Chicoine, Michael

Abstract Glioblastoma is a highly lethal malignancy with dismal overall survival and near universal recurrence despite maximal multimodal therapy. Patients with unmethylated O6-methylguanine methyltransferase (MGMT) promoters do not derive survival benefit from adjuvant temozolomide. Immunotherapies have revolutionized cancer care; however, this modality has yet to translate into survival benefits in glioblastoma in part due to both local and systemic immunosuppressive states. Here, we report the results of a phase 1 clinical trial (NCT04015700) evaluating the safety and feasibility of GNOS-PV01, a personalized DNA vaccination platform that safely immunized against up to 40 patient-specific neoantigens in a clinically relevant timescale following surgical resection and radiation for MGMT-unmethylated glioblastoma patients. Multisector tumor sampling at time of resection enabled personalized and spatially representative neoantigen identification through an established pipeline. In the nine participants receiving vaccines, there were no unexpected toxicities or serious adverse events with a median vaccine delivery time of 10 weeks post-radiation. The vaccination was strongly immunogenic and induced activation and expansion of both local infiltrating CD8+ and CD4+ T-cells and circulating peripheral T-cells. T-cell receptor sequencing revealed both expanded pre-existing populations as well as novel neoantigen-specific populations, suggesting that vaccination both reinvigorates pre-existing immunity and generates novel immune reactivity. We developed a new technology to profile T-cells at single-nuclei resolution from frozen tissue revealing that vaccination altered gene expression signatures involved in inflammatory response and lymphocyte activation in the tumor microenvironment. Exposure to dexamethasone greatly suppressed immune reactivity, while PD-1 blockade enhanced local immune responses. With respect to efficacy, one third of patients survived longer than 24 months with one long-term survivor living >40 months from time of diagnosis, exceeding survival of recently published trials. Thus, our study demonstrates the safety, feasibility, and preliminary clinical efficacy of a personalized multivalent neoantigen vaccination platform in a devastating cancer.

Abstract Craniopharyngiomas are rare parasellar tumors, and papillary craniopharyngiomas (PCPs) represent 8 to 20% of cases. Interim analysis of retrospective data collected from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). Fourteen U.S.-based academic skull base centers between 2011 and 2023. Patients with PCPs. Demographic, imaging, surgical, and outcome variables. Ninety-nine patients with PCPs were included. The mean age was 51.8 ± 14.7, and 57.6% were male. Most tumors showed mixed cystic/solid components (67.5%), were transinfundibular (50.0%), and were treated with an endoscopic endonasal approach (74.5%), with 51.1% demonstrating gross total resection (GTR). Pituitary stalk was preserved in 51.9%. Permanent arginine vasopressin deficiency was seen in 67.1% and was associated with pituitary stalk sacrifice (p = 0.003). Cerebrospinal fluid leak was the most common nonendocrine postsurgical, 30-day complication (9.1%), reason for return to the operating room (3.1%), and reason for 90-day readmission (8.1%). Most patients (63.9%) received no adjuvant therapy; GTR was associated with decreased radiotherapy use (p = 0.0001). BRAFV600E mutation was detected in 64/69 tumors tested, although only one patient was treated with a BRAF inhibitor. A mean follow-up of 12.3 ± 14.6 months was seen for the group. RAPID consortium enabled the largest real-world clinical information dataset for PCPs. Early findings support that GTR and stalk preservation are important to outcomes. Iterative analysis and discussion of data led to the generation of a framework for future studies to fully leverage the capabilities of multicenter registries.

OBJECTIVE Reports of surgical outcomes for Cushing’s disease are mostly limited to single-center experiences by expert surgeons. Therefore, no generalizable surgical outcome metrics for endoscopic endonasal Cushing’s disease surgery are available for practitioners to guide quality-improvement efforts. This is potentially problematic, given the high morbidity and excess mortality observed in patients who do not achieve remission. This study proposes a bundle of evidence-based metrics for low-risk patients with Cushing’s disease, for whom optimal outcomes would be expected, that focus on the cost efficiency of care and surgical outcomes from multicenter collaboration of US pituitary centers. METHODS The steering committee of the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) consortium proposed the metrics based on available data from 12 US pituitary centers. A benchmarking population of low-risk patients undergoing first-time surgery was identified. Patient characteristics and outcomes were aggregated and analyzed by a data coordinating center. Metrics were reported using 2 approaches. RESULTS A total of 431 patients from 12 centers who underwent primary endoscopic transsphenoidal surgery from January 1, 2006, to December 31, 2022, were included. There were 227 patients in the low-risk cohort (age < 70 years, BMI < 50, microadenoma, and Knosp grade 0–2). For the cost-efficiency metrics, the mean (SD) length of stay was 3.8 (4.8) midnights, and the percentage of patients readmitted was 11.1%. The rate of disposition to a skilled nursing facility was 2.2%. For surgical outcomes, the rate of postoperative CSF leakage was 1.3%, and the rate of 1-year sustained surgical remission was 81.2%. The rates of permanent and temporary arginine vasopressin deficiencies were 1.8% and 11.9%, respectively. The 75th percentile performance by center was 3.0 midnights for length of stay, 6.3% for 90-day unplanned readmission, < 1% for disposition to a skilled nursing facility, < 1% for CSF leakage, and 92.2% for 1-year sustained remission. The 75th percentile was < 1% for both permanent and temporary arginine vasopressin deficiencies. CONCLUSIONS An evidence-based bundle of metrics in a Cushing’s disease patient population at low risk who underwent first-time endoscopic pituitary surgery is proposed. Surgeons can use these metrics to assess and improve the quality of their clinical pathways.

