Salvage Stereotactic Radiosurgery for Recurrent WHO Grade 2 and 3 Meningiomas: A Multicenter Study (STORM).

PURPOSE: The role of stereotactic radiosurgery (SRS) in the management of grade 2 and 3 meningiomas is not well elucidated. Unfortunately, local recurrence rates are high, and guidelines for management of recurrent disease are lacking. To address this knowledge gap, we conducted STORM, a multicenter retrospective cohort study of patients treated with primary SRS for recurrent grade 2 and 3 meningiomas. METHODS AND MATERIALS: Data on patients with recurrent grade 2 and 3 meningioma treated with SRS at first recurrence were retrospectively collected from eight academic centers in the United States. Patients with multiple lesions at the time of initial diagnosis or more than two lesions at the time of first recurrence were excluded from this analysis. Patient demographics and treatment parameters were extracted at time of diagnosis, first recurrence, and second recurrence. Oncologic outcomes including progression-free survival (PFS) and overall survival (OS) as well as toxicity outcomes were reported at the patient level. RESULTS: From 2000-2022, 108 patients were identified (94% grade 2, 6.0% grade 3). 106 patients (98%) had upfront surgical resection (60% gross-total resection) with 18% receiving adjuvant radiotherapy (RT). Median time to first progression was 2.5 years (IQR 1.34-4.30). At first recurrence, patients were treated with single or fractionated SRS to a median marginal dose of 16 Gy to a maximum of two lesions (87% received single fraction SRS). Median follow-up time after SRS was 2.6 years. 1-, 2-, and 3-year PFS was 90%, 75%, and 57%, respectively after treatment with SRS. 1-, 2-, and 3-year OS was 97%, 94%, and 92%, respectively. On multivariable analysis, grade 3 disease (HR 6.80; 95% CI 1.61-28.6), male sex (HR 3.48; 95% CI 1.47-8.26), and receipt of prior RT (HR 2.69; 95% CI 1.23-5.86) were associated with worse PFS. SRS dose and tumor volume were not correlated with progression. Treatment was well-tolerated, with a 3.0% incidence of grade 2+ radiation necrosis. CONCLUSIONS: This is the largest multi-center study to evaluate salvage SRS in recurrent grade 2 and 3 meningiomas. In this select cohort of patients with primarily grade 2 meningioma with potentially more favorable natural history of delayed, localized first recurrence amenable to salvage SRS, local control rates and toxicity profiles were favorable, warranting further prospective validation.

Elucidation and Pharmacologic Targeting of Master Regulator Dependencies in Coexisting Diffuse Midline Glioma Subpopulations.

Diffuse Midline Gliomas (DMGs) are universally fatal, primarily pediatric malignancies affecting the midline structures of the central nervous system. Despite decades of clinical trials, treatment remains limited to palliative radiation therapy. A major challenge is the coexistence of molecularly distinct malignant cell states with potentially orthogonal drug sensitivities. To address this challenge, we leveraged established network-based methodologies to elucidate Master Regulator (MR) proteins representing mechanistic, non-oncogene dependencies of seven coexisting subpopulations identified by single-cell analysis-whose enrichment in essential genes was validated by pooled CRISPR/Cas9 screens. Perturbational profiles of 372 clinically relevant drugs helped identify those able to invert the activity of subpopulation-specific MRs for follow-up in vivo validation. While individual drugs predicted to target individual subpopulations-including avapritinib, larotrectinib, and ruxolitinib-produced only modest tumor growth reduction in orthotopic models, systemic co-administration induced significant survival extension, making this approach a valuable contribution to the rational design of combination therapy.

Focused ultrasound-mediated blood-brain barrier opening is safe and feasible with moderately hypofractionated radiotherapy for brainstem diffuse midline glioma.

