Joshua S. Silverman

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.

The biology of radiosurgery and its clinical applications for brain tumors

Stereotactic radiosurgery (SRS) was developed decades ago but only began to impact brain tumor care when it was coupled with high-resolution brain imaging techniques such as computed tomography and magnetic resonance imaging. The technique has played a key role in the management of virtually all forms of brain tumor. We reviewed the radiobiological principles of SRS on tissue and how they pertain to different brain tumor disorders. We reviewed the clinical outcomes on the most common indications. This review found that outcomes are well documented for safety and efficacy and show increasing long-term outcomes for benign tumors. Brain metastases SRS is common, and its clinical utility remains in evolution. The role of SRS in brain tumor care is established. Together with surgical resection, conventional radiotherapy, and medical therapies, patients have an expanding list of options for their care. Clinicians should be familiar with radiosurgical principles and expected outcomes that may pertain to different brain tumor scenarios.

Resection Followed by Involved-Field Fractionated Radiotherapy in the Management of Single Brain Metastasis

Introduction We expanded upon our previous experience using involved-field fractionated radiotherapy (IFRT) as an alternative to whole brain radiotherapy or stereotactic radiosurgery for patients with surgically resected brain metastases (BM). Materials and methods All patients with single BM who underwent surgical resection followed by IFRT at our institution from 2006 to 2013 were evaluated. Local recurrence (LR)-free survival, distant failure (DF)-free survival, and overall survival (OS) were determined. Analyses were performed associating clinical variables with LR and DF. Salvage approaches and toxicity of treatment for each patient were also assessed. Results Median follow-up was 19.1 months. Fifty-six patients were treated with a median dose of 40.05 Gy/15 fractions with IFRT to the resection cavity. LR-free survival was 91.4%, DF-free survival was 68.4%, and OS was 77.7% at 12 months. No variables were associated with increased LR; however, melanoma histopathology and infratentorial location were associated with DF on multivariate analysis. LRs were salvaged in 5/8 patients, and DFs were salvaged in 24/29 patients. Two patients developed radionecrosis. Conclusion Adjuvant IFRT is feasible and safe for well-selected patients with surgically resected single BM. Acceptable rates of local control and salvage of distal intracranial recurrences continue to be achieved with continued follow-up.

Dose-Response Relationships for Meningioma Radiosurgery.

Objective:Dose-response relationships for meningioma radiosurgery are poorly characterized. We evaluated determinants of local recurrence for meningiomas treated with Gamma Knife radiosurgery (GKRS), to guide future treatment approaches to optimize tumor control. Materials and Methods:A total of 101 consecutive patients (108 tumors) who underwent GKRS for benign, atypical, or malignant meningiomas between 1998 and 2011 were studied. Local recurrence was assessed. Cox proportional hazards and logistic regression analyses were used to determine the association of patient-related, tumor-related, and treatment-related characteristics with local recurrence. Acute and late toxicity was evaluated. Results:World Health Organization (2007 classification) tumor grade was I (82%), II (11%), or III (7%). Median dose was 14 Gy (range, 10 to 18 Gy) for grade I tumors and 16 Gy (range, 12 to 20 Gy) for grade II and III tumors. Median follow-up was 25 months (maximum, 17 y). Two- /5-year actuarial local control rates were 100%/98% for grade I tumors and 76%/56% for grade II/III tumors. Higher tumor grade and lower GKRS dose were associated with local failure. In this cohort, there was a 42% relative reduction in local recurrence for each 1 Gy of dose escalation. Conclusions:Treatment was well tolerated with no moderate or severe toxicity. Tumor control was excellent in benign tumors and suboptimal in higher grade tumors. Because the main determinant of local recurrence was GKRS dose, we recommend dose escalation for atypical or malignant tumors to doses between 16 and 20 Gy where critical structures allow.

Toward the complete control of brain metastases using surveillance screening and stereotactic radiosurgery

OBJECTIVE The incidence of brain metastases is increasing with improved systemic therapies, many of which have a limited impact on intracranial disease. Stereotactic radiosurgery (SRS) is a first-line management option for brain metastases. The purpose of this study was to determine if there is a threshold tumor size below which local control (LC) rates approach 100%, and to relate these findings to the use of routine surveillance brain imaging. METHODS From a prospective registry, 200 patients with 1237 brain metastases were identified who underwent SRS between December 2012 and May 2015. The median imaging follow-up duration was 7.9 months, and the median margin dose was 18 Gy. The maximal diameter and volume of tumors were measured. Histological analysis included 96 patients with non-small cell lung cancers (NSCLCs), 40 with melanoma, 35 with breast cancer, and 29 with other histologies. RESULTS Almost 50% of brain metastases were NSCLCs and commonly measured less than 6 mm in maximal diameter or 70 mm3 in volume. Thirty-three of 1237 tumors had local progression at a median of 8.8 months. The 1- and 2-year actuarial LC rates were 97% and 93%, respectively. LC of 100% was achieved for all intracranial metastases less than 100 mm3 in volume or 6 mm in diameter. Patients whose tumors at first SRS were less than 10 mm maximal diameter or a volume of 250 mm3 had improved overall survival. CONCLUSIONS SRS can achieve LC rates approaching 100% for subcentimeter metastases. The earlier initial detection and prompt treatment of small intracranial metastases may prevent the development of neurological symptoms and the need for resection, and improve overall survival. To identify tumors when they are small, routine surveillance brain imaging should be considered as part of the standard of care for lung, breast, and melanoma metastases. ■ CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort; evidence: Class II.

Weekly versus every-three-weeks platinum-based chemoradiation regimens for head and neck cancer.

BackgroundThe majority of chemoradiation (CRT) trials for locally advanced head and neck squamous cell carcinoma (HNSCC) have relied on platinum-based chemotherapy regimens administered every-3-weeks. However, given the increased utilization of weekly platinum regimens, it remains unclear how different chemotherapy schedules compare regarding efficacy and toxicity.MethodsWe retrospectively identified 212 patients with HNSCC who were treated at a single academic medical center with concurrent platinum-based CRT given weekly (N = 68) or every-three-weeks (N = 144). JMP version 10 (SAS Institute) was used for statistical analysis. Discrete variables were compared with the chi-square test and differences in the medians were assessed using the Wilcoxon test. Survival curves were constructed using the Kaplan-Meier method and significance was assessed using the log rank test. For univariate analysis and multivariate analysis, we used Cox proportional hazard or logistic regression models to compare differences in survival or differences in categorical variables, respectively.ResultsPatients receiving weekly platinum regimens were more likely to be older (median age 61.4 vs. 55.5 y; P < .001), have high or very high Charlson comorbidity index (45.6% vs. 27.8%; P = .01), and receive carboplatin-based chemotherapy (6.3% vs. 76.5%; P < .001). Weekly and every-3-week platinum regimens had similar locoregional control (HR 1.10; 95% CI 0.63–1.88; P = .72), progression-free survival (HR 1.13; 95% CI 0.75–1.69; P = .55), and overall survival (HR 1.11; 95% CI 0.64–1.86; P = .71). Every-3-weeks platinum regimens were associated with increased days of hospitalization (median: 3 days vs. 0 days; P = .03) and acute kidney injury (AKI) during radiotherapy (50.0% vs. 22.1%; P < .001). On multivariate analysis, AKI was significantly associated with every-3-weeks regimens (OR: 24.38; 95% CI 3.00–198.03; P = .003) and high comorbidity scores (OR: 2.74; 95% CI 2.15–5.99; P = .01).ConclusionsOur results suggest that every-3-weeks and weekly platinum-containing CRT regimens have similar disease control but weekly platinum regimens are associated with less acute toxicity.

Feasibility and Efficacy of Local Radiotherapy With Concurrent Novel Agents in Patients With Multiple Myeloma

INTRODUCTION This study evaluated the safety and efficacy of radiotherapy (RT) with concurrent novel agents (NAs), cytotoxic therapy (CTx), or both in the management of osteolytic bone lesions in multiple myeloma (MM). PATIENTS AND METHODS A total of 39 patients with MM received RT to 64 different bone sites during the 2007-2012 period, with a dose of 8 to 37.5 Gy (mean, 26.8 Gy) delivered in 1 to 15 fractions (median, 10 fractions). Of these patients, 21 also received concurrent NAs or CTx. Pain response, M protein and κ light chain response, and adverse events were evaluated. RESULTS RT was completed in 35 of 39 patients (89.7%) in this study. Pain relief was observed in 30 of 31 patients (96.7%). Hematologic toxicity (grade 3 or 4 by the Radiation Therapy Oncology Group system) was seen in 43.2% of treated patients, and NA therapy was stopped in 2 patients owing to grade 4 toxicity. RT adverse effects resolved at 4 to 6 weeks posttreatment. Changes in pre- and posttreatment levels of M protein trended toward significance in patients treated with RT + systemic therapy (ST) versus. RT alone (ΔM ProteinRT+ST = 5.6 g/L; ΔM ProteinRT = 0 g/L; P = .089). CONCLUSION Treating MM with RT concurrently with CTx including NAs was safe and well tolerated in the majority of patients (14 of 16 [87.5%] for those taking NAs and 19 of 21 [90.5%] for all patients). Excellent clinical pain response (> 95%) was also seen in patients regardless if they were treated with RT + ST or RT alone.

The relationship of dose to nerve volume in predicting pain recurrence after stereotactic radiosurgery in trigeminal neuralgia

OBJECTIVE Approximately 75%-92% of patients with trigeminal neuralgia (TN) achieve pain relief after Gamma Knife surgery (GKS), although a proportion of these patients will experience recurrence of their pain. To evaluate the reasons for durability or recurrence, this study determined the impact of trigeminal nerve length and volume, the nerve dose-volume relationship, and the presence of neurovascular compression (NVC) on pain outcomes after GKS for TN. METHODS Fifty-eight patients with 60 symptomatic nerves underwent GKS for TN between 2013 and 2015, including 15 symptomatic nerves secondary to multiple sclerosis (MS). High-resolution MRI was acquired the day of GKS. The median maximum dose was 80 Gy for initial GKS and 65 Gy for repeat GKS. NVC, length and volume of the trigeminal nerve within the subarachnoid space of the posterior fossa, and the ratio of dose to nerve volume were assessed as predictors of recurrence. RESULTS Follow-up was available on 55 patients. Forty-nine patients (89.1%) reported pain relief (Barrow Neurological Institute [BNI] Grades I-IIIb) after GKS at a median duration of 1.9 months. The probability of maintaining pain relief (BNI Grades I-IIIb) without requiring resumption or an increase in medication was 93% at 1 year and 84% at 2 years for patients without MS, and 68% at 1 year and 51% at 2 years for all patients. The nerve length, nerve volume, target distance from the brainstem, and presence of NVC were not predictive of pain recurrence. Patients with a smaller volume of nerve (< 35% of the total nerve volume) that received a high dose (≥ 80% isodose) were less likely to experience recurrence of their TN pain after 1 year (mean time to recurrence: < 35%, 32.2 ± 4.0 months; > 35%, 17.9 ± 2.8 months, log-rank test, χ2 = 4.3, p = 0.039). CONCLUSIONS The ratio of dose to nerve volume may predict recurrence of TN pain after GKS. Prospective studies are needed to determine the optimal dose to nerve volume ratio and whether this will result in longer pain-free outcomes.

Early Palliative Care for Patients With Brain Metastases Decreases Inpatient Admissions and Need for Imaging Studies

Background: Early encounters with palliative care (PC) can influence health-care utilization, clinical outcome, and cost. Aim: To study the effect of timing of PC encounters on brain metastasis patients at an academic medical center. Setting/Participants: All patients diagnosed with brain metastases from January 2013 to August 2015 at a single institution with inpatient and/or outpatient PC records available for review (N = 145). Design: Early PC was defined as having a PC encounter within 8 weeks of diagnosis with brain metastases; late PC was defined as having PC after 8 weeks of diagnosis. Propensity score matched cohorts of early (n = 46) and late (n = 46) PC patients were compared to control for differences in age, gender, and Karnofsky Performance Status (KPS) at diagnosis. Details of the palliative encounter, patient outcomes, and health-care utilization were collected. Results: Early PC versus late PC patients had no differences in baseline KPS, age, or gender. Early PC patients had significantly fewer number of inpatient visits per patient (1.5 vs 2.9; P = .004), emergency department visits (1.2 vs 2.1; P = .006), positron emission tomography/computed tomography studies (1.2 vs 2.7, P = .005), magnetic resonance imaging scans (5.8 vs 8.1; P = .03), and radiosurgery procedures (0.6 vs 1.3; P < .001). There were no differences in overall survival (median 8.2 vs 11.2 months; P = .2). Following inpatient admissions, early PC patients were more likely to be discharged home (59% vs 35%; P = .04). Conclusions: Timely PC consultations are advisable in this patient population and can reduce health-care utilization.

Osimertinib Dose Escalation Induces Regression of Progressive EGFR T790M–Mutant Leptomeningeal Lung Adenocarcinoma

context of multifocal pulmonary adenocarcinomas is herein reported for the first time. Unfortunately, there is still no validated treatment for KRAS-driven NSCLC and the patient died of progressive disease related to the KRAS-positive tumor despite neuronavigation-guided microsurgical excision andadjuvantwhole brain irradiation. Testing a single lesion for the purpose of identifying actionable alterations may not be sufficient for multifocal NSCLC. Adding a comprehensive liquid biopsy to the initial work-up of these patients could help increase diagnostic and therapeutic precision.