Abstract Purpose: Craniopharyngiomas are rare parasellar tumors, and papillary craniopharyngiomas (PCP) represent 8-20% of cases. We assessed surgical outcomes of these very rare tumors among patients treated in the last decade. Methods: Retrospective data from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) were used to evaluate patients with PCP treated between 2011 and 2023 at 14 US-based academic skull base centers. Demographic, imaging, surgical, and outcome variables were analyzed. Results: Ninety-nine patients with PCP were included. Mean age was 51.8±14.7 and 57.6% were male. Most tumors showed mixed cystic/solid components (67.5%), were trans-infundibular (50.0%), and were treated endoscopically (74.5%), with 51.1% demonstrating gross total resection (GTR). Pituitary stalk was preserved in 51.9%. Permanent arginine vasopressin deficiency was seen in 68.8% and was associated with pituitary stalk sacrifice (p=0.02). Cerebrospinal fluid leak was the most common nonendocrine postsurgical, 30-day complication (9.1%), reason for return to the operating room (3.1%), and reason for 90-day readmission (8.1%). Return to the operating room was associated with discharge to a skilled nursing or rehabilitation facility (p=0.0001). Most patients (63.9%) received no adjuvant therapy; GTR was associated with decreased radiotherapy use (p=0.0001). BRAFV600E mutation was detected in 64/69 tumors tested, although only 1 patient was treated with a BRAF inhibitor. Conclusion: To our knowledge, the RAPID consortium enabled the largest real-world clinical information dataset for PCP. Our data can be used as a benchmark for short-term surgical outcomes. Longer-term follow-up studies are needed to understand how to optimize outcomes from each treatment modality.

BACKGROUND AND OBJECTIVE: Cushing disease (CD) affects mortality and quality of life along with limited long-term remission, underscoring the need to better identify recurrence risk. The identification of surgical or imaging predictors for CD remission after transsphenoidal surgery has yielded some inconsistent results and has been limited by single-center, single-surgeon, or meta-analyses studies. We sought to evaluate the multicenter Registry of Adenomas of the Pituitary and Related Disorders (RAPID) database of academic US pituitary centers to assess whether robust nonhormonal recurrence predictors could be elucidated. METHODS: Patients with treated CD from 2011 to 2023 were included. The perioperative and long-term characteristics of CD patients with and without recurrence were assessed using univariable and multivariable analyses. RESULTS: Of 383 patients with CD from 26 surgeons achieving postoperative remission, 288 (75.2%) maintained remission at last follow-up while 95 (24.8%) showed recurrence (median time to recurrence 9.99 ± 1.34 years). Patients with recurrence required longer postoperative hospital stays (5 ± 3 vs 4 ± 2 days, P = .002), had larger average tumor volumes (1.76 ± 2.53 cm 3 vs 0.49 ± 1.17 cm 3 , P = .0001), and more often previously failed prior treatment (31.1% vs 14.9%, P = .001) mostly being prior surgery. Multivariable hazard prediction models for tumor recurrence found younger age (odds ratio [OR] = 0.95, P = .002) and Knosp grade of 0 (OR = 0.09, reference Knosp grade 4, P = .03) to be protective against recurrence. Comparison of Knosp grade 0 to 2 vs 3 to 4 showed that lower grades had reduced risk of recurrence (OR = 0.27, P = .04). Other factors such as length of stay, surgeon experience, prior tumor treatment, and Knosp grades 1, 2, or 3 failed to reach levels of statistical significance in multivariable analysis. CONCLUSION: This multicenter study centers suggests that the strongest predictors of recurrence include tumor size/invasion and age. This insight can help with patient counseling and prognostication. Long-term follow-up is necessary for patients, and early treatment of small tumors may improve outcomes.