BRCA1 Protein Expression Predicts Survival in Glioblastoma Patients from an NRG Oncology RTOG Cohort.

PURPOSE: Glioblastoma, the most common malignant brain tumor, was associated with a median survival of <1 year in the pre-temozolomide (TMZ) era. Despite advances in molecular and genetic profiling studies identifying several predictive biomarkers, none has been translated into routine clinical use. Our aim was to investigate the prognostic significance of a panel of diverse cellular molecular markers of tumor formation and growth in an annotated glioblastoma tissue microarray (TMA). METHODS AND MATERIALS: A TMA composed of archived glioblastoma tumors from patients treated with surgery, radiation, and non-TMZ chemother-apy, was provided by RTOG. RAD51, BRCA-1, phosphatase and tensin homolog tumor suppressor gene (PTEN), and miRNA-210 expression levels were assessed using quantitative in situ hybridization and automated quantitative protein analysis. The objectives of this analysis were to determine the association of each biomarker with overall survival (OS), using the Cox proportional hazard model. Event-time distributions were estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: A cohort of 66 patients was included in this study. Among the 4 biomarkers assessed, only BRCA1 expression had a statistically significant correlation with survival. From univariate analysis, patients with low BRCA1 protein expression showed a favorable outcome for OS (p = 0.04; hazard ratio = 0.56) in comparison with high expressors, with a median survival time of 18.9 versus 4.8 months. CONCLUSIONS: BRCA1 protein expression was an important survival predictor in our cohort of glioblastoma patients. This result may imply that low BRCA1 in the tumor and the consequent low level of DNA repair cause vulnerability of the cancer cells to treatment.

Survival benefit of concomitant chemoradiation in adult supratentorial primary glioblastoma. A propensity score weighted population-based analysis.

BACKGROUND: This population study aims to assess the impact of the implementation of the original Stupp protocol on overall survival in patients with new-diagnosed supratentorial primary GBM. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to study the survival of histologically confirmed adult supratentorial GBM patients diagnosed between 1998 and 2016. Kaplan-Meier, and a univariate and propensity-score weighted multivariate Cox proportional hazard model adjusted for age at diagnosis, sex, race, marital status and extent of resection was used to assess the survival of patients prior to implementation of the Stupp protocol in 2005 (Pre-Stupp) and following implementation of the Stupp Protocol until 2016 (Post Stupp). RESULTS: Overall, 6390 patients satisfied inclusion exclusion criteria. Median survival times were 13 months for the Pre-Stupp and 15 months for Post-Stupp groups (P<0.001). The 1-, 2-, 5- and 10-year survival rates for the Pre-Stupp group were 51%, 18%, 5% and 2% respectively compared to 59%, 27%, 8% and 4% on the Post-Stupp group. Propensity-score weighted analysis showed a lower mortality risk for patients who underwent concomitant chemoradiation during the Post-Stupp era (HR=0.77, 95% CI 0.62-0.94). There was a 42% relative reduction in the risk of death for patients treated during the Post-Stupp era. CONCLUSIONS: This population-based propensity-score study with long-term follow-up suggests that the implementation of the Stupp protocol in 2005 had a positive impact on the survival of patients with supratentorial GBM. This "real-world" analysis validates the results of the original randomized control trial on which this protocol is based.

Socioeconomic Disparities in Non-Small Cell Lung Cancer With Brain Metastases at Presentation: A Population-Based Study.

OBJECTIVE/BACKGROUND: The purpose of this study was to characterize the impact of household income disparities in the survival of patients with non-small cell lung cancer (NSCLC) presenting with brain metastasis on a population-based level. METHODS: This is a population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database from 2010-2016 including 15,808 NSCLC patients presenting with brain metastasis. RESULTS: This study comprises 15,808 adult patients with NSCLC presenting with brain metastases having an age range 64 ± 10 years with 51% male, 76% white, 52% married, 61% insured, and with 85% of lung adenocarcinoma histopathology. The 1-, 2- and 5-year survival rates for living in the lower household income quartile were 21%, 10%, and 3%, respectively, for the second quartile 24%, 10%, and 3%; for the third quartile 28%, 14%, and 4%; and for the top quartile 31%, 17%, and 4%, respectively. Multivariate Cox proportional hazard analysis showed that living in a higher quartile household income county is associated with increased survival (P < 0.0001), hazard ratio 0.87, 95% confidence interval (0.82-0.92). CONCLUSIONS: This population-based study suggests that living in higher median household income counties is associated with increased survival time and reduced risk of mortality for patients with NSCLC who have brain metastases present at diagnosis, independent of other factors. These findings underscore the importance of ensuring adequate and easy access to care for all patients, irrespective of their economic background.

Impact of Concurrent Coincident Use of Metformin During Lung Stereotactic Body Radiation Therapy.

Introduction Recent data suggest synergy of chemoradiotherapy and metformin in locally-advanced non-small cell lung cancer (NSCLC). It remains unclear if similar synergy exists with stereotactic lung body radiation therapy (SBRT) and metformin. We analyzed the role of metformin on progression-free survival (PFS) and toxicity in the setting of lung SBRT. Methods We identified 31 patients on metformin-treated with SBRT for early-stage NSCLC. Eighty-nine similarly treated patients were chosen as controls. Kaplan-Meier method was used to estimate cumulative PFS probabilities. Results Median follow-up was 30.7 months. Forty-two patients had diabetes, 31 (74%) of which were taking metformin concurrent with SBRT. Median PFS for metformin-users vs. metformin non-users was 36.4 months vs 48.9 months, respectively (p = 0.29). Among diabetic patients, median PFS for metformin users was 36.4 months and was unobserved for non-users (p= 0.40). On univariable analysis, male sex (p = 0.03) and tumor size (p = 0.01) were associated with the risk of progression or death; use of metformin was not significant (p = 0.34). There was no difference in grade ≥2 radiation pneumonitis between metformin users vs non-users (p = 0.51) Conclusion In this retrospective sample of lung SBRT patients, we did not detect a meaningful effect of concurrent metformin use on PFS. Since SBRT and conventional RT may have different cell kill mechanisms, the previously described beneficial effects of metformin may not apply in a hypofractionated setting. These results should be validated in an independent dataset, and we await the results of ongoing clinical trials.

Failure mode and effects analysis of linac-based liver stereotactic body radiotherapy.

PURPOSE: Although stereotactic body radiation therapy (SBRT) is an attractive noninvasive approach for liver irradiation, it presents specific challenges associated with respiration-induced liver motion, daily tumor localization due to liver deformation, and poor visualization of target with respect to adjacent normal liver in computed tomography (CT). We aim to identify potential hazards and develop a set of mitigation strategies to improve the safety of our liver SBRT program, using failure mode and effect analysis (FMEA). MATERIALS AND METHODS: A multidisciplinary group consisting of two physicians, three physicists, two dosimetrists, and two therapists was formed. A process map covering ten major stages of the liver SBRT program from the initial diagnosis to posttreatment follow-up was generated. A total of 102 failure modes (FM), together with their causes and effects, were identified. The occurrence (O), severity (S), and lack of detectability (D) were independently scored using a scale from 1 (lowest risk) to 10 (largest risk). The ranking was done using the risk probability number (RPN) defined as the product of average O, S, and D numbers for each mode. Two fault tree analyses were performed. The failure modes with the highest RPN values as well as highest severity score were considered for investigation and a set of mitigation strategies was developed to address these. RESULTS: The median RPN (RPNmed ) values for all modes ranged from of 9 to 105 and the highest median S score (Smed ) was 8. Fourteen FMs were identified to be significant by both RPNmed and Smed (top ten RPNmed ranked and highest Smed FMs) and 12 of them were considered for risk mitigation efforts. The remaining two were omitted due to either sufficient checks already in place, or lack of practical mitigation strategies. Implemented measures consisted of five physics tasks, two physician tasks, and three workflow changes. CONCLUSIONS: The application of FMEA to our liver SBRT program led to the identification of potential FMs and allowed improvement measures to enhance the safety of our clinical practice.

Oligometastatic Disease State Is Associated with Improved Local Control in Patients Undergoing Three or Five Fraction Spine Stereotactic Body Radiotherapy.

BACKGROUND: The objective of our study was to describe the local control (LC) outcomes with 3- or 5-fraction stereotactic body radiotherapy (SBRT) to the spine in patients with oligometastatic (≤5 systemic metastases) versus polymetastatic disease (>5 metastases). METHODS: We retrospectively reviewed the outcomes of patients who had undergone SBRT for spinal metastases. No patients had undergone previous surgical intervention or had spinal cord compression. All patients were treated with 3-fraction (median dose, 27 Gy; range, 24-30 Gy) or 5-fraction (median dose, 35 Gy; range, 25-40 Gy) SBRT. The Kaplan-Meier method and Spine Response Assessment in Neuro-Oncology criteria were used to determine LC. RESULTS: We included 61 patients with a total of 72 distinct SBRT targets who had been treated from August 2007 to June 2017. The median follow-up period was 13.58 months. We treated 20 targets and 52 targets with 3 and 5 fractions, respectively. Thirteen patients (18.1%) had undergone previous RT to the SBRT area. Twenty patients (35% of the distinct SBRT targets) had an oligometastatic disease state. The 1-year LC rate was 83% for the entire cohort. On univariable analysis, polymetastases (1-year LC, 73.8% vs. 100%; P = 0.07) showed a trend toward worse LC. On multivariable analysis, patients with an oligometastatic state (hazard ratio, 0.21; P = 0.04) had improved LC. CONCLUSIONS: Our study was hypothesis-generating in that patients with an oligometastatic disease state appear to have improved LC after SBRT, suggesting a biological advantage exists with local therapy for this group of patients not seen for patients with polymetastatic disease.

Value of K i -67 Labeling Index in Predicting Recurrence of WHO Grade I Cranial Base Meningiomas.

Objectives Assess impact of K i -67 labeling index (LI; K i -67 LI) on risk of recurrence or progression of WHO grade I meningiomas. Study Design Retrospective study of adult patients who underwent resection of cranial base meningioma between 2004 and 2016. Results 272 patients fulfilled criteria for inclusion in the study. Average age was 61.8 years; 196 (72%) were females. Simpson's grade 1 resection was noted in 77 patients (32%), grade 2 in 39 (16%), grade 3 in 36 (15%), and grade 4 in 88 (37%). The K i -67 LI was low (1-4%) in 214 (78.7%), intermediate (5-9%) in 44 (16.2%), and high (>10%) in 14 (5.2%). Median follow-up was 39 months (IQR: 16-71 months); 221 (87.1%) tumors remained stable or did not recur, 19 (7.4%) recurred, and 14 (5.5%) progressed. Compared with tumors with low K i -67 LI, those with intermediate K i -67 LI had 2.47 times (2.47 [1.09-5.59], p = 0.03), and those with high K i -67 LI had 3.38 times (3.38 [1.16-9.89], p = 0.03) higher risk of recurrence or progression. Tumors with K i -67 LI > 4% had a shorter time to recurrence or progression ( p = 0.01). Recurrence or progression-free survival rates at 3, 5, and 10 years for tumors with low K i -67 LI were 95%, 89%, and 75%, respectively; tumors with intermediate K i -67 LI, 87%, 69%, and 52%, respectively; tumors with high K i -67 LI, 78%, 49%, and 49%, respectively. Conclusions Following surgical resection of a WHO grade I cranial base meningioma, K i -67 LI > 4% may predict an increased risk of recurrence or progression of residual tumor.

Stereotactic Radiation for Palliation of Skull Base Recurrences of Salivary Gland Carcinomas: Implications for Tumor Targeting.

Background Approximately 3 to 13% of salivary carcinomas recur at the skull base. We report our experience treating these recurrences with stereotactic radiation. Methods In total, 14 patients with skull base recurrence of salivary gland carcinoma were identified. Patient characteristics, treatment parameters, response to treatment, local recurrence-free/overall survival, and patterns of failure were studied. Results All 12 symptomatic patients experienced palliation of symptoms. Two grade 3 toxicities were observed. Local recurrence-free survival after skull base treatment was 28 months (74 months after allowing for additional course of salvage radiotherapy). Overall survival was 153 months from primary diagnosis and 67 months from first skull base failure. Of 13 treatment failures, 8 occurred at margins; the rest were infield. All intracranial failures occurred along meningeal surfaces. Conclusions Stereotactic radiation provides well-tolerated palliation for the majority of patients, but with a high rate of local failure. Due to the propensity for meningeal failures, we suggest increasing margins along the meningeal surfaces when treating these patients.

Multiple Primary Merkel Cell Carcinomas Presenting as Pruritic, Painful Lower Leg Tumors.

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine tumor of the skin which almost exclusively presents as a solitary tumor. It is most often seen on sun-exposed regions, historically almost exclusively on the head and neck, with only rare case reports on the extremities. Although recent studies have shown increased incidence with up to 20% on the extremities, here we present one of these rare emerging presentations, with the addition of a unique treatment option. Our patient is an 80-year-old male with a 3-month history of multiple raised, rapidly enlarging tumors on the right ankle. Two separate biopsies were performed and demonstrated sheets and clusters of small blue cells filling the dermis with scant cytoplasm, dusty chromatin, and nuclear molding. Subsequent immunohistochemical stains confirmed the diagnosis of multiple primary MCC. Despite the characteristic immunohistochemical profile of primary MCC, the possibility of a metastatic neuroendocrine carcinoma from an alternate primary site was entertained, given his unusual clinical presentation. A complete clinical workup including CT scans of the chest, abdomen, and pelvis showed no evidence of disease elsewhere. Instead of amputation, the patient opted for nonsurgical treatment with radiation therapy alone, resulting in a rapid and complete response. This case represents an unusual presentation of primary MCC and demonstrates further evidence that radiation as monotherapy is an effective local treatment option for inoperable MCC.

Primary radiotherapy for optic nerve sheath meningioma.

Radiotherapy has recently been recognized as the treatment of choice for most primary optic nerve sheath meningiomas (ONSM). Radiotherapy is incorporated into the treatment of non optic nerve sheath meningiomas for unresectable or subtotally resected tumors. Most primary ONSM are not surgically approachable without a high risk of visual deterioration. Radiotherapy has been found to prevent or delay tumor growth for the majority of patients and improve vision in some. We review the rational and current methods of the use of radiotherapy for these tumors.

An immobilization and localization technique for SRT and IMRT of intracranial tumors.

A noninvasive localization and immobilization technique that facilitates planning and accurate delivery of both intensity modulated radiotherapy (IMRT) and linac based stereotactic radiotherapy (SRT) of intracranial tumors has been developed and clinically tested. Immobilization of a patient was based on a commercially available Gill-Thomas-Cossman (GTC) relocatable frame. A stereotactic localization frame (LF) with the attached NOMOS localization device (CT pointer) was used for CT scanning of patients. Thus, CT slices contained fiducial marks for both IMRT and SRT. The patient anatomy and target(s) were contoured on a stand-alone CT-based imaging system. CT slices and contours were then transmitted to both IMRT and SRT treatment planning systems (TPSs) for concurrent development of IMRT and SRT plans. The treatment method that more closely approached the treatment goals could be selected. Since all TPSs used the same contour set, the accuracy of competing treatment plans comparison was improved. SRT delivery was done conventionally. For IMRT delivery patients used the SRT patient immobilization system. For the patient setup, the IMRT target box was attached to the SRT LF, replacing the IMRT CT Pointer. A modified and lighter IMRT target box compatible with SRT LF was fabricated. The proposed technique can also be used for planning and delivery of 3D CRT, thus improving its accuracy. Day-to-day reproducibility of the patient setup can be evaluated using a SRT Depth Helmet.

Radiation therapy in neurologic disease.

Radiotherapy is a primary mode of treatment of many of the disease entities seen by the neurologist. Therefore knowledge of how ionizing radiation works and when it is indicated is a crucial part of the field of Neurology. The neurologist may also be confronted with some of the side effects and complications or radiotherapy treatment. This chapter attempts to serve as a review of the current day process of radiotherapy, a brief review of biology and physics of radiation, and how it is used in the treatment diseases which are common to the Neurologist. In addition we review the more commonly seen side effects and complications of treatment which may be seen by the neurologist.

Unusual clinical presentation of cutaneous angiosarcoma masquerading as eczema: a case report and review of the literature.

An unusual case of cutaneous angiosarcoma clinically mimicking eczema is described. A 98-year-old Caucasian male presented with a 6-month history of a flesh-colored, subcutaneous nodule on his left forehead with contralateral facial erythema and scaling that had been previously diagnosed as eczema. Despite treatments with topical steroids and moisturizers, the condition did not resolve. At our clinic, excisional biopsy of the forehead lesion and scouting biopsies from the contralateral cheek were performed which revealed cutaneous angiosarcoma. The described case illustrates that dermatitis-like features should be considered as a rare clinical manifestation of cutaneous angiosarcoma. It also demonstrates that these lesions may respond well to radiotherapy as a single modality.

A system for continual quality improvement of normal tissue delineation for radiation therapy treatment planning.

PURPOSE: To implement the "plan-do-check-act" (PDCA) cycle for the continual quality improvement of normal tissue contours used for radiation therapy treatment planning. METHODS AND MATERIALS: The CT scans of patients treated for tumors of the brain, head and neck, thorax, pancreas and prostate were selected for this study. For each scan, a radiation oncologist and a diagnostic radiologist, outlined the normal tissues ("gold" contours) using Radiation Therapy Oncology Group (RTOG) guidelines. A total of 30 organs were delineated. Independently, 5 board-certified dosimetrists and 1 trainee then outlined the same organs. Metrics used to compare the agreement between the dosimetrists' contours and the gold contours included the Dice Similarity Coefficient (DSC), and a penalty function using distance to agreement. Based on these scores, dosimetrists were re-trained on those organs in which they did not receive a passing score, and they were subsequently re-tested. RESULTS: Passing scores were achieved on 19 of 30 organs evaluated. These scores were correlated to organ volume. For organ volumes <8 cc, the average DSC was 0.61 vs organ volumes ≥8 cc, for which the average DSC was 0.91 (P=.005). Normal tissues that had the lowest scores included the lenses, optic nerves, chiasm, cochlea, and esophagus. Of the 11 organs that were considered for re-testing, 10 showed improvement in the average score, and statistically significant improvement was noted in more than half of these organs after education and re-assessment. CONCLUSIONS: The results of this study indicate the feasibility of applying the PDCA cycle to assess competence in the delineation of individual organs, and to identify areas for improvement. With testing, guidance, and re-evaluation, contouring consistency can be obtained across multiple dosimetrists. Our expectation is that continual quality improvement using the PDCA approach will ensure more accurate treatments and dose assessment in radiotherapy treatment planning and delivery.