Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma.

PURPOSE: Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma. PATIENTS AND METHODS: Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers. RESULTS: Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4-31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months-undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms. CONCLUSIONS: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.

Critical appraisal of minimally invasive keyhole surgery for intracranial meningioma in a large case series.

BACKGROUND: Meningioma surgery has evolved over the last 20 years with increased use of minimally invasive approaches including the endoscopic endonasal route and endoscope-assisted and gravity-assisted transcranial approaches. As the "keyhole" concept remains controversial, we present detailed outcomes in a cohort series. METHODS: Retrospective analysis was done for all patients undergoing meningioma removal at a tertiary brain tumor referral center from 2008-2021. Keyhole approaches were defined as: use of a minimally invasive "retractorless" approach for a given meningioma in which a traditional larger approach is often used instead. The surgical goal was maximal safe removal including conservative (subtotal) removal for some invasive locations. Primary outcomes were resection rates, complications, length of stay and Karnofsky Performance Scale (KPS). Secondary outcomes were endoscopy use, perioperative treatments, tumor control and acute MRI FLAIR/T2 changes to assess for brain manipulation and retraction injury. RESULTS: Of 329 patients, keyhole approaches were utilized in 193(59%) patients (mean age 59±13; 30 (15.5%) had prior surgery) who underwent 213 operations; 205(96%) were skull base location. Approaches included: endoscopic endonasal (n = 74,35%), supraorbital (n = 73,34%), retromastoid (n = 38,18%), mini-pterional (n = 20,9%), suboccipital (n = 4,2%), and contralateral transfalcine (n = 4,2%). Primary outcomes: Gross total/near total (>90%) resection was achieved in 125(59%) (5% for petroclival, cavernous sinus/Meckel's cave, spheno-cavernous locations vs 77% for all other locations). Major complications included: permanent neurological worsening 12(6%), CSF leak 2(1%) meningitis 2(1%). There were no DVTs, PEs, MIs or 30-day mortality. Median LOS decreased from 3 to 2 days in the last 2 years; 94% were discharged to home with favorable 90-day KPS in 176(96%) patients. Secondary outcomes: Increased FLAIR/T2 changes were noted on POD#1/2 MRI in 36/213(17%) cases, resolving in all but 11 (5.2%). Endoscopy was used in 87/139(63%) craniotomies, facilitating additional tumor removal in 55%. Tumor progression occurred in 26(13%) patients, mean follow-up 42±36 months. CONCLUSIONS & RELEVANCE: Our experience suggests minimally invasive keyhole transcranial and endoscopic endonasal meningioma removal is associated with comparable resection rates and low complication rates, short hospitalizations and high 90-day performance scores in comparison to prior reports using traditional skull base approaches. Subtotal removal may be appropriate for invasive/adherent meningiomas to avoid neurological deficits and other post-operative complications, although longer follow-up is needed. With careful patient selection and requisite experience, these approaches may be considered reasonable alternatives to traditional transcranial approaches.

Complication avoidance protocols in endoscopic pituitary adenoma surgery: a retrospective cohort study in 514 patients.

PURPOSE: To evaluate the impact of using consistent complication-avoidance protocols in patients undergoing endoscopic pituitary adenoma surgery including techniques for avoiding anosmia, epistaxis, carotid artery injury, hypopituitarism, cerebrospinal fluid leaks and meningitis. METHODS: All patients undergoing endoscopic adenoma resection from 2010 to 2020 were included. Primary outcomes included 90-day complication rates, gland function outcomes, reoperations, readmissions and length of stay. Secondary outcomes were extent of resection, short-term endocrine remission, vision recovery. RESULTS: Of 514 patients, (mean age 51 ± 16 years; 78% macroadenomas, 19% prior surgery) major complications occurred in 18(3.5%) patients, most commonly CSF leak (9, 1.7%) and meningitis (4, 0.8%). In 14 of 18 patients, complications were deemed preventable. Four (0.8%) had complications with permanent sequelae (3 before 2016): one unexplained mortality, one stroke, one oculomotor nerve palsy, one oculoparesis. There were no internal carotid artery injuries, permanent visual worsening or permanent anosmia. New hypopituitarism occurred in 23/485(4.7%). Partial or complete hypopituitarism resolution occurred in 102/193(52.8%) patients. Median LOS was 2 days; 98.3% of patients were discharged home. Comparing 18 patients with major complications versus 496 without, median LOS was 7 versus 2 days, respectively p < 0.001. Readmissions occurred in 6%(31/535), mostly for hyponatremia (18/31). Gross total resection was achieved in 214/312(69%) endocrine-inactive adenomas; biochemical remission was achieved in 148/209(71%) endocrine-active adenomas. Visual field or acuity defects improved in 126/138(91.3%) patients. CONCLUSION: This study suggests that conformance to established protocols for endoscopic pituitary surgery may minimize complications, re-admissions and LOS while enhancing the likelihood of preserving gland function, although there remains opportunity for further improvements.

