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 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.

Radiographic patterns of progression with associated outcomes after bevacizumab therapy in glioblastoma patients.

Treatment response and survival after bevacizumab failure remains poor in patients with glioblastoma. Several recent publications examining glioblastoma patients treated with bevacizumab have described specific radiographic patterns of disease progression as correlating with outcome. This study aims to scrutinize these previously reported radiographic prognostic models in an independent data set to inspect their reproducibility and potential for clinical utility. Sixty four patients treated at MD Anderson matched predetermined inclusion criteria. Patients were categorized based on previously published data by: (1) Nowosielski et al. into: T2-diffuse, cT1 Flare-up, non-responders and T2 circumscribed groups (2) Modified Pope et al. criteria into: local, diffuse and distant groups and (3) Bahr et al. into groups with or without new diffusion-restricted and/or pre-contrast T1-hyperintense lesions. When classified according to Nowosielski et al. criteria, the cT1 Flare-up group had the longest overall survival (OS) from bevacizumab initiation, with non-responders having the worst outcomes. The T2 diffuse group had the longest progression free survival (PFS) from start of bevacizumab. When classified by modified Pope at al. criteria, most patients did not experience a shift in tumor pattern from the pattern at baseline, while the PFS and OS in patients with local-to-local and local-to-diffuse/distant patterns of progression were similar. Patients developing restricted diffusion on bevacizumab had worse OS. Diffuse patterns of progression in patients treated with bevacizumab are rare and not associated with worse outcomes compared to other radiographic subgroups. Emergence of restricted diffusion during bevacizumab treatment was a radiographic marker of worse OS.

Dorsal column myelopathy after intrathecal chemotherapy for leukemia.

Intrathecal chemotherapy with methotrexate, a folate antagonist, is widely used to treat central nervous system malignancies. The mechanisms underlying methotrexate-induced neurotoxicity are unclear but may be related to increased homocysteine levels. Intrathecal methotrexate-induced myelopathy mimicking subacute combined degeneration, with normal B12 levels, has been documented. We examined treatment and magnetic resonance imaging (MRI) characteristics of 13 patients with leukemia who received intrathecal methotrexate and developed urinary and bowel incontinence, ascending motor weakness, and sensory loss with dorsal column hyperintensity on MRI between 2000 and 2016. Cerebrospinal fluid evaluation was negative for leukemia in all patients and positive for elevated protein in 12 patients. Seven of eight patients with available data had reduced serum folate, increased serum homocysteine, or both, implicating methotrexate as the cause of neurotoxicity. Autopsy of one patient revealed loss of myelinated axons in the posterior columns. These findings suggest that methotrexate neurotoxicity may be mediated by folate antagonism. Awareness and a high index of suspicion of these characteristic clinical and radiographic features in patients who develop myelopathy after intrathecal methotrexate may help to avoid additional neurotoxic therapy in such patients.

Outcome of patients with malignant glioma and synchronous or metachronous non-central nervous system primary neoplasms.

Patients with malignant glioma who are also diagnosed with one or more primary neoplasms of other organs present a unique challenge in both determining prognosis and clinical management. The overlapping impact of the malignancies and their treatment result in confounding variables that may adversely affect optimal management of such patients. Additionally, the glioma-related characteristics and survival outcome of these patients is not well-defined. In this retrospective chart and data review from our longitudinal database, we identified patients with malignant glioma including anaplastic glioma and glioblastoma, diagnosed between January 2005 and June 2011, who were also diagnosed with other non-CNS primary neoplasms. Patients with known genetic syndromes were excluded. The data was analyzed to determine the clinical characteristics and glioma-related survival. A total of 204 patients with malignant glioma (165 glioblastoma and 39 anaplastic glioma) were identified. There was no significant difference in the overall survival or progression-free survival between patients with malignant glioma plus non-CNS primary neoplasm when compared with patients with malignant glioma only. In patients with glioblastoma and non-CNS malignancy, the duration between diagnosis of glioblastoma and non-CNS neoplasms did not significantly alter glioma-related survival. Patients with malignant glioma who were diagnosed with other non-CNS malignancy have survival outcome comparable to those with malignant glioma only. The duration between diagnosis of glioblastoma and diagnosis of non-CNS neoplasms did not affect survival. Further prospective studies specifically addressing survival and molecular characteristics of patients with malignant glioma plus non-CNS cancers are recommended.

Posterior reversible encephalopathy syndrome in cancer patients: a single institution retrospective study.

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiologic entity. Its management and outcome in the oncology population is limited because it is still difficult to identify despite an increasingly recognized occurrence. This is the largest retrospective study of PRES in cancer patients reported from a single institution. We explore the clinical manifestations and radiologic features to comprehensively assess PRES in order to prevent permanent neurologic deficits and mortality. We retrospectively identified 69 patients with cancer who developed PRES at MDACC between 01/2006 to 06/2012. Clinical and radiographic data were abstracted from their records and reviewed for our analysis. Mean age at PRES onset was 52 ± 17.8 years. Fifty-two (75 %; p < 0.001) patients were women. Most common diagnoses were leukemia (30 %) and lymphoma (12 %). Forty-eight (70 %) patients were treated with chemotherapy, 21 (30 %) bone marrow transplant and 14 (20 %) tacrolimus. Most common clinical presentation was seizures (67 %). PRES was associated with hypertension in 62 (90 %) patients. On brain MRI, 33 (44 %) patients had some evidence of hemorrhage, 22 (73 %) of these were thrombocytopenic. Thirty-five (51 %) patients fully recovered and 19 (28 %) had permanent neurological deficits. Morbidity and mortality were associated with continuation with offending agent, thrombocytopenia, variations in mean arterial pressure ≥20 mmHg, electrographic seizures at onset, atypical MRI pattern and delay in diagnostic imaging (7.4 ± 4.8 days vs. 1.9 ± 1.8 days; p = 0.031) as half of them did not receive a prompt intervention. Special attention should be given to patients who present with high-risk factors in order to prevent development of PRES or decrease patient morbidity and mortality. Management of PRES should be guided by the radiographic findings. Overall, early recognition, discontinuation of the offending agents, correction of thrombocytopenia and blood pressure control are still the main strategies to manage PRES.

Radiotherapy with concurrent temozolomide for the management of extraneural metastases in pituitary carcinoma.

BACKGROUND: Pituitary carcinomas (PC) are uncommon neuroendocrine tumors, accounting for 0.1 % of all pituitary tumors. The diagnosis of PC is based on the presence of metastases from a pituitary adenoma, and not by local invasion or pathological features alone. PC is typically resistant to therapy, with a median overall survival of only 31 months. There is no standard treatment for PC, but maximal safe resection and radiation are performed when possible. Encouraging preliminary data on the use of temozolomide (TMZ)-based therapy has been previously reported. METHODS: We report the response to therapy and safety of radiation with concurrent temozolomide (RT/TMZ) in 2 adult patients with heavily pretreated PC and extraneural metastases. RESULTS: Both patients had prior history of pituitary macroadenoma. At the time of diagnosis of PC, Ki-67 % was 24.2 and 10 %, with positive p53 staining in one case. Metastatic sites included lymph nodes, liver and bone. Case-1 received RT/TMZ to the tumor bed in the skull base and to the metastases in the cervical lymph nodes. Case-2 received RT/TMZ to recurrent tumor involving portacaval lymph nodes. Both patients achieved excellent long-term control of the sites of treated extraneural metastases, with no significant acute or delayed toxicity. CONCLUSIONS: RT/TMZ was safely delivered and might provide sustained control of extraneural metastases in PC. Although this retrospective report has limitations, RT/TMZ can be considered as a therapeutic option for the management of extraneural metastases in PC.

Alternating ptosis associated with asialo-GM1 and GD1b antibodies.

Miller Fisher syndrome (MFS), variant of acute inflammatory demyelinating polyradiculoneuropathy, is recognized as clinical triad (ophthalmoplegia-ataxia-areflexia). Ganglioside antibodies play an important role in the pathogenesis of acute polyradiculoneuropathy including MFS. To our knowledge, there has been no report of MFS presenting with atypical alternating ptosis or with concurrent elevation of serum GD1 and asialo-GM1 antibody titers, and negative titers of GQ1b antibody such as our patient. Our objective is to report MFS with unusual symptoms and to share our diagnostic approach. We report a rare case of MFS presenting with alternating eyelid ptosis, paresthesia, and ataxia after a respiratory infection. Initial neurological examination revealed left eyelid ptosis, hyporeflexia, positive Romberg sign, and ataxia. The ice pack test was negative. Three days later, contralateral ptosis was observed, associated with areflexia and worsened ataxia. However, there was significant improvement of the previous left eyelid ptosis. Serology revealed elevated asialo-GM1 and GD1b antibodies. Acetylcholine receptor antibodies were negative. Cerebral spinal fluid revealed elevated IgG index. Nerve conduction studies (NCS) performed four days after the onset of symptoms showed normal nerve conduction velocities and F-waves, and absent bilateral H-reflexes. Repetitive nerve stimulation (3 Hz) showed no decrement of compound muscle action potentials. Trial with a single dose of pyridostigmine showed no clinical improvement. The symptoms resolved without intervention. NCS 18 days after onset of symptoms showed mildly prolonged F-waves and absent H-reflexes. This case highlights an atypical presentation of MFS and raises the awareness of a rare autoantibody associated with it.

