Proton versus photon craniospinal irradiation for adult medulloblastoma: A dosimetric, toxicity, and exploratory cost analysis.

Background: This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients. Methods: This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients. Results: Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18-66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all P < .001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% versus 35%, P = .044) and decreased median weight loss during radiation (+1.0 versus -2.8 kg, P = .011). Weight loss was associated with acute hospitalization (P = .009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At the last follow-up, 5 photon patients had died (2 of progressive disease, 3 without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. Conclusions: This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Pre-operative vs. post-operative stereotactic radiosurgery for operative metastatic brain tumors: study protocol for a phase III clinical trial.

BACKGROUND AND OBJECTIVES: Almost one third of cancer patients in the United States will develop brain metastases on an annual basis. Surgical resection is indicated in the setting of brain metastases for reasons, such as maximizing local control in select patients, decompression of mass effect, and/or tissue diagnosis. The current standard of care following resection of a brain metastasis has shifted from whole brain radiation therapy to post-operative stereotactic radiosurgery (SRS). However, there is a significant rate of local recurrence within one year of postoperative SRS. Emerging retrospective and prospective data suggest pre-operative SRS is a safe and potentially effective treatment paradigm for surgical brain metastases. This trial intends to determine, for patients with an indication for resection of a brain metastasis, whether there is an increase in the time to a composite endpoint of adverse outcomes; including the first occurrence of either: local recurrence, leptomeningeal disease, or symptomatic radiation brain necrosis - in patients who receive pre-operative SRS as compared to patients who receive post-operative SRS. METHODS: This randomized phase III clinical trial compares pre-operative with post-operative SRS for brain metastases. A dynamic random allocation procedure will allocate an equal number of patients to each arm: pre-operative SRS followed by surgery or surgery followed by post-operative SRS. EXPECTED OUTCOMES: If pre-operative SRS improves outcomes relative to post-operative SRS, this will establish pre-operative SRS as superior. If post-operative SRS proves superior to pre-operative SRS, it will remain a standard of care and halt the increasing utilization of pre-operative SRS. If there is no difference in pre- versus post-operative SRS, then pre-operative SRS may still be preferred, given patient convenience and the potential for a condensed timeline. DISCUSSION: Emerging retrospective and prospective data have demonstrated some benefits of pre-op SRS vs. post-op SRS. This study will show whether there is an increase in the time to the composite endpoint. Additionally, the study will compare overall survival; patient-reported outcomes; morbidity; completion of planned therapies; time to systemic therapy; time to regional progression; time to CNS progression; time to subsequent treatment; rate of radiation necrosis; rate of local recurrence; and rate of leptomeningeal disease. TRIAL REGISTRATION NUMBER: NCT03750227 (Registration date: 21/11/2018).

The longitudinal risk of hemorrhage of melanoma brain metastases after Gamma Knife radiosurgery.

OBJECTIVE: The objective of this study was to analyze the hemorrhagic risk of melanoma brain metastases after Gamma Knife radiosurgery (GKRS). METHODS: A prospective institutional database was retrospectively queried to identify patients who underwent GKRS for melanoma brain metastases between 1990 and 2021. Lesional hemorrhage was defined as definite or possible based on radiologists' readings, and severity was graded according to Common Terminology Criteria for Adverse Events. RESULTS: Two hundred ninety-one patients with 1083 lesions treated in 419 sessions were identified. The mean (± SD) patient age was 60 ± 15 years, and 61% were male. The median follow-up period for overall survival (OS) was 11 (range 0-214) months with 581 patient-years. Definite/possible lesional hemorrhages occurred in 13% of lesions, with grade 3 hemorrhages observed in 4% of lesions. Surgical intervention was required in 2% of cases (5% of patients), and all resected lesions were pathologically consistent with melanoma. A decreased risk of definite/possible lesional hemorrhage was associated with a later time period between 2015 and 2021 (OR 0.45, 95% CI 0.266-0.75, p = 0.0021), increased marginal dose (OR 0.91, 95% CI 0.83-0.99, p = 0.037), antiplatelet use post-GKRS (OR 0.195, 95% CI 0.083-0.46, p < 0.001), and whole-brain radiotherapy (WBRT; OR 0.53, 95% CI 0.344-0.82, p = 0.0042). After 2015, more patients received anticoagulation, B-Raf proto-oncogene inhibitors, and immune checkpoint inhibitors, and fewer received bevacizumab (p < 0.001). The cumulative risk of lesional hemorrhage was 17%-20% at 36 months from GKRS, with 95%-96% of cases occurring within 12 months. The median patient OS was 11 (95% CI 9-13) months, and multivariate Cox regression analysis revealed that antiplatelet agents (hazard ratio [HR] 0.66, 95% CI 0.45-0.96, p = 0.031) and immune checkpoint inhibitors (HR 0.35, 95% CI 0.26-0.48, p < 0.001) were associated with longer OS, while WBRT (HR 1.36, 95% CI 1.02-1.81, p = 0.037) and definite/possible hemorrhage (HR 1.39, 95% CI 1.04-1.85, p = 0.024) were associated with shorter OS. CONCLUSIONS: The definite hemorrhage risk of melanoma brain metastases after GKRS was 17% in the first 3 years and 95% of the lesional hemorrhage occurred within the 1st year. Surgical intervention was needed in 5% of patients. Antiplatelet agents and immune checkpoint inhibitors were associated with improved OS, while definite/possible hemorrhage was associated with worse OS.

Immunomodulatory drugs have divergent effects on humoral and cellular immune responses to SARS-CoV-2 vaccination in people living with rheumatoid arthritis.

Understanding the efficacy of SARS-CoV-2 vaccination in people on immunosuppressive drugs, including those with rheumatoid arthritis (RA), is critical for their protection. Vaccine induced protection requires antibodies, CD4+ T cells, and CD8+ T cells, but it is unclear if these are equally affected by immunomodulatory drugs. Here, we determined how humoral and cellular SARS-CoV-2 vaccination responses differed between people with RA and controls, and which drug classes impacted these responses. Blood was collected from participants with RA on immunomodulatory drugs and controls after their second, third, and fourth SARS-CoV-2 vaccinations. Receptor binding domain (RBD)-specific antibodies were quantified by ELISA. Spike-specific memory T cells were quantitated using flow cytometry. Linear mixed models assessed the impact of age, sex, and immunomodulatory drug classes on SARS-CoV-2 vaccination responses. Compared to non-RA controls (n = 35), participants with RA on immunomodulatory drugs (n = 62) had lower anti-RBD IgG and spike-specific CD4+ T cell levels, but no deficits in spike-specific CD8+ T cells, following SARS-CoV-2 vaccination. Use of costimulation inhibitors was associated with lower humoral responses. JAK inhibitors were associated with fewer spike-specific CD4+ T cells. Participants with RA on immunomodulatory drugs mounted weaker responses to SARS-CoV-2 vaccination, with different drug classes impacting the cellular and humoral compartments.

Presentation and outcomes of KRASG12C mutant non-small cell lung cancer patients with stage IV disease at diagnosis (de novo) versus at recurrence.

Close monitoring after diagnosis of patients with stage I-III non-small cell lung cancer (NSCLC) may result in fitter patients with lower disease burden at the time of metastatic recurrence or progression compared to patients diagnosed initially as stage IV (de novo). We compared the presentation, treatments, and outcomes of patients with KRASG12C-mutated NSCLC with de novo versus recurrent stage IV disease. Of 109 patients, 94% had a smoking history. When compared to patients with KRASG12C-mutated NSCLC who developed stage IV disease at recurrence (n = 38), de novo stage IV patients (n = 71) had worse ECOG performance status (p = 0.007), greater numbers of extra-thoracic metastatic sites (p = 0.001), and were less likely to receive 2nd/3rd line systemic therapy (p = 0.05, p = 0.002) or targeted therapy (p = 0.001). De novo metastatic patients had shorter overall survival than metastatic patients at recurrence (9.1 versus 24.2 months; adjusted-hazard-ratio=1.94 (95% CI: 1.14-3.28; p = 0.01)). There is a critical need for well-tolerated targeted therapies in the first-line setting for metastatic patients with de novo, high-burden, stage IV KRASG12C-mutated NSCLCs.

Conventional versus hypofractionated postmastectomy proton radiotherapy in the USA (MC1631): a randomised phase 2 trial.

BACKGROUND: Proton therapy is under investigation in breast cancer as a strategy to reduce radiation exposure to the heart and lungs. So far, studies investigating proton postmastectomy radiotherapy (PMRT) have used conventional fractionation over 25-28 days, but whether hypofractionated proton PMRT is feasible is unclear. We aimed to compare conventional fractionation and hypofractionation in patients with indications for PMRT, including those with immediate breast reconstruction. METHODS: We did a randomised phase 2 trial (MC1631) at Mayo Clinic in Rochester (MN, USA) and Mayo Clinic in Arizona (Phoenix, AZ, USA) comparing conventional fractionated (50 Gy in 25 fractions of 2 Gy [relative biological effectiveness of 1·1]) and hypofractionated (40·05 Gy in 15 fractions of 2·67 Gy [relative biological effectiveness of 1·1]) proton PMRT. All patients were treated with pencil-beam scanning. Eligibility criteria included age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0-2, and breast cancer resected by mastectomy with or without immediate reconstruction with indications for PMRT. Patients were randomly assigned (1:1) to either conventional fractionation or hypofractionation, with presence of immediate reconstruction (yes vs no) as a stratification factor, using a biased-coin minimisation algorithm. Any patient who received at least one fraction of protocol treatment was evaluable for the primary endpoint and safety analyses. The primary endpoint was 24-month complication rate from the date of first radiotherapy, defined as grade 3 or worse adverse events occurring from 90 days after last radiotherapy or unplanned surgical interventions in patients with immediate reconstruction. The inferiority of hypofractionation would not be ruled out if the upper bound of the one-sided 95% CI for the difference in 24-month complication rate between the two groups was greater than 10%. This trial is registered with ClinicalTrials.gov, NCT02783690, and is closed to accrual. FINDINGS: Between June 2, 2016, and Aug 23, 2018, 88 patients were randomly assigned (44 to each group), of whom 82 received protocol treatment (41 in the conventional fractionation group and 41 in the hypofractionation group; median age of 52 years [IQR 44-64], 79 [96%] patients were White, two [2%] were Black or African American, one [1%] was Asian, and 79 [96%] were not of Hispanic ethnicity). As of data cutoff (Jan 30, 2023), the median follow-up was 39·3 months (IQR 37·5-61·2). The median mean heart dose was 0·54 Gy (IQR 0·30-0·72) for the conventional fractionation group and 0·49 Gy (0·25-0·64) for the hypofractionation group. Within 24 months of first radiotherapy, 14 protocol-defined complications occurred in six (15%) patients in the conventional fractionation group and in eight (20%) patients in the hypofractionation group (absolute difference 4·9% [one-sided 95% CI 18·5], p=0·27). The complications in the conventionally fractionated group were contracture (five [12%] of 41 patients]) and fat necrosis (one [2%] patient) requiring surgical intervention. All eight protocol-defined complications in the hypofractionation group were due to infections, three of which were acute infections that required surgical intervention, and five were late infections, four of which required surgical intervention. All 14 complications were in patients with immediate expander or implant-based reconstruction. INTERPRETATION: After a median follow-up of 39·3 months, non-inferiority of the hypofractionation group could not be established. However, given similar tolerability, hypofractionated proton PMRT appears to be worthy of further study in patients with and without immediate reconstruction. FUNDING: The Department of Radiation Oncology, Mayo Clinic, Rochester, MN, the Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, USA, and the US National Cancer Institute.

KCCs, NKCCs, and NCC: Potential targets for cardiovascular therapeutics? A comprehensive review of cell and region specific expression and function.

Cardiovascular diseases, the leading life-threatening conditions, involve cardiac arrhythmia, coronary artery disease, myocardial infarction, heart failure, cardiomyopathy, and heart valve disease that are associated with the altered functioning of cation-chloride cotransporters. The decreased number of cation-chloride cotransporters leads to reduced reactivity to adrenergic stimulation. The KCC family is crucial for numerous physiological processes including cell proliferation and invasion, regulation of membrane trafficking, maintaining ionic and osmotic homeostasis, erythrocyte swelling, dendritic spine formation, maturation of postsynaptic GABAergic inhibition, and inhibitory/excitatory signaling in neural tracts. KCC2 maintains intracellular chlorine homeostasis and opposes ß-adrenergic stimulation-induced Cl- influx to prevent arrhythmogenesis. KCC3-inactivated cardiac tissue shows increased vascular resistance, aortic distensibility, heart size and weight (i.e. hypertrophic cardiomyopathy). Due to KCC4's high affinity for K+, it plays a vital role in cardiac ischemia with increased extracellular K+. The NKCC and NCC families play a vital role in the regulation of saliva volume, establishing the potassium-rich endolymph in the cochlea, sodium uptake in astrocytes, inhibiting myogenic response in microcirculatory beds, regulation of smooth muscle tone in resistance vessels, and blood pressure. NKCC1 regulates chlorine homeostasis and knocking it out impairs cardiomyocyte depolarization and cardiac contractility as well as impairs depolarization and contractility of vascular smooth muscle rings in the aorta. The activation of NCC in vascular cells promotes the formation of the abdominal aortic aneurysm. This narrative review provides a deep insight into the structure and function of KCCs, NKCCs, and NCC in human physiology and cardiac pathobiology. Also, it provides cell-specific (21 cell types) and region-specific (6 regions) expression of KCC1, KCC2, KCC3, KCC4, NKCC1, NKCC2, and NCC in heart.

Intensity Modulated Proton Therapy for Bilateral Breast or Chest Wall and Comprehensive Nodal Irradiation for Synchronous Bilateral Breast Cancer: Initial Clinical Experience and Dosimetric Comparison.

Purpose: Synchronous bilateral breast cancer (SBBC) poses distinct challenges for radiation therapy planning. We report our proton therapy experience in treating patients with SBBC. We also provide a dosimetric comparison of intensity modulated proton therapy (IMPT) versus photon therapy. Methods and Materials: Patients with SBBC who received IMPT at our institution were retrospectively analyzed. The clinical target volume (CTV) included the breast or chest wall and comprehensive regional lymph nodes, including axilla, supraclavicular fossa, and the internal mammary chain. Intensity modulated proton therapy and volumetric modulated arc therapy (VMAT) plans were generated with the goal that 90% of the CTV would recieve at least 90% of the prescription dose (D90>=90%). Comparisons between modalities were made using the Wilcoxon signed rank test. Physician-reported acute toxic effects and photography were collected at baseline, end of treatment, and each follow-up visit. Results: Between 2015 and 2018, 11 patients with SBBC were treated with IMPT. The prescription was 50 Gy in 25 fractions. The median CTV D90 was 99.9% for IMPT and 97.6% for VMAT (P = .001). The mean heart dose was 0.7 Gy versus 7.2 Gy (P = .001), the total lung mean dose was 7.8 Gy versus 17.3 Gy (P = .001), and the total lung volume recieving 20 Gy was 13.0% versus 27.4% (P = .001). The most common acute toxic effects were dermatitis (mostly grade 1-2 with 1 case of grade 3) and grade 1 to 2 fatigue. The most common toxic effects at the last-follow up (median, 32 months) were grade 1 skin hyperpigmentation, superficial fibrosis, and extremity lymphedema. No nondermatologic or nonfatigue adverse events of grade >1 were recorded. Conclusions: Bilateral breast and/or chest wall and comprehensive nodal IMPT is technically feasible and associated with low rates of severe acute toxic effects. Treatment with IMPT offered improved target coverage and normal-tissue sparing compared with photon therapy. Long-term follow-up is ongoing to assess efficacy and toxic effects.

The role of single-fraction stereotactic radiosurgery for atypical meningiomas (WHO grade II): treatment results based on a 25-year experience.

PURPOSE: To clarify the role of stereotactic radiosurgery (SRS) for atypical meningiomas (AM). METHODS: A retrospective analysis of 68 patients with AM having SRS from 1995 until 2019. RESULTS: Nineteen patients (28%) had undergone prior external beam radiation therapy (EBRT) (median dose, 54 Gy). The median follow-up period was 52 months. Eighteen (26%), 17 (25%), and 33 (49%) patients received SRS as an upfront adjuvant (≤ 6 months), early salvage (7-18 months), or late salvage treatment (> 18 months), respectively. The 3-, 5-, and 10-year progression-free survivals (PFSs) were 52%, 35%, and 25%, respectively. The 3-, 5-, and 10-year disease-specific survivals were 85%, 78%, and 61%, respectively. Adverse radiation events (AREs) were observed in 12 patients (18%), with increased or new seizures being the most frequent complication (n = 7). Prior EBRT was associated with reduced PFS (HR 5.92, P < 0.01), reduced DSS (HR 5.84, P < 0.01), and an increased risk of ARE (HR 3.31, P = 0.04). Timing of SRS was correlated with reduced PFS for patients having early salvage treatment compared to upfront adjuvant (HR 3.17, P = 0.01) or late salvage treatment (HR 4.39, P < 0.01). CONCLUSION: PFS for patients with residual/recurrent AM remains poor despite SRS. Prior EBRT was associated with worse tumor control, higher tumor-related mortality, and an increased risk of ARE. Further study on the timing of SRS is needed to determine if upfront adjunctive SRS improves tumor control compared to salvage SRS.

Does the dural resection bed need to be irradiated? Patterns of recurrence and implications for postoperative radiotherapy for temporal lobe gliomas.

BACKGROUND: Patterns of recurrence and survival with different surgical and radiotherapy (RT) techniques were evaluated to guide RT target volumes for patients with temporal lobe glioma. METHODS AND MATERIALS: This retrospective cohort study included patients with World Health Organization grades II to IV temporal lobe glioma treated with either partial (PTL) or complete temporal lobectomy (CTL) followed by RT covering both the parenchymal and dural resection bed (whole-cavity radiotherapy [WCRT]) or the parenchymal resection bed only (partial-cavity radiotherapy [PCRT]). Patterns of recurrence, progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Fifty-one patients were included and 84.3% of patients had high-grade glioma (HGG). CTL and PTL were performed for 11 (21.6%) and 40 (78.4%) patients, respectively. Median RT dose was 60 Gy (range, 40-76 Gy). There were 82.4% and 17.6% of patients who received WCRT and PCRT, respectively. Median follow-up time was 18.4 months (range, 4-161 months). Forty-six patients (90.2%) experienced disease recurrence, most commonly at the parenchymal resection bed (76.5%). No patients experienced an isolated dural recurrence. The median PFS and OS for the PCRT and WCRT cohorts were 8.6 vs 10.8 months (P = .979) and 19.9 vs 18.6 months (P = .859), respectively. PCRT was associated with a lower RT dose to the brainstem, optic, and ocular structures, hippocampus, and pituitary. CONCLUSION: We identified no isolated dural recurrence and similar PFS and OS regardless of postoperative RT volume, whereas PCRT was associated with dose reduction to critical structures. Omission of dural RT may be considered a reasonable alternative approach. Further validation with larger comparative studies is warranted.

Initial Results of a Phase 2 Trial of 18F-DOPA PET-Guided Dose-Escalated Radiation Therapy for Glioblastoma.

PURPOSE: Our previous work demonstrated that 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) positron emission tomography (PET) is sensitive and specific for identifying regions of high density and biologically aggressive glioblastoma. The purpose of this prospective phase 2 study was to determine the safety and efficacy of biologic-guided, dose-escalated radiation therapy (DERT) using 18F-DOPA PET in patients with glioblastoma. METHODS AND MATERIALS: Patients with newly diagnosed, histologically confirmed glioblastoma aged ≥18 years without contraindications to 18F-DOPA were eligible. Target volumes included 51, 60, and 76 Gy in 30 fractions with a simultaneous integrated boost, and concurrent and adjuvant temozolomide for 6 months. 18F-DOPA PET imaging was used to guide DERT. The study was designed to detect a true progression-free survival (PFS) at 6 months (PFS6) rate ≥72.5% in O6-methylguanine methyltransferase (MGMT) unmethylated patients (DE-Un), with an overall significance level (alpha) of 0.20 and a power of 80%. Kaplan-Meier analysis was performed for PFS and overall survival (OS). Historical controls (HCs) included 139 patients (82 unmethylated) treated on prospective clinical trials or with standard RT at our institution. Toxicities were evaluated with Common Terminology Criteria for Adverse Events v4.0. RESULTS: Between January 2014 and December 2018, 75 evaluable patients were enrolled (39 DE-Un, 24 methylated [DE-Mth], and 12 indeterminate). PFS6 for DE-Un was 79.5% (95% confidence interval, 63.1%-90.1%). Median PFS was longer for DE-Un patients compared with historical controls (8.7 months vs 6.6 months; P = .017). OS was similarly longer, but the difference was not significant (16.0 vs 13.5 months; P = .13). OS was significantly improved for DE-Mth patients compared with HC-Mth (35.5 vs 23.3 months; P = .049) despite nonsignificant improvement in PFS (10.7 vs 9.0 months; P = .26). Grade 3 central nervous system necrosis occurred in 13% of patients, but treatment with bevacizumab improved symptoms in all cases. CONCLUSIONS: 18F-DOPA PET-guided DERT appears to be safe, and it significantly improves PFS in MGMT unmethylated glioblastoma. OS is significantly improved in MGMT methylated patients. Further investigation of 18F-DOPA PET biologic guided DERT for glioblastoma is warranted.

Health Inequalities During COVID-19 and Their Effects on Morbidity and Mortality.

Inequalities in health have existed for many decades and have led to unjust consequences in morbidity and mortality. These have become even more apparent during the COVID-19 pandemic with individuals from black and minority ethnic groups, poorer socioeconomic backgrounds, urban and rurally deprived locations, and vulnerable groups of society suffering the full force of its effects. This review is highlighting the current disparities that exist within different societies, that subsequently demonstrate COVID-19, does in fact, discriminate against disadvantaged individuals. Also explored in detail are the measures that can and should be taken to improve equality and provide equitable distribution of healthcare resources amongst underprivileged communities.

Reirradiation for Locoregional Recurrent Breast Cancer.

PURPOSE: Reirradiation poses a distinct therapeutic challenge owing to risks associated with exceeding normal tissue tolerances and possibly more therapeutically resistant disease biology. We report our experience with reirradiation for locoregional recurrent or second primary breast cancer. METHODS AND MATERIALS: Between 1999 and 2019, all patients with breast cancer treated with repeat breast/chest wall radiation therapy (RT) at our institution were identified. Adverse events were assessed using the Common Terminology Criteria for Adverse Events v5.0. Fisher exact, Mann-Whitney rank-sum, and unpaired t tests were used for statistical analysis. Freedom from locoregional recurrence and distant metastasis as well as overall survival were calculated using the Kaplan-Meier method. RESULTS: Seventy-two patients underwent reirradiation. Median prior RT dose, reirradiation dose, and cumulative dose were 60 Gy (interquartile range [IQR], 50-60.4 Gy), 45 Gy (IQR, 40-50 Gy), and 103.54 Gy2 (IQR, 95.04-109.62 Gy2), respectively. Median time between RT courses was 73 months (IQR, 29-129 months). Thirty-four patients (47%) had gross residual disease at time of reirradiation. Course intent was described as curative in 44 patients (61%) and palliative in 28 (39%). Fifty-two patients (72%) were treated with photons ± electrons and 20 (28%) with protons. With a median follow-up of 22 months (IQR, 10-43 months), grade 3 adverse events were experienced by 13% of patients (10% acute skin toxicity and 3% late skin necrosis). Time between RT courses and reirradiation fields was significantly associated with the development of grade 3 toxicity at any point. Proton therapy conferred a dosimetric advantage without difference in toxicity. At 2 years, locoregional recurrence-free survival was 74.6% and overall survival was 65.5% among all patients, and 93.1% and 76.8%, respectively, among curative intent patients treated without gross disease. Distant metastasis-free survival was 59.0% among all curative intent patients. CONCLUSIONS: Reirradiation for locoregional recurrent breast cancer is feasible with acceptable rates of toxicity. Disease control and survival are promising among curative intent reirradiation patients without gross disease.

Adjuvant radiation for WHO grade II and III intracranial meningiomas: insights on survival and practice patterns from a National Cancer Registry.

INTRODUCTION: WHO grades II (atypical) and III (malignant) meningiomas are associated with significant morbidity and mortality. The role of adjuvant radiotherapy (RT) in management remains controversial. The goal of this study was to evaluate the impact of adjuvant RT on 5-year survival in patients with atypical and malignant meningiomas. We secondarily aimed to assess contemporary practice patterns and the impact of sociodemographic factors on outcome. METHODS: We queried the National Cancer Database for patients ≥ 18 years of age with cranial atypical or malignant meningiomas from 2010 through 2015 who underwent surgical resection with or without adjuvant radiotherapy. Subjects with unknown WHO grade or radiation status and those not receiving any surgical procedure were excluded from analysis. RESULTS: The study includes 7486 patients, 6788 with atypical and 698 with malignant meningiomas. Overall 5-year survival was 76.9% (95% CI 75.5-78.3%) and 43.3% (95% CI 38.8-48.2%) among patients with WHO grades II and III meningiomas, respectively. Adjuvant RT correlated with improved survival in a multivariable model in patients with grade II tumors (HR 0.78; p = 0.029) regardless of the extent of resection. Age (HR 2.33; p < 0.001), male sex (HR 1.27; p < 0.001), Black race (HR 1.27; p = 0.011) and Charlson-Deyo Score ≥ 2 (1.35; p = 0.001) correlated with poorer survival whereas private insurance (HR 0.71; p < 0.001) correlated with improved survival. Adjuvant RT was also associated with improved 5-year survival among those with grade III tumors on univariate analysis (log-rank p = 0.006) but was underpowered for multivariable modeling. Utilization of adjuvant radiotherapy was only 28.4% and correlated with private insurance status. Academic institutions (25.3%) and comprehensive community cancer programs (21.4%) had lower radiotherapy utilization rates compared with integrated network cancer programs (30.5%) and community cancer programs (29.7%). CONCLUSIONS: Adjuvant RT may correlate with improved overall survival in patients with grades II and III intracranial meningiomas regardless of the extent of resection. There is poor utilization of adjuvant RT for patients with grades II and III meningiomas likely due to a paucity of quality data on the subject. These findings will be strengthened with prospective data evaluating the role of adjuvant RT.

Preliminary exploration of a computerized cognitive battery and comparison with traditional testing in patients with high-grade glioma.

BACKGROUND: Cognitive function is an important outcome measure in many brain tumor clinical trials, and investigators are interested in employing the most efficient methods of cognitive assessment for this purpose. Computerized testing can be appealing because of the perceived ease of use and electronic data generated. Traditional tests may have the advantage of accumulated validity evidence and comparability across historic trials. METHODS: We evaluated feasibility of a Cogstate battery in 39 patients with high-grade glioma, and compared it with a commonly used paper-and-pencil battery. RESULTS: Both batteries were well tolerated and rated equally likeable. Correlations between the batteries were low to low-moderate. More patients showed impairment at baseline and decline across trials on traditional tests. CONCLUSIONS: Both batteries were well tolerated, but the most complicated tasks (from both batteries) could not be completed by all subjects. Preliminary validity evidence for the Cogstate tasks was mixed, but a larger sample is needed.

Contralateral Axillary Metastases in Breast Cancer: Stage IV Disease or a Locoregional Event?

Contralateral axillary metastasis (CAM) in breast cancer is presently treated as a stage IV disease. We hypothesized that this disease pattern is a manifestation of direct aberrant lymphatic drainage and would behave more similar to advanced locoregional disease. This is a single-site, retrospective review of patients with biopsy-proven CAM from 2008-2017. Descriptive analysis was performed. Twenty-three patients met the inclusion criteria. The median disease-free interval from primary tumor treatment to diagnosis of CAM was 68 months (range, 36-155 months). This population had aggressive disease (74% local recurrences and 61% clinical evidence of cutaneous or underlying muscular invasion) and extensive locoregional therapy (70% radiated, 57% mastectomy, and 65% axillary lymph node dissection) before their presentation with CAM. Fifteen (65.2%) patients recurred after treatment of CAM; the median recurrence-free interval was 11 months (range, 5-23 months), and 12 (52.2%) patients developed distant metastases. The median distant metastasis-free survival was 14 months (range, 11-23 months), and the median overall survival was 31 months (range, 22-67.5 months). Development of CAM is associated with aggressive disease and extensive prior locoregional surgery and/or radiation. The short recurrence-free interval and high progression to additional stage IV disease suggest these patients behave similar to traditional stage IV patients with resected oligometastatic disease.

Carbon Fiducial Image Guidance Increases the Accuracy of Lumpectomy Cavity Localization in Radiation Therapy for Breast Cancer.

PURPOSE: We investigated the feasibility and accuracy of using carbon fiducials to localize the lumpectomy cavity with 2-dimensional kV imaging for early stage breast cancer radiation therapy. METHODS AND MATERIALS: Carbon fiducials were placed intraoperatively in the periphery of the lumpectomy cavity. Nine patients received whole breast irradiation with a boost, and 2 patients received 3-dimensional conformal partial breast irradiation. A total of 89 fractions were assessed for setup errors relative to a predefined gold standard, cone beam computed tomography (CBCT) match to the lumpectomy cavity, using the following 4 setup methods: (1) Align skin tattoos with lasers; (2) match bone with 2-dimensional-2-dimensional (2D/2D) kV onboard imaging (OBI); (3) match the whole breast with CBCT; and (4) match carbon fiducials with 2D/2D kV OBI. The margin for the planning target volume (PTV) was calculated by 2 standard deviations of the setup errors, and compared among the 4 setup methods. Setup errors for patients treated with free breathing and patients with deep inspiration breath hold were also compared. RESULTS: The carbon fiducials were sufficiently visible on OBI for matching and introduced minimal artifacts. Of the 4 alignment methods, 2D/2D OBI match to fiducials resulted in the smallest setup errors. The PTV margin was 12 mm for aligning skin tattoos using lasers, 9.2 mm for matching bone on OBI, 6.5 mm for matching breast on CBCT, and 3.5 mm for matching fiducials on 2D/2D OBI. Compared with free breathing, deep inspiration breath hold generally reduced the standard deviations of the setup errors, but further investigation would be needed. CONCLUSIONS: Matching to carbon fiducials increased the localization accuracy to the lumpectomy cavity. This reduces residual setup error and PTV margins, facilitating tissue sparing without diminishing treatment efficacy.

Preoperative Stereotactic Radiosurgery for Brain Metastases.

Stereotactic radiosurgery (SRS) is increasingly utilized to treat the resection cavity following resection of brain metastases and recent randomized trials have confirmed postoperative SRS as a standard of care. Postoperative SRS for resected brain metastases improves local control compared to observation, while also preserving neurocognitive function in comparison to whole brain radiation therapy (WBRT). However, even with surgery and SRS, rates of local recurrence at 1 year may be as high as 40%, especially for larger cavities, and there is also a known risk of leptomeningeal disease after surgery. Additional treatment strategies are needed to improve control while maintaining or decreasing the toxicity profile associated with treatment. Preoperative SRS is discussed here as one such approach. Preoperative SRS allows for contouring of an intact metastasis, as opposed to an irregularly shaped surgical cavity in the post-op setting. Delivering SRS prior to surgery may also allow for a "sterilizing" effect, with the potential to increase tumor control by decreasing intra-operative seeding of viable tumor cells beyond the treated cavity, and decreasing risk of leptomeningeal disease. Because there is no need to treat brain surrounding tumor in the preoperative setting, and since the majority of the high dose volume can then be resected at surgery, the rate of symptomatic radiation necrosis may also be reduced with preoperative SRS. In this mini review, we explore the potential benefits and risks of preoperative vs. postoperative SRS for brain metastases as well as the existing literature to date, including published outcomes with preoperative SRS.

FOXC1, the new player in the cancer sandbox.

In recent years, rapidly accumulating evidence implicates forkhead box C1 (FOXC1) in cancer, especially in studies of basal-like breast cancer (BLBC). Other studies have followed suit, demonstrating that FOXC1 is not only a major player in this breast cancer subtype, but also in hepatocellular carcinoma (HCC), endometrial cancer, Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL). The FOXC1 gene encodes a transcription factor that is crucial to mesodermal, neural crest, and ocular development, and mutations found in FOXC1 have been found to cause dominantly inherited Axenfeld-Rieger Syndrome (ARS). Interestingly, while FOXC1 missense mutations that are associated with ARS usually reduce gene activity, increased FOXC1 function now appears to be often linked to more aggressive cancer phenotypes in BLBC, HCC, HL, and NHL. This review discusses not only the role of FOXC1 in cancer cell progression, proliferation, differentiation, and metastasis, but also the underlying mechanisms of how FOXC1 can contribute to aggressive cancer phenotypes.