Volumetric growth rate of incidentally found meningiomas on immunotherapy.

PURPOSE: The expression of PD-L1 in high-grade meningiomas made it a potential target for immunotherapy research in refractory cases. Several prospective studies in this field are still on going. We sought to retrospectively investigate the effects of check-point inhibitors (CI) on meningiomas that had been naïve to either surgical or radiation approaches by following incidental meningiomas found during treatment with CI for various primary metastatic cancers. METHODS: We used the NYU Perlmutter Cancer Center Data Hub to find patients treated by CI for various cancers, who also had serial computerized-tomography (CT) or magnetic-resonance imaging (MRI) reports of intracranial meningiomas. Meningioma volumetric measurements were compared between the beginning and end of the CI treatment period. Patients treated with chemotherapy during this period were excluded. RESULTS: Twenty-five patients were included in our study, of which 14 (56%) were on CI for melanoma, 5 (20%) for non-small-cell lung cancer and others. CI therapies included nivolumab (n = 15, 60%), ipilimumab (n = 11, 44%) and pembrolizumab (n = 9, %36), while 9 (36%) were on ipilimumab/nivolumab combination. We did not find any significant difference between tumor volumes before and after treatment with CI (1.31 ± 0.46 vs. 1.34 ± 0.46, p=0.8, respectively). Among patients beyond 1 year of follow-up (n = 13), annual growth was 0.011 ± 0.011 cm3/year. Five patients showed minor volume reduction of 0.12 ± 0.10 cm3 (21 ± 6% from baseline). We did not find significant predictors of tumor volume reduction. CONCLUSION: Check-point inhibitors may impact the natural history of meningiomas. Additional research is needed to define potential clinical indications and treatment goals.

Improved outcomes for triple negative breast cancer brain metastases patients after stereotactic radiosurgery and new systemic approaches.

PURPOSE: Although ongoing studies are assessing the efficacy of new systemic therapies for patients with triple negative breast cancer (TNBC), the overwhelming majority have excluded patients with brain metastases (BM). Therefore, we aim to characterize systemic therapies and outcomes in a cohort of patients with TNBC and BM managed with stereotactic radiosurgery (SRS) and delineate predictors of increased survival. METHODS: We used our prospective patient registry to evaluate data from 2012 to 2023. We included patients who received SRS for TNBC-BM. A competing risk analysis was conducted to assess local and distant control. RESULTS: Forty-three patients with 262 tumors were included. The median overall survival (OS) was 16 months (95% CI 13-19 months). Predictors of increased OS after initial SRS include Breast GPA score > 1 (p < 0.001) and use of immunotherapy such as pembrolizumab (p = 0.011). The median time on immunotherapy was 8 months (IQR 4.4, 11.2). The median time to new CNS lesions after the first SRS treatment was 17 months (95% CI 12-22). The cumulative rate for development of new CNS metastases after initial SRS at 6 months, 1 year, and 2 years was 23%, 40%, and 70%, respectively. Thirty patients (70%) underwent multiple SRS treatments, with a median time of 5 months (95% CI 0.59-9.4 months) for the appearance of new CNS metastases after second SRS treatment. CONCLUSIONS: TNBC patients with BM can achieve longer survival than might have been previously anticipated with median survival now surpassing one year. The use of immunotherapy is associated with increased median OS of 23 months.

EGFR-mutated non-small lung cancer brain metastases and radiosurgery outcomes with a focus on leptomeningeal disease.

PURPOSE: Patients with EGFR-mutated NSCLC represent a unique subset of lung cancer patients with distinct clinical and molecular characteristics. Previous studies have shown a higher incidence of brain metastases (BM) in this subgroup of patients, and neurologic death has been reported to be as high as 40% and correlates with leptomeningeal disease (LMD). METHODS: Between 2012 and 2021, a retrospective review of our prospective registry identified 606 patients with BM from NSCLC, with 170 patients having an EGFR mutation. Demographic, clinical, radiographic, and treatment characteristics were correlated to the incidence of LMD and survival. RESULTS: LMD was identified in 22.3% of patients (n = 38) at a median follow-up of 19 (2-98) months from initial SRS. Multivariate regression analysis showed targeted therapy and a cumulative number of metastases as significant predictors of LMD (p = 0.034, HR = 0.44), (p = .04, HR = 1.02). The median survival time after SRS of the 170 patients was 24 months (CI 95% 19.1-28.1). In a multivariate Cox regression analysis, RPA, exon 19 deletion, and osimertinib treatment were significant predictors of overall survival. The cumulative incidence of neurological death at 2 and 4 years post initial stereotactic radiosurgery (SRS) was 8% and 11%, respectively, and correlated with LMD. CONCLUSION: The study shows that current-generation targeted therapy for EGFR-mutated NSCLC patients may prevent the development and progression of LMD, leading to improved survival outcomes. Nevertheless, LMD is associated with poor outcomes and neurologic death, making innovative strategies to treat LMD essential.

Up-front single-session radiosurgery for large brain metastases-volumetric responses and outcomes.

BACKGROUND: Patients presenting with large brain metastases (LBM) pose a management challenge to the multidisciplinary neuro-oncologic team. Treatment options include surgery, whole-brain or large-field radiation therapy (WBRT), stereotactic radiosurgery (SRS), or a combination of these. OBJECTIVE: To determine if corticosteroid therapy followed by SRS allows for efficient minimally invasive care in patients with LBMs not compromised by mass effect. METHODS: We analyzed the change in tumor volume to determine the efficacy of single-session SRS in the treatment of LBM in comparison to other treatment modalities. Twenty-nine patients with systemic cancer and brain metastasis (≥ 2.7 cm in greatest diameter) who underwent single-session SRS were included. RESULTS: Among 29 patients, 69% of patients had either lung, melanoma, or breast cancer. The median initial tumor size (maximal diameter) was 32 mm (range 28-43), and the median initial tumor volume was 9.56 cm3 (range 1.56-25.31). The median margin dose was 16 Gy (range 12-18). The average percent decrease in tumor volume compared to pre-SRS volume was 55% on imaging at 1-2 months, 58% at 3-5 months, 64% at 6-8 months, and 57% at > 8 months. There were no adverse events immediately following SRS. Median corticosteroid use after SRS was 21 days. Median survival after radiosurgery was 15 months. CONCLUSION: Initial high-dose corticosteroid therapy followed by prompt single-stage SRS is a safe and efficacious method to manage patients with LBMs (defined as ≥ 2.7 cm).

How many brain metastases can be treated with stereotactic radiosurgery before the radiation dose delivered to normal brain tissue rivals that associated with standard whole brain radiotherapy?

INTRODUCTION: Clinical trial data comparing outcomes after administration of stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT) to patients with brain metastases (BM) suggest that SRS better preserves cognitive function and quality of life without negatively impacting overall survival. Here, we estimate the maximum number of BM that can be treated using single and multi-session SRS while limiting the dose of radiation delivered to normal brain tissue to that associated with WBRT. METHODS: Multiple-tumor SRS was simulated using a Monte Carlo - type approach and a pre-calculated dose kernel method. Tumors with diameters ≤36 mm were randomly placed throughout the contoured brain parenchyma until the brain mean dose reached 3 Gy, equivalent to the radiation dose delivered during a single fraction of a standard course of WBRT (a total dose of 30 Gy in 10 daily fractions of 3 Gy). Distribution of tumor sizes, dose coverage, selectivity, normalization, and maximum dose data used in the simulations were based on institutional clinical metastases data. RESULTS: The mean number of tumors treated, mean volume of healthy brain tissue receiving > 12 Gy (V12) per tumor, and total tumor volume treated using mixed tumor size distributions were 12.7 ± 4.2, 2.2 cc, and 12.9 cc, respectively. Thus, we estimate that treating 12-13 tumors per day over 10 days would deliver the dose of radiation to healthy brain tissue typically associated with a standard course of WBRT. CONCLUSION: Although in clinical practice, treatment with SRS is often limited to patients with ≤15 BM, our findings suggest that many more lesions could be targeted while still minimizing the negative impacts on quality of life and neurocognition often associated with WBRT. Results from this in silico analysis require clinical validation.

Significant survival improvements for patients with melanoma brain metastases: can we reach cure in the current era?

PURPOSE: New therapies for melanoma have been associated with increasing survival expectations, as opposed to the dismal outcomes of only a decade ago. Using a prospective registry, we aimed to define current survival goals for melanoma patients with brain metastases (BM), based on state-of-the-art multimodality care. METHODS: We reviewed 171 melanoma patients with BM receiving stereotactic radiosurgery (SRS) who were followed with point-of-care data collection between 2012 and 2020. Clinical, molecular and imaging data were collected, including systemic treatment and radiosurgical parameters. RESULTS: Mean age was 63 ± 15 years, 39% were female and 29% had BRAF-mutated tumors. Median overall survival after radiosurgery was 15.7 months (95% Confidence Interval 11.4-27.7) and 25 months in patients managed since 2015. Thirty-two patients survived [Formula: see text] 5 years from their initial SRS. BRAF mutation-targeted therapies showed a survival advantage in comparison to chemotherapy (p = 0.009), but not to immunotherapy (p = 0.09). In a multivariable analysis, both immunotherapy and the number of metastases at 1st SRS were predictors of long-term survival ([Formula: see text] 5 years) from initial SRS (p = 0.023 and p = 0.018, respectively). Five patients (16%) of the long-term survivors required no active treatment for [Formula: see text] 5 years. CONCLUSION: Long-term survival in patients with melanoma BM is achievable in the current era of SRS combined with immunotherapies. For those alive [Formula: see text] 5 years after first SRS, 16% had been also off systemic or local brain therapy for over 5 years. Given late recurrences of melanoma, caution is warranted, however prolonged survival off active treatment in a subset of our patients raises the potential for cure.

Adenoidectomy: Inpatient criteria study.

OBJECTIVES: Current practices for admission for overnight observation after an adenoidectomy alone vary from hospital to hospital, as there are currently no studies that provide evidence for overnight observation criteria. The objective of this study is to determine any relationships between risk factors and postoperative complications or interventions in patients under 2-years-old who undergo adenoidectomy and use this data to form a set of guidelines that may be used to stratify patients for inpatient observation. METHODS: Consecutive pediatric adenoidectomy without tonsillectomy cases in children younger than 2-years-old with subsequent inpatient observation from January 2014 to October 2018 were reviewed at a single tertiary children's institution using electronic medical records. Patient demographics, surgical data, and comorbidities were analyzed for correlations with postoperative complications or interventions. RESULTS: Out of the 76 patients with sleep-disordered breathing (SDB) examined, one patient (1.3%) required readmission for postoperative dehydration and seven patients (9.2%) required intervention. The presence of at least one major comorbidity was significantly associated with increased incidence of complication or intervention compared to patients with no major comorbidities (18.9% vs. 2.6%, p = 0.03). Specifically, O2 nadir <80% (p = 0.01), craniofacial syndrome (p = 0.01) and seizure history (p = 0.007) were significant factors of complication or intervention. CONCLUSIONS: Otherwise healthy children (>18-month-old) with SDB may be considered for discharge the same day of surgery. Children younger than 2-years-old with ≥1 major comorbidities may benefit from overnight inpatient observation. Otherwise healthy children younger than 18-months-old or children with a history of RAD or CLD should be managed on a case-by-case basis.

Seizures induce obstructive apnea in DBA/2J audiogenic seizure-prone mice: Lifesaving impact of tracheal implants.

The mechanism(s) for sudden death in epilepsy (SUDEP) remain(s) unknown, but seizure spread to brainstem areas serving autonomic and respiratory function is critical. In a rat model, we established a mechanism for SUDEP that involves seizure-induced laryngospasm and obstructive apnea lasting until respiratory arrest. We hypothesized that DBA/2J mice, which display lethal audiogenic seizures, would be protected from death by implanting a tracheal T-tube as a surrogate airway. In a 2 × 2 design, mice were implanted with either open or closed tracheal T-tubes and treated with either low-dose ketamine/xylazine to moderate thoracic spasm during the tonic seizure phase or no drug. Animals receiving both treatments had the highest survival rate, followed by animals receiving the open tube without ketamine/xylazine. The odds ratio for survival was >20 higher with an open T-tube (odds ratio = 24.14). The impact of open tracheal tubes indicates that the mechanism of death in DBA/2J mice involves seizure-induced upper airway obstruction until respiratory arrest. These results, our rat work, and our demonstration of inspiratory effort-based electromyographic signals and electrocardiographic abnormalities in rats and humans suggest that seizure-induced laryngospasm and obstructive apnea directly link seizure activity to respiratory arrest in these sudden death examples.

Treatment of sellar metastases with gamma knife radiosurgery in patients with advanced cancer.

PURPOSE: Metastases should be considered in a patient with a cancer history and a sellar/suprasellar lesion, as this diagnosis can change the management strategy in such patients. Once the diagnosis is established, stereotactic radiosurgery (SRS) can be a safe and effective approach for these patients. METHODS: This case series describes five patients with pituitary metastases managed with GKRS at a single institution, taken from our prospective registry. All patients had SRS using the Gamma Knife Perfexion or Icon (Elekta), according to our standard institutional protocol. The optic nerves and chiasm were contoured, and the plan was adjusted to restrict dose to the optic apparatus as necessary. The tumor margin doses delivered were 11 Gy, 12 Gy, 14 Gy, 18 Gy (3 sessions of 6 Gy), and 12 Gy at the 50% isodose line. RESULTS: In this series, all sellar metastases were treated successfully with good radiographic and clinical response. The histology of the tumors included endometrial, gastrointestinal, and lung adenocarcinomas. Typically, histology is taken into consideration when choosing the treatment dose, along with size and location. In these patients, however, the dose used for the sellar metastases was chosen primarily for visual safety. This was typically lower than the dose for brain metastases in other locations. CONCLUSION: SRS provides an alternative treatment approach for sellar/suprasellar metastases with excellent local control, symptom improvement and maintenance of systemic therapy as desired. As such, CNS failure is rarely the proximate cause of demise in pituitary metastases provided that endocrinopathies are recognized and managed appropriately.

Full automation of spinal stereotactic radiosurgery and stereotactic body radiation therapy treatment planning using Varian Eclipse scripting.

The purpose of this feasibility study is to develop a fully automated procedure capable of generating treatment plans with multiple fractionation schemes to improve speed, robustness, and standardization of plan quality. A fully automated script was implemented for spinal stereotactic radiosurgery/stereotactic body radiation therapy (SRS/SBRT) plan generation using Eclipse v15.6 API. The script interface allows multiple dose/fractionation plan requests, planning target volume (PTV) expansions, as well as information regarding distance/overlap between spinal cord and targets to drive decision-making. For each requested plan, the script creates the course, plans, field arrangements, and automatically optimizes and calculates dose. The script was retrospectively applied to ten computed tomography (CT) scans of previous cervical, thoracic, and lumbar spine SBRT patients. Three plans were generated for each patient - simultaneous integrated boost (SIB) 1800/1600 cGy to gross tumor volume (GTV)/PTV in one fraction; SIB 2700/2100 cGy to GTV/PTV in three fractions; and 3000 cGy to PTV in five fractions. Plan complexity and deliverability patient-specific quality assurance (QA) was performed using ArcCHECK with an Exradin A16 chamber inserted. Dose objectives were met for all organs at risk (OARs) for each treatment plan. Median target coverage was GTV V100% = 87.3%, clinical target volume (CTV) V100% = 95.7% and PTV V100% = 88.0% for single fraction plans; GTV V100% = 95.6, CTV V100% = 99.6% and PTV V100% = 97.2% for three fraction plans; and GTV V100% = 99.6%, CTV V100% = 99.1% and PTV V100% = 97.2% for five fraction plans. All plans (n = 30) passed patient-specific QA (>90%) at 2%/2 mm global gamma. A16 chamber dose measured at isocenter agreed with planned dose within 3% for all cases. Automatic planning for spine SRS/SBRT through scripting increases efficiency, standardizes plan quality and approach, and provides a tool for target coverage comparison of different fractionation schemes without the need for additional resources.

Risk of radiation-associated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study.

BACKGROUND: A major concern of patients who have stereotactic radiosurgery is the long-term risk of having a secondary intracranial malignancy or, in the case of patients with benign tumours treated with the technique, the risk of malignant transformation. The incidence of stereotactic radiosurgery-associated intracranial malignancy remains unknown; therefore, our aim was to estimate it in a population-based study to assess the long-term safety of this technique. METHODS: We did a population-based, multicentre, cohort study at five international radiosurgery centres (Na Homolce Hospital, Prague, Czech Republic [n=2655 patients]; Ruber International Hospital, Madrid, Spain [n=1080], University of Pittsburgh Medical Center, Pittsburgh, PA, USA [n=1027]; University of Virginia, Charlottesville, VA, USA [n=80]; and NYU Langone Health System, New York, NY, USA [n=63]). Eligible patients were of any age, and had Gamma Knife radiosurgery for arteriovenous malformation, trigeminal neuralgia, or benign intracranial tumours, which included vestibular or other benign schwannomas, WHO grade 1 meningiomas, pituitary adenomas, and haemangioblastoma. Patients were excluded if they had previously had radiotherapy or did not have a minimum follow-up time of 5 years. The primary objective of the study was to estimate the incidence of stereotactic radiosurgery-associated intracranial malignancy, including malignant transformation of a benign lesion or development of radiation-associated secondary intracranial cancer, defined as within the 2 Gy isodose line. Estimates of age-adjusted incidence of primary CNS malignancies in the USA and European countries were retrieved from the Central Brain Tumor Registry of the United States (CBTRUS) and the International Agency for Research on Cancer (IARC) Global Cancer statistics. FINDINGS: Of 14 168 patients who had Gamma Knife stereotactic radiosurgery between Aug 14, 1987, and Dec 31, 2011, in the five contributing centres, 4905 patients were eligible for the analysis (had a minimum follow-up of 5 years and no history of previous radiation therapy). Diagnostic entities included vestibular schwannomas (1011 [20·6%] of 4905 patients), meningiomas (1490 [30·4%]), arteriovenous malformations (1089 [22·2%]), trigeminal neuralgia (565 [11·5%]), pituitary adenomas (641 [13·1%]), haemangioblastoma (29 [0·6%]), and other schwannomas (80 [1·6%]). With a median follow-up of 8·1 years (IQR 6·0-10·6), two (0·0006%) of 3251 patients with benign tumours were diagnosed with suspected malignant transformation and one (0·0002%) of 4905 patients was considered a case of radiosurgery-associated intracranial malignancy, resulting in an incidence of 6·87 per 100 000 patient-years (95% CI 1·15-22·71) for malignant transformation and 2·26 per 100 000 patient-years (0·11-11·17) for radiosurgery-associated intracranial malignancy. Two (0·0004%) of 4905 patients developed intracranial malignancies, which were judged unrelated to the radiation field. Overall incidence of radiosurgery-associated malignancy was 6·80 per 100 000 patients-years (95% CI 1·73-18·50), or a cumulative incidence of 0·00045% over 10 years (95% CI 0·00-0·0034). The overall incidence of 6·8 per 100 000, which includes institutions from Europe and the USA, after stereotactic radiosurgery was found to be similar to the risk of developing a malignant CNS tumour in the general population of the USA and some European countries as estimated by the CBTRUS and IARC data, respectively. INTERPRETATION: These data show that the estimated risk of an intracranial secondary malignancy or malignant transformation of a benign tumour in patients treated with stereotactic radiosurgery remains low at long-term follow-up, and is similar to the risk of the general population to have a primary CNS tumour. Although prospective cohort studies with longer follow-up are warranted to support the results of this study, the available evidence suggests the long-term safety of stereotactic radiosurgery and could support physicians counselling patients on Gamma Knife stereotactic radiosurgery. FUNDING: None.

Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence.

Epigenetic patterns on the level of DNA methylation have already been shown to separate clinically relevant subgroups of meningiomas. We here set out to identify potential prognostic implications of epigenetic modification on the level of histones with focus on H3K27 trimethylation (H3K27me3). H3K27me3 was assessed by immunohistochemistry on 232 meningiomas from 232 patients. In 194 cases, trimethylation was detected in tumor cells. In 25 cases, staining was limited to vessels while all tumor cells were negative. Finally, 13 cases yielded equivocal staining patterns. Reduced abundance of H3K27me3 in cases with staining limited to vessels was confirmed by mass spectrometry on a subset of cases. Lack of staining for H3K27me3 in all tumor cells was significantly associated with more rapid progression (p = 0.009). In line, H3K27me3-negative cases were associated with a DNA methylation pattern of the more aggressive types among the recently introduced DNA methylation groups. Also, NF2 and SUFU mutations were enriched among cases with complete lack of H3K27me3 staining in tumor cells (p < 0.0001 and p = 0.029, respectively). H3K27me3 staining pattern added significant prognostic insight into WHO grade II cases and in the compound subset of WHO grade I and II cases (p = 0.04 and p = 0.007, respectively). However, it did not further stratify within WHO grade III cases. Collectively, these data indicate that epigenetic modifications beyond DNA methylation are involved in the aggressiveness of meningioma. It also suggests that H3K27me3 immunohistochemistry might be a useful adjunct in meningioma diagnostics, particularly for cases with WHO grade II histology or at the borderline between WHO grade I and II.

Obstructive apnea due to laryngospasm links ictal to postictal events in SUDEP cases and offers practical biomarkers for review of past cases and prevention of new ones.

Seizure spread into autonomic and respiratory brainstem regions is thought to play an important role in sudden unexpected death in epilepsy (SUDEP). As the clinical dataset of cases of definite SUDEP available for study grows, evidence points to a sequence of events that includes postictal apnea, bradycardia, and asystole as critical events that can lead to death. One possible link between the precipitating seizure and the critical postictal sequence is seizure-driven laryngospasm sufficient to completely obstruct the airway for an extended period, but ictal laryngospasm is difficult to fully assess. Herein, we demonstrate in a rat model how the electrical artifacts of attempts to inspire during airway obstruction and features of the cardiac rhythm establish this link between ictal and postictal activity and can be used as practical biomarkers of obstructive apnea due to laryngospasm or other causes of airway obstruction.

Stereotactic radiosurgery for focal leptomeningeal disease in patients with brain metastases.

Leptomeningeal disease (LMD) is well described in patients with brain metastases, presenting symptomatically in approximately 5% of patients. Conventionally, the presence of LMD is an indication for whole brain radiation therapy (WBRT) and not suitable for stereotactic radiosurgery (SRS). The purpose of the study was to evaluate the local control and overall survival of patients who underwent SRS to focal LMD. We reviewed our prospective registry and identified 32 brain metastases patients with LMD, from a total of 465 patients who underwent SRS between 2013 and 2015. Focal LMD was targeted with SRS in 16 patients. The median imaging follow-up time was 7 months. The median volume of LMD was 372 mm3 and the median margin dose was 16 Gy. Five patients underwent prior WBRT. Histology included non-small cell lung (8), breast (5), melanoma (1), gastrointestinal (1) and ovarian cancer (1). Follow-up MR imaging was available for 14 patients. LMD was stable in 5 and partially regressed in 8 patients at follow-up. One patient had progression of LMD with hemorrhage 5 months after SRS. Seven patients developed distant LMD at a median time of 7 months. The median actuarial overall survival from SRS for LMD was 10.0 months. The 6-month and 1-year actuarial overall survival was 60% and 26% respectively. Six patients underwent WBRT after SRS for focal LMD at a median time of 6 months. Overall, focal LMD may be may be treated successfully with radiosurgery, potentially delaying WBRT in some patients.

Aquablation of the Prostate for Symptomatic Benign Prostatic Hyperplasia: Early Results.

Aquablation is a novel technique for the surgical management of bladder outlet obstruction secondary to benign prostatic hyperplasia. Following first-in-man studies, a multicenter trial was conducted with results now out to 1 year. Aquablation resulted in a mean International Prostate Symptom Score improvement of 16 points (p < 0.01) and a mean maximum urinary flow rate increase from 8.7 to 18.3 ml/s (p < 0.01) at 12 months. Due to the precise prostate mapping, aquablation has also demonstrated favorable sexual and urinary outcomes with no new erectile dysfunction, retrograde ejaculation, or urinary incontinence as often experienced with other techniques. These improvements in functional outcomes at 12 months confirm that aquablation is a safe and effective alternative for BPH treatment.

SCF ubiquitin ligases in the maintenance of genome stability.

In response to genotoxic stress, eukaryotic cells activate the DNA damage response (DDR), a series of pathways that coordinate cell cycle arrest and DNA repair to prevent deleterious mutations. In addition, cells possess checkpoint mechanisms that prevent aneuploidy by regulating the number of centrosomes and spindle assembly. Among these mechanisms, ubiquitin-mediated degradation of key proteins has an important role in the regulation of the DDR, centrosome duplication and chromosome segregation. This review discusses the functions of a group of ubiquitin ligases, the SCF (SKP1-CUL1-F-box protein) family, in the maintenance of genome stability. Given that general proteasome inhibitors are currently used as anticancer agents, a better understanding of the ubiquitylation of specific targets by specific ubiquitin ligases may result in improved cancer therapeutics.

Survival but not brain metastasis response relates to lung cancer mutation status after radiosurgery.

We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012-2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non-squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7%, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe.

Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases.

