Leveraging a natural murine meiotic drive to suppress invasive populations.

Invasive rodents are a major cause of environmental damage and biodiversity loss, particularly on islands. Unlike insects, genetic biocontrol strategies including population-suppressing gene drives with biased inheritance have not been developed in mice. Here, we demonstrate a gene drive strategy (tCRISPR) that leverages super-Mendelian transmission of the t haplotype to spread inactivating mutations in a haplosufficient female fertility gene (Prl). Using spatially explicit individual-based in silico modeling, we show that tCRISPR can eradicate island populations under a range of realistic field-based parameter values. We also engineer transgenic tCRISPR mice that, crucially, exhibit biased transmission of the modified t haplotype and Prl mutations at levels our modeling predicts would be sufficient for eradication. This is an example of a feasible gene drive system for invasive alien rodent population control.

Therapeutic Role of Tamoxifen for Triple-Negative Breast Cancer: Leveraging the Interaction Between ERß and Mutant p53.

The absence of effective therapeutic targets and aggressive nature of triple-negative breast cancer (TNBC) renders this disease subset difficult to treat. Although estrogen receptor beta (ERß) is expressed in TNBC, studies on its functional role have yielded inconsistent results. However, recently, our preclinical studies, along with other observations, have shown the potential therapeutic utility of ERß in the context of mutant p53 expression. The current case study examines the efficacy of the selective estrogen receptor modulator tamoxifen in p53-mutant TNBC with brain metastases. Significant increase in ERß protein expression and anti-proliferative interaction between mutant p53 and ERß were observed after cessation of tamoxifen therapy, with significant regression of brain metastases. This case study provides supporting evidence for the use of tamoxifen in p53-mutant, ERß+TNBC, especially in the setting of brain metastasis.

Artificial intelligence modelling in differentiating core biopsies of fibroadenoma from phyllodes tumor.

Breast fibroepithelial lesions (FEL) are biphasic tumors which consist of benign fibroadenomas (FAs) and the rarer phyllodes tumors (PTs). FAs and PTs have overlapping features, but have different clinical management, which makes correct core biopsy diagnosis important. This study used whole-slide images (WSIs) of 187 FA and 100 PT core biopsies, to investigate the potential role of artificial intelligence (AI) in FEL diagnosis. A total of 9228 FA patches and 6443 PT patches was generated from WSIs of the training subset, with each patch being 224 × 224 pixel in size. Our model employed a two-stage architecture comprising a convolutional neural network (CNN) component for feature extraction from the patches, and a recurrent neural network (RNN) component for whole-slide classification using activation values from the global average pooling layer in the CNN model. It achieved an overall slide-level accuracy of 87.5%, with accuracies of 80% and 95% for FA and PT slides respectively. This affirms the potential role of AI in diagnostic discrimination between FA and PT on core biopsies which may be further refined for use in routine practice.

Axes of multivariate sexual signal divergence among incipient species: Concordance with selection, genetic variation and phenotypic plasticity.

Sexual signalling traits are often observed to diverge rapidly among populations, thereby playing a potentially key early role in the evolution of reproductive isolation. While often assumed to reflect divergent sexual selection among populations, patterns of sexual trait diversification might sometimes be biased along axes of standing additive genetic variation and covariation among trait components. Additionally, theory predicts that environmentally induced phenotypic variation might facilitate rapid trait evolution, suggesting that patterns of divergence between populations should mirror phenotypic plasticity within populations. Here, we evaluate the concordance between observed axes of multivariate sexual trait divergence and predicted divergence based on (1) interpopulation variation in sexual selection, (2) additive genetic variances and (3) temperature-related phenotypic plasticity in male courtship song among geographically isolated populations of the Hawaiian swordtail cricket, Laupala cerasina, which exhibit sexual isolation due acoustic signalling traits. The major axis of multivariate divergence, dmax , accounted for 76% of variation among population male song trait means and was moderately correlated with interpopulation differences in directional sexual selection based on female preferences. However, the majority of additive genetic variance was largely oriented away from the direction of divergence, suggesting that standing genetic variation may not play a dominant role in the patterning of signal divergence. In contrast, the axis of phenotypic plasticity strongly mirrored patterns of interpopulation phenotypic divergence, which is consistent with a role for temperature-related plasticity in facilitating instead of inhibiting male song evolution and sexual isolation in these incipient species. We propose potential mechanisms by which sexual selection might interact with phenotypic plasticity to facilitate the rapid acoustic diversification observed in this species and clade.

