Accelerated tumor progression after COVID-19 infection in patients with glioblastoma: A retrospective case-control study.

Background: We observed rapid tumor progression following COVID-19 infection among patients with glioblastoma and sought to systematically characterize their disease course in a retrospective case-control study. Methods: Using an institutional database, we retrospectively identified a series of COVID-19-positive glioblastoma cases and matched them by age and sex 1:2 to glioblastoma controls who had a negative COVID-19 test during their disease course. Demographic and clinical data were analyzed. Hyperprogression was defined using modified response evaluation criteria in solid tumors criteria. Time to progression and overall survival were estimated using the Kaplan-Meier method. Results: Thirty-two glioblastoma cases with positive COVID-19 testing were matched to 64 glioblastoma controls with negative testing; age, sex, and molecular profiles did not differ between groups. Progression events occurred in 27 cases (84%) and 46 controls (72%). Of these, 14 cases (52%) presented with multifocal disease or leptomeningeal disease at progression compared with 10 controls (22%; P = .0082). Hyperprogression was identified in 13 cases (48%) but only 4 controls (9%; P = .0001). Cases had disease progression at a median of 35 days following COVID-19 testing, compared with 164 days for controls (P = .0001). Median survival from COVID-19 testing until death was 8.3 months for cases but 17 months for controls (P = .0016). Median overall survival from glioblastoma diagnosis was 20.7 months for cases and 24.6 months for controls (P = .672). Conclusions: Patients with glioblastoma may have accelerated disease progression in the first 2 months after COVID-19 infection. Infected patients should be monitored vigilantly. Future investigations should explore tumor-immune microenvironment changes linking tumor progression and COVID-19.

NRG-BN002: Phase I Study of Ipilimumab, Nivolumab, and the Combination in Patients with Newly Diagnosed GBM.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting. METHODS: The primary endpoint was dose limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results. RESULTS: Thirty-two patients were enrolled at 9 institutions; 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% white. Treatment was well tolerated with a 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. Median follow-up was 19.6 mo. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 mo. and 16.1 mo., respectively. CONCLUSIONS: IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant TMZ for newly diagnosed GBM. Combination IPI+NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in a phase II/III for patients with newly diagnosed GBM.

Therapeutic Strategies for Gliomas Associated With Cancer Predisposition Syndromes.

PURPOSE: The purpose of this article was to provide an overview of syndromic gliomas. DESIGN: The authors conducted a nonsystematic literature review. RESULTS: Cancer predisposition syndromes (CPSs) are genetic conditions that increase one's risk for certain types of cancer compared with the general population. Syndromes that can predispose one to developing gliomas include neurofibromatosis, Li-Fraumeni syndrome, Lynch syndrome, and tuberous sclerosis complex. The standard treatment for sporadic glioma may involve resection, radiation therapy, and/or alkylating chemotherapy. However, DNA-damaging approaches, such as radiation and alkylating agents, may increase the risk of secondary malignancies and other complications in patients with CPSs. In some cases, depending on genetic aberrations, targeted therapies or immunotherapeutic approaches may be considered. Data on clinical characteristics, therapeutic strategies, and prognosis of syndromic gliomas remain limited. CONCLUSION: In this review, we provide an overview of syndromic gliomas with a focus on management for patients with CPSs and the role of novel treatments that can be considered.

The risk and burden of thromboembolic and hemorrhagic events in patients with malignant gliomas receiving bevacizumab.

PURPOSE: Bevacizumab has evolved as an integral treatment option for patients with high-grade gliomas. Little is known about clinical risk factors that predispose patients with high-grade gliomas receiving bevacizumab to VTE or ICH. We sought to characterize the clinical risk factors associated with risk of either event. METHODS: In this multi-institutional retrospective study, we first evaluated patients with high-grade gliomas who were treated with bevacizumab at University of Texas MD Anderson Cancer Center from 2015-2021. We compared clinical and treatment-related factors among three cohorts: those who developed VTE, ICH, or neither. We further compared survival outcomes of these patients from the time of bevacizumab initiation. Then to further confirm our results in a non-cancer center hospital setting we evaluated patients from two Ascension Seton Hospitals in Austin, Texas which are affiliated with Dell Medical School at the University of Texas at Austin from 2017-2022. RESULTS: We found that the presence of cerebral macrobleeding, defined as a magnetic susceptibility of > 1 cm3 on magnetic resonance imaging, was highly associated with risk of developing ICH after initiation of bevacizumab. Development of ICH was significantly associated with poorer survival outcomes. We did not find a statistically significant effect of VTE on survival after bevacizumab initiation. CONCLUSION: In order to stratify the risk for developing ICH before the initiation of bevacizumab, we recommend to assess for the presence of cerebral macrobleeding as it is associated with ICH development.

The Role of Immunotherapy in the Treatment of Rare Central Nervous System Tumors.

Establishing novel therapies for rare central nervous system (CNS) tumors is arduous due to challenges in conducting clinical trials in rare tumors. Immunotherapy treatment has been a rapidly developing field and has demonstrated improvements in outcomes for multiple types of solid malignancies. In rare CNS tumors, the role of immunotherapy is being explored. In this article, we review the preclinical and clinical data of various immunotherapy modalities in select rare CNS tumors, including atypical meningioma, aggressive pituitary adenoma, pituitary carcinoma, ependymoma, embryonal tumor, atypical teratoid/rhabdoid tumor, and meningeal solitary fibrous tumor. Among these tumor types, some studies have shown promise; however, ongoing clinical trials will be critical for defining and optimizing the role of immunotherapy for these patients.

Impact of salvage surgery with or without reirradiation for skull base meningiomas recurring after prior radiotherapy.

OBJECTIVE: Long-term follow-up of meningiomas has demonstrated recurrence rates ranging from 2.5% to 48% after 10 years, depending on histology grade. There are limited data available to guide the management of recurrent and previously irradiated skull base meningiomas, and challenges related to salvage surgery, reirradiation, and lack of clear systemic therapy strategies remain. In this study, the authors analyzed data from their experience with recurrent and previously irradiated meningiomas to assess the impact of salvage surgery and reirradiation on progression-free survival (PFS). METHODS: A retrospective cohort study of 48 patients with recurrent and previously irradiated meningiomas who were treated between 1995 and 2021 was conducted. Data were extracted from medical records and included clinical, radiological, and pathologic reports. Patients were clustered according to WHO grades. The authors analyzed the complications related to reirradiation and salvage surgery and the impact of different treatment modalities on PFS using Cox proportional hazard ratios. RESULTS: Forty-eight patients (33 with WHO grade I, 11 with WHO grade II, and 4 with WHO grade III meningiomas) were treated for 143 recurrences after their first radiation treatment. For WHO grade I meningiomas, there was no change in tumor control rates with adjuvant repeat radiotherapy (HR 0.784, 95% CI 0.349-1.759; p = 0.55), and in terms of extent of resection (EOR), subtotal resection (STR) alone was associated with an increased risk of recurrence when compared with gross-total resection (GTR) (HR 3.38, 95% CI 1.268-9.036; p = 0.0189). For WHO grade II meningiomas, GTR did not significantly confer improved tumor control relative to STR (HR 0.42, 95% CI 0.17-1.037; p = 0.055), but adjuvant repeat radiotherapy after STR was associated with improved outcomes (HR 0.316, 95% CI 0.13-0.768; p = 0.0029). Finally, for WHO grade III meningiomas, EOR did not correlate with outcomes (HR 0.75, 95% CI 0.22-2.482; p = 0.588), but repeat radiotherapy alone was associated with a decreased odds of progression (HR 0.276, 95% CI 0.078-0.97; p = 0.0028). CONCLUSIONS: This study examined the impact of retreatment on PFS in a large cohort of patients with recurrent meningiomas that had been previously irradiated. At the time of recurrence, WHO grade I meningiomas exhibited improved PFS with GTR, subtotally resected WHO grade II meningiomas appeared to have improved PFS when reirradiated, and reirradiation in WHO grade III meningiomas showed improved PFS.

Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.

Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors.

PURPOSE: Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space. METHODS: This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry. RESULTS: A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression. CONCLUSION: Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

Patterns of failure after radiation therapy in primary spinal high-grade gliomas: A single institutional analysis.