Endoscopic Endonasal and Supraorbital Removal of Tuberculum Sellae Meningiomas: Anatomic Guides and Operative Nuances for Keyhole Approach Selection.

BACKGROUND: With growing worldwide endoscopy experience, endonasal and supraorbital removal of tuberculum sellae meningiomas (TSM) has increased. OBJECTIVE: To describe anatomic factors for guiding approach selection and outcomes. METHODS: Retrospective analysis of patients undergoing endonasal or supraorbital TSM resection: approach criteria, clinical outcomes, acute magnetic resonance imaging (MRI) fluid-attenuated inversion-recovery (FLAIR)/T2 changes. RESULTS: From 2008 to 2020, 33 patients (mean age 55 ± 11 yr) were identified: 20 (61%) had endonasal and 13 (39%) supraorbital removal. Comparing endonasal and supraorbital approaches, mean tumor volume (3.7 ± 3.5 cm3 vs 7.7 ± 8.5 cm3, P = .07); percent tumor above planum (42% vs 65%, P = .02), and lateral tumor beyond supraclinoid internal carotid arteries (1.4 ± 2.0 mm vs 4.0 ± 3.2 mm, P = .006) were greater for supraorbital route. Sellar depth was greater for endonasal route tumors (12.2 ± 2.6 mm vs 9.3 ± 2.4 mm, P = .003). Endoscopy, used in 10/13(77%) supraorbital cases, was helpful in additional tumor removal in 4/10(40%). Gross total removal and mean volumetric tumor resection were 16/20(80%) and 97.5% by endonasal, and 5/13(39%) and 96% by supraorbital route. Vision improved in 12/17 (71%) endonasal, 6/8 (75%) supraorbital operations, and worsened in 1 (3%) supraorbital case. Endonasal approach with optic canal decompression increased over study period: 15/20 (75%) endonasal patients vs 1/13(8%) supraorbital (P < .001). Postoperative FLAIR/T2 MRI changes occurred in 2/12 supraorbital and 0/20 endonasal cases. CONCLUSION: In our experience, both endonasal and supraorbital routes are safe and effective for TSM removal. Greater tumor extension below planum and medial optic canal invasion favor endonasal route, while larger size and lateral extension favor supraorbital route. Given high frequency of TSM growth into optic canals and better access for medial optic canal tumor removal, endonasal route may be preferred for most TSMs.

Orbital Surgical Guidelines-Clinical Evaluation.

Orbital disorders may present with change in form or function or may be discovered incidentally during clinical or imaging evaluations. A standardized orbital clinical examination, with appropriate ancillary tests, is helpful in narrowing the differential diagnosis and in the development of plans for management, with an eye toward minimizing the morbidity of the disease or its treatment. Evaluation and management may best be performed with a multidisciplinary team, which has become more common in skull base surgery.

Pituitary adenomas in older adults (≥ 65 years): 90-day outcomes and readmissions: a 10-year endoscopic endonasal surgical experience.

INTRODUCTION: Longer lifespan and newer imaging protocols have led to more older adults being diagnosed with pituitary adenomas. Herein, we describe outcomes of patients ≥ 65 years undergoing endoscopic adenoma removal. To address selection criteria, we also assess a conservatively managed cohort. METHODS: A retrospective analysis of 90-day outcomes of patients undergoing endoscopic pituitary adenomectomy from 2010 to 2019 by a neurosurgical/ENT team was performed. Tumor subtype, cavernous sinus invasion, extent of resection/early remission, endocrinology outcomes, complications, re-operations and readmissions were analyzed. A comparator cohort ≥ 65 years undergoing clinical surveillance without surgery was also analyzed. RESULTS: Of 468 patients operated on for pituitary adenoma, 123 (26%) were ≥ 65 years (range 65-93 years); 106 (86.2%) had endocrine-inactive adenomas; 18 (14.6%) had prior surgery. Of 106 patients with endocrine-inactive adenomas, GTR was achieved in 70/106 (66%). Of 17 patients with endocrine-active adenomas, early biochemical remission was: Cushing's 6/8; acromegaly 1/4; prolactinomas 1/5. Gland function recovery occurred in 28/58 (48.3%) patients with various degrees of preoperative hypopituitarism. New anterior hypopituitarism occurred in 3/110 (2.4%) patients; permanent DI in none. Major complications in 123 patients were: CSF leak 2 (1.6%), meningitis 1 (0.8%), vision decline 1 (0.8%). There were no vascular injuries, operative hematomas, anosmia, deaths, MIs, or thromboembolic events. Median length of stay was 2 days. Readmissions occurred in 14/123 (11.3%) patients, 57% for delayed hyponatremia. Intra-cohort analysis by age (65-69, 70-74, 75-79, ≥ 80 years) revealed no outcome differences. Cavernous sinus invasion (OR 7.7, CI 1.37-44.8; p = 0.02) and redo-surgery (OR 8.5, CI 1.7-42.8; p = 0.009) were negative predictors for GTR/NTR. Of 105 patients evaluated for presumed pituitary adenoma beginning in 2015, 72 (69%) underwent surgery, 8 (7%) had prolactinomas treated with cabergoline and 25 (24%) continue clinical surveillance without surgery, including two on new hormone replacement. CONCLUSION: This study suggests that elderly patients carefully selected for endoscopic adenoma removal can have excellent short-term outcomes including high resection rates, low complication rates and short length of stay. Our experience supports a multidisciplinary approach and the concept of pituitary centers of excellence. Based on our observations, approximately 25% of elderly patients with pituitary adenomas referred for possible surgery can be monitored closely without surgery.

Minimally invasive surgical treatment of intracranial meningiomas in elderly patients (≥ 65 years): outcomes, readmissions, and tumor control.

OBJECTIVE: Increased lifespan has led to more elderly patients being diagnosed with meningiomas. In this study, the authors sought to analyze and compare patients ≥ 65 years old with those < 65 years old who underwent minimally invasive surgery for meningioma. To address surgical selection criteria, the authors also assessed a cohort of patients managed without surgery. METHODS: In a retrospective analysis, consecutive patients with meningiomas who underwent minimally invasive (endonasal, supraorbital, minipterional, transfalcine, or retromastoid) and conventional surgical treatment approaches during the period from 2008 to 2019 were dichotomized into those ≥ 65 and those < 65 years old to compare resection rates, endoscopy use, complications, and length of hospital stay (LOS). A comparator meningioma cohort of patients ≥ 65 years old who were observed without surgery during the period from 2015 to 2019 was also analyzed. RESULTS: Of 291 patients (median age 60 years, 71.5% females, mean follow-up 36 months) undergoing meningioma resection, 118 (40.5%) were aged ≥ 65 years and underwent 126 surgeries, including 20% redo operations, as follows: age 65-69 years, 46 operations; 70-74 years, 40 operations; 75-79 years, 17 operations; and ≥ 80 years, 23 operations. During 2015-2019, of 98 patients referred for meningioma, 67 (68%) had surgery, 1 (1%) had radiosurgery, and 31 (32%) were observed. In the 11-year surgical cohort, comparing 173 patients < 65 years versus 118 patients ≥ 65 years old, there were no significant differences in tumor location, size, or outcomes. Of 126 cases of surgery in 118 elderly patients, the approach was a minimally invasive approach to skull base meningioma (SBM) in 64 cases (51%) as follows: endonasal 18, supraorbital 28, minipterional 6, and retrosigmoid 12. Endoscope-assisted surgery was performed in 59.5% of patients. A conventional approach to SBM was performed in 15 cases (12%) (endoscope-assisted 13.3%), and convexity craniotomy for non-skull base meningioma (NSBM) in 47 cases (37%) (endoscope-assisted 17%). In these three cohorts (minimally invasive SBM, conventional SBM, and NSBM), the gross-total/near-total resection rates were 59.5%, 60%, and 91.5%, respectively, and an improved or stable Karnofsky Performance Status score occurred in 88.6%, 86.7%, and 87.2% of cases, respectively. For these 118 elderly patients, the median LOS was 3 days, and major complications occurred in 10 patients (8%) as follows: stroke 4%, vision decline 3%, systemic complications 0.7%, and wound infection or death 0. Eighty-three percent of patients were discharged home, and readmissions occurred in 5 patients (4%). Meningioma recurrence occurred in 4 patients (3%) and progression in 11 (9%). Multivariate regression analysis showed no significance of American Society of Anesthesiologists physical status score, comorbidities, or age subgroups on outcomes; patients aged ≥ 80 years showed a trend of longer hospitalization. CONCLUSIONS: This analysis suggests that elderly patients with meningiomas, when carefully selected, generally have excellent surgical outcomes and tumor control. When applied appropriately, use of minimally invasive approaches and endoscopy may be helpful in achieving maximal safe resection, reducing complications, and promoting short hospitalizations. Notably, one-third of our elderly meningioma patients referred for possible surgery from 2015 to 2019 were managed nonoperatively.

Tuberculum Sellae Meningiomas in Pregnancy: 3 Cases Treated in the Second Trimester and Literature Review.

BACKGROUND: Tuberculum sella meningiomas typically present with progressive visual loss. It is also known that meningiomas can become symptomatic during pregnancy. Herein we report on 3 patients who presented with progressive visual decline during pregnancy, prompting urgent surgical removal of their meningiomas. CASE DESCRIPTIONS: From our prospectively collected brain tumor database, all women surgically treated for tuberculum sella meningioma since 2006 were retrospectively reviewed. Clinical presentation, surgical approach, perioperative management, and pathology of pregnant patients were reviewed and compared with those of the nonpregnant cohort. Of 43 women with newly diagnosed tuberculum sella meningioma, 3 (7%) presented in pregnancy with progressive visual loss, 1 in the late first trimester and 2 in the early second trimester. One woman pregnant with twins had a broad-based meningioma and underwent a supraorbital craniotomy and gross total tumor removal in her second trimester. Two women with singleton pregnancies both underwent endoscopic endonasal gross total tumor removal during their second trimesters. All 3 patients had visual recovery, 2 of which were complete, and all went on to have successful uncomplicated deliveries of their children and maintain normal pituitary gland function. CONCLUSIONS: Presentation of tuberculum sella meningioma during pregnancy is uncommon but not rare, accounting for 7% of women in our series. Ideally, surgery is performed in the second trimester, ensuring fetal safety while restoring maternal vision and maintaining pituitary gland function are essential. Depending on tumor size and sellar anatomy, endoscopic endonasal or supraorbital keyhole craniotomy approaches are both viable options.

Ophthalmic and orbital considerations in the evaluation of skull base malignancies.

INTRODUCTION: The orbital contents, afferent and efferent visual pathways, and the cranial nerves involved in eye movement, corneal sensation and eyelid closure traverse the skull base, a region bounded by the intracranial cavity, the paranasal sinuses, and the deep spaces of the face and head. As such, tumors from above or below have potential to affect some aspect of the visual system. METHODS: We discuss here the clinical ophthalmologic and orbital considerations in the evaluation of patients with these tumors, as well as the ophthalmic sequelae of treatment with radiation or surgery (or both). And for the surgeon, we discuss the ophthalmic and orbital considerations in surgical planning, the role of the orbital surgeon in skull base surgery, and briefly discuss transorbital approaches to the skull base. RESULTS AND CONCLUSION: Ophthalmic and orbital dysfunction may be the main source of disability in patients with skull base malignancy; it is thus incumbent on those who manage patients with tumors of this region to be aware of the ophthalmic, neuro-ophthalmic and orbital manifestations, so as to best tailor therapy and monitor treatment outcomes.

Strategy and Technique of Endonasal Endoscopic Bony Decompression and Selective Tumor Removal in Symptomatic Skull Base Meningiomas of the Cavernous Sinus and Meckel's Cave.

BACKGROUND: Parasellar meningiomas involving the cavernous sinus and Meckel's cave pose a management challenge because of invasion around neurovascular structures and the pituitary gland. The management options range from aggressive resection to focused radiotherapy alone. We present a strategy for these tumors that includes endonasal bony decompression, partial tumor removal, and stereotactic radiotherapy (SRT) in select cases. METHODS: The tumor location, previous treatments, cranial neuropathies, pituitary dysfunction, tumor control rates, use of stereotactic radiosurgery, SRT, and complications were retrospectively evaluated. RESULTS: Twenty patients (age range, 43-81 years; 65% women; 90% with World Health Organization grade I; median follow-up, 57 months; 14 without previous debulking and RT; 6 with previous debulking and RT) underwent endonasal bony decompression and partial tumor removal. The most common tumor locations were cavernous sinus (95%), Meckel's cave (95%), sella (75%), petroclival (60%), and optic canal/orbit (30%). Three patients with large meningiomas underwent staged transcranial and endonasal debulking. Of the 14 patients without previous debulking and RT, 11 had undergone postoperative SRT, with tumor shrinkage in 3 (27%). At the last follow-up examination, for these 14 patients and the 6 patients who had undergone previous surgery and RT, tumor control was 100% and 33% (P < 0.001) and the cranial neuropathies had improved in 57% and 33%, respectively. Major complications occurred in 2 patients: a permanent sixth cranial nerve palsy and cerebrospinal fluid leakage requiring reoperation. CONCLUSIONS: Endonasal bony decompression and selective tumor removal, followed by SRT, appears to be a reasonable treatment option for most previously untreated parasellar meningiomas. For patients who have undergone previous debulking and RT, new targeted treatment strategies are needed.

The Most Common Causes of Eye Pain at 2 Tertiary Ophthalmology and Neurology Clinics.

BACKGROUND: Eye pain is a common complaint, but no previous studies have determined the most common causes of this presenting symptom. Our objective was to determine the most common causes of eye pain in 2 ophthalmology and neurology departments at academic medical centers. METHODS: This was a retrospective cross-sectional analysis and chart review at the departments of ophthalmology and neurology at the University Hospital Zurich (USZ), University of Zürich, Switzerland, and the University of Utah (UU), USA. Data were analyzed from January 2012 to December 2013. We included patients aged 18 years or older presenting with eye pain as a major complaint. RESULTS: Two thousand six hundred three patient charts met inclusion criteria; 742 were included from USZ and 1,861 were included from UU. Of these, 2,407 had been seen in an ophthalmology clinic and 196 had been seen in a neurology clinic. Inflammatory eye disease (conjunctivitis, blepharitis, keratitis, uveitis, dry eye, chalazion, and scleritis) was the underlying cause of eye pain in 1,801 (69.1%) of all patients analyzed. Although only 71 (3%) of 2,407 patients had migraine diagnosed in an ophthalmology clinic as the cause of eye pain, migraine was the predominant cause of eye pain in the neurology clinics (100/196; 51%). Other causes of eye pain in the neurology clinics included optic neuritis (44 patients), trigeminal neuralgia, and other cranial nerve disorders (8 patients). CONCLUSIONS: Eye pain may be associated with a number of different causes, some benign and others sight- or life-threatening. Because patients with eye pain may present to either a neurology or an ophthalmology clinic and because the causes of eye pain may be primarily ophthalmic or neurologic, the diagnosis and management of these patients often requires collaboration and consultation between the 2 specialties.

Role of Endoscopic Skull Base and Keyhole Surgery for Pituitary and Parasellar Tumors Impacting Vision.

Significant advances over the last 2 decades in imaging technology, instrumentation, anatomical knowledge, and reconstructive techniques have resulted in the endonasal endoscopic approach becoming an integral part of modern skull base surgery. With growing use and greater experience, surgical outcomes continue to incrementally improve across many skull base pathologies, including those tumors that impact vision and ocular motility. The importance of the learning curve and use of a multi-disciplinary approach is critical to maximizing success, minimizing complications, and enhancing quality of life in these patients. Realizing the limits of the endonasal route and reasonable use of transcranial approaches such as the supraorbital eyebrow craniotomy, it may br appropriate to consider nonsurgical therapy including various forms of radiotherapy [corrected] and medical treatment options.