The field of cancer immunotherapy has made exciting progress for some cancer types in recent years. However, recent failures of late-phase clinical trials evaluating checkpoint blockade in patients with glioblastoma (GBM) represent continued challenges for brain cancer immunotherapy. This is likely due to multiple factors including but not limited to marked genetic and antigenic heterogeneity, relatively low mutational loads, and paucity of GBM-infiltrating T cells. We review recent and ongoing studies targeting the checkpoint molecules as monotherapy or in combination with other modalities, and discuss the mechanisms underlying the unresponsiveness of GBM to single-modality immunotherapy approaches. We also discuss other novel immunotherapy approaches that may promote T-cell responses and overcome the "cold tumor" status of GBM, including oncolytic viruses and adoptive T-cell therapy. Clin Cancer Res; 24(21); 5198-205. ©2018 AACR.

Abstract

BACKGROUND

Nearly 80,000 new cases of primary brain tumors are expected to be diagnosed this year, 32% of CNS tumors are malignant. Anecdotally, patients who report use of cannabis, frequently describe higher quality of life scores (QOL) in standardized instruments. However, the lack of available tools that allow systematic documentation of cannabis use results in a barrier to accurately assess efficacy, potential benefits and risks.

METHODS

We conducted a single center, observational study: patients with primary brain tumors answered a previously validated instrument to explore cannabis use. QOL was assessed using the instruments from the European Organisation for Research and Treatment of Cancer: QLQ-C30 and its complementary module BN-20 as well as the EuroQol instrument EQ-5D-5L. Eligible participants were identified as cannabis users or non-users, completing the instruments in a self-administered fashion.

RESULTS

To date, 51 patients who signed informed consent were enrolled and answered the questionnaires, mean age was 51 (SD 12.95) years, 34 were male, 30 were considered active cannabis users (66.6% males and 33.3% females). The mean global health score in the QLQ-C30 instrument was 68.4 (SD: 20.7) among cannabis users and 82.2 (SD: 17.5) among non-users. The mean difference in QOL scores between users and non-users was 13.8 (95%CI: 2.8, 24.8; p=0.01). In contrast the difference between cannabis users and non-users in QOL index in the EQ-5D-5L instrument was 0.13 (95% CI: 0.06, 0.2; p=0.001). Among cannabis users, patients perceive their symptoms as moderate before using cannabis and mild after using cannabis (p >0.001)

CONCLUSIONS

In our analysis, patients who use cannabis reported, on average, lower QOL scores. Potentially, sicker patients resort to cannabis to improve their symptoms and ultimately quality of life. The perception of patients is that cannabis usage improves overall quality of life. Findings provide support to perform prospective studies.

Abstract

BACKGROUND

Histone H3.3 or H3.1 mutant protein is commonly expressed in pediatric and adult diffuse midline gliomas, including diffuse intrinsic pontine gliomas (DIPGs), and portends a poor prognosis, regardless of histologic features. As such, “Diffuse midline glioma, H3-K27M-mutant” (DMG-H3K27M) was added to the 2016 WHO Classification as a grade IV entity. Knowledge of the clinical experience and natural history of this recently defined tumor in adults is limited.

METHODS

We retrospectively reviewed the pathology of adult (age ≥ 18) DMG-H3K27Ms diagnosed at our institution either via H3-K27M mutant-specific immunohistochemistry or via the UCSF500 targeted next-generation sequencing panel that includes the H3F3A, HIST1H3B, and HIST1H3C genes. Treatment, outcome, and imaging characteristics were reviewed.

RESULTS

We identified 26 adults with DMG-H3K27M and 2 with non-midline-H3K27M. Tumor locations included thalamus/basal ganglia (15), hypothalamus (2), pineal region (1), cerebellum (3), brainstem (2), spinal cord (2), mesial temporal (1), and non-midline sites (2). MRI imaging for 21/25 evaluable cases demonstrated enhancement. Of the 26 DMG-H3K27M cases, median age was 35 years (22–68 years). Of these, 17 patients had biopsy only. Median OS was 41 months (95%-CI 31-NA). In the 22 DMG-H3K27M patients with available clinical treatment data, 21 received radiation (19 with temozolomide) at initial diagnosis. At progression/recurrence, 11 patients received bevacizumab, 5 were re-treated with temozolomide, 8 received other chemotherapy, and 8 received > 1 course of re-irradiation.

CONCLUSION

While still poor overall, clinical outcome in adults with DMG-H3K27M is often better than that of pediatric DIPGs and other IDH-wildtype high-grade gliomas, such as glioblastoma. This may reflect a different cell of origin or other distinct biologic differences. Further investigation of both DMG-H3K27M and non-midline H3K27M mutant tumors in adults is warranted to study the genetic and epigenetic features of these rare tumors, as well as optimal treatment strategies.

Background

Primary CNS tumors constitute a heterogeneous group of neoplasms that share a considerable morbidity and mortality rate. To help control tumor growth and clinical outcomes (overall survival, progression-free survival, quality of life) symptoms, patients often resort to alternative therapies, including the use of cannabis. Despite rapidly growing popularity, cannabis and its impact on patients with primary malignant CNS tumors is understudied.

Methods

To shed light on the lack of scientific evidence in this field, in November 2018 we conducted a search and examination of cannabis in neuro-oncology in major journal databases and bibliographies of selected articles, and through abstracts of annual meetings using prespecified criteria in line with the Cochrane Collaboration guidelines.