Neurologic complications of melanoma.

Neurologic complications are common in patients with melanoma and are often associated with a poor prognosis. In an era with new, effective treatments, patients are living longer, and this has resulted in an increase in complications of both the disease and the therapy. A multidisciplinary approach to neurologic complications in patients with melanoma, with involvement from medical oncology, neuro-oncology, radiation oncology, and often neurosurgery, is necessary. In this review, neurologic complications of melanoma, including clinical implications and treatment strategies, are described.

Early experience with hippocampal avoidance whole brain radiation therapy and simultaneous integrated boost for brain metastases.

PURPOSE: Cranial irradiation results in cognitive decline, which is hypothesized to be partially attributable to hippocampal injury and stem cell loss. Recent advances allow for targeted reduction of radiation dose to the hippocampi while maintaining adequate dose coverage to the brain parenchyma and additional increasing dose to brain metastases, a approach called hippocampal avoidance whole brain radiation therapy with a simultaneous integrated boost (HA-WBRT + SIB.) We review our early clinical experience with HA-WBRT + SIB. MATERIALS AND METHODS: We evaluated treatments and clinical outcomes for patients treated with HA-WBRT + SIB between 2014 and 2018. RESULTS: A total of 32 patients (median age, 63.5 years, range 45.3-78.8 years) completed HA-WBRT + SIB. Median follow-up for patients alive at the time of analysis was 11.3 months. The most common histology was non-small cell lung cancer (n = 22). Most patients (n = 25) were prescribed with WBRT dose of 30 Gy with SIB to 37.5 Gy in 15 fractions. Volumetric modulated arc therapy reduced treatment time (p < 0.0001). Median freedom from intracranial progression and overall survival from completion of treatment were 11.4 months and 19.6 months, respectively. Karnofsky Performance Status was associated with improved survival (p = 0.008). The most common toxicities were alopecia, fatigue, and nausea. Five patients developed cognitive impairment, including grade 1 (n = 3), grade 2 (n = 1), and grade 3 (n = 1). CONCLUSION: HA-WBRT + SIB demonstrated durable intracranial disease control with modest side effects and merits further investigation as a means of WBRT toxicity reduction while improving long-term locoregional control in the brain.

Upfront Surgical Resection of Melanoma Brain Metastases Provides a Bridge Toward Immunotherapy-Mediated Systemic Control.

BACKGROUND: Immune checkpoint blockade has systemic efficacy in patients with metastatic melanoma, including those with brain metastases (MBMs). However, immunotherapy-induced intracranial tumoral inflammation can lead to neurologic compromise, requiring steroids, which abrogate the systemic efficacy of this approach. We investigated whether upfront neurosurgical resection of MBM is associated with a therapeutic advantage when performed prior to initiation of immunotherapy. MATERIAL AND METHODS: An institutional review board-approved, retrospective study identified 142 patients with MBM treated with immune checkpoint blockade between 2010 and 2016 at Massachusetts General Hospital, of whom 79 received surgery. Patients were classified based on the temporal relationship between immunotherapy, surgery, and development of central nervous system metastases. Overall survival (OS) was calculated from the date of diagnosis of MBM until death from any cause. Multivariate model building included a prognostic Cox model of OS, the effect of immunotherapy and surgical sequencing on OS, and the effect of immunotherapy and radiation sequencing on OS. RESULTS: The 2-year overall survival for patients treated with cytotoxic T-lymphocyte antigen 4, programmed death 1, or combinatorial blockade was 19%, 54%, and 57%, respectively. Among immunotherapy-naïve melanoma brain metastases, surgery followed by immunotherapy had a median survival of 22.7 months (95% confidence interval [CI], 12.6-39.2) compared with 10.8 months for patients treated with immunotherapy alone (95% CI, 7.8-16.3) and 9.4 months for patients treated with immunotherapy followed by surgery (95% CI, 4.1 to ∞; p = .12). On multivariate analysis, immunotherapy-naïve brain metastases treated with immunotherapy alone were associated with increased risk of death (hazard ratio, 1.72; 95% CI, 1.00-2.99) compared with immunotherapy-naïve brain metastases treated with surgery followed by immunotherapy. CONCLUSION: In treatment-naïve patients, early surgical resection for local control should be considered prior to commencing immunotherapy. A prospective, randomized trial comparing the sequence of surgery and immunotherapy for treatment-naïve melanoma brain metastases is warranted. IMPLICATIONS FOR PRACTICE: In this retrospective study of 142 patients with melanoma brain metastases treated with immune checkpoint blockade, the development of melanoma brain metastases following immunotherapy was associated with decreased survival compared with diagnosis of immunotherapy-naïve brain metastases. The benefit of surgical intervention was seen in immunotherapy-naïve brain metastases in contrast to brain metastases that developed on immunotherapy. These results suggest that upfront local control with surgery for immunotherapy-naïve melanoma brain metastasis may provide a bridge toward immunotherapy-mediated systemic control.