Background: Primary spinal high-grade gliomas (S-HGG) are rare aggressive tumors; radiation therapy (RT) often plays a dominant role in management. We conducted a single-institution retrospective review to study the clinicopathological features and management of S-HGGs. Methods: Patients with biopsy-proven S-HGG who received RT from 2001 to 2020 were analyzed for patient, tumor, and treatment characteristics. Kaplan-Meier estimates were used for survival analyses. Results: Twenty-nine patients were identified with a median age of 25.9 years (range 1-74 y). Four patients had GTR while 25 underwent subtotal resection or biopsy. All patients were IDH wildtype and MGMT-promoter unmethylated, where available. H3K27M mutation was present in 5 out of 10 patients tested, while one patient harbored p53 mutation. Median RT dose was 50.4 Gy (range 39.6-54 Gy) and 65% received concurrent chemotherapy, most commonly temozolomide. Twenty-three (79%) of patients had documented recurrence. Overall, 16 patients relapsed locally, 10 relapsed in the brain and 8 developed leptomeningeal disease; only 8 had isolated local relapse. Median OS from diagnosis was 21.3 months and median PFS was 9.7 months. On univariate analysis, age, gender, GTR, grade, RT modality, RT dose and concurrent chemotherapy did not predict for survival. Patients with H3K27M mutation had a poorer PFS compared to those without mutation (10.1 m vs 45.1 m) but the difference did not reach statistical significance (P = .26). Conclusions: The prognosis of patients with spinal HGGs remains poor with two-thirds of the patients developing distant recurrence despite chemoradiation. Survival outcomes were similar in patients ≤ 29 years compared to adults > 29 years. A better understanding of the molecular drivers of spinal HGGs is needed to develop more effective treatment options.

Molecular, Histological, and Clinical Characteristics of Oligodendrogliomas: A Multi-Institutional Retrospective Study.

BACKGROUND: Reports suggest that phosphatidylinositol 3-kinase pathway alterations confer increased risk of progression and poor prognosis in oligodendroglioma, IDH-mutant, and 1p/19q-codeleted molecular oligodendrogliomas (mODG). However, factors that affect prognosis in mODG have not been thoroughly studied. In addition, the benefits of adjuvant radiation and temozolomide (TMZ) in mODGs remain to be determined. OBJECTIVE: To evaluate the role of PIK3CA mutations in mODGs. METHODS: One hundred seven mODGs (2008-2019) diagnosed at 2 institutions were included. A retrospective review of clinical characteristics, molecular alterations, treatments, and outcomes was performed. RESULTS: The median age was 37 years, and 61 patients (57%) were male. There were 64 (60%) World Health Organization (WHO) grade 2 and 43 (40%) WHO grade 3 tumors. Eighty-two patients (77%) were stratified as high risk (age 40 years or older and/or subtotal resection per Radiation Treatment Oncology Group-9802). Gross-total resection was achieved in 47 patients (45%). Treatment strategies included observation (n = 15), TMZ (n = 11), radiation (n = 13), radiation/TMZ (n = 62), and others (n = 6). Our results show a benefit of TMZ vs observation in progression-free survival (PFS). No difference in PFS or overall survival (OS) was observed between radiation and radiation/TMZ. PIK3CA mutations were detected in 15 (14%) mODG, and shorter OS was observed in PIK3CA-mutant compared with PIK3CA wild-type mODGs (10.7 years vs 15.1 years, P = .009). WHO grade 3 tumors showed a shorter PFS, but no significant difference in OS was observed between WHO grades. CONCLUSION: Our findings suggest that mODGs harboring PIK3CA mutations have worse OS. Except for an advantage in PFS with TMZ treatment, adjuvant TMZ, radiation, or a combination of the two showed no significant improvement in OS.

Outcome of patients with primary glioblastoma in Chile: single centre series.