BACKGROUND: Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic strategies have been unsuccessful and radiotherapy (RT) remains the standard-of-care. A central impediment to treatment is the blood-brain barrier (BBB), which precludes drug delivery to the central nervous system (CNS). Focused ultrasound (FUS) with microbubbles can transiently and non-invasively disrupt the BBB to enhance drug delivery. This study aimed to determine the feasibility of brainstem FUS in combination with clinical doses of RT. We hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT. METHODS: To establish a safety timeline, we administered FUS to the brainstem of non-tumor bearing mice concurrent with or adjuvant to RT; our findings were validated in a syngeneic brainstem murine model of DMG receiving repeated sonication concurrent with RT. The brainstems of male B6 (Cg)-Tyrc-2J/J albino mice were intracranially injected with mouse DMG cells (PDGFB+, H3.3K27M, p53-/-). A clinical RT dose of 39 Gy in 13 fractions (39 Gy/13fx) was delivered using the Small Animal Radiation Research Platform (SARRP) or XRAD-320 irradiator. FUS was administered via a 0.5 MHz transducer, with BBBO and tumor volume monitored by magnetic resonance imaging (MRI). RESULTS: FUS-mediated BBBO did not affect cardiorespiratory rate, motor function, or tissue integrity in non-tumor bearing mice receiving RT. Tumor-bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy/13fx offered local control, though disease progression occurred 3-4 weeks post-RT. CONCLUSION: Repeated FUS-mediated BBBO is safe and feasible concurrent with RT. In our syngeneic DMG murine model, progression occurs, serving as an ideal model for future combination testing with RT and FUS-mediated drug delivery.

The role of radiotherapy in immunotherapy strategies in the central nervous system.

The clinical efficacy and relative tolerability of adverse effects of immune checkpoint immunotherapy have led to its increasingly routine use in the management of multiple advanced solid malignancies. Radiation therapy (RT) is well-known to have both local and distant immunomodulatory effects, which has led to extensive investigation into the synergism of these 2 therapies. While the central nervous system (CNS) has historically been thought to be a sanctuary site, well-protected by the blood-brain barrier from the effects of immunotherapy, over the last several years studies have shown the benefits of these drugs, particularly in metastatic disease involving the CNS. This review explores current progress and the future of combination therapy with immune checkpoint inhibitors and RT.

Immune Response following FLASH and Conventional Radiation in Diffuse Midline Glioma.

PURPOSE: Diffuse midline glioma (DMG) is a fatal tumor traditionally treated with radiation therapy (RT) and previously characterized as having a noninflammatory tumor immune microenvironment (TIME). FLASH is a novel RT technique using ultra-high dose rate that is associated with decreased toxicity and effective tumor control. However, the effect of FLASH and conventional (CONV) RT on the DMG TIME has not yet been explored. METHODS AND MATERIALS: Here, we performed single-cell RNA sequencing (scRNA-seq) and flow cytometry on immune cells isolated from an orthotopic syngeneic murine model of brainstem DMG after the use of FLASH (90 Gy/sec) or CONV (2 Gy/min) dose-rate RT and compared to unirradiated tumor (SHAM). RESULTS: At day 4 post-RT, FLASH exerted similar effects as CONV in the predominant microglial (MG) population, including the presence of two activated subtypes. However, at day 10 post-RT, we observed a significant increase in the type 1 interferon α/ß receptor (IFNAR+) in MG in CONV and SHAM compared to FLASH. In the non-resident myeloid clusters of macrophages (MACs) and dendritic cells (DCs), we found increased type 1 interferon (IFN1) pathway enrichment for CONV compared to FLASH and SHAM by scRNA-seq. We observed this trend by flow cytometry at day 4 post-RT in IFNAR+ MACs and DCs, which equalized by day 10 post-RT. DMG control and murine survival were equivalent between RT dose rates. CONCLUSIONS: Our work is the first to map CONV and FLASH immune alterations of the DMG TIME with single-cell resolution. Although DMG tumor control and survival were similar between CONV and FLASH, we found that changes in immune compartments differed over time. Importantly, although both RT modalities increased IFN1, we found that the timing of this response was cell-type and dose-rate dependent. These temporal differences, particularly in the context of tumor control, warrant further study.

Multiparametric MRI as a Predictor of PSA Response in Patients Undergoing Stereotactic Body Radiation Therapy for Prostate Cancer.

Purpose: To maximize the therapeutic ratio, it is important to identify adverse prognostic features in men with prostate cancer, especially among those with intermediate risk disease, which represents a heterogeneous group. These men may benefit from treatment intensification. Prior studies have shown pretreatment mpMRI may predict biochemical failure in patients with intermediate and/or high-risk prostate cancer undergoing conventionally fractionated external beam radiation therapy and/or brachytherapy. This study aims to evaluate pretreatment mpMRI findings as a marker for outcome in patients undergoing stereotactic body radiation therapy (SBRT). Methods and Materials: We identified all patients treated at our institution with linear accelerator based SBRT to 3625 cGy in 5 fractions, with or without androgen deprivation therapy (ADT) from November 2015 to March 2021. All patients underwent pretreatment Magnetic Resonance Imaging (MRI). Posttreatment Prostate Specific Imaging (PSA) measurements were typically obtained 4 months after SBRT, followed by every 3 to 6 months thereafter. A 2 sample t test was used to compare preoperative mpMRI features with clinical outcomes. Results: One hundred twenty-three men were included in the study. Pretreatment MRI variables including median diameter of the largest intraprostatic lesion, median number of prostate lesions, and median maximal PI-RADS score, were each predictive of PSA nadir and time to PSA nadir (P < .0001). When separated by ADT treatment, this association remained for patients who were not treated with ADT (P < .001). In patients who received ADT, the pretreatment MRI variables were each significantly associated with time to PSA nadir (P < .01) but not with PSA nadir (P > 0.30). With a median follow-up time of 15.9 months (IQR: 8.5-23.3), only 3 patients (2.4%) experienced biochemical recurrence as defined by the Phoenix criteria. Conclusions: Our experience shows the significant ability of mpMRI for predicting PSA outcome in prostate cancer patients treated with SBRT with or without ADT. Since PSA nadir has been shown to correlate with biochemical failure, this information may help radiation oncologists better counsel their patients regarding outcome after SBRT and can help inform future studies regarding who may benefit from treatment intensification with, for example, ADT and/or boosts to dominant intraprostatic lesions.

Radiation-Induced Sensorineural Hearing Loss and Potential Management.

The cochlear apparatus is one of the major organs at risk when considering radiation therapy (RT) for brain, head, and neck tumors. Radiation oncologists currently consider mean dose constraints of <35 Gy for conventionally fractioned radiation therapy (RT), <4 Gy for single fraction stereotactic radiosurgery, and <17.1 or 25 Gy for 3- or 5-fraction stereotactic radiosurgery, respectively, as the standard of care. Indeed, dose adjustments are made in the setting of concurrent platinum-based chemotherapy or when prioritizing tumor coverage during treatment planning. Despite guidelines, in many patients, RT to the cochlea may still cause sensorineural hearing loss through progressive degeneration and ossification of the inner ear. There are several audiologic and otolaryngologic interventions for incident RT-induced hearing loss, including hearing aids, cochlear implants, or, in the context of vestibular schwannoma due to neurofibromatosis type 2, auditory brain stem implantation. Cochlear implants are the most effective at restoring hearing and improving quality of life for those with an intact cochlear nerve. An early multidisciplinary approach is essential to optimally manage RT-induced hearing loss, and this topic discussion serves as a guide for radiation oncologists on cochlear dosimetric considerations as well as how to address potential RT-induced adverse effects.

MGMT promoter methylation in 1p19q-intact gliomas.

OBJECTIVE: Standard-of-care for 1p19q-intact anaplastic gliomas is defined by the international randomized phase III CATNON trial, which found an overall survival (OS) benefit for adjuvant temozolomide (TMZ) when added to radiotherapy. Paradoxically, TMZ did not appear to benefit patients with IDH-wildtype gliomas, regardless of MGMT promoter status. The authors concluded that well-powered prospective study on the clinical efficacy of TMZ for patients with IDH-wildtype anaplastic gliomas (meeting criteria for glioblastoma) is warranted. Given that the prognostic and predictive role of MGMT status for grade 2-3 gliomas is unresolved, we determined the effect of MGMT status on OS in patients with 1p19q-intact gliomas in the National Cancer Database (NCDB). METHODS: We queried the NCDB from 2018 to 2019 for patients with diffuse (grade 2) and anaplastic (grade 3) IDH-wildtype or -mutant astrocytomas who received chemotherapy with follow-up through 2022. The Kaplan-Meier method and Cox proportional hazards regressions models were used to determine the association of MGMT with OS. RESULTS: We identified 1514 patients who were newly diagnosed with IDH-wildtype (n = 802, 33% methylated) or -mutant astrocytomas (n = 712, 48% methylated) and received chemotherapy during initial management. An unmethylated promoter was associated with poorer survival in patients with IDH-wildtype (3-year OS 34% [95%CI 29-39%] vs. 46% [95%CI 39-54%], p < .001, adjusted HR 1.53 [95%CI 1.24-1.89]) but not IDH-mutant astrocytomas (3-year OS 79% [95%CI 74-84%] vs. 80% [95%CI 75-86%], p =0 .81, HR 1.04 [95%CI 0.73-1.50]). CONCLUSIONS: This ancillary analysis supports conclusions from the CATNON trial for adjuvant TMZ as standard-of-care for anaplastic astrocytomas (IDH-mutant and 1p19q-intact), irrespective of MGMT status. Determining the optimal strategy for diffuse gliomas that are IDH-wildtype will be particularly important. MGMT promoter methylation should be considered as a stratification factor in future clinical trials for these patients.

MGMT promoter methylation in 1p19q-intact gliomas.

Objective: Standard-of-care for 1p19q-intact anaplastic gliomas is defined by the international randomized phase III CATNON trial, which found an overall survival (OS) benefit for adjuvant temozolomide (TMZ) when added to radiotherapy. Paradoxically, TMZ did not appear to benefit patients with IDH-wildtype gliomas, regardless of MGMT promoter status. The authors concluded that well-powered prospective study on the clinical efficacy of TMZ for patients with IDH-wildtype anaplastic gliomas (meeting criteria for glioblastoma) is warranted. Given that the prognostic and predictive role of MGMT status for grade 2-3 gliomas is unresolved, we determined the effect of MGMT status on OS in patients with 1p19q-intact gliomas in the National Cancer Database (NCDB). Methods: We queried the NCDB from 2018-2019 for patients with IDH-wildtype or -mutant astrocytomas who received chemotherapy with follow-up through 2022. The Kaplan-Meier method and Cox proportional hazards regressions models were used to determine the association of MGMT with OS. Results: We identified 1,514 patients who were newly diagnosed with IDH-wildtype (n = 802, 33% methylated) or - mutant astrocytomas (n = 712, 48% methylated) and received chemotherapy during initial management. An unmethylated promoter was associated with poorer survival in patients with IDH-wildtype (3-year OS 34% [95%CI 29-39%] vs. 46% [95%CI 39-54%], p < .001, adjusted HR 1.53 [95%CI 1.24-1.89]) but not IDH-mutant astrocytomas (3-year OS 79% [95%CI 74-84%] vs. 80% [95%CI 75-86%], p = .81, HR 1.04 [95%CI 0.73-1.50]). Conclusions: This ancillary analysis supports adjuvant TMZ as standard-of-care for anaplastic astrocytomas (IDH-mutant and 1p19q-intact), irrespective of MGMT status. Determining the optimal strategy for diffuse gliomas that are IDH-wildtype will be particularly important. MGMT promoter methylation should be considered as a stratification factor in future clinical trials for these patients.

The Use of Stereotactic Radiosurgery to Treat Functional Disorders: A Topic Discussion.

Stereotactic radiosurgery (SRS) is a well-known modality for the treatment of malignant brain tumors. SRS, however, can also be used to treat non-malignant functional disorders such as epilepsy, tremor, trigeminal neuralgia (TN), obsessive compulsive disorder (OCD), and intractable pain among others. Given the limited prospective data guiding treatment of these benign disorders, this article serves as a consolidated discussion of the application of SRS for functional ailments, hopefully serving as a reference for those considering application of this technique in clinical practice.