Enrichment of HER2 Amplification in Brain Metastases from Primary Gastrointestinal Malignancies.

BACKGROUND: In nongastric gastrointestinal (GI) cancers, HER2-positive (HER2+) disease is not common. In breast cancer, HER2 status is associated with increased risk of brain metastases and response to HER2-targeted therapy. The purpose of this project was to compare HER2 status in GI cancer brain metastases versus matched prior sites of disease in order to determine if HER2+ disease is more common intracranially. MATERIALS AND METHODS: We identified 28 patients with GI cancer who had craniotomy for brain metastases between 1999 and 2017 with intracranial metastatic tissue available at Massachusetts General Hospital. Twenty-four patients also had tissue from a prior site of disease. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for HER2 were performed on all samples. A tumor was defined as HER2+ if it had 3+ staining by IHC or amplification by FISH. RESULTS: A prior site of disease (including intracranial metastases) was HER2+ for 13% of evaluable patients: 3 of 11 patients with colorectal cancer and no patients with esophageal or pancreatic cancer. The most recent brain metastases were HER2+ for 32% of patients: 2 of 3 esophageal squamous cell carcinomas, 3 of 10 esophageal adenocarcinomas (ACs), 3 of 14 colorectal ACs, and 1 of 1 pancreatic AC. Only 37.5% of patients with HER2+ brain metastasis had concordant HER2+ prior tissue (κ = 0.38, p = .017). CONCLUSION: In this cohort of patients with GI cancer with brain metastases, HER2+ status was more common intracranially compared with prior sites of disease. These findings suggest that testing HER2 in patients with GI cancer with brain metastases may lead to additional therapeutic options, regardless of HER2 status in previously examined tissue. IMPLICATIONS FOR PRACTICE: HER2 amplification is a well-known driver of oncogenesis in breast cancer, with associated increased risk of brain metastases and response to HER2-directed therapy. In nongastric gastrointestinal (GI) cancers, HER2 amplification is not common and consequently is infrequently tested. The current study shows that brain metastases in patients with GI primary malignancies have a relatively high likelihood of being HER2 positive despite HER2 amplification or overexpression being less commonly found in matched tissue from prior sites of disease. This suggests that regardless of prior molecular testing, patients with GI cancer with brain metastases who have tissue available are likely to benefit from HER2 assessment to identify potential novel therapeutic options.

Parallel genomic architecture underlies repeated sexual signal divergence in Hawaiian Laupala crickets.

When the same phenotype evolves repeatedly, we can explore the predictability of genetic changes underlying phenotypic evolution. Theory suggests that genetic parallelism is less likely when phenotypic changes are governed by many small-effect loci compared to few of major effect, because different combinations of genetic changes can result in the same quantitative outcome. However, some genetic trajectories might be favoured over others, making a shared genetic basis to repeated polygenic evolution more likely. To examine this, we studied the genetics of parallel male mating song evolution in the Hawaiian cricket Laupala. We compared quantitative trait loci (QTL) underlying song divergence in three species pairs varying in phenotypic distance. We tested whether replicated song divergence between species involves the same QTL and whether the likelihood of QTL sharing is related to QTL effect size. Contrary to theoretical predictions, we find substantial parallelism in polygenic genetic architectures underlying repeated song divergence. QTL overlapped more frequently than expected based on simulated QTL analyses. Interestingly, QTL effect size did not predict QTL sharing, but did correlate with magnitude of phenotypic divergence. We highlight potential mechanisms driving these constraints on cricket song evolution and discuss a scenario that consolidates empirical quantitative genetic observations with micro-mutational theory.

Rodent gene drives for conservation: opportunities and data needs.

