients surgically treated for pituitary adenoma from January 2017 through December 2020 were included. RESULTS: Among 2826 patients from 12 international centers, 20 patients with CCA and 480 patients with sCTA were identified. No difference in baseline demographics, tumor characteristics, or postoperative complications was seen. Microsurgical approaches (60% CCA vs. 62.3% sCTA) were most common. Gross total resection was higher in CCA patients (100% vs. 83%, P = 0.05). Among patients with gross total resection according to intraoperative findings, fewer CCA patients had postoperative hormone normalization of pituitary function (50% vs. 77.8%, P < 0.01) and remission of hypersecretion by 3-6 months (75% vs. 84.3%, P < 0.01). This was the case despite CCA having better local control rates (100% vs. 96%, P < 0.01) and fewer patients with remnant on magnetic resonance imaging (0% vs. 7.2%, P < 0.01). A systematic literature review of 35 studies reporting on various treatment strategies reiterated the high rate of residual tumor, persistent hypercortisolism, and tumor-related mortality in CCA patients. CONCLUSIONS: This modern, multicenter series of patients with CCA reflects their poor prognosis and reduced postsurgical hormonal normalization. Further work is necessary to better understand the pathophysiology of CCA to devise more targeted treatment approaches.

Defining benchmark outcomes for transsphenoidal surgery of pituitary adenomas: a multicenter analysis.

IMPORTANCE: Benchmarks aid in improve outcomes for surgical procedures. However, best achievable results that have been validated internationally for transsphenoidal surgery (TS) are not available. OBJECTIVE: We aimed to establish standardized outcome benchmarks for TS of pituitary adenomas. DESIGN: A total of 2685 transsphenoidal tumor resections from 9 expert centers in 3 continents were analyzed. SETTING: Patients were risk stratified, and the median values of each center's outcomes were established. The benchmark was defined as the 75th percentile of all median values for a particular outcome. The postoperative benchmark outcomes included surgical factors, endocrinology-specific values, and neurology-specific values. RESULTS: Of 2685 patients, 1149 (42.8%) defined the low-risk benchmark cohort. Within these benchmark cases, 831 (72.3%) patients underwent microscopic TS, and 308 (26.8%) patients underwent endoscopic endonasal resection. Of all tumors, 799 (29.8%) cases invaded the cavernous sinus. The postoperative complication rate was 19.6% with mortality between 0.0% and 0.8%. Benchmark cutoffs were ≤2.9% for reoperation rate, ≤1.9% for cerebrospinal fluid leak requiring intervention, and ≤15.5% for transient diabetes insipidus. At 6 months, benchmark cutoffs were calculated as follows: readmission rate: ≤6.9%, new hypopituitarism ≤6.0%, and tumor remnant ≤19.2%. CONCLUSIONS: This analysis defines benchmark values for TS targeting morbidity and mortality and represents the best outcomes in the best patients in expert centers. These cutoffs can be used to assess different centers, patient populations, and novel surgical techniques. It should be noted that the benchmark values may influence each other and must be evaluated in their own context.

Clinical characteristics of familial and sporadic pediatric cerebral cavernous malformations and outcomes.

OBJECTIVE: Cerebral cavernous malformation (CCM) is a subtype of the vascular malformations found within the cerebral cortex. Although rare and usually discovered incidentally, these vascular abnormalities can predispose patients to spontaneous cerebral hemorrhage and subsequently lead to a myriad of neurological symptoms at presentation such as seizures and other focal neurological deficits. Although the symptoms and presentations of CCM have been adequately described in the adult population, disease characteristics and outcomes have not been extensively described in the pediatric population. Furthermore, the etiology of CCM-e.g., familial versus sporadic disease, as well as the risk factors for hemorrhage and neurological deficits and predictors of clinical and surgical outcomes-has not been adequately explored in the pediatric population. The current study attempts to classify and characterize differences in the clinical presentation, characteristics, and outcomes of CCMs between familial and sporadic cases within the pediatric population. METHODS: A retrospective review identified 131 pediatric patients with radiographically confirmed diagnosis of CCM. All pertinent demographic and clinical variables were collected. CCM lesions were characterized using T2-weighted and susceptibility-weighted angiography (SWAN) MRI. Statistical analysis was conducted using the t-test for continuous variables, whereas categorical variables were analyzed with the Fisher exact test or chi-square test. Multivariate analysis was performed using a Cox proportional hazards model with R version 4.2.0. RESULTS: This retrospective study identified 131 pediatric CCM patients with a mean age of 8.4 years, and 54% (n = 71) were male. Twenty-seven percent (n = 35) were identified as cases with familial CCM, with the remainder classified as sporadic. The most common symptoms at presentation included generalized symptoms (headaches, nausea, and vomiting) or seizures, with a large proportion of patients also presenting as asymptomatic. No significant differences were observed in severity of symptoms between patients harboring different forms of the disease. Patients with familial CCM were noted to have a larger lesion size on average (5.26 cm3 vs 1.6 cm3, p = 0.047). These patients also had a shorter progression-free follow-up interval, with 50% of patients showing progression by 888 days, compared with only 15% of sporadic CCM patients during the same period (p = 0.0019). Familial etiology of the disease and larger average lesion volume were independent, significant predictors of disease progression (p = 0.001, HR 3.29, 95% CI 1.65-6.54) and future hemorrhage (p = 0.023, HR 1.1, 95% CI 1.01-1.10), respectively. CONCLUSIONS: Familial and sporadic CCMs tend to present with similar characteristics within the pediatric population. Patients with the familial form of the disease have an increased risk of progressive disease in terms of further hemorrhagic events.

Bibliometric Analysis of the Top 100 Cited Articles on Stereotactic Radiosurgery for Trigeminal Neuralgia.

Background Stereotactic radiosurgical rhizolysis of the trigeminal nerve is an established modality increasingly employed to alleviate the symptoms of refractory trigeminal neuralgia. This study analyzes the academic impact of the top 100 cited articles on the radiosurgical management of trigeminal neuralgia. Methods The Scopus database was searched for articles containing "radiosurgery" and one or more of "trigeminal neuralgia," "trigeminus neuralgia," and "tic douloureux." The top 100 articles written in English were arranged in descending order by citation count. Documents were evaluated for authors, publication year, journal and impact factor, total citations, nationality, study type, radiosurgical modality, and the affiliated institution. Quantitative and qualitative analyses were performed on the data. Results The most cited articles were published between 1971 and 2019. The average citation per year was 4.3. The most targeted anatomic area was the "root entry zone" or proximal portion of the cisternal segment of the trigeminal nerve. The most utilized modality was Gamma Knife radiosurgery. The country with the highest number of publications was the United States. Thirty-six percent of the articles were published in the Journal of Neurosurgery . Lunsford, Kondziolka, Flickinger, and Régis, respectively, were the most frequently listed co-authors. The most prolific institute was the University of Pittsburgh Medical Center. Conclusion Stereotactic radiosurgery is an important modality in the management of medically or surgically refractory trigeminal neuralgia. This analysis assesses its contributions over the past five decades to identify trends in treatment practices for neurosurgeons and to highlight areas where further study is needed.

A Multicenter, Propensity Score-Matched Assessment of Endoscopic Versus Microscopic Approaches in the Management of Pituitary Adenomas.

BACKGROUND AND OBJECTIVES: There is considerable controversy as to which of the 2 operating modalities (microsurgical or endoscopic transnasal surgery) currently used to resect pituitary adenomas (PAs) is the safest and most effective intervention. We compared rates of clinical outcomes of patients with PAs who underwent resection by either microsurgical or endoscopic transnasal surgery. METHODS: To independently assess the outcomes of each modality type, we sought to isolate endoscopic and microscopic PA surgeries with a 1:1 tight-caliper (0.01) propensity score-matched analysis using a multicenter, neurosurgery-specific database. Surgeries were performed between 2017 and 2020, with data collected retrospectively from 12 international institutions on 4 continents. Matching was based on age, previous neurological deficit, American Society of Anesthesiologists (ASA) score, tumor functionality, tumor size, and Knosp score. Univariate and multivariate analyses were performed. RESULTS: Among a pool of 2826 patients, propensity score matching resulted in 600 patients from 9 surgery centers being analyzed. Multivariate analysis showed that microscopic surgery had a 1.91 odds ratio (OR) ( P = .03) of gross total resection (GTR) and shorter operative duration ( P < .01). However, microscopic surgery also had a 7.82 OR ( P < .01) for intensive care unit stay, 2.08 OR ( P < .01) for intraoperative cerebrospinal fluid (CSF) leak, 2.47 OR ( P = .02) for postoperative syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was an independent predictor for longer postoperative stay (ß = 2.01, P < .01). Overall, no differences in postoperative complications or 3- to 6-month outcomes were seen by surgical approach. CONCLUSION: Our international, multicenter matched analysis suggests microscopic approaches for pituitary tumor resection may offer better GTR rates, albeit with increased intensive care unit stay, CSF leak, SIADH, and hospital utilization. Better prospective studies can further validate these findings as matching patients for outcome analysis remains challenging. These results may provide insight into surgical benchmarks at different centers, offer room for further registry studies, and identify best practices.

Polycystic ovary syndrome preceding the diagnosis of acromegaly: a retrospective study in 97 reproductive-aged women.

BACKGROUND: Acromegaly is a disease of growth hormone excess that results in enlargement of extremities, abnormal glucose and lipid metabolism, and gonadal disruption. Manifestations of the disease are insidious and typically lead to a diagnostic delay of 7-10 years. Classically the polycystic ovary syndrome (PCOS) phenotype is described in women with irregular menses, clinical or biochemical evidence of androgen excess, and/or multiple ovarian follicles on pelvic ultrasonography. Women with acromegaly may present with some or all of these symptoms. Our objective was to evaluate the prevalence of PCOS in patients with acromegaly and to determine if diagnosis of PCOS results in a delay in diagnosing acromegaly. METHODS: Using patient databases at two academic health centers, we identified 97 premenopausal women aged 18-49 years old presenting with acromegaly. Data were collected regarding pelvic sonography and reproductive history, including the diagnosis of PCOS. Patients carrying the diagnosis of PCOS before their diagnosis of acromegaly were identified and the remaining patients were screened using the Rotterdam criteria to identify additional patients meeting the criteria for PCOS prior to their diagnosis of acromegaly. RESULTS: Mean age of the population (n = 97) at the time of diagnosis of acromegaly was 33.4 ± 7.5 years (SD). Thirty-three percent of patients (n = 32) either carried a diagnosis of PCOS or met diagnostic criteria for PCOS before their diagnosis of acromegaly. In the subset of patients in whom data on symptom onset were available, those who met criteria for PCOS were diagnosed with acromegaly a median of 5 years [4, 9] after the onset of symptoms compared to 2 years [0.92, 3] (p = 0.006) in the patients who did not meet criteria for PCOS. CONCLUSIONS: Our data demonstrate a high prevalence of signs and symptoms of PCOS in reproductive-aged women with acromegaly and a longer time to diagnosis in women who meet the clinical criteria for PCOS. As screening for acromegaly is relatively simple and done with measurement of a random, non-fasting IGF-1 level that can be drawn at any time during the menstrual cycle, screening patients with PCOS for acromegaly may lessen the delay in diagnosis for reproductive-aged women with this disease.

Gamma Knife radiosurgery for meningiomas of the confluence of the falx and tentorium.

PURPOSE: Meningiomas arising from the confluence of the falx and tentorium (CFT) are a rare and challenging subset of meningiomas. Gamma Knife radiosurgery (GKRS) is well-established as a safe and effective management strategy for intracranial meningiomas, but its role in treating CFT meningiomas is not well-described. This paper reports the largest series focused exclusively on the outcomes of GKRS for CFT meningiomas. METHODS: We retrospectively identified 20 CFT meningiomas out of 2031 meningioma patients who underwent GKRS at our institution between 1987 and 2021. Tumor control, overall survival (OS), and complications were recorded and analyzed. The median tumor margin dose was 13 Gy at the 50% isodose line. The median tumor volume treated was 4.4 cc (IQR 3.5-7.7). The median patient age was 58 years (range 33-83), the median MRI surveillance duration was 59 months (IQR 34-92), and the median overall follow-up duration was 92 months (IQR 42-201). RESULTS: The local tumor control rate (PFS) at 5 and 10-years were 100% (N=10) and 83% (N=4), respectively. Eight patients had stable tumor volumes and 11 patients had regression. One patient with a twice-operated tumor had delayed progression at 7.5 years and was retreated with GKRS. No patient had adverse radiation effects during the period of MRI surveillance. The 5 and 10-year OS were 100% (N=13) and 100% (N=7), respectively. CONCLUSIONS: GKRS is a valuable therapeutic strategy for patients with newly diagnosed CFT meningiomas or progressive residual tumors after surgical resection.

Reduction of giant parietooccipital fibrous dysplasia using dynamic mirror image guidance: a case report and review of the literature.

BACKGROUND: Craniofacial fibrous dysplasia (CFD) typically occurs in the facial bones and anterior cranial vault and can produce both disfigurement and functional limitations for patients disfigurement. Treatment consists of reducing the abnormal bone. Bone contouring can become challenging when the exposure does not extend to the corresponding normal contralateral structures for comparison or when normal landmarks are not available, which may compromise the overall aesthetic outcome. We describe a technique using dynamic mirroring to accurately contour the involved part of the cranium in a case of giant CFD. OBSERVATIONS: A 49-year-old male presented with a giant deforming fibrous dysplasia of the right mastoid and parieto-temporo-occiput that was causing functional limitations due to the size of the bony mass. This was managed with multidisciplinary bony reduction. Several neurovascular structures were in proximity to the areas of planned drilling of the expansile lesion, and dynamic mirroring of the uninvolved left skull was utilized to maximize safety and symmetry of reduction. High-speed drilling of the right occipital bone was performed until the navigation system alerted the surgeon that symmetric depth had been achieved. There were no complications from the procedure and this technique maximized the limits of symmetric reduction without significantly increasing surgical complexity or duration. LESSONS: Dynamic mirroring of bony structures in the posterior cranium is not commonly employed in neurosurgical practice. This technique may help improve the aesthetic outcomes of bony reduction in craniofacial dysplasia and a variety of similarly managed bony lesions, contour cranioplasties, and in unilateral craniosynostosis surgery.

Adjuvant chemotherapy for pulmonary sarcomatoid carcinoma: A retrospective analysis of the National Cancer Database.

OBJECTIVES: Pulmonary sarcomatoid carcinoma (PSC) is a rarely occurring variant of non-small cell lung cancer with sarcoma-like features. Compared with traditional non-small cell lung cancer, PSC patients typically present later and have poorer prognoses, irrespective of stage. The standard of care is resection, but guidelines for the use of adjuvant chemotherapy have not been established. To advance the development of evidence-based management algorithms for PSC after resection, a statistical analysis on a nationwide representative sample of patients was performed. METHODS: A retrospective cohort study was performed by querying the National Cancer Database for patients with a diagnosis of PSC between 2004 and 2015. Patients who received complete anatomical resection with or without adjuvant chemotherapy were included. Multivariable regression was used to detect factors associated with the receipt of adjuvant chemotherapy. Multivariable Cox regression of overall survival and Kaplan-Meier survival analysis on propensity-matched groups was conducted to study the association between adjuvant chemotherapy and prognosis. RESULTS: We included 1497 patients with PSC in the final analysis. Factors associated with receiving adjuvant chemotherapy were age, histology, and receipt of adjuvant radiation. The results of multivariable Cox analysis and Kaplan-Meier analysis on propensity matched groups yielded similar trends: adjuvant chemotherapy was associated with improved 5-year overall survival for stage II and III disease, but not for stage I disease. CONCLUSIONS: Multiple factors are associated with receipt of adjuvant chemotherapy for PSC, and this treatment appears to be associated with improved survival in stage II and stage III, but not stage I patients.

An Integrated Management Paradigm for Skull Base Chordoma Based on Clinical and Molecular Characteristics.

Objective Previous work categorized skull base chordoma (SBC) into three genetic risk groups based on 1p36 and homozygous 9p21(p16) deletions, accounting for a wide variability in prognosis (A = low-risk, B = intermediate-risk, C = high-risk). However, it remains unclear how these groups could guide management. Study Design By integrating surgical outcome and adjuvant radiation (AdjXRT) information with genetic data on 152 tumors, we sought to develop an evidence-based management algorithm for SBC. Results Gross total resections (GTRs) were associated with improved progression free survival (PFS) in all genetic groups. For Group C tumors, GTR and AdjXRT independently contributed to PFS (multivariate Cox proportional hazard ratio [HR] = 0.14, p = 0.002, and HR = 0.40, p = 0.047, respectively). For Group B tumors, AdjXRT improved outcomes only when GTR was not feasible (log-rank p = 0.008), but not following GTR (log-rank p = 0.54). However, 24 of 25 Group A tumors underwent GTR, and AdjXRT for these did not confer any benefit (log-Rank p = 0.285). The high GTR rates in Group A could be explained by smaller tumor sizes (mean = 0.98cc/4.08cc/4.92cc for Group A/B/C, respectively, p = 0.031) and lack of invasiveness. Group A tumors were also more frequently diagnosed in young people ( p = 0.002) as asymptomatic lesions ( p = 0.001), suggesting that they could be precursors to tumors in higher risk groups. Conclusion Genotypic grouping by 1p36 and homozygous 9p21(p16) deletions can predict prognosis in SBC and guide management. GTR remains the cornerstone of SBC treatment and can be sufficient without AdjXRT in low and intermediate risk tumors. Low-risk tumors are associated with a less invasive phenotype, which makes them more amenable to GTR.

A Minimal Physiologically-Based Pharmacokinetic Model Demonstrates Role of the Neonatal Fc Receptor (FcRn) Competition in Drug-Disease Interactions With Antibody Therapy.

Disease trajectories following antibody therapy can have a significant impact on the pharmacokinetics of the antibody. Although this phenomenon can often be explained by reduced target-expressing cells, other mechanisms may play a role. We use a novel minimal physiologically-based pharmacokinetic model to evaluate an alternative drug-disease interaction mechanism involving competitive inhibition of neonatal Fc receptor (FcRn)-mediated Immunoglobulin G recycling by paraproteins. The model is validated with clinical data from the anti-FcRn antibody M281 and is used to conduct a scenario test to quantify the interaction among M-protein, the characteristic paraprotein of multiple myeloma (MM), and the anti-CD38 antibody daratumumab indicated for MM treatment. Simulations predict up to a 3.6-fold increase in daratumumab half-life following M-protein reduction, which lends credence to the hypothesis that FcRn competition in MM can manifest as time-dependent reduction of clearance for daratumumab. This model can inform optimal dosing strategies for antibodies in MM and other pathologies of paraprotein excess.