Sexual health and treatment-related sexual dysfunction in sexual and gender minorities with prostate cancer.

Prostate cancer treatment has substantial effects on sexual health and function. Sexual function is a vital aspect of human health and a critical component of cancer survivorship, and understanding the potential effects of different treatment modalities on sexual health is crucial. Existing research has extensively described the effects of treatment on male erectile tissues necessary for heterosexual intercourse; however, evidence regarding their effects on sexual health and function in sexual and gender minority populations is minimal. These groups include sexual minority - gay and bisexual - men, and transgender women or trans feminine people in general. Such unique effects in these groups might include altered sexual function in relation to receptive anal and neovaginal intercourse and changes to patients' role-in-sex. Sexual dysfunctions following prostate cancer treatment affecting quality of life in sexual minority men include climacturia, anejaculation, decreased penile length, erectile dysfunction, and problematic receptive anal intercourse, including anodyspareunia and altered pleasurable sensation. Notably, clinical trials investigating sexual outcomes after prostate cancer treatment do not collect sexual orientation and gender identity demographic data or outcomes specific to members of these populations, which perpetuates the uncertainty regarding optimal management. Providing clinicians with a solid evidence base is essential to communicate recommendations and tailor interventions for sexual and gender minority patients with prostate cancer.

The evolving tale of Pol2 function.

DNA replication is complex and highly regulated, and DNA replication errors can lead to human diseases such as cancer. DNA polymerase ε (polε) is a key player in DNA replication and contains a large subunit called POLE, which possesses both a DNA polymerase domain and a 3'-5' exonuclease domain (EXO). Mutations at the EXO domain and other missense mutations on POLE with unknown significance have been detected in a variety of human cancers. Based on cancer genome databases, Meng and colleagues (pp. 74-79) previously identified several missense mutations in POPS (pol2 family-specific catalytic core peripheral subdomain), and mutations at the conserved residues of yeast Pol2 (pol2-REL) showed reduced DNA synthesis and growth. In this issue of Genes & Development, Meng and colleagues (pp. 74-79) found unexpectedly that mutations at the EXO domain rescue the growth defects of pol2-REL. They further discovered that EXO-mediated polymerase backtracking impedes forward movement of the enzyme when POPS is defective, revealing a novel interplay between the EXO domain and POPS of Pol2 for efficient DNA synthesis. Additional molecular insight into this interplay will likely inform the impact of cancer-associated mutations found in both the EXO domain and POPS on tumorigenesis and uncover future novel therapeutic strategies.

Feasibility of fractionated gamma knife radiosurgery in the management of newly diagnosed Glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with overall survival remaining poor despite ongoing efforts to explore new treatment paradigms. Given these outcomes, efforts have been made to shorten treatment time. Recent data report on the safety of CyberKnife (CK) fractionated stereotactic radiosurgery (SRS) in the management of GBM using a five-fraction regimen. The latest Gamma Knife (GK) model also supports frameless SRS, and outcomes using GK SRS in the management of primary GBM have not yet been reported. OBJECTIVE: To report on the feasibility of five-fraction SRS with the GammaKnife ICON in the management of newly diagnosed GBM. METHODS: In this single institutional study, we retrospectively reviewed all patients from our medical center from January 2017 through December 2021 who received fractionated SRS with Gamma Knife ICON for newly diagnosed GBM. Patient demographics, upfront surgical margins, molecular subtyping, radiation treatment volumes, systemic therapies, and follow-up imaging findings were extracted to report on oncologic outcomes. RESULTS: We identified six patients treated within the above time frame. Median age at diagnosis was 73.5 years, 66% were male, and had a median Karnofsky Performance Status (KPS) of 70. All tumors were IDH wild-type, and all but one were MGMT methylated and received concurrent temozolomide (TMZ). Within this group, progression free survival was comparable to that of historical data without significant radiation-induced toxicities. CONCLUSION: Gamma Knife ICON may be discussed as a potential treatment option for select GBM patients and warrants further investigation in the prospective setting.

