Ocular toxicities of FDA-approved antibody drug conjugates.

Antibody-drug conjugates (ADCs) are an emerging field of cancer treatments that are becoming more widespread in their use. However, there are potential ocular toxicities associated with these drugs that ophthalmologists need to be aware of to better maintain ocular health as patients undergo rigorous medical treatment for their conditions. While many ADCs have been approved by the Food and Drug Administration (FDA), many subsequent reports have been published regarding additional ocular side effects these drugs may cause. This review provides ophthalmologists with a practical guide on how to treat ocular toxicities associated with all FDA-approved ADCs to date. The potential pathophysiology of side effects is also discussed.

Frailty and postoperative outcomes in brain tumor patients: a systematic review subdivided by tumor etiology.

PURPOSE: Frailty has gained prominence in neurosurgical oncology, with more studies exploring its relationship to postoperative outcomes in brain tumor patients. As this body of literature continues to grow, concisely reviewing recent developments in the field is necessary. Here we provide a systematic review of frailty in brain tumor patients subdivided by tumor type, incorporating both modern frailty indices and traditional Karnofsky Performance Status (KPS) metrics. METHODS: Systematic literature review was performed using PRISMA guidelines. PubMed and Google Scholar were queried for articles related to frailty, KPS, and brain tumor outcomes. Only articles describing novel associations between frailty or KPS and primary intracranial tumors were included. RESULTS: After exclusion criteria, systematic review yielded 52 publications. Amongst malignant lesions, 16 studies focused on glioblastoma. Amongst benign tumors, 13 focused on meningiomas, and 6 focused on vestibular schwannomas. Seventeen studies grouped all brain tumor patients together. Seven studies incorporated both frailty indices and KPS into their analyses. Studies correlated frailty with various postoperative outcomes, including complications and mortality. CONCLUSION: Our review identified several patterns of overall postsurgical outcomes reporting for patients with brain tumors and frailty. To date, reviews of frailty in patients with brain tumors have been largely limited to certain frailty indices, analyzing all patients together regardless of lesion etiology. Although this technique is beneficial in providing a general overview of frailty's use for brain tumor patients, given each tumor pathology has its own unique etiology, this combined approach potentially neglects key nuances governing frailty's use and prognostic value.

The integrated multiomic diagnosis of sporadic meningiomas: a review of its clinical implications.

INTRODUCTION: Meningiomas are generally considered "benign," however, these tumors can demonstrate variability in behavior and a surprising aggressiveness with elevated rates of recurrence. The advancement of next-generation molecular technologies have led to the understanding of the genomic and epigenomic landscape of meningiomas and more recent correlations with clinical characteristics and behavior. METHODS: Based on a thorough review of recent peer-reviewed publications (PubMed) and edited texts, we provide a molecular overview of meningiomas with a focus on relevant clinical implications. RESULTS: The identification of specific somatic driver mutations has led to the classification of several major genomic subgroups, which account for more than 80% of sporadic meningiomas, and can be distinguished using noninvasive clinical variables to help guide management decisions. Other somatic genomic modifications, including non-coding alterations and copy number variations, have also been correlated with tumor characteristics. Furthermore, epigenomic modifications in meningiomas have recently been described, with DNA methylation being the most widely studied and potentially most clinically relevant. Based on these molecular insights, several clinical trials are currently underway in an effort to establish effective medical therapeutic options for meningioma. CONCLUSION: As we enhance our multiomic understanding of meningiomas, our ability to care for patients with these tumors will continue to improve. Further biological insights will lead to additional progress in precision medicine for meningiomas.

Type of bony involvement predicts genomic subgroup in sphenoid wing meningiomas.

PURPOSE: As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature. METHODS: Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as no bone invasion (Type I), hyperostosis only (Type II), tumor invasion only (Type III), or both hyperostosis and tumor invasion (Type IV). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Machine-learning approaches were used to predict genomic subgroups based on pre-operative clinical features. RESULTS: Among 64 SWMs, 53% had Type-II, 9% had Type-III, and 14% had Type-IV bone involvement; nine SOMs were identified. Tumors with invasion (i.e., Type III or IV) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR 27.6; p: 0.004), while hyperostosis only were over 4 times more likely to have a TRAF7 mutation (OR 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR 10.21; p: 0.004). CONCLUSIONS: SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers and grade.

Surgical strategies for older patients with glioblastoma.

OBJECTIVE: While adjuvant treatment regimens have been modified for older patients with glioblastoma (GBM), surgical strategies have not been tailored. METHODS: Clinical data of 48 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination with intraoperative MRI (IoMRI) at Yale New Haven Hospital were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed. RESULTS: The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (P = 0.306), Karnofsky Performance Score (KPS) at postoperative 6 weeks (P = 0.704) or extent of resection (P = 0.263). Length of surgery (LOSx), however, was significantly longer (P = 0.0002) in the IoMRI group. LOSx (P = 0.015) and hospital stay (P = 0.025) were predictors of postoperative complications. Increased EOR (GTR or NTR) (P = 0.030), postoperative adjuvant treatment (P < 0.0001) and postoperative complications (P = 0.006) were predictive for OS. Patients with relatively lower preoperative KPS scores (<70) showed significant improvement at postoperative 6 weeks (P<0.0001). Patients with complications (P = 0.038) were more likely to have lower KPS at postoperative 6 weeks. CONCLUSIONS: Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS. The use of ioMRI in this population does not appear to confer any measurable benefit over ioUS in experienced hands, but prolongs the length of surgery significantly, which is a preventable prognostic factor for impeding care.

Variations in the genomic profiles and clinical behavior of meningioma by racial and ethnic group.

OBJECTIVE: The influence of socioeconomic factors on racial disparities among patients with sporadic meningiomas is well established, yet other potential causative factors warrant further exploration. The authors of this study aimed to determine whether there is significant variation in the genomic profile of meningiomas among patients of different races and ethnicities and its correlation with clinical outcomes. METHODS: The demographic, genomic, and clinical data of patients aged 18 years and older who had undergone surgery for sporadic meningioma between September 2008 and November 2021 were analyzed. Statistical analyses were performed to detect differences across all racial/ethnic groups, as were direct comparisons between Black and non-Black groups plus Hispanic and non-Hispanic groups. RESULTS: This study included 460 patients with intracranial meningioma. Hispanic patients were significantly younger at surgery (53.9 vs 60.2 years, p = 0.0006) and more likely to show symptoms. Black patients had a higher incidence of anterior skull base tumors (OR 3.2, 95% CI 1.7-6.3, p = 0.0008) and somatic hedgehog mutations (OR 5.3, 95% CI 1.6-16.6, p = 0.003). Hispanics were less likely to exhibit the aggressive genomic characteristic of chromosome 1p deletion (OR 0.28, 95% CI 0.07-1.2, p = 0.06) and displayed higher rates of TRAF7 somatic driver mutations (OR 2.96 95% CI 1.1-7.8, p = 0.036). Black patients had higher rates of recurrence (OR 2.6, 95% CI 1.3-5.2, p = 0.009) and shorter progression-free survival (PFS; HR 2.9, 95% CI 1.6-5.4, p = 0.002) despite extents of resection (EORs) similar to those of non-Black patients (p = 0.745). No significant differences in overall survival were observed among groups. CONCLUSIONS: Despite similar EORs, Black patients had worse clinical outcomes following meningioma resection, characterized by a higher prevalence of somatic hedgehog mutations, increased recurrence rates, and shorter PFS. Meanwhile, Hispanic patients had less aggressive meningiomas, a predisposition for TRAF7 mutations, and no difference in PFS. These findings could inform the care and treatment strategies for meningiomas, and they establish the foundation for future studies focusing on the genomic origins of these observed differences.

The clinical and genomic features of seizures in meningiomas.