Invasive rodents impact biodiversity, human health and food security worldwide. The biodiversity impacts are particularly significant on islands, which are the primary sites of vertebrate extinctions and where we are reaching the limits of current control technologies. Gene drives may represent an effective approach to this challenge, but knowledge gaps remain in a number of areas. This paper is focused on what is currently known about natural and developing synthetic gene drive systems in mice, some key areas where key knowledge gaps exist, findings in a variety of disciplines relevant to those gaps and a brief consideration of how engagement at the regulatory, stakeholder and community levels can accompany and contribute to this effort. Our primary species focus is the house mouse, Mus musculus, as a genetic model system that is also an important invasive pest. Our primary application focus is the development of gene drive systems intended to reduce reproduction and potentially eliminate invasive rodents from islands. Gene drive technologies in rodents have the potential to produce significant benefits for biodiversity conservation, human health and food security. A broad-based, multidisciplinary approach is necessary to assess this potential in a transparent, effective and responsible manner.

Increase of pseudoprogression and other treatment related effects in low-grade glioma patients treated with proton radiation and temozolomide.

INTRODUCTION: Concurrent radiotherapy and temozolomide (TMZ) is associated with radiographic pseudoprogression (PsP) in glioblastoma. The occurrence of PsP and other treatment effects is less well understood in low-grade gliomas (LGG). The purpose of this study is to evaluate whether the addition of TMZ to radiotherapy increases the incidence of PsP in adults with LGG treated with proton radiotherapy (PRT). METHODS: Chart review and volumetric MRI-analysis was performed on radiotherapy-naive adults with WHO grade II or IDH mutant WHO grade III gliomas treated with PRT between 2005 and 2015. Progression was defined by histology, new chemotherapy initiation, or progressive increase in lesion volume beyond 40% from baseline. Post treatment related effects (PTRE) were defined as new/increased T2/FLAIR or abnormal enhancement which eventually resolved or stabilized without evidence of progression for a period of 6-12 months. PsP was defined as the subset of PRTE suspicious for progression or volumetrically increased at least 40% from baseline. Pearson's chi-squared test and Cox-proportional hazards models were used for statistical analysis. RESULTS: There were 119 patients meeting inclusion criteria. There was an increased risk of PsP following PRT + TMZ versus PRT-alone (HR = 2.2, p = 0.006, on Cox univariate analysis). Presence of PsP was associated with improved OS (p = 0.02 with PsP as time-varying covariate). CONCLUSIONS: TMZ use, when added to PRT, was associated with increased PsP in patients with LGG; however, patients with PsP tended to achieve longer survival.

The impact of timing of immunotherapy with cranial irradiation in melanoma patients with brain metastases: intracranial progression, survival and toxicity.

Immunotherapy (IT) is increasingly incorporated in the management of metastatic melanoma patients with brain metastases, but the impact of timing of IT with stereotactic radiosurgery (SRS) remains unclear. The aim of this study was to determine the temporal significance of IT in melanoma patients treated with cranial radiation therapy (RT) with respect to patterns of intracranial progression, overall survival (OS), and toxicity. We retrospectively reviewed consecutive melanoma patients with brain metastases undergoing cranial RT and IT between 2008 and 2015. Concurrent IT/RT was defined as IT administration within 30 days of RT. Intracranial progression, OS and radionecrosis were assessed. We identified 74 patients with 136 treated brain metastases. Median OS was 13.9 months. Performance status, pre-SRS surgery, and intracranial progression were correlated with OS. Concurrent IT/RT was used in 35 (47.3%) patients. Patients receiving concurrent IT/RT were less likely to have a BRAF mutation (p = 0.027) and more likely to be treated after 2013 (p = 0.010) compared to non-concurrently treated patients. Patients receiving concurrent IT/RT were more likely to have intracranial progression within 60-days (54.3% vs. 30.8%, p = 0.041). However, 25.7% of concurrent IT/RT patients attained ≥ 1 year intracranial progression-free survival. There were no significant differences in symptomatic radionecrosis (11.4% vs. 12.8%, p = 0.67). In conclusion, although melanoma patients with brain metastases receiving concurrent IT/RT were more likely to exhibit early intracranial disease progression, a significant proportion of non-early-progressors attained durable intracranial control. The combination of IT and cranial RT appears to be efficacious and safe. Prospective studies are required to clarify these retrospective findings.

Neurocognitive effects of proton radiation therapy in adults with low-grade glioma.

To understand neurocognitive effects of proton radiation therapy (PRT) in patients with low-grade glioma, we evaluated 20 patients who received this therapy prospectively and over 5 years with a comprehensive neuropsychological battery. 20 patients were evaluated at baseline and at yearly intervals for up to 5 years with a battery of neuropsychological measures that assessed intellectual, attention, executive, visuospatial and memory functions as well as mood and functional status. We evaluated change in cognitive functioning over time. We analyzed the relationship between cognitive performance and tumor location and also examined whether patients' performance differed from that reported in a study of normative practice effects. Overall, patients exhibited stability in cognitive functioning. Tumor location played a role in performance; those with tumors in the left hemisphere versus in the right hemisphere were more impaired at baseline on verbal measures (p < .05). However, we found greater improvement in verbal memory over time in patients with left than with right hemisphere tumors (p < .05). Results of our study, the first to investigate, in depth, neurocognitive effects of PRT in adults with low-grade gliomas, are promising. We hypothesize that the conformal advantage of PRT may contribute to preservation of cognitive functioning, although larger sample sizes and a longer period of study are required. Our study also highlights the need to consider normative practice effects when studying neurocognitive functioning in response to treatment over time, and the need to utilize comprehensive neuropsychological batteries given our findings that differentiate patients with left and right hemisphere tumors.

Proton therapy for low-grade gliomas: Results from a prospective trial.

BACKGROUND: In this prospective study, the authors evaluated potential treatment toxicity and progression-free survival in patients with low-grade glioma who received treatment with proton radiation therapy. METHODS: Twenty patients with World Health Organization grade 2 glioma who were eligible for radiation therapy were enrolled in a prospective, single-arm trial of proton therapy. The patients received proton therapy at a dose of 54 Gy (relative biological effectiveness) in 30 fractions. Comprehensive baseline and regular post-treatment evaluations of neurocognitive function, neuroendocrine function, and quality of life (QOL) were performed. RESULTS: All 20 patients (median age, 37.5 years) tolerated treatment without difficulty. The median follow-up after proton therapy was 5.1 years. At baseline, intellectual functioning was within the normal range for the group and remained stable over time. Visuospatial ability, attention/working memory, and executive functioning also were within normal limits; however, baseline neurocognitive impairments were observed in language, memory, and processing speed in 8 patients. There was no overall decline in cognitive functioning over time. New endocrine dysfunction was detected in 6 patients, and all but 1 had received direct irradiation of the hypothalamic-pituitary axis. QOL assessment revealed no changes over time. The progression-free survival rate at 3 years was 85%, but it dropped to 40% at 5 years. CONCLUSIONS: Patients with low-grade glioma tolerate proton therapy well, and a subset develops neuroendocrine deficiencies. There is no evidence for overall decline in cognitive function or QOL.

Management of patients with recurrence of diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

TARGET POPULATION: These recommendations apply to adult patients with recurrent low-grade glioma (LGG) with initial pathologic diagnosis of a WHO grade II infiltrative glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). QUESTION: Do pathologic and molecular characteristics predict outcome/malignant transformation at recurrence? RECOMMENDATIONS: IDH STATUS AND RECURRENCE: (Level III) IDH mutation status should be determined as LGGs with IDH mutations have a shortened time to recurrence. It is unclear whether knowledge of IDH mutation status provides benefit in predicting time to progression or overall survival. TP53 STATUS AND RECURRENCE: (Level III) TP53 mutations occur early in LGG pathogenesis, remain stable, and are not recommended as a marker of predisposition to malignant transformation at recurrence or other measures of prognosis. MGMT STATUS AND RECURRENCE: (Level III) Assessment of MGMT status is recommended as an adjunct to assessing prognosis as LGGs with MGMT promoter methylation are associated with shorter PFS (in the absence of TMZ) and longer post-recurrence survival (in the presence of TMZ), ultimately producing similar overall survival to LGGs without MGMT methylation. The available retrospective reports are conflicting and comparisons between reports are limited CDK2NA STATUS AND RECURRENCE: (Level III) Assessment of CDK2NA status is recommended when possible as the loss of expression of the CDK2NA via either methylation or loss of chromosome 9p is associated with malignant progression of LGGs. PROLIFERATIVE INDEX AND RECURRENCE: (Level III) It is recommended that proliferative indices (MIB-1 or BUdR) be measured in LGGs as higher proliferation indices are associated with increased likelihood of recurrence and shorter progression free and overall survival. 1P/19Q STATUS AND RECURRENCE: There is insufficient evidence to make any recommendations. QUESTION: What role does chemotherapy have in LGG recurrence? RECOMMENDATIONS: TEMOZOLOMIDE AND RECURRENCE: (Level III) Temozolomide is recommended in the therapy of recurrent LGG as it may improve clinical symptoms. Oligodendrogliomas and tumors with 1p/19q co-deletion may derive the most benefit. PCV AND RECURRENCE: (Level III) PCV is recommended in the therapy of LGG at recurrence as it may improve clinical symptoms with the strongest evidence being for oligodendrogliomas. CARBOPLATIN AND RECURRENCE : (Level III) Carboplatin is not recommended as there is no significant benefit from carboplatin as single agent therapy for recurrent LGGs. OTHER TREATMENTS (NITROSUREAS, HYDROXYUREA/IMANITIB, IRINOTECAN, PACLITAXEL) AND RECURRENCE: There is insufficient evidence to make any recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess these chemotherapeutic agents. QUESTION: What role does radiation have in LGG recurrence? RECOMMENDATIONS: RADIATION AT RECURRENCE WITH NO PREVIOUS IRRADIATION: (Level III) Radiation is recommended at recurrence if there was no previous radiation treatment. RE-IRRADIATION AT RECURRENCE: (Level III) It is recommended that re-irradiation be considered in the setting of LGG recurrence as it may provide benefit in disease control. SURGERY AT RECURRENCE: There is insufficient evidence to make any specific recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess the role of surgery at recurrence.

Survival patterns following brain metastases for patients with melanoma in the MAP-kinase inhibitor era.

Survival with BRAF-mutant metastatic melanoma is prolonged with MAP-kinase pathway inhibitors (MAPKi). Among patients with brain metastases (BM), however, the clinical course of MAPKi-treated patients is not well described. We therefore explored these patients' survival patterns compared to contemporary patients not treated with MAPKi. We analyzed 106 patients who developed melanoma BM between 2007 and 2013. Of these, 37 (35%) received de novo MAPKi for BRAF-mutant disease, which preceded BM in 49%. Immunotherapy was given to 54% of MAPKi-treated patients and 94% of those who did not receive MAPKi. We evaluated the potential influence of patient characteristics, systemic therapies, and BM-directed treatments on time to appearance of new BM and overall survival. With a median follow-up of 8.0 months after initial BM, MAPKi use was an independent predictor of prolonged survival after BM diagnosis (median 14.1 vs 7.0 months, P = 0.03, adjusted hazard ratio 0.39). This survival advantage was driven by the 16.6-month median survival of patients who initiated MAPKi after BM were diagnosed, versus 5.6 months if initiated prior to BM development (P = 0.03). Median survival from the onset of any systemic metastases was 22 months regardless of the timing of MAPKi relative to BM appearance. Time to in-brain progression was longer among patients whose MAPKi course was started after BM diagnosis, but MAPKi initiation prior to BM diagnosis was associated with longer time to intracranial involvement. These findings are consistent with potential MAPKi activity in intracranial melanoma.

Underutilization of radiation therapy in patients with glioblastoma: predictive factors and outcomes.

BACKGROUND: Randomized trials have demonstrated that radiation improves survival in patients with glioblastoma. The purpose of this study was to characterize the risk factors and impact of omission of radiation therapy in such patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) program was used to identify 22,777 patients diagnosed with glioblastoma between 1988 and 2007. Multivariable logistic regression was employed to identify predictors associated with omission of radiation. Cox regression was used to characterize the impact of omitting radiation on all-cause mortality. RESULTS: Among the entire cohort, 16,863 of 22,777 patients (74%) received radiation, whereas 5914 of 22,777 patients (26%) did not. Factors associated with omission of radiation included older age (OR=1.048 per year increase, 95% CI=1.046-1.051, P<.001), lower annual income (OR=0.93 per $10,000 increase, 95% CI=0.90-0.96, P<.001), African American race (reference=white, OR=1.19, 95% CI=1.03-1.37, P=.02), Hispanic race (OR=1.34, 95% CI=1.19-1.50, P< .001), Asian American race (OR=1.24, 95% CI=1.04-1.48, P<.001), unmarried status (OR=1.71, 95% CI=1.60-1.83, P< .001), and subtotal resection/biopsy (OR=1.82, 95% CI=1.69-1.96, P<.001). The use of radiation was significantly associated with improved overall survival (2-year survival: 14.6% versus 4.2%, P<.001; adjusted HR=2.09, 95% CI=2.02-2.16, P<.001). When the population was restricted to patients <50 years old, these findings remained largely unchanged. CONCLUSIONS: Radiation therapy is associated with survival benefit in patients with glioblastoma, and sociodemographic factors play a significant role in the underutilization of radiation. The underlying causes for these disparities in care require further research.

Exploring patterns of female house mouse spatial organisation among outbreaking and stable populations.

The size and distribution of home ranges reflect how individuals within a population use, defend, and share space and resources, and may thus be an important predictor of population-level dynamics. Eruptive species, such as the house mouse in Australian grain-growing regions, are an ideal species in which to investigate variations in space use and home range overlap between stable and outbreaking populations. In this study, we use spatially explicit capture-recapture models to explore if space use and home range overlap among female mice could serve as indicators of changes in population density leading into summer. Additionally, we assess the sensitivity of space use and home range estimates to reduced recapture rates. Our analysis did not reveal variations in the spring spatial organisation of female mice based on existing capture-mark-recapture data. However, our study highlights the need to balance monitoring efforts within regions, emphasising the importance of exploring studies that can improve spatial recaptures by optimising trapping efforts. This is particularly important in Australian agricultural systems, where varying farm management practices may drive differences in population dynamics.

Survival in Patients With Spinal Metastatic Disease Treated Nonoperatively With Radiotherapy: Are the SORG-ML Algorithms Relevant?

SUMMARY OF BACKGROUND DATA: The SORG-ML algorithms for survival in spinal metastatic disease were developed in patients who underwent surgery and were externally validated for patients managed operatively. OBJECTIVE: To externally validate the SORG-ML algorithms for survival in spinal metastatic disease in patients managed nonoperatively with radiation. STUDY DESIGN: Retrospective cohort. METHODS: The performance of the SORG-ML algorithms was assessed by discrimination [receiver operating curves and area under the receiver operating curve (AUC)], calibration (calibration plots), decision curve analysis, and overall performance (Brier score). The primary outcomes were 90-day and 1-year mortality. RESULTS: Overall, 2074 adult patients underwent radiation for spinal metastatic disease and 29% (n=521) and 59% (n=917) had 90-day and 1-year mortality, respectively. On complete case analysis (n=415), the AUC was 0.76 (95% CI: 0.71-0.80) and 0.78 (95% CI: 0.73-0.83) for 90-day and 1-year mortality with fair calibration and positive net benefit confirmed by the decision curve analysis. With multiple imputation (n=2074), the AUC was 0.85 (95% CI: 0.83-0.87) and 0.87 (95% CI: 0.85-0.89) for 90-day and 1-year mortality with fair calibration and positive net benefit confirmed by the decision curve analysis. CONCLUSION: The SORG-ML algorithms for survival in spinal metastatic disease generalize well to patients managed nonoperatively with radiation.

Multivariate sexual selection in a rapidly evolving speciation phenotype.

Estimating the fitness surface of rapidly evolving secondary sexual traits can elucidate the origins of sexual isolation and thus speciation. Evidence suggests that sexual selection is highly complex in nature, often acting on multivariate sexual characters that sometimes include non-heritable components of variation, thus presenting a challenge for predicting patterns of sexual trait evolution. Laupala crickets have undergone an explosive species radiation marked by divergence in male courtship song and associated female preferences, yet patterns of sexual selection that might explain this diversification remain unknown. We used female phonotaxis trials to estimate the fitness surface for acoustic characters within one population of Laupala cerasina, a species with marked geographical variation in male song and female preferences. Results suggested significant directional sexual selection on three major song traits, while canonical rotation of the matrix of nonlinear selection coefficients (γ) revealed the presence of significant convex (stabilizing) sexual selection along combinations of characters. Analysis of song variation within and among males indicated significantly higher repeatability along the canonical axis of greatest stabilizing selection than along the axis of greatest linear selection. These results are largely consistent with patterns of song divergence that characterize speciation and suggest that different song characters have the potential to indicate distinct information to females during courtship.