Graded Prognostic Assessment (GPA) for Patients With Lung Cancer and Brain Metastases: Initial Report of the Small Cell Lung Cancer GPA and Update of the Non-Small Cell Lung Cancer GPA Including the Effect of Programmed Death Ligand 1 and Other Prognostic Factors.

PURPOSE: Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly. METHODS AND MATERIALS: A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA. RESULTS: Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P < .01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies. CONCLUSIONS: Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.

Embryo Injections for CRISPR-Mediated Mutagenesis in the Ant Harpegnathos saltator.

The unique traits of eusocial insects, such as social behavior and reproductive division of labor, are controlled by their genetic system. To address how genes regulate social traits, we have developed mutant ants via delivery of CRISPR complex into young embryos during their syncytial stage. Here, we provide a protocol of CRISPR-mediated mutagenesis in Harpegnathos saltator, a ponerine ant species that displays striking phenotypic plasticity. H. saltator ants are readily reared in a laboratory setting. Embryos are collected for microinjection with Cas9 proteins and in vitro synthesized small guide RNAs (sgRNAs) using home-made quartz needles. Post-injection embryos are reared outside the colony. Following emergence of the first larva, all embryos and larvae are transported to a nest box with a few nursing workers for further development. This protocol is suitable for inducing mutagenesis for analysis of caste-specific physiology and social behavior in ants, but may also be applied to a broader spectrum of hymenopterans and other insects.

Redefining risk of contralateral cervical nodal disease in early stage oropharyngeal cancer in the human papillomavirus era.

BACKGROUND: The optimal extent of surgery and/or radiation to the contralateral lymph node region is unknown in early-stage human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). METHODS: To investigate the pathologic incidence of and risk factors for contralateral nodal disease (CND) in cT1-T2 HPV-related OPSCC treated with transoral robotic surgery (TORS) and bilateral neck dissection (BND), the records of 120 patients were reviewed. RESULTS: Eleven patients displayed pathologic contralateral nodal disease (pCND), including 7.1% of tonsil and 10.9% of base of tongue (BOT) cases. Medial hemistructure involvement and cN2 disease were significantly associated with pCND. Zero cN0 patients had pCND, and on multivariate analysis only cN classification remained significantly associated with pCND. Four percent of BOT patients and 2% of tonsil patients with a well-lateralized primary and cN0/N1 neck demonstrated pCND. CONCLUSIONS: HPV-related OPSCC that are cN0-N1 have exceedingly low rates of pCND. Well-lateralized HPV-related BOT primaries with limited clinical nodal disease may be candidates for ipsilateral only treatment.

Epigenetic preconditioning with decitabine sensitizes glioblastoma to temozolomide via induction of MLH1.

INTRODUCTION: To improve the standard treatment paradigm for glioblastoma (GBM), efforts have been made to explore the efficacy of epigenetic agents as chemosensitizers. Recent data suggest possible synergy between decitabine (DAC), a DNA hypomethylating agent, and temozolomide (TMZ) in GBM, but the mechanism remains unclear. The objective of this study was to determine the effects of DAC on TMZ sensitization in a consecutively derived set of primary GBM cultures, with a focus on mismatch repair (MMR) proteins. METHODS: Half maximal inhibitory concentrations (IC50) of TMZ were calculated in eleven consecutive patient-derived GBM cell lines before and after preconditioning with DAC. MMR protein expression changes were determined by quantitative immunoblots and qPCR arrays. Single-molecule real-time (SMRT) sequencing of bisulfite (BS)-converted PCR amplicons of the MLH1 promoter was performed to determine methylation status. RESULTS: TMZ IC50 significantly changed in 6 of 11 GBM lines of varying MGMT promoter methylation status in response to DAC preconditioning. Knockdown of MLH1 after preconditioning reversed TMZ sensitization. SMRT-BS sequencing of the MLH1 promoter region revealed higher levels of baseline methylation at proximal CpGs in desensitized lines compared to sensitized lines. CONCLUSIONS: DAC enhances TMZ cytotoxicity in a subset of GBM cell lines, comprising lines both MGMT methylated and unmethylated tumors. This effect may be driven by levels of MLH1 via E2F1 transcription factor binding. Using unbiased long-range next-generation bisulfite-sequencing, we identified a region of the proximal MLH1 promoter with differential methylation patterns that has potential utility as a clinical biomarker for TMZ sensitization.

Role of Radiation Therapy in the Management of Diffuse Intrinsic Pontine Glioma: A Systematic Review.

PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is the most aggressive primary pediatric brain tumor, with <10% of children surviving 2 years. Radiation therapy (RT) remains the mainstay of treatment, but there is a great clinical need for improvements and advancements in treatment strategies. The aim of this systematic review was to identify all available studies in which RT was used to treat patients with DIPG. METHODS AND MATERIALS: A literature search for studies published up to March 10, 2018 was conducted using the PubMed database. We identified 384 articles using search items "diffuse intrinsic pontine glioma" and 221 articles using search items "diffuse brainstem glioma radiotherapy." Included studies were prospective and retrospective series that reported outcomes of DIPG treatment with RT. RESULTS: We identified 49 studies (1286 patients) using upfront conventionally fractionated RT, 5 studies (92 patients) using hypofractionated RT, and 8 studies (348 patients) using hyperfractionated RT. The mean median overall survival (OS) was 12.0 months, 10.2 months, and 7.9 months in patients who received conventional, hyperfractionated, and hypofractionated RT regimens, respectively. Patients undergoing radiosensitizing therapy had a mean median OS of 11.5 months, and patients who did not receive concomitant systemic therapy had an OS of 9.4 months. In patients who received salvage RT, the mean median OS from initial diagnosis was 16.3 months. CONCLUSIONS: As one of the largest systematic reviews examining RT for DIPG, this report may serve as a useful tool to help clinicians choose the most appropriate treatment approach, while also providing a platform for future investigations into the utility of RT and systemic therapy.

Trimodality therapy for oropharyngeal cancer in the TORS era: Is there a cohort that may benefit?

BACKGROUND: With increasing adoption of transoral robotic surgery (TORS) for oropharyngeal cancer (OPC), more patients may receive trimodality therapy. We sought to investigate outcomes and toxicities in this cohort. METHODS: A retrospective study of patients with OPC treated with trimodality therapy at a tertiary-care hospital, comparing those receiving bilateral vs unilateral neck radiation. RESULTS: Four hundred thirty-six patients underwent TORS, 17% receiving adjuvant chemoradiation. Of the 46 patients completing adjuvant treatment in-house, contralateral neck was spared in 20%. There were no significant differences in survival, and patient-reported outcomes in salivary function, mood, and anxiety were superior in those patients receiving unilateral neck radiation and directly correlated with mean dose to local structures. CONCLUSIONS: Surgery for OPC offers the potential for reduction in radiation volumes by omitting the contralateral neck in those who may have required definitive chemoradiation. Even in patients receiving concurrent chemotherapy, unilateral neck radiation has a favorable toxicity profile without compromising survival.

An Engineered orco Mutation Produces Aberrant Social Behavior and Defective Neural Development in Ants.

Ants exhibit cooperative behaviors and advanced forms of sociality that depend on pheromone-mediated communication. Odorant receptor neurons (ORNs) express specific odorant receptors (ORs) encoded by a dramatically expanded gene family in ants. In most eusocial insects, only the queen can transmit genetic information, restricting genetic studies. In contrast, workers in Harpegnathos saltator ants can be converted into gamergates (pseudoqueens) that can found entire colonies. This feature facilitated CRISPR-Cas9 generation of germline mutations in orco, the gene that encodes the obligate co-receptor of all ORs. orco mutations should significantly impact olfaction. We demonstrate striking functions of Orco in odorant perception, reproductive physiology, and social behavior plasticity. Surprisingly, unlike in other insects, loss of OR functionality also dramatically impairs development of the antennal lobe to which ORNs project. Therefore, the development of genetics in Harpegnathos establishes this ant species as a model organism to study the complexity of eusociality.