Impact of Previous Surgery and/or Radiation Therapy on Endoscopic Reconstruction Outcomes.

BACKGROUND AND OBJECTIVES: The impact of prior local therapies, including radiation and surgery, on reconstruction outcomes after endonasal surgery is currently not well known. Reconstruction nuances in the preoperative setting merit further evaluation to avoid potential postoperative complications that can hinder overall tumor management and negatively impact patient outcome. We sought to determine whether prior treatments increase risk of reconstruction-related postoperative morbidity and to evaluate the effectiveness of our current treatment paradigm for skull base reconstruction. METHODS: A retrospective review of all endonasal surgeries for tumor resection between March 2000 and March 2022 was performed. Patients were grouped based on treatment history. Patient demographics, operative, and postoperative reconstruction-related morbidity data were collected, including cerebrospinal fluid leak, sinonasal morbidity, and infectious complications. Variables significantly associated with postoperative complications in the univariate analysis were included in the multivariate Cox proportional hazards regression model. Complication-free survival curves were generated, and the log-rank test evaluated the relationship between complication-free survival and the different clinical, surgical, and treatment parameters. All statistical analyses were performed with SPSS 26 (IBM Corp) and Graph Pad 9.0 (GraphPad Software). RESULTS: A total of 418 patients were included. 291 patients had no prior treatments, 49 patients had previously received radiation, and 78 patients had prior surgeries. Of the 49 patients who had prior radiation, 27% underwent reconstruction with tunneled pericranial flaps vs 16% of treatment-naïve patients. On multivariate analysis, prior treatment was not significantly associated with reconstruction-related complications. Negative smoking history, no leak or small intraoperative leak, and use of vascularized flap in reconstruction were protective factors. CONCLUSION: In patients undergoing endonasal surgery, prior radiation and/or surgery does not appear to significantly increase the risk of immediate or delayed reconstruction complications using our current reconstructive management plan, which incorporates an upfront regional flap for high-risk cases.

The role of systemic therapy in advanced skull base chordomas: overview of the current state and the MD Anderson protocol.

The role of systemic therapy in primary or advanced and metastatic chordoma has been traditionally limited because of the inherent resistance to cytotoxic therapies and lack of specific or effective therapeutic targets. Despite resection and adjuvant radiation therapy, local recurrence rates in clival chordoma remain high and the risk of systemic metastases is not trivial, leading to significant morbidity and mortality. Recently, molecular targeted therapies (MTTs) and immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic avenues in chordoma. In recent years, preclinical studies have identified potential targets based on intrinsic genetic dependencies, epigenetic modulators, or newly identified tumor-associated cell populations driving treatment resistance and recurrence. Nonetheless, the role of systemic therapies in the neoadjuvant or adjuvant setting for primary, locally progressive, and distant metastatic chordomas is still being investigated. Herein, an overview of current and emerging systemic treatment strategies in advanced clival chordoma is provided. Furthermore, several molecular biomarkers have been recently uncovered as potential predictors of the response to specific molecular therapeutics. The authors describe the recently discovered role of 1p36 and 9p21 deletions as biomarkers capable of guiding drug selection. Then they discuss completed and ongoing clinical trials of MTTs, including several tyrosine kinase inhibitors used as monotherapy or in combination, such as imatinib, sorafenib, dasatinib, and lapatinib, among others, as well as mammalian target of rapamycin inhibitors such as everolimus and rapamycin. They present their experience and other recent studies demonstrating vast benefits in advanced chordoma from ICIs. Additionally, they provide a brief overview of novel systemic strategies such as adoptive cell transfer (CAR-T and NK cells), oncolytic viruses, epigenetic targeting (KDM6, HDAC, and EZH2 inhibitors), and several promising preclinical studies with high translational potential. Finally, the authors present their institutional multidisciplinary protocol for the incorporation of systemic therapy for both newly diagnosed and recurrent chordomas based on molecular studies including upfront enrollment in MTT trials in patients with epidermal growth factor receptor upregulation or INI-1 deficiency or enrollment in ICI clinical trials for patients with high tumor mutational burden or high PD-L1 expression on tumor cells or in the tumor microenvironment.

Clinical Outcomes and Complication Profile of Spine Surgery in Septuagenarians and Octogenarians: Case Series.

OBJECTIVE: The aging global population presents an increasing challenge for spine surgeons. Advancements in spine surgery, including minimally invasive techniques, have broadened treatment options, potentially benefiting older patients. This study aims to explore the clinical outcomes of spine surgery in septuagenarians and octogenarians. METHODS: This retrospective analysis, conducted at a US tertiary center, included patients aged 70 and older who underwent elective spine surgery for degenerative conditions. Data included the Charlson Comorbidity Index (CCI), ASA classification, surgical procedures, intraoperative and postoperative complications, and reoperation rates. The objective of this study was to describe the outcomes of our cohort of older patients and discern whether differences existed between septuagenarians and octogenarians. RESULTS: Among the 120 patients meeting the inclusion criteria, there were no significant differences in preoperative factors between the age groups (P > 0.05). Notably, the septuagenarian group had a higher average number of fused levels (2.36 vs. 0.38, P = 0.001), while the octogenarian group underwent a higher proportion of minimally invasive procedures (P = 0.012), resulting in lower overall bleeding in the oldest group(P < 0.001). Mobility outcomes were more favorable in septuagenarians, whereas octogenarians tended to maintain or experience a decline in mobility(P = 0.012). A total of 6 (5%) intraoperative complications and 12 (10%) postoperative complications were documented, with no statistically significant differences observed between the groups. CONCLUSIONS: This case series demonstrates that septuagenarians and octogenarians can achieve favorable clinical outcomes with elective spine surgery. Spine surgeons should be well-versed in the clinical and surgical care of older adults, providing optimal management that considers their increased comorbidity burden and heightened fragility.

Oral Treprostinil is Associated with Improved Survival in FREEDOM-EV and its Open-Label Extension.

INTRODUCTION: In the event-driven FREEDOM-EV trial, oral treprostinil delayed clinical worsening in patients with pulmonary arterial hypertension (PAH). Open-label extension studies offer additional data about tolerability, efficacy, and survival, especially for those initially assigned placebo. The aim of the current study was to determine if oral treprostinil changed survival when considering the parent and extension study, if treprostinil provides functional benefits for participants initially assigned to placebo, and if the benefits observed for those treated with treprostinil were durable. METHODS: Both active and placebo participants from FREEDOM-EV could enroll in the FREEDOM-EV open-label extension (OLE) study after experiencing an investigator-assessed clinical worsening event or after parent study closure. All participants in the OLE were offered open-label oral treprostinil. Previously assigned placebo participants titrated to maximally tolerated doses; previously assigned treprostinil participants continued dose titration. We repeated assessments including functional class and 6-min walk distance (6MWD) at 12-week intervals and measured N-terminal pro-brain natriuretic peptide (NT-proBNP) at week 48. Survival was estimated by Kaplan-Meier analysis, and we estimated hazard ratio (HR) using Cox proportional hazards. RESULTS: Of 690 FREEDOM-EV participants, 470 enrolled in the OLE; vital status was available for 89% of initial Freedom-EV participants. When considering the combined parent and open-label data, initial assignment to oral treprostinil reduced mortality (HR 0.64, 95% confidence interval 0.46-0.91, p = 0.013); absolute risk reduction was 9%. Participants randomized to placebo who initiated oral treprostinil after clinical worsening and tolerated treatment through week 48 demonstrated favorable shifts in functional class (p < 0.0001), 6MWD improvements of + 84 m (p < 0.0001), and a reduction in NT-proBNP of - 778 pg/mL (p = 0.02), compared to OLE baseline. Modest trends toward benefit were measured for those initially assigned placebo who did not have clinical worsening, and 132/144 (92%) of treprostinil assigned participants without clinical worsening remained on drug at week 48 in the OLE study. Adverse events were consistent with FREEDOM-EV. CONCLUSION: Initial treprostinil assignment improved survival in the entire data set; those who began treprostinil after a clinical worsening in the placebo arm and tolerated drug to week 48 enjoyed substantial functional gains. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01560637.

Parenteral treprostinil induction for rapid attainment of therapeutic doses of oral treprostinil.

RATIONALE: Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint. OBJECTIVES: EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension. METHODS: Parenteral treprostinil was titrated for 2-8 weeks, followed by cross-titration of oral treprostinil. The primary endpoint was percentage of patients reaching ≥12 mg daily of oral treprostinil at Week 16. Secondary endpoints included clinical changes from baseline to Week 16. RESULTS: Twenty-nine prostacyclin-naïve patients were included in efficacy analyses. At Week 16, the mean daily oral treprostinil dose was 16.4 mg; 79% of patients met the primary endpoint. From baseline to Week 16, median REVEAL Lite 2 score improved (decreased) from 6 to 3.5 (p = 0.0006). Statistically significant improvements were also seen in World Health Organization Functional Class, N-terminal-pro brain natriuretic peptide levels, 6-minute walk distance, right atrial area, Borg Dyspnea Score, and emPHasis-10 score. Favorable trends were seen in risk stratification, echocardiography parameters, disease symptoms, and treatment satisfaction. CONCLUSION: Short-course parenteral treprostinil induction resulted in oral treprostinil doses over twice those reported in de novo initiations and may be a useful approach to quickly achieve the therapeutic benefits of oral treprostinil.

Implementing the EXPEDITE parenteral induction protocol: Rapid parenteral treprostinil titration and transition to oral treprostinil.

Treprostinil is a prostacyclin analogue that targets multiple cellular receptors to treat pulmonary arterial hypertension (PAH). In certain scenarios, patients may require aggressive treprostinil titration. Several studies have demonstrated that higher doses of treprostinil lead to greater clinical benefit. Data supports successful transitions from parenteral to oral treprostinil; however, administration routes, transition duration, and transition setting vary in the real-world. The EXPEDITE clinical trial (NCT03497689) prospectively studied whether rapid parenteral treprostinil induction can be used to achieve high doses of oral treprostinil (total daily dose: ≥12 mg) in prostacyclin naïve PAH patients. Parenteral prostacyclin induction may be more appropriate for patients who need to reach therapeutic dosing more urgently than longer titration durations reported with conventional de novo oral treprostinil initiation. This summary provides strategies utilized in EXPEDITE. Parenteral treprostinil was initiated at 2 ng/kg/min intravenously or subcutaneously; clinicians determined the frequency and dose increment of up-titration. Two distinct transition schedules from parenteral to oral treprostinil were employed: rapid cross-titration in an inpatient setting (median: 2 days) or gradual cross-titration in an outpatient setting (median: 5 days). Patient status was closely monitored after transition; oral treprostinil dose was titrated to clinical effect and tolerability. Factors considered when individualizing dosing strategies included parenteral and oral treprostinil target doses, nursing support, patient education, medication counseling and adverse events management. EXPEDITE demonstrated the time to a therapeutic dose of oral treprostinil is significantly shorter when utilizing a short-term parenteral induction strategy and may be suitable for patients requiring aggressive titration of oral treprostinil.

The Adjustable Cranial Plate: A Novel Implant Designed to Eliminate the Need for Cranioplasty Surgery Following a Hemicraniectomy Operation.

BACKGROUND: Decompressive hemicraniectomy (DHC) is performed to relieve life-threatening intracranial pressure elevations. After swelling abates, a cranioplasty is performed for mechanical integrity and cosmesis. Cranioplasty is costly with high complication rates. Prior attempts to obviate second-stage cranioplasty have been unsuccessful. The Adjustable Cranial Plate (ACP) is designed for implantation during DHC to afford maximal volumetric expansion with later repositioning without requiring a second major operation. METHODS: The ACP has a mobile section held by a tripod fixation mechanism. Centrally located gears adjust the implant between the up and down positions. Cadaveric ACP implantation was performed. Virtual DHC and ACP placement were done using imaging data from 94 patients who had previously undergone DHC to corroborate our cadaveric results. Imaging analysis methods were used to calculate volumes of cranial expansion. RESULTS: The ACP implantation and adjustment procedures are feasible in cadaveric testing without wound closure difficulties. Results of the cadaveric study showed total volumetric expansion achieved was 222 cm3. Results of the virtual DHC procedure showed the volume of cranial expansion achieved by removing a standardized bone flap was 132 cm3 (range, 89-171 cm3). Applied to virtual craniectomy patients, the total volume of expansion achieved with the ACP implantation operation was 222 cm3 (range, 181-263 cm3). CONCLUSIONS: ACP implantation during DHC is technically feasible. It achieves a volume of cranial expansion that will accommodate that observed following survivable hemicraniectomy operations. Moving the implant from the up to the down position can easily be performed as a simple outpatient or inpatient bedside procedure, thus potentially eliminating second-stage cranioplasty procedures.

Human Brainstem and Cerebellum Atlas: Chemoarchitecture and Cytoarchitecture Paired to MRI.

Lesion localization is the basis for understanding neurologic disease, which is predicated on neuroanatomical knowledge carefully cataloged from histology and imaging atlases. However, it is often difficult to correlate clinical images of brainstem injury obtained by MRI scans with the details of human brainstem neuroanatomy represented in atlases, which are mostly based on cytoarchitecture using Nissl stain or a single histochemical stain, and usually do not include the cerebellum. Here, we report a high-resolution (200 µm) 7T MRI of a cadaveric male human brainstem and cerebellum paired with detailed, coregistered histology (at 2 µm single-cell resolution) of the immunohistochemically stained cholinergic, serotonergic, and catecholaminergic (dopaminergic, noradrenergic, and adrenergic) neurons, in relationship to each other and to the cerebellum. These immunohistochemical findings provide novel insights into the spatial relationships of brainstem cell types and nuclei, including subpopulations of melanin and TH+ neurons, and allows for more informed structural annotation of cell groups. Moreover, the coregistered MRI-paired histology helps validate imaging findings. This is useful for interpreting both scans and histology, and to understand the cell types affected by lesions. Our detailed chemoarchitecture and cytoarchitecture with corresponding high-resolution MRI builds on previous atlases of the human brainstem and cerebellum, and makes precise identification of brainstem and cerebellar cell groups involved in clinical lesions accessible for both laboratory scientists and clinicians alike.SIGNIFICANCE STATEMENT Clinicians and neuroscientists frequently use cross-sectional anatomy of the human brainstem from MRI scans for both clinical and laboratory investigations, but they must rely on brain atlases to neuroanatomical structures. Such atlases generally lack both detail of brainstem chemical cell types, and the cerebellum, which provides an important spatial reference. Our current atlas maps the distribution of key brainstem cell types (cholinergic, serotonergic, and catecholaminergic neurons) in relationship to each other and the cerebellum, and pairs this histology with 7T MR images from the identical brain. This atlas allows correlation of the chemoarchitecture with corresponding MRI, and makes the identification of cell groups that are often discussed, but rarely identifiable on MRI scan, accessible to clinicians and clinical researchers.