Results

We identified 45 publications, of which 9 were selected. Five studies were included. Publication dates ranged from 2004 to 2018 and included varying histologies of primary brain tumors. The average survival at 1 year was 56.09% (95% CI: 48.28-63.9). There was no difference in risk ratio (RR) for death at 1 year between groups (RR: 1.069 [95% CI: 0.139-8.25]). We found strong evidence of heterogeneity (Q = 74.0%; P = .021). We found no statistical evidence of publication bias (P = .117; SD = 1.91).

Conclusions

There was limited moderate-quality evidence that supports the use of cannabinoids as adjuvant to the standard of care in the treatment of brain and CNS tumors. There was very low-quality evidence suggesting that cannabinoids were associated with adult-onset gliomas. Further prospective clinical trials are necessary to adequately evaluate the impact of cannabinoids on CNS tumors, specifically on survival and quality of life.

Background

Poor socioeconomic and health-related quality of life (HRQOL) outcomes in survivors of childhood cancer can lead to distress and overall negatively impact the lives of these individuals. The current report has highlighted the impact of stroke and stroke recurrence on mortality, psychological HRQOL, and socioeconomic outcomes within the Childhood Cancer Survivor Study (CCSS).

Methods

The CCSS is a retrospective cohort study with longitudinal follow-up concerning survivors of pediatric cancer who were diagnosed between 1970 and 1986. Mortality rates per 100 person-years were calculated across 3 periods: 1) prior to stroke; 2) after first stroke and before recurrent stroke; and 3) after recurrent stroke. Socioeconomic outcomes, the standardized Brief Symptoms Inventory-18, the Medical Outcomes Study 36-Item Short Form Health Survey, and the CCSS-Neurocognitive Questionnaire also were assessed.

Results

Among 14,358 participants (median age, 39.7 years), 224 had a stroke after their cancer diagnosis (single stroke in 161 patients and recurrent stroke in 63 patients). Based on 2636 deaths, all-cause late mortality rates were 0.70 (95% CI, 0.68-0.73) prior to stroke, 1.03 (95% CI, 0.73-1.46) after the first stroke, and 2.42 (95% CI, 1.48-3.94) after the recurrent stroke. Among 7304 survivors, those with stroke were more likely to live with a caregiver (single stroke odds ratio [OR], 2.3 [95% CI, 1.4-3.8]; and recurrent stroke OR, 5.3 [95% CI, 1.7-16.8]) compared with stroke-free survivors. Stroke negatively impacted task efficiency (single stroke OR, 2.4 [95% CI, 1.4-4.1] and recurrent stroke OR, 3.3 [95% CI, 1.1-10.3]) and memory (single stroke OR, 2.1 [95% CI, 1.2-3.7]; and recurrent stroke OR, 3.5 [95% CI, 1.1-10.5]).

Conclusions

Stroke and stroke recurrence are associated with increased mortality and negatively impact HRQOL measures in survivors of pediatric cancer.

Abstract

BACKGROUND

“Diffuse midline glioma, H3 K27M-mutant” is a new tumor entity established in the 2016 WHO Classification of Tumors of the CNS that comprises a set of diffuse gliomas arising in midline structures that is molecularly defined by a recurrent K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited. Given the more frequent origin in the thalamus or spinal cord in adults versus the brainstem in children, gliomas with this mutation may encompass a heterogeneous population of tumor subtypes that vary based on patient age, anatomic site of origin, and concurrent genetic alterations.

METHODS

The 60 patients included were 18 years or older at initial diagnosis, during the period of 2014-2019 at UCSF. Cases were identified using immunohistochemistry with a H3 K27M-mutant specific antibody and/or next-generation sequencing of histone 3 genes H3F3A, HIST1H3B and HIST1H3C. Targeted NGS was performed on tumors from 21 patients, utilizing an UCSF institutional panel or a variety of commercial sources.

RESULTS

Patients presented primarily in the 3rd decade of life, and 57% of tumors were located in the thalamus. Genomic profiling revealed p.K27M mutations exclusively in H3F3A and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric diffuse midline gliomas. Additionally, these adult H3 K27M-mutant diffuse midline gliomas are universally IDH-wildtype, and have frequent mutations in TP53, PPM1D, FGFR1, NF1, and ATRX. The overall survival of this adult cohort is longer than historical averages for both H3 K27M-mutant diffuse midline glioma in children and IDH-wildtype glioblastomas in adults.

CONCLUSIONS

Together, these findings indicate that H3 K27M-mutant diffuse midline glioma represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in children versus adults.

Background

"Diffuse midline glioma (DMG), H3 K27M-mutant" is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited.

Methods

Patient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan-Meier modeling, and univariate and multivariate analysis.

Results

Median patient age was 32 years (range 18-71 years). Tumors were centered in the thalamus (n = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the H3F3A gene and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric DMGs. Accompanying mutations in TP53, PPM1D, FGFR1, NF1, and ATRX were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults.

Conclusions

Together, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.

Abstract: BACKGROUND: Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS: We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS: The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION: Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation.

Abstract

BACKGROUND

Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component.

METHODS

We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway.

RESULTS

The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia.

CONCLUSION

Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation.