Beneath the surface: A systematic review on intraoperative imaging techniques for deep margin assessment in oral squamous cell carcinoma.

Resection margins of oral squamous cell carcinoma (SCC) are often inadequate. A systematic review on clinical intraoperative whole-specimen imaging techniques to obtain adequate deep resection margins in oral SCC is lacking. Such a review may render better alternatives for the current insufficient intraoperative techniques: palpation and frozen section analyses (FSA). This review resulted in ten publications investigating ultrasound (US), four investigating fluorescence, and three investigating MRI. Both US and fluorescence were able to image the tumor intraorally and perform ex-vivo imaging of the resection specimen. Fluorescence was also able to image residual tumor tissue in the wound bed. MRI could only be used on the ex-vivo specimen. The 95 % confidence intervals for sensitivity and specificity were large, due to the small sample sizes for all three techniques. The sensitivity and specificity of US for identifying < 5 mm margins ranged from 0 % to 100 % and 60 % to 100 %, respectively. For fluorescence, this ranged from 0 % to 100 % and 76 % to 100 %, respectively. For MRI, this ranged from 7 % to 100 % and 81 % to 100 %, respectively. US, MRI and fluorescence are the currently available imaging techniques that can potentially be used intraoperatively and which can image the entire tumor-free margin, although they have insufficient sensitivity for identifying < 5 mm margins. Further research on larger cohorts is needed to improve the sensitivity by determining cut-off points on imaging for inadequate margins. This improves the number of adequate resections of oral SCC's and pave the way for routine clinical implementation of these techniques.

Prevalence of obstructive sleep apnea after treatment for advanced T-stage head and neck cancer.

PURPOSE: Treatment of head and neck cancer (HNC) may lead to obstructive sleep apnea (OSA), but conclusive results on the prevalence of OSA are lacking. The objective of this study is to investigate the prevalence of OSA in a cohort of patients treated for advanced T-stage HNC. METHODS: A cross-sectional study was conducted in two tertiary cancer care centers including patients at least 1 year after treatment with curative intent with surgery and/or (chemo)radiotherapy ((C)RT) for advanced T-staged (T3-4) cancer of the oral cavity, oropharynx, hypopharynx, or larynx. A polysomnography (PSG) was performed in all participants. OSA was defined as an apnea-hypopnea index (AHI) of 15 events/h or higher or an AHI of 5 events/h and higher with OSA related symptoms, such as sleeping problems, daytime dysfunction and/or cardiac/metabolic comorbidities collected through file review and questionnaires. RESULTS: Of the 67 participants, 48 (72%, 95% CI 59-82%) were diagnosed with OSA. Possible risk factors are male gender, higher BMI, greater neck circumference, more nicotine pack years, cardiometabolic comorbidities, use of medication with sleepiness as side effect, present tonsils, lower T-stage (T3 vs. T4 stage), higher AJCC stage and a HPV-negative tumor. CONCLUSION: In this population of advanced T-stage HNC patients, the prevalence of OSA was 72%, which is considerably higher than in the general population (2-50%). Given the high prevalence, screening of this entire subgroup for OSA may be indicated. Future studies to identify high risk factors and develop an OSA screening protocol are needed.

Primary Diffuse Leptomeningeal Melanomatosis in a Child with Extracranial Metastasis: Case Report.

Primary meningeal melanomatosis is an extremely rare tumor with very few documented responses to treatment. A 3-year-old male with a complex past medical history, including prematurity and shunted hydrocephalus, was diagnosed with primary meningeal melanomatosis with peritoneal implants. Molecular testing revealed an NRAS Q61R mutation. The patient received proton craniospinal radiation followed by immunotherapy with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) IV every 3 weeks and, upon progression, he was switched to a higher dose of nivolumab (3 mg/kg IV every 2 weeks) and binimetinib (24 mg/m2/dose, twice a day). The patient had significant improvement of CNS disease with radiation therapy and initial immunotherapy but progression of extracranial metastatic peritoneal and abdominal disease. Radiation was not administered to the whole abdomen. After two cycles of nivolumab and treatment with the MEK inhibitor binimetinib, he had radiographic and clinical improvement in abdominal metastasis and ascitis. He ultimately died from RSV infection, Klebsiella sepsis, and subdural hemorrhage without evidence of tumor progression. This is the first report of a child with primary meningeal melanomatosis with extracranial metastatic disease with response to a combination of radiation, immunotherapy and MEK inhibitor therapy.

Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial.

BACKGROUND: Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy. METHODS: We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing. RESULTS: Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype. CONCLUSIONS: Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.

Management of clinically node-negative early-stage oral cancer: network meta-analysis of randomized clinical trials.

The best treatments for the clinically node-negative (cN0) neck in early-stage oral squamous cell carcinoma (OSCC) patients are a subject of ongoing debate and there is no consensus. A network meta-analysis (NMA) of randomized clinical trials (RCTs) was conducted to determine the most effective treatment and to rank treatments based on their effectiveness. A systematic search was performed in accordance with the PRISMA guidelines to retrieve RCTs that compared therapeutic neck dissection (TND), sentinel lymph node biopsy (SLNB), and elective neck dissection (END). The outcomes analysed were overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and nodal recurrence. Hazard ratios and risk ratios were calculated by direct meta-analysis and NMA. Ten RCTs with a total of 1858 patients were eligible for inclusion. Direct meta-analysis showed END to be superior to TND and comparable to SLNB. The NMA revealed no statistically significant difference between END and SLNB (very low quality evidence) regarding OS, DSS, DFS, and nodal recurrence. However, END was found to significantly improve OS and DFS, and reduce nodal recurrence when compared to TND (moderate quality evidence). END ranked as probably the top treatment option for maximizing OS and DSS, and reducing nodal recurrence in early-stage OSCC, followed by SLNB and TND. There was very low quality evidence supporting SLNB as non-inferior to END for patients with early-stage OSCC. This NMA yielded favourable results for the use of END (with moderate quality evidence) in early-stage OSCC patients, although excellent results have also been obtained with SLNB. However, data in the literature for SLNB are scarce, as this technique has not yet been formalized in many countries. There is a need to further explore SLNB for early-stage OSCC patients, as well as its value in detecting occult lymph node metastases on the contralateral side. More studies comparing morbidity, quality of life, and costs between the different management strategies for the clinically negative neck in early-stage OSCC patients are needed.

Personalized neck irradiation guided by sentinel lymph node biopsy in patients with squamous cell carcinoma of the oropharynx, larynx or hypopharynx with a clinically negative neck: (Chemo)radiotherapy to the PRIMary tumor only. Protocol of the PRIMO study.

Background: Elective neck irradiation (ENI) is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy (SLNB). It is expected that ENI can be omitted to one or both sides of the neck in 9 out of 10 patients, resulting in less radiation side effects with better quality of life. Methods/design: This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with SLNB guided neck irradiation versus standard bilateral ENI in 242 patients with cN0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral ENI is indicated. Patients randomized to the experimental-arm will undergo SLNB. Based on the histopathologic status of the SLNs, patients will receive no ENI (if all SLNs are negative), unilateral neck irradiation only (if a SLN is positive at one side of the neck) or bilateral neck irradiation (if SLNs are positive at both sides of the neck). Patients randomized to the control arm will not undergo SLNB but will receive standard bilateral ENI. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment. Discussion: If this trial demonstrates that the experimental treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the new standard of care.

The Pediatric Proton and Photon Therapy Comparison Cohort: Study Design for a Multicenter Retrospective Cohort to Investigate Subsequent Cancers After Pediatric Radiation Therapy.

Purpose: The physical properties of protons lower doses to surrounding normal tissues compared with photons, potentially reducing acute and long-term adverse effects, including subsequent cancers. The magnitude of benefit is uncertain, however, and currently based largely on modeling studies. Despite the paucity of directly comparative data, the number of proton centers and patients are expanding exponentially. Direct studies of the potential risks and benefits are needed in children, who have the highest risk of radiation-related subsequent cancers. The Pediatric Proton and Photon Therapy Comparison Cohort aims to meet this need. Methods and Materials: We are developing a record-linkage cohort of 10,000 proton and 10,000 photon therapy patients treated from 2007 to 2022 in the United States and Canada for pediatric central nervous system tumors, sarcomas, Hodgkin lymphoma, or neuroblastoma, the pediatric tumors most frequently treated with protons. Exposure assessment will be based on state-of-the-art dosimetry facilitated by collection of electronic radiation records for all eligible patients. Subsequent cancers and mortality will be ascertained by linkage to state and provincial cancer registries in the United States and Canada, respectively. The primary analysis will examine subsequent cancer risk after proton therapy compared with photon therapy, adjusting for potential confounders and accounting for competing risks. Results: For the primary aim comparing overall subsequent cancer rates between proton and photon therapy, we estimated that with 10,000 patients in each treatment group there would be 80% power to detect a relative risk of 0.8 assuming a cumulative incidence of subsequent cancers of 2.5% by 15 years after diagnosis. To date, 9 institutions have joined the cohort and initiated data collection; additional centers will be added in the coming year(s). Conclusions: Our findings will affect clinical practice for pediatric patients with cancer by providing the first large-scale systematic comparison of the risk of subsequent cancers from proton compared with photon therapy.

Impact of low skeletal muscle mass on postoperative complications in head and neck cancer patients undergoing free flap reconstructive surgery - A systematic review and meta-analysis.

Low skeletal muscle mass is emerging as an adverse predictive and prognostic factor in cancer patients. The use of this parameter as a risk factor for complications after surgery is not currently used in clinical practice. This meta-analysis aims to assess the association of low skeletal muscle mass defined by radiological criteria and complications after reconstructive microsurgery in head and neck cancer patients. A systematic review for articles was performed using the PubMed, EMBASE database and by manual search. Articles that assessed low skeletal muscle mass and its impact on postoperative complications in head and neck cancer patients undergoing free flap surgery were selected. Pooled estimates of postoperative outcome data were calculated by extracting the odds ratio (OR) and 95% confidence interval (CI). The search strategy returned with 6 studies meeting the inclusion criteria. A total of 1082 patients were analyzed. The prevalence of low skeletal muscle mass between studies ranged from 24.6% to 61.5%. The meta-analysis showed an OR for complications after surgery of 2.42 (95% CI 1.53-3.32, p = 0.00). The study therefore concludes that skeletal muscle mass is an independent risk factor for postoperative complications in head and neck cancer reconstructive surgery patients. This argues for implementing screening for low skeletal muscle in preoperative management to optimize surgical decision making.

Optimized Production and Analysis of Recombinant Protein-Filled Vesicles from E. coli.

This innovative system, using a short peptide tag, that exports multiple recombinant proteins in membrane bound vesicles from E. coli, provides an effective solution to a range of problems associated with bacterial recombinant protein expression. These recombinant vesicles compartmentalise proteins within a micro-environment that facilitates the production of otherwise challenging, toxic, insoluble, or disulfide-bond containing proteins from bacteria. Protein yield is increased considerably when compared to typical bacterial expression in the absence of the vesicle-nucleating peptide tag. The release of vesicle-packaged proteins supports isolation from the culture medium and permits long-term active protein storage. This technology gives rise to increased yields of vesicle-packaged, functional proteins for simplified downstream processing for a diverse range of applications from applied biotechnology to discovery science and medicine. In the present article and the associated video, a detailed protocol of the method is provided, which highlights key steps in the methodology to maximize recombinant protein-filled vesicle production.

Use of Perirectal Hyaluronic Acid Spacer Prior to Radiotherapy in a Pediatric Patient With Bladder Rhabdomyosarcoma: A Case Report.

Rhabdomyosarcoma (RMS) treatment involves surgery, chemotherapy, and radiotherapy. A radioprotective space between the bladder/prostate and rectum reduces postradiation complications, as reported in adult patients. Describe pediatric preradiotherapy perirectal hyaluronic acid (HA) spacer injection for bladder/prostate RMS. We present a case of a 17-month-old male with bladder/prostate RMS. Before radiotherapy, an HA spacer was injected peri-rectally. Under general anesthesia, a transrectal ultrasound was positioned and 1mL of HA spacer was injected into the perirectal space. No complications were reported at 6-month follow-up. This is the first report of pre-radiation therapy spacer injection for pediatric bladder/prostate RMS.

Early in vivo Radiation Damage Quantification for Pediatric Craniospinal Irradiation Using Longitudinal MRI for Intensity Modulated Proton Therapy.

Purpose: Proton vertebral body sparing craniospinal irradiation (CSI) treats the thecal sac while avoiding the anterior vertebral bodies in an effort to reduce myelosuppression and growth inhibition. However, robust treatment planning needs to compensate for proton range uncertainty, which contributes unwanted doses within the vertebral bodies. This work aimed to develop an early in vivo radiation damage quantification method using longitudinal magnetic resonance (MR) scans to quantify the dose effect during fractionated CSI. Methods and Materials: Ten pediatric patients were enrolled in a prospective clinical trial of proton vertebral body sparing CSI, in which they received 23.4 to 36 Gy. Monte Carlo robust planning was used, with spinal clinical target volumes defined as the thecal sac and neural foramina. T1/T2-weighted MR scans were acquired before, during, and after treatments to detect a transition from hematopoietic to less metabolically active fatty marrow. MR signal intensity histograms at each time point were analyzed and fitted by multi-Gaussian models to quantify radiation damage. Results: Fatty marrow filtration was observed in MR images as early as the fifth fraction of treatment. Maximum radiation-induced marrow damage occurred 40 to 50 days from the treatment start, followed by marrow regeneration. The mean damage ratios were 0.23, 0.41, 0.59, and 0.54, corresponding to 10, 20, 40, and 60 days from the treatment start. Conclusions: We demonstrated a noninvasive method for identifying early vertebral marrow damage based on radiation-induced fatty marrow replacement. The proposed method can be potentially used to quantify the quality of CSI vertebral sparing and preserve metabolically active hematopoietic bone marrow.

Impact of Age on Overall Survival Among Children With Wilms Tumor: A Population-based Registry Analysis.

OBJECTIVES: International trials have reported conflicting findings on whether the association between age and worse overall survival (OS) among children with Wilms tumor (WT) is due to age as an independent prognostic factor or the observation of more advanced disease at older ages. We sought to further elucidate this relationship using a population-based registry analysis. METHODS: The Surveillance, Epidemiology, and End Results database was queried for all patients diagnosed with WT under the age of 20. The association between age and OS was assessed using multivariable Cox proportional hazards regression. RESULTS: In this study, 3463 patients (54% female) were diagnosed with WT between 1975 and 2016. More advanced stage, larger primary tumor size, lymph node involvement, disease requiring radiotherapy, and omission of surgery were associated with worse OS ( P <0.05). More advanced stage, larger primary tumor size, and disease requiring radiotherapy were also associated with older age, whereas bilateral disease was associated with younger age ( P <0.001). On average, each year of age conferred an incremental hazard ratio (HR) of 1.07 (95% CI, 1.01 to 1.12, P =0.018) independent of relevant covariates. The rise in adjusted OS HR was most pronounced after the transitions in diagnosis age from 2 to 3 (HR age 3-15 vs. 0-2 1.77, 95% CI, 1.11 to 2.82, P =0.016) and from 15 to 16 (HR age 16-19 vs. 3-15 2.58, 95% CI, 1.06 to 6.25, P =0.036). CONCLUSIONS: Diagnosis of pediatric WT at an older age was found to be independently associated with worse OS. Although additional prospective studies are warranted to examine tumor biology and other potential correlates, more aggressive treatment of older children based on age, especially as they approach early adulthood, may be considered in the multidisciplinary management of WT.

Spectroscopic MRI-Guided Proton Therapy in Non-Enhancing Pediatric High-Grade Glioma.

Radiation therapy (RT) is a critical part of definitive therapy for pediatric high-grade glioma (pHGG). RT is designed to treat residual tumor defined on conventional MRI (cMRI), though pHGG lesions may be ill-characterized on standard imaging. Spectroscopic MRI (sMRI) measures endogenous metabolite concentrations in the brain, and Choline (Cho)/N-acetylaspartate (NAA) ratio is a highly sensitive biomarker for metabolically active tumor. We provide a preliminary report of our study introducing a novel treatment approach of whole brain sMRI-guided proton therapy for pHGG. An observational cohort (c1 = 10 patients) receives standard of care RT; a therapeutic cohort (c2 = 15 patients) receives sMRI-guided proton RT. All patients undergo cMRI and sMRI, a high-resolution 3D whole-brain echo-planar spectroscopic imaging (EPSI) sequence (interpolated resolution of 12 µL) prior to RT and at several follow-up timepoints integrated into diagnostic scans. Treatment volumes are defined by cMRI for c1 and by cMRI and Cho/NAA ≥ 2x for c2. A longitudinal imaging database is used to quantify changes in lesion and metabolite volumes. Four subjects have been enrolled (c1 = 1/c2 = 3) with sMRI imaging follow-up of 4-18 months. Preliminary data suggest sMRI improves identification of pHGG infiltration based on abnormal metabolic activity, and using proton therapy to target sMRI-defined high-risk regions is safe and feasible.

High-yield vesicle-packaged recombinant protein production from E. coli.

We describe an innovative system that exports diverse recombinant proteins in membrane-bound vesicles from E. coli. These recombinant vesicles compartmentalize proteins within a micro-environment that enables production of otherwise challenging insoluble, toxic, or disulfide-bond containing proteins from bacteria. The release of vesicle-packaged proteins supports isolation from the culture and allows long-term storage of active protein. This technology results in high yields of vesicle-packaged, functional proteins for efficient downstream processing for a wide range of applications from discovery science to applied biotechnology and medicine.

Radiotherapy for Atypical Teratoid/Rhabdoid Tumor (ATRT) on the Pediatric Proton/Photon Consortium Registry (PPCR).

PURPOSE: Atypical teratoid/rhabdoid tumors (ATRT) of the central nervous system (CNS) are rare tumors with a poor prognosis and variable use of either focal or craniospinal (CSI) radiotherapy (RT). Outcomes on the prospective Pediatric Proton/Photon Consortium Registry (PPCR) were evaluated according to RT delivered. METHODS: Pediatric patients receiving RT were prospectively enrolled on PPCR to collect initial patient, disease, and treatment factors as well as provide follow-up for patient outcomes. All ATRT patients with evaluable data were included. Kaplan-Meier analyses with log-rank p-values and cox proportional hazards regression were performed. RESULTS: The PPCR ATRT cohort includes 68 evaluable ATRT patients (median age 2.6 years, range 0.71-15.40) from 2012 to 2021. Median follow-up was 40.8 months (range 3.4-107.7). Treatment included surgery (65% initial gross total resection or GTR), chemotherapy (60% with myeloablative therapy including stem cell rescue) and RT. For patients with M0 stage (n = 60), 50 (83%) had focal RT and 10 (17%) had CSI. Among patients with M + stage (n = 8), 3 had focal RT and 5 had CSI. Four-year overall survival (OS, n = 68) was 56% with no differences observed between M0 and M + stage patients (p = 0.848). Local Control (LC) at 4 years did not show a difference for lower primary dose (50-53.9 Gy) compared to ≥ 54 Gy (73.3% vs 74.7%, p = 0.83). For patients with M0 disease, four-year OS for focal RT was 54.6% and for CSI was 60% (Hazard Ratio 1.04, p = 0.95. Four-year event free survival (EFS) among M0 patients for focal RT was 45.6% and for CSI was 60% (Hazard Ratio 0.71, p = 0.519). For all patients, the 4-year OS comparing focal RT with CSI was 54.4% vs 60% respectively (p = 0.944), and the 4-year EFS for focal RT or CSI was 42.8% vs 51.4% respectively (p = 0.610). CONCLUSION: The PPCR ATRT cohort found no differences in outcomes according to receipt of either higher primary dose or larger RT field (CSI). However, most patients were M0 and received focal RT. A lower primary dose (50.4 Gy), regardless of patient age, is appealing for further study as part of multi-modality therapy.

Palliative radiotherapy for children: Symptom response and treatment-associated toxicity according to radiation therapy dose and fractionation.

BACKGROUND/OBJECTIVES: Radiotherapy is an effective palliative treatment in advanced cancer. Shorter palliative treatment courses are recommended for adults, though pediatric data addressing treatment efficacy and toxicity according to radiation therapy (RT) dose and fractionation are limited. DESIGN/METHODS: Total 213 patients aged 21 years or younger receiving 422 palliative radiotherapy treatment courses from 2003 to 2016 were included. Symptom response and treatment-associated toxicity were recorded and analyzed in relationship to demographic and treatment variables. RESULTS: Common diagnoses included sarcoma (32.5%), neuroblastoma (24.9%), leukemia/lymphoma (14.9%), and central nervous system tumors (10.9%). The most common indication for treatment was pain (46.7%). Patients received a median of 10 fractions, 2.5 Gy dose per fraction, and 21 Gy total dose. Number of RT fractions was five or less in 166 (39.3%), six to 10 fractions in 117 (27.2%), and 10 or more fractions in 139 (32.9%) of courses. Complete or partial pain relief was achieved in 85% (151 of 178 evaluable patients), including 77.8% receiving five or less fractions and 89.6% receiving more than five fractions. Highest toxicity was grade 1 in 159 (38.9%), grade 2 in 26 (6.4%), and grade 3 in two (0.5%) treatments. On multivariable analysis, RT delivered 30 or more days from death (OR 12.13, 95% CI: 2.13-69.2, p = .005) and no adjuvant chemotherapy (OR 0.14, 95% CI: 0.03-0.54, p = .005) were significantly associated with pain response, and five or less fractions were significantly associated with lower toxicity (OR 0.24, 95% CI: 0.06-0.97, p = .045). CONCLUSIONS: Palliative RT courses of five or less fractions result in high rates of pain control and are associated with low toxicity in pediatric patients with cancer.

Development and validation of a prognostic gene expression signature for lower-grade glioma following surgery and adjuvant radiotherapy.

BACKGROUND AND PURPOSE: Standard of care for lower-grade glioma (LGG) is maximal safe resection and risk-adaptive adjuvant therapy. While patients who benefit the most from adjuvant chemotherapy have been elucidated in prospective randomized studies, comparable insights for adjuvant radiotherapy (RT) are lacking. We sought to identify and validate patterns of gene expression that are associated with differential outcomes among LGG patients treated by RT from two large genomics databases. MATERIALS AND METHODS: Patients from The Cancer Genome Atlas (TCGA) with LGG (WHO grade II-III glioma) treated by surgery and adjuvant RT were randomized 1:1 to a discovery cohort or an internal validation cohort. Using the discovery cohort only, associations between tumor RNA-seq expression and progression-free survival (PFS) as well as overall survival (OS) were evaluated with adjustment for clinicopathologic covariates. A Genomic Risk Score (GRS) was then constructed from the expression levels of top genes also screened for involvement in glioma carcinogenesis. The prognostic value of GRS was further assessed in the internal validation cohort of TCGA and a second distinct database, compiled by the Chinese Glioma Genome Association (CGGA). RESULTS: From TCGA, 289 patients with LGG received adjuvant RT alone (38 grade II, 30 grade III) or chemoradiotherapy (CRT) (51 grade II, 170 grade III) between 2009 and 2015. From CGGA, 178 patients with LGG received adjuvant RT alone (40 grade II, 13 grade III) or CRT (41 grade II, 84 grade III) between 2004 and 2016. The genes comprising GRS are involved in MAP kinase activity, T cell chemotaxis, and cell cycle transition: MAP3K15, MAPK10, CCL3, CCL4, and ADAMTS1. High GRS, defined as having a GRS in the top third, was significantly associated with poorer outcomes independent of age, sex, glioma histology, WHO grade, IDH mutation, 1p/19q co-deletion, and chemotherapy status in the discovery cohort (PFS HR 1.61, 95% CI 1.10-2.36, P = 0.014; OS HR 2.74, 95% CI 1.68-4.47, P < 0.001). These findings were replicated in the internal validation cohort (PFS HR 1.58, 95% CI 1.05-2.37, P = 0.027; OS HR 1.84, 95% CI 1.13-3.00, P = 0.015) and the CGGA external validation cohort (OS HR 1.72, 95% CI 1.27-2.34, P < 0.001). Association between GRS and outcomes was observed only among patients who underwent RT, in both TCGA and CGGA. CONCLUSION: This study successfully identified an expression signature of five genes that stratified outcomes among LGG patients who received adjuvant RT, with two rounds of validation leveraging independent genomics databases. Expression levels of the highlighted genes were associated with PFS and OS only among patients whose treatment included RT, but not among those with omission of RT, suggesting that expression of these genes may be predictive of radiation treatment response. While additional prospective studies are warranted, interrogation of these genes may be considered in the multidisciplinary management of LGG.

Adjuvant Radiotherapy in Grade II, Atypical Meningioma of the Skull Base.

Introduction Atypical meningiomas (AM) are meningiomas that are more aggressive than their grade-I counterparts and have a higher rate of recurrence. The effect of adjuvant radiotherapy (ART) on AM of the skull base is not defined. Methods A retrospective review of all AM's of the skull base primarily resected at our institution from 1996 to 2018 was completed. ART was defined as radiotherapy (RT) that occurred within 6 months of initial resection, regardless of Simpson's grade. Minimum time length of follow-up after resection was 2 years. Statistical analysis was performed using SAS. Results There were a total of 59 skull base-located (SBL) AMs resected at our institution from 1996 to 2018. The average age of our cohort was 53.2 years. Gross total resection, defined as Simpson's grades I to III resection, was achieved in 36 (61%) of cases. Thirty-five of 59 (59%) patients received ART. Recurrence was observed in 14 patients (24%), and mean time to recurrence was 63.8 months. Patients who received ART had a lower observed rate of recurrence (8 vs. 46%); however, time to recurrence was not significantly different between the two populations. Conclusion We observe that AM in the skull base location have higher recurrence rates than we would expect from grade-I meningioma. These data suggest that ART may offer benefit to the overall observed frequency of recurrence of SBL AM; however, the time to recurrence between patients who received ART and those who did not was not statistically significant in survival analysis.