The aim of this study was to evaluate the impact of BRAF inhibitors on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases. We prospectively collected treatment parameters and outcomes for 80 patients with melanoma brain metastases who underwent SRS. Thirty-five patients harbored the BRAF mutation (BRAF-M) and 45 patients did not (BRAF-WT). Univariate and multivariate analyses were performed to identify predictors of overall survival. The median overall survival from first SRS procedure was 6.7, 11.2 months if treated with a BRAF inhibitor and 4.5 months for BRAF-WT. Actuarial survival rates for BRAF-M patients on an inhibitor were 54 % at 6 months and 41 % at 12 months from the time of SRS. In contrast, BRAF-WT had overall survival rates of 28 % at 6 months and 19 % at 12 months. Overall survival was extended for patients on a BRAF inhibitor at or after the first SRS. The median time to intracranial progression was 3.9 months on a BRAF inhibitor and 1.7 months without. The local control rate for all treated tumors was 92.5 %, with no difference based on BRAF status. Patients with higher KPS, fewer treated intracranial metastases, controlled systemic disease, RPA Class 1 and BRAF-M patients had extended overall survival. Overall, patients with BRAF-M treated with both SRS and BRAF inhibitors, at or after SRS, have increased overall survival from the time of SRS. As patients live longer as a result of more effective systemic and local therapies, close surveillance and early management of intracranial disease with SRS will become increasingly important.

Quality of the Patient Experience during Radiosurgery: Measurement toward Improvement.

BACKGROUND: All physicians seek to improve the patient experience. In an awake surgical procedure, the patient has a unique opportunity to comment on all aspects of care. The provision of a positive experience is part of quality health care. Our purpose was to define this experience to determine areas for improvement. METHODS: We evaluated 125 patients who underwent stereotactic radiosurgery using a frame-based, gamma knife technique. Patients were surveyed by a nurse practitioner across all elements of their procedural experience prior to same-day discharge. RESULTS: The radiosurgery was completed in all patients with same-day discharge. In an initial 100-patient cohort, 89 patients said they had received adequate oral and/or intravenous sedation before the procedure. All 100 patients said that they felt comfortable before stereotactic frame application, and all patients later remembered frame application. These patients described frame application as very or adequately comfortable (n = 73), minimally uncomfortable (n = 18), or very uncomfortable (n = 9). Neuroimaging was described as very or adequately comfortable (n = 93), minimally uncomfortable (n = 3), or very uncomfortable (n = 4). Radiosurgery in the gamma knife unit was found to be very or adequately comfortable (n = 99) or very uncomfortable (n = 1). We evaluated how 8 separate factors may have contributed to survey responses related to procedural comfort. These factors included intravenous line placement, delivery of sedation medications, application of the head frame, having the MRI, having radiosurgery on the gamma knife bed, removal of the stereotactic frame, communication with caregivers, and knowing what to expect beforehand. We asked the patients to rate their nursing care during the radiosurgery experience, and 'excellent' was chosen by all initial 100 patients. Other elements of the procedure were also studied as well as suggestions for improvement. As a secondary objective, we then modified our protocol to include sodium bicarbonate added to the local anesthetic for frame application and evaluated an additional cohort of 25 patients. CONCLUSIONS: Utilizing a system of physician and nursing education, together with pharmacological sedation and efficient procedural steps, patients said that intravenous line placement (91%), stereotactic frame application (74%), MRI (93%), receiving radiosurgery in the unit (99%), frame removal (84%), communication with caregivers (100%), and knowing what to expect beforehand (97%) were either very or adequately comfortable. Specific evaluations of care processes can lead to care improvement.

Primary large cell neuroendocrine carcinoma of the breast, a case report with an unusual clinical course.

Large cell neuroendocrine carcinoma of the breast (NECB) is an extremely rare type of breast cancer; little is known about effective chemotherapies, and data on pathologic response to treatment are unavailable. We report the case of a 34-years-old woman with large cell NECB with initial clinical and pathologic evidence of treatment response to anthracycline-containing neo-adjuvant therapy. Histologic reassessment early during anthracycline chemotherapy revealed cell death with necrosis of 50% of the tumor cells seen in the biopsy specimen. After completing neo-adjuvant chemotherapy, the patient underwent breast-conserving surgery. Pathologic evaluation of the surgical specimen showed a partial response but margins were positive for residual carcinoma. Despite repeated neo-adjuvant chemotherapy, radiotherapy, and surgical resection, the tumor grew rapidly between surgeries and recurred systemically. Therefore, we review the literature on large cell NECB and its treatment options.