BACKGROUND: Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumour. The standard of care is surgical resection, followed by radiotherapy with concurrent and adjuvant temozolomide. In Latin America, there is scarcity of information about the incidence of GBM and even less data regarding outcomes. In this study, we describe the clinicopathologic features, management and outcomes of GBM patients. METHODS: We describe a single-centre multidisciplinary team experience in managing GBM patients over an 11-year period (Jan 2005 to Dec 2016). Pathology was reviewed by the pathology collaborator and retrospective chart review performed for treatment and clinical outcomes. RESULTS: We identified 74 patients (50 males) with diagnosis of GBM. Median age at diagnosis was 58 years (range 24-79 years), and median Karnofsky performance status was 80%. Forty-three (58.1%) went to gross total resection, 20 (27%) partial resection and 11 (14.9%) biopsy. Sixty-four (87%) patients received Stupp regimen. The median overall survival (OS) was 13.9 months (standard error (SE) 1.71; 95% confidence interval (CI), 10.56-17.23). In patients treated according to Stupp regimen, the progression-free survival (PFS) was 10 months (SE 1.8; 95% CI, 6.481-13.519), the selfcare survival was 11.8 months (SE 1.61; 95% CI, 8.632-14.968) and the OS was 16.1 months (SE 1.53; 95% CI, 13.01-19.099). CONCLUSIONS: This study reports the most complete analysis of epidemiology, clinical management and outcomes of patients with diagnosis of GBM in Chile treated with Stupp regimen. The PFS and OS are consistent with reports of US and Europe.

Laser Interstitial Thermal Therapy for Glioblastoma: A Single-Center Experience.

BACKGROUND: Surgical resection has been shown to prolong survival in patients with glioblastoma multiforme (GBM), although this benefit has not been demonstrated for reoperation following tumor recurrence. Laser interstitial thermal therapy (LITT) is a minimally invasive ablation technique that has been shown to effectively reduce tumor burden in some patients with intracranial malignancy. The aim of this study was to describe the safety and efficacy of LITT for recurrent and newly diagnosed GBM at a large tertiary referral center. METHODS: Patients with GBM receiving LITT were retrospectively analyzed. Overall survival from the time of LITT was the primary end point measured. RESULTS: There were 69 patients identified for inclusion in this study. The median age of the cohort was 56 years (range, 15-77 years). Median tumor volume was 10.4 cm3 (range, 1.0-64.0 cm3). A Kaplan-Meier estimate of median overall survival for the series from the time of LITT was 12 months (95% confidence interval 8-16 months). Median progression-free survival for the cohort from LITT was 4 months (95% confidence interval 3-7 months). Adjuvant chemotherapy significantly prolonged progression-free survival and overall survival (P < 0.01 for both) in the cohort. Gross total ablation was not significantly associated with progression-free survival (P = 0.09). CONCLUSIONS: LITT can safely reduce intracranial tumor burden in patients with GBM who have exhausted other adjuvant therapies or are poor candidates for conventional resection techniques.

Pineal parenchymal tumor of intermediate differentiation: a single-institution experience.

BACKGROUND: Pineal parenchymal tumors are exceedingly rare brain tumors responsible for less than 1% of all adult primary intracranial malignancies in the United States. In this study, we describe the clinicopathologic features, management, and outcomes of patients with pineal parenchymal tumor of intermediate differentiation (PPTID). METHODS: We describe a single-center, multidisciplinary team experience in managing PPTID patients over a 15-year period (January 2000 to January 2015) at The University of Texas MD Anderson Cancer Center (MDACC). Pathology was reviewed by the pathology collaborators (A.G. and G.N.F.) and retrospective chart review was performed for treatment and clinical outcomes. RESULTS: We identified 17 patients (9 male) with diagnosis of PPTID. Median age at diagnosis of PPTID was 37 years (range, 15-57 years). Follow-up ranged from 0.1 to 162.8 months with 6 reported deaths. Most patients presented with headaches and diplopia. Three patients had neuroaxial dissemination at initial diagnosis, and recurrence of tumor was common (7/16) despite treatment. CONCLUSIONS: No clear prognostic factors were identified in this series. Extension of resection showed a trend toward improved survival. PPTID with neuroaxial dissemination benefits from aggressive initial treatment including craniospinal irradiation and adjuvant chemotherapy, whereas localized disease may be treated traditionally with maximum debulking followed by adjuvant radiotherapy alone. Long-term monitoring is recommended for neurotoxicity and/or late recurrence.

Association Between Facility Volume and Overall Survival for Patients with Grade II Meningioma after Gross Total Resection.

BACKGROUND: The role of adjuvant radiation after gross total resection (GTR) for grade II meningioma is evolving, prompting further evaluation in NRG-BN003, a phase 3 national trial. Furthermore, the relationship between facility volume and outcomes in patients with grade II meningioma after GTR has not been examined at a national level. We aim to assess overall survival (OS) of patients with grade II meningioma after GTR by surgical case volume and OS by receipt of adjuvant radiation. METHODS: We used the National Cancer Database to identity 2823 patients diagnosed with grade II meningioma who underwent GTR. Propensity score matching was applied to balance covariates in patients with grade II meningioma after GTR stratified by adjuvant radiation status. Multivariable logistic regression was used to assess factors associated with radiation receipt. Kaplan-Meier and log-rank tests were used to assess OS by facility volume. RESULTS: As facility volume increased, OS increased, with a 5-year OS of 72.8% for facilities with GTR grade II meningioma volumes of ≤8 cases per decade and 87.5% for >8 cases per decade (P < 0.0001). There was no difference in 5-year OS between GTR alone and GTR with adjuvant radiation (84.8% vs. 86.4%; P = 0.151). Covariates significantly associated with radiation receipt included facility location, facility volume, distance, and tumor size. CONCLUSIONS: Treatment at higher surgical case volume facilities is associated with improved OS for GTR grade II meningioma. These facilities also have more patients receiving adjuvant radiation. However, we observed no difference in OS between adjuvant radiation and surgery alone.

Glioblastoma-mediated Immune Dysfunction Limits CMV-specific T Cells and Therapeutic Responses: Results from a Phase I/II Trial.

PURPOSE: Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets. PATIENTS AND METHODS: Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m2) treatment. The phase I component used a 3+3 design, ascending through four dose levels (5 × 106-1 × 108 cells). Treatment occurred every 6 weeks for four cycles. In vivo persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment. RESULTS: We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0-8.3 months]; 6-month PFS was 19% (95% CI, 7%-52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV+ CD8+ T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas. CONCLUSIONS: Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.

Impact of adverse events of bevacizumab on survival outcomes of patients with recurrent glioblastoma.

BACKGROUND: Bevacizumab is widely used for treatment of recurrent glioblastoma (rGB). It is well known that adverse events (AEs) due to bevacizumab can cause early discontinuation of treatment. However, the association between AEs and survival outcomes is not well defined. METHODS: We retrospectively identified patients with rGB, who were treated with single-agent bevacizumab or bevacizumab-based combination regimens from 07/2005 through 07/2014, and who discontinued bevacizumab due to either AEs or physician's decision. Those who discontinued bevacizumab because of tumor progression were excluded. Demographic, treatment, and survival data were collected from the database. RESULTS: Of 298 adults with rGB treated with bevacizumab in our database, 65 patients discontinued bevacizumab due to AEs (n = 39, 60%) or physician's decision (n = 26, 40%). There were no statistically significant differences in regards to age, performance status, extent of resection, number of lesions, the time between diagnosis and first recurrence, time between diagnosis and initiation of bevacizumab, number of recurrences before bevacizumab initiation, and duration of bevacizumab treatment between the two groups. Interestingly, patients who discontinued bevacizumab because of AEs progressed earlier after bevacizumab discontinuation (3.9 months vs 5.7 months; p = 0.02), had significantly shorter progression-free survival (PFS) (10.4 months vs 14.2 months; p = 0.01) and shorter overall survival (OS) from bevacizumab initiation (13.9 months vs 32.5 months; p = 0.01) as well as shorter OS from tumor diagnosis (20 months vs 49.3 months; p = 0.007) when compared to patients who discontinued bevacizumab due to a physician's decision. CONCLUSIONS: Our results indicate that the development of AEs to bevacizumab or bevacizumab-containing regimens is associated with unfavorable glioma-related survival outcomes in patients with rGB.

Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study.

Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region. Symptoms can be debilitating due to hormonal excess and survival is poor. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there has been interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated 4 patients with pituitary carcinoma with pembrolizumab as part of a phase II clinical trial. Two patients (patients 1 and 2) with functioning corticotroph pituitary carcinomas (refractory to surgery, radiotherapy and chemotherapy) had partial radiographic (60% and 32% per Immune-Related Response Evaluation Criteria In Solid Tumors, respectively) and hormonal responses. Patient 1's response continues 42 months after initiation of pembrolizumab and his tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2's tumor after exposure to temozolomide was not sampled, but prior somatic mutational testing was negative. One patient with a non-functioning corticotroph tumor (patient 3) had a best response of stable disease for 4 months. One patient with a prolactin-secreting carcinoma (patient 4) had progressive disease. The latter 2 patients' tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. Programmed death-ligand 1 staining was negative in all tumors. We report 2 cases of corticotroph pituitary carcinoma responsive to pembrolizumab after prior exposure to alkylating agents. The role of CPIs in treating patients with pituitary carcinoma, the relationship between tumor subtype and response to immunotherapy and mechanisms of hypermutation in this orphan disease require further study.Trial registration number: NCT02721732.

Genetic and immune profiling for potential therapeutic targets in adult human craniopharyngioma.

Craniopharyngioma is a rare tumor in adults. Although histologically benign, it can be locally aggressive and may require additional therapeutic modalities to surgical resection. Analyses including next generation sequencing, chromogenic and in situ hybridization, immunohistochemistry, and gene amplification were used to profile craniopharyngiomas (n=6) for frequently altered therapeutic targets. Four of six patients had the BRAF V600E missense mutation, frequent in the papillary craniopharyngioma subtype. One patient had a missense mutation in the WNT pathway, specifically CTNNB1, often associated with the adamantinomatous subtype. Craniopharyngiomas lacked microsatellite instability, had low tumor mutational burden, but did express PD-L1 protein, indicating potential therapeutic value for immune checkpoint inhibition. We identified mutations not previously described, including an E318K missense mutation in the MITF gene, an R1407 frameshift in the SETD2 gene of the PIK3CA pathway, R462H in the NF2 gene, and a I463V mutation in TSC2. Two patients testing positive for EGFR expression were negative for the EGFRvIII variant. Herein, we identified several alterations such as those in BRAF V600E and PD-L1, which may be considered as targets for combination therapy of residual craniopharygiomas.

The path forward for anti-programmed cell death-1 therapy in gliomas.

PURPOSE OF REVIEW: Checkpoint inhibitors (CPIs) represent the forefront of novel immunotherapeutic approaches for the treatment of solid cancers. However, the clinical development of CPIs in glioblastoma (GBM) has been challenging owing to an immunosuppressive tumor microenvironment and, possibly, low tumor mutation burden. Here, we review possible mechanisms responsible for the success of programmed cell death-1 (PD-1) blockade in patients with hypermutated GBM, recent clinical trials of anti-PD-1 monotherapy, trials incorporating neoadjuvant strategies, and trials of immunotherapy combination approaches in GBM. Mechanisms of resistance to immunotherapy and methods to overcome these challenges are also discussed. RECENT FINDINGS: Although two large phase III trials failed to demonstrate the superior efficacy of CPI in comparison with the standard of care in newly diagnosed and recurrent GBM, recent studies suggest that opportunities exist in some patients with GBM. A phase II study showed longer survival in patients with recurrent GBM who received neoadjuvant anti-PD-1 therapy than in those who received it as adjuvant therapy. In addition, cases of response to anti-PD-1 therapy in GBM patients with clonal hypermutator tumors have been reported. SUMMARY: Even though anti-PD-1 therapy does not seem to provide a benefit for molecularly unselected GBM patients, the success of PD-1 blockade in certain subsets of patients is encouraging.

Treatment and long-term outcomes in pituitary carcinoma: a cohort study.

BACKGROUND: Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and develop multiple recurrences despite surgery, radiotherapy and chemotherapy. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits assessment of benefit. METHODS: We describe a single-center multidisciplinary experience in managing PC patients over a 22-year period and review previously published PC series. RESULTS: Seventeen patients were identified. Median age at PC diagnosis was 44 years (range 16-82 years), and the median time from PA to PC transformation was 5 years (range 1-29 years). Median follow-up time was 28 months. Most PCs were hormone-positive (n = 12): ACTH (n = 5), PRL (n = 4), LH/FSH (n = 2) and GH (n = 1). All patients underwent at least one resection and at least one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had only central nervous system (CNS) metastases; six (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest PFS in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression (median 30 months). The 2, 3 and 5-year survival rate of the entire cohort was 71, 59 and 35%, respectively. All patients surviving >5 years had been treated with TMZ-based therapy. CONCLUSIONS: PC management benefits from multidisciplinary care and multimodality therapy. TMZ-based regimens were associated with high survival rates and long disease control.