Meningiomas are the most common central nervous system tumors. Although these tumors are extra-axial, a relatively high proportion (10%-50%) of meningioma patients have seizures that can substantially impact the quality of life. Meningiomas are believed to cause seizures by inducing cortical hyperexcitability that results from mass effect and cortical irritation, brain invasion, or peritumoral brain edema. In general, meningiomas that are associated with seizures have aggressive features, with risk factors including atypical histology, brain invasion, and higher tumor grade. Somatic NF2 mutated meningiomas are associated with preoperative seizures, but the effect of the driver mutation is mediated through atypical features. While surgical resection is effective in controlling seizures in most patients with meningioma-related epilepsy, a history of seizures and uncontrolled seizures prior to surgery is the most significant predisposing factor for persistent postoperative seizures. Subtotal resection (STR) and relatively larger residual tumor volume are positive predictors of postoperative seizures. Other factors, including higher WHO grade, peritumoral brain edema, and brain invasion, are inconsistently associated with postoperative seizures, suggesting they might be crucial in the development of an epileptogenic focus, but do not appear to play a substantial role after seizure activity has been established. Herein, we review and summarize the current literature surrounding meningioma-related epilepsy and underscore the interaction of multiple factors that relate to seizures in patients with meningioma.

Clinical and genomic differences in supratentorial versus infratentorial NF2 mutant meningiomas.

OBJECTIVE: Mutations in NF2 are the most common somatic driver mutation in sporadic meningiomas. NF2 mutant meningiomas preferentially arise along the cerebral convexities-however, they can also be found in the posterior fossa. The authors investigated whether NF2 mutant meningiomas differ in clinical and genomic features based on their location relative to the tentorium. METHODS: Clinical and whole exome sequencing (WES) data for patients who underwent resection of sporadic NF2 mutant meningiomas were reviewed and analyzed. RESULTS: A total of 191 NF2 mutant meningiomas were included (165 supratentorial, 26 infratentorial). Supratentorial NF2 mutant meningiomas were significantly associated with edema (64.0% vs 28.0%, p < 0.001); higher grade-i.e., WHO grade II or III (41.8% vs 3.9%, p < 0.001); elevated Ki-67 (55.0% vs 13.6%, p < 0.001); and larger volume (mean 45.5 cm3 vs 14.9 cm3, p < 0.001). Furthermore, supratentorial tumors were more likely to harbor the higher-risk feature of chromosome 1p deletion (p = 0.038) and had a larger fraction of the genome altered with loss of heterozygosity (p < 0.001). Infratentorial meningiomas were more likely to undergo subtotal resection than supratentorial tumors (37.5% vs 15.8%, p = 0.021); however, there was no significant difference in overall (p = 0.2) or progression-free (p = 0.4) survival. CONCLUSIONS: Supratentorial NF2 mutant meningiomas are associated with more aggressive clinical and genomic features as compared with their infratentorial counterparts. Although infratentorial tumors have higher rates of subtotal resection, there is no associated difference in survival or recurrence. These findings help to better inform surgical decision-making in the management of NF2 mutant meningiomas based on location, and may guide postoperative management of these tumors.

Application of novel PACS-based informatics platform to identify imaging based predictors of CDKN2A allelic status in glioblastomas.

Gliomas with CDKN2A mutations are known to have worse prognosis but imaging features of these gliomas are unknown. Our goal is to identify CDKN2A specific qualitative imaging biomarkers in glioblastomas using a new informatics workflow that enables rapid analysis of qualitative imaging features with Visually AcceSAble Rembrandtr Images (VASARI) for large datasets in PACS. Sixty nine patients undergoing GBM resection with CDKN2A status determined by whole-exome sequencing were included. GBMs on magnetic resonance images were automatically 3D segmented using deep learning algorithms incorporated within PACS. VASARI features were assessed using FHIR forms integrated within PACS. GBMs without CDKN2A alterations were significantly larger (64 vs. 30%, p = 0.007) compared to tumors with homozygous deletion (HOMDEL) and heterozygous loss (HETLOSS). Lesions larger than 8 cm were four times more likely to have no CDKN2A alteration (OR: 4.3; 95% CI 1.5-12.1; p < 0.001). We developed a novel integrated PACS informatics platform for the assessment of GBM molecular subtypes and show that tumors with HOMDEL are more likely to have radiographic evidence of pial invasion and less likely to have deep white matter invasion or subependymal invasion. These imaging features may allow noninvasive identification of CDKN2A allele status.

Simultaneous microvascular decompression for trigeminal neuralgia and hemifacial spasm involving a dolichoectatic vertebral artery in an elderly patient: illustrative case.

BACKGROUND: Hyperactive cranial neuropathies refractory to medical management can often be debilitating to patients. While microvascular decompression (MVD) surgery can provide relief to such patients when an aberrant vessel is compressing the root entry zone (REZ) of the nerve, the arteries of elderly patients over 65 years of age can be less amenable to manipulation because of calcifications and other morphological changes. A dolichoectatic vertebral artery (DVA), in fact, can lead to multiple cranial neuropathies; therefore, a strategy for MVDs in elderly patients is useful. OBSERVATIONS: A 76-year-old man presented with medically refractory trigeminal neuralgia (TN) and hemifacial spasm (HFS). A DVA was the conflicting vessel at the left REZs of the trigeminal and facial nerves. The authors performed a retrosigmoid craniotomy for MVD of the DVA with Teflon padding at both REZs in approximately 1 hour of operative time. The patient was free of facial pain and spasm immediately after surgery and at follow-up. LESSONS: The authors described the case of an elderly patient with both TN and HFS caused by compression of a DVA. Simultaneous MVD with Teflon padding at both REZs provided symptomatic relief with limited surgical time. This can be a particularly useful and straightforward surgical strategy in the elderly population.

Criteria for Cerebrospinal Fluid Diversion in Retractorless Sphenoid Wing Meningioma Surgery: A Technical Report.

Objective Sphenoid wing meningiomas (SWMs) can present surgical challenges, in that they are often obscured by overlying brain, encase critical neurovascular structures, and obliterate cerebrospinal fluid (CSF) cisterns. While brain retraction can enable access, its use can have potentially deleterious effects. We report the benefits and outcomes of the criteria we have developed for use of cerebrospinal diversion to perform retractorless surgery for SWMs. Design Technical report. Setting Yale School of Medicine and Yale New Haven Hospital. Participants Between May, 2019 and December, 2020, ten consecutive patients were included who met the presented criteria for SWM surgery with preoperative lumbar drain (LD) placement. Main Outcome Measures Length of hospital stay, surgical complications, and extent of resection. Results We have developed the following criteria for LD placement in patients with SWMs such that LDs are preoperatively placed in patients with tumors with one or more of the following criteria: (1) medial location along the sphenoid wing, (2) vascular encasement resulting in obliteration of the optic carotid cistern and/or proximal sylvian fissure, and/or (3) the presence of associated edema. CSF release, after craniotomy and sphenoid wing removal, allowed for optimization of exposure, leading to the maximal safe extent of tumor resection without brain retraction or any complications. Conclusions Preoperative LD placement is effective in allowing for maximal extent of resection of SWMs and may be considered in cases where local CSF release is not possible. This technique is useful in those tumors located more medially, with encasement of the vasculature and/or associated with edema.

Genomic profiling of sporadic multiple meningiomas.

BACKGROUND: Multiple meningiomas (MMs) rarely occur sporadically. It is unclear whether each individual tumor in a single patient behaves similarly. Moreover, the molecular mechanisms underlying the formation of sporadic MMs and clonal formation etiology of these tumors are poorly understood. METHODS: Patients with spatially separated MMs without prior radiation exposure or a family history who underwent surgical resection of at least two meningiomas were included. Unbiased, comprehensive next generation sequencing was performed, and relevant clinical data was analyzed. RESULTS: Fifteen meningiomas and one dural specimen from six patients were included. The majority of tumors (12/15) were WHO Grade I; one patient had bilateral MMs, one of which was Grade II, while the other was Grade I. We found 11/15 of our cohort specimens were of NF2-loss subtype. Meningiomas from 5/6 patients had a monoclonal origin, with the tumor from the remaining patient showing evidence for independent clonal formation. We identified a novel case of non-NF2 mutant MM with monoclonal etiology. MMs due to a monoclonal origin did not always display a homogenous genomic profile, but rather exhibited heterogeneity due to branching evolution. CONCLUSIONS: Both NF2-loss and non-NF2 driven MMs can form due to monoclonal expansion and those tumors can acquire inter-tumoral heterogeneity through branched evolution. Grade I and II meningiomas can occur in the same patient. Thus, the molecular make-up and clinical behavior of one tumor in MMs, cannot reliably lend insight into that of the others and suggests the clinical management strategy for MMs should be tailored individually.

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients With Myelofibrosis-A Systematic Review and Meta-Analysis.

Allogeneic hematopoietic cell transplant (allo-HCT) remains the only potentially curative therapeutic modality for patients with primary or secondary myelofibrosis (MF). However, many patients are considered ineligible for allo-HCT, and transplant-related mortality can be substantial. Data on the efficacy and safety of allo-HCT are mixed and largely derived from retrospective studies. We aimed to synthesize the available evidence on the safety and efficacy of allo-HCT in MF and to identify patient, disease, and transplant characteristics with prognostic impact on outcomes of patients with MF undergoing allo-HCT. For this systematic review and meta-analysis, Cochrane Library, Google Scholar, Ovid Medline, Ovid Embase, PubMed, Scopus, and Web of Science Core Collection were searched from inception to October 11, 2020, for studies on allo-HCT in MF. Random-effects models were used to pool response rates for the co-primary outcomes of 1-year, 2-year, and 5-year overall survival (OS). Rates of non-relapse mortality and acute and chronic graft-versus-host-disease (GVHD) were studied as secondary endpoints. Subgroup analyses on the effect of conditioning regimen intensity, baseline dynamic international prognostic scoring system (DIPSS) score, and patient age were performed. The study protocol has been registered on PROSPERO (CRD42020188706). Forty-three studies with 8739 patients were identified and included in this meta-analysis. Rates of 1-year, 2-year, and 5-year OS were 66.7% (95% confidence interval [CI], 63.5%-69.8%), 64.4% (95% CI, 57.6%-70.6%), and 55.0% (95% CI, 51.8%-58.3%), respectively. Rates of 1-year, 2-year, and 5-year nonrelapse mortality were 25.9% (95% CI, 23.3%-28.7%), 29.7% (95% CI, 24.5%-35.4%), and 30.5% (95% CI, 25.9%-35.5%), respectively. The combined rate of graft failure was 10.6% (95% CI, 8.9%-12.5%) with primary and secondary graft failure occurring in 7.3% (95% CI, 5.7%-9.4%) and 5.9% (95% CI, 4.3%-8.0%) of patients, respectively. Rates of acute and chronic graft-versus-host disease were 44.0% (95% CI, 39.6%-48.4%; grade III/IV: 15.2%) and 46.5% (95% CI, 42.2%-50.8%; extensive or moderate/severe: 26.1%), respectively. Subgroup analyses did not show any significant difference between conditioning regimen intensity (myeloablative versus reduced-intensity), median patient age, and proportion of DIPSS-intermediate-2/high patients. The quality of the evidence is limited by the absence of randomized clinical trials in the field and the heterogeneity of patient and transplant characteristics across included studies. Given the poor prognosis of patients not receiving transplants and in the absence of curative nontransplantation therapies, our results support consideration of allo-HCT for eligible patients with MF.