Ischemic stroke in patients with gliomas at The University of Texas-M.D. Anderson Cancer Center.

Patients with gliomas are at risk of cerebrovascular accidents (CVA) with potential consequences on survival, function, and local tumor control. Our objective was to provide information about CVA in patients with gliomas and to estimate survival in this group. We reviewed all adult glioma patients with ischemic CVA at the University of Texas-M.D. Anderson Cancer Center from 2003 through 2014. We extracted demographic, clinical, imaging, treatment and outcome data. We used descriptive summary data and estimated or compared survival rates where appropriate. 60 of 6500 patients (0.1%) with high-grade (HGG, n = 47) or low-grade glioma (LGG, n = 13) had ischemic CVA Thirty-two (53%) patients had postoperative strokes, and 20 (33%) had CVA after 2 weeks of surgery. Forty-one patients (68%) had gross total resection. For HGG and CVA, the poststroke median overall survival was 17 months versus 61 months in LGG and CVA (P = 0.03; hazard ratio (HR): 2.8; 95% CI 1.07-4.60). Survival stratified by modified Rankin Scale grade was significant (X(2) = 9.8, P = 0.007). Five patients received bevacizumab before stroke onset; none responded to antiangiogenic therapy. There was no stroke-related death. At our institution for 10 years, ischemic CVA in glioma patients was a rare complication, clearly associated in half of cases to surgery, and with a variable negative impact on performance status and neurologic function. In this group, patients with more neurological deficits lived less. The survival difference between and within subgroups was most likely due to tumor grade. More research is necessary to improve prevention of postoperative stroke in glioma patients.

Primary and secondary gliosarcomas: clinical, molecular and survival characteristics.

Gliosarcoma is classified by the World Health Organization as a variant of glioblastoma. These tumors exhibit biphasic histologic and immunophenotypic features, reflecting both glial and mesenchymal differentiation. Gliosarcomas can be further classified into primary (de novo) tumors, and secondary gliosarcomas, which are diagnosed at recurrence after a diagnosis of glioblastoma. Using a retrospective review, patients seen at MD Anderson Cancer Center between 2004 and 2014 with a pathology-confirmed diagnosis of gliosarcoma were identified. 34 patients with a diagnosis of gliosarcoma seen at the time of initial diagnosis or at recurrence were identified (24 primary gliosarcomas (PGS), 10 secondary gliosarcomas (SGS)). Molecular analysis performed on fourteen patients revealed a high incidence of TP53 mutations and, rarely, EGFR and IDH mutations. Median overall survival (OS) for all patients was 17.5 months from the diagnosis of gliosarcoma, with a progression free survival (PFS) of 6.4 months. Comparing PGS with SGS, the median OS was 24.7 and 8.95 months, respectively (from the time of sarcomatous transformation in the case of SGS). The median OS in SGS patients from the initial diagnosis of GB was 25 months, with a PFS of 10.7 months. Molecular analysis revealed a higher than expected rate of TP53 mutations in GS patients and, typical of primary glioblastoma, IDH mutations were uncommon. Though our data shows improved outcomes for both PGS and SGS when compared to the literature, this is most likely a reflection of selection bias of patients treated on clinical trials at a quaternary center.

Myelopathy following intrathecal chemotherapy in adults: a single institution experience.

Methotrexate and cytarabine arabinoside are frequently administered intrathecally in the prophylaxis and treatment of patients with hematological malignancies. Myelopathy as a complication of intrathecal (IT) chemotherapy is rare in adults, with most of the cases described in the literature occurring in the pediatric population. Between January 2010 and March 2014, 587 newly diagnosed B cell acute lymphoblastic leukemia and 24 chronic myeloid leukemia lymphoid blast phase patients were seen at The University of Texas MD Anderson Cancer Center. This case series discusses seven adult cases deemed to have IT chemotherapy-induced myelopathy between 2010 and 2014 at MD Anderson Cancer Center. Five out of the seven patients had T2 abnormalities involving the dorsal columns of the spinal cord. An elevated myelin basic protein level was noted in the two patients in whom it was checked. The wide range of dosage and timing with respect to IT chemotherapy administration suggests an idiosyncratic reaction or individual threshold to the development of myelopathy. By describing the largest case series of myelopathy in adults, we aim to raise awareness about this rare albeit devastating complication. Based on the seven cases described we would recommend-MRI of the spine with T2-weighted imaging in the sagittal and axial planes in leukemia patients with unexplained myelopathy and consideration to delay IT chemotherapy until after an extensive work-up to rule out CNS leukemia. Though more data are needed on the use of folate metabolites, preliminary results have shown some promise in the treatment of methotrexate-induced myelopathy and may be a potential consideration for future patients suspected to have chemotherapy induced myelopathy.

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.

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.

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.

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.

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.

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.

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.

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.