Epidemiological connectivity between humans and animals across an urban landscape.

Urbanization is predicted to be a key driver of disease emergence through human exposure to novel, animal-borne pathogens. However, while we suspect that urban landscapes are primed to expose people to novel animal-borne diseases, evidence for the mechanisms by which this occurs is lacking. To address this, we studied how bacterial genes are shared between wild animals, livestock, and humans (n = 1,428) across Nairobi, Kenya-one of the world's most rapidly developing cities. Applying a multilayer network framework, we show that low biodiversity (of both natural habitat and vertebrate wildlife communities), coupled with livestock management practices and more densely populated urban environments, promotes sharing of Escherichia coli-borne bacterial mobile genetic elements between animals and humans. These results provide empirical support for hypotheses linking resource provision, the biological simplification of urban landscapes, and human and livestock demography to urban dynamics of cross-species pathogen transmission at a landscape scale. Urban areas where high densities of people and livestock live in close association with synanthropes (species such as rodents that are more competent reservoirs for zoonotic pathogens) should be prioritized for disease surveillance and control.

Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? A Mendelian randomization study.

Morning-preference chronotype has been found to be protective against breast and prostate cancer. Sex hormones have been implicated in relation to chronotype and the development of both cancers. This study aimed to assess whether sex hormones confound or mediate the effect of chronotype on breast and prostate cancer using a Mendelian Randomization (MR) framework. Genetic variants associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin, and oestradiol) (p<5×10-8) were obtained from published genome-wide association studies (n≤244,207 females and n≤205,527 males). These variants were used to investigate causal relationships with breast (nCases/nControls = 133,384/113,789) and prostate (nCases/nControls = 79,148/61,106) cancer using univariable, bidirectional and multivariable MR. In females, we found evidence for: I) Reduced risk of breast cancer per category increase in morning-preference (OR = 0.93, 95% CI:0. 88, 1.00); II) Increased risk of breast cancer per SD increase in bioavailable testosterone (OR = 1.10, 95% CI: 1.01, 1.19) and total testosterone (OR = 1.15, 95% CI:1.07, 1.23); III) Bidirectional effects between morning-preference and both bioavailable and total testosterone (e.g. mean SD difference in bioavailable testosterone = -0.08, 95% CI:-0.12, -0.05 per category increase in morning-preference vs difference in morning-preference category = -0.04, 95% CI: -0.08, 0.00 per SD increase in bioavailable testosterone). In males, we found evidence for: I) Reduced risk of prostate cancer per category increase in morning-preference (OR = 0.90, 95% CI: 0.83, 0.97) and II) Increased risk of prostate cancer per SD increase in bioavailable testosterone (OR = 1.22, 95% CI: 1.08, 1.37). No bidirectional effects were found between morning-preference and testosterone in males. While testosterone levels were causally implicated with both chronotype and cancer, there was inconsistent evidence for testosterone as a mediator of the relationship. The protective effect of morning-preference on both breast and prostate cancer is clinically interesting, although it may be difficult to effectively modify chronotype. Further studies are needed to investigate other potentially modifiable intermediates.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

Drivers of habitat availability for terrestrial mammals: Unravelling the role of livestock, land conversion and intrinsic traits in the past 50 years.

The global decline of terrestrial species is largely due to the degradation, loss and fragmentation of their habitats. The conversion of natural ecosystems for cropland, rangeland, forest products and human infrastructure are the primary causes of habitat deterioration. Due to the paucity of data on the past distribution of species and the scarcity of fine-scale habitat conversion maps, however, accurate assessment of the recent effects of habitat degradation, loss and fragmentation on the range of mammals has been near impossible. We aim to assess the proportions of available habitat within the lost and retained parts of mammals' distribution ranges, and to identify the drivers of habitat availability. We produced distribution maps for 475 terrestrial mammals for the range they occupied 50 years ago and compared them to current range maps. We then calculated the differences in the percentage of 'area of habitat' (habitat available to a species within its range) between the lost and retained range areas. Finally, we ran generalized linear mixed models to identify which variables were more influential in determining habitat availability in the lost and retained parts of the distribution ranges. We found that 59% of species had a lower proportion of available habitat in the lost range compared to the retained range, thus hypothesizing that habitat loss could have contributed to range declines. The most important factors negatively affecting habitat availability were the conversion of land to rangeland and high density of livestock. Significant intrinsic traits were those related to reproductive timing and output, habitat breadth and medium body size. Our findings emphasize the importance of implementing conservation strategies to mitigate the impacts caused by human activities on the habitats of mammals, and offer evidence indicating which species have the potential to reoccupy portions of their former range if other threats cease to occur.

Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

Preclinical assessment of novel longer-duration wear negative pressure wound therapy dressing in a porcine model.

While reticulated open cell foam (ROCF) is a well-established dressing for negative pressure wound therapy (NPWT), there is the known potential for granulation tissue ingrowth if left in place for longer than 72 h. This may cause wound bed disruption, bleeding, and pain upon dressing removal. In addition, any retained foam fragments may elicit an adverse tissue reaction. A novel, easy to use dressing designed to utilise the advantages of ROCF while addressing its challenges has recently been created. This 7 day study investigated the utility of a novel NPWT dressing under longer-duration wear circumstances while assessing the prevalence of tissue ingrowth and ease of dressing removal in full-thickness excisional wounds utilising a porcine model. Histopathology and morphometry evaluations indicated thicker granulation tissue with, depending on the parameters assessed, either comparable or better tissue quality for wounds treated with the novel dressing. Greater re-epithelialization levels were also evident compared with ROCF. Three-dimensional imaging analysis indicated faster wound fill with a corresponding decrease in wound area with the novel dressing. Furthermore, tissue ingrowth was limited to only ROCF-treated wounds, which was not unexpected in this longer-duration wear study. The force required to remove the novel dressing was considerably lower compared with ROCF, correlating to the tissue ingrowth results. Results of this study illustrate that the novel dressing provided more favourable wound healing results compared with traditional ROCF. In addition, reduction in the risk of tissue ingrowth and low dressing peel force may allow it to be used as a longer-wear dressing.

Genomic epidemiology of Escherichia coli: antimicrobial resistance through a One Health lens in sympatric humans, livestock and peri-domestic wildlife in Nairobi, Kenya.

BACKGROUND: Livestock systems have been proposed as a reservoir for antimicrobial-resistant (AMR) bacteria and AMR genetic determinants that may infect or colonise humans, yet quantitative evidence regarding their epidemiological role remains lacking. Here, we used a combination of genomics, epidemiology and ecology to investigate patterns of AMR gene carriage in Escherichia coli, regarded as a sentinel organism. METHODS: We conducted a structured epidemiological survey of 99 households across Nairobi, Kenya, and whole genome sequenced E. coli isolates from 311 human, 606 livestock and 399 wildlife faecal samples. We used statistical models to investigate the prevalence of AMR carriage and characterise AMR gene diversity and structure of AMR genes in different host populations across the city. We also investigated household-level risk factors for the exchange of AMR genes between sympatric humans and livestock. RESULTS: We detected 56 unique acquired genes along with 13 point mutations present in variable proportions in human and animal isolates, known to confer resistance to nine antibiotic classes. We find that AMR gene community composition is not associated with host species, but AMR genes were frequently co-located, potentially enabling the acquisition and dispersal of multi-drug resistance in a single step. We find that whilst keeping livestock had no influence on human AMR gene carriage, the potential for AMR transmission across human-livestock interfaces is greatest when manure is poorly disposed of and in larger households. CONCLUSIONS: Findings of widespread carriage of AMR bacteria in human and animal populations, including in long-distance wildlife species, in community settings highlight the value of evidence-based surveillance to address antimicrobial resistance on a global scale. Our genomic analysis provided an in-depth understanding of AMR determinants at the interfaces of One Health sectors that will inform AMR prevention and control.

Concurrent prescribing of opioids with other sedating medications after cancer diagnosis: a population-level analysis.

PURPOSE: Cancer is a major reason for concurrent prescription of opioids with other sedating medications-particularly benzodiazepines and gabapentinoids-yet population-based assessments of the extent and predictors of concurrent prescribing among clinically and demographically diverse patients with cancer are lacking. METHODS: We conducted a retrospective cohort study of patients with non-metastatic cancer using North Carolina cancer registry data linked with Medicare and private insurance claims (2013-2016). We used modified Poisson regression to assess associations of patient characteristic with adjusted relative risk (aRR) of new concurrent prescribing of opioids with benzodiazepines or gabapentinoids after diagnosis. RESULTS: Overall, 15% of patients were concurrently prescribed opioids with benzodiazepines or gabapentinoids. Characteristics independently associated with an increased risk of concurrent prescribing included cancer type (e.g., aRR cervical vs. colorectal cancer: 1.55, 95% CI: 1.12-2.14); prior use of opioids (aRR: 2.43, 95% CI:2.21-2.67), benzodiazepines (aRR: 4.08, 95% CI: 3.72-4.48), or gabapentinoids (3.82, 95% CI: 3.31-4.39), and premorbid mental health conditions, including substance use disorder (aRR: 1.27, 95% CI: 1.05-1.54). Black and Hispanic patients were less likely to experience concurrent prescribing (aRR, Black vs. White: 0.35, 95% CI: 0.15-0.83; aRR, Hispanic vs. White: 0.75, 95% CI: 0.66-0.85). CONCLUSION: Approximately 1 in 7 patients with cancer was concurrently prescribed opioids with other sedating medications. Associations between patient characteristics and risk of concurrent prescribing highlight predictors of concurrent prescribing and suggest a rationale for systematic assessment of substance use history at diagnosis. Future research could explore inequitable pain and symptom management and investigate risk of adverse medication-related events.

Invited review: Current enteric methane mitigation options.

Ruminant livestock are an important source of anthropogenic methane (CH4). Decreasing the emissions of enteric CH4 from ruminant production is strategic to limit the global temperature increase to 1.5°C by 2050. Research in the area of enteric CH4 mitigation has grown exponentially in the last 2 decades, with various strategies for enteric CH4 abatement being investigated: production intensification, dietary manipulation (including supplementation and processing of concentrates and lipids, and management of forage and pastures), rumen manipulation (supplementation of ionophores, 3-nitrooxypropanol, macroalgae, alternative electron acceptors, and phytochemicals), and selection of low-CH4-producing animals. Other enteric CH4 mitigation strategies are at earlier stages of research but rapidly developing. Herein, we discuss and analyze the current status of available enteric CH4 mitigation strategies with an emphasis on opportunities and barriers to their implementation in confined and partial grazing production systems, and in extensive and fully grazing production systems. For each enteric CH4 mitigation strategy, we discuss its effectiveness to decrease total CH4 emissions and emissions on a per animal product basis, safety issues, impacts on the emissions of other greenhouse gases, as well as other economic, regulatory, and societal aspects that are key to implementation. Most research has been conducted with confined animals, and considerably more research is needed to develop, adapt, and evaluate antimethanogenic strategies for grazing systems. In general, few options are currently available for extensive production systems without feed supplementation. Continuous research and development are needed to develop enteric CH4 mitigation strategies that are locally applicable. Information is needed to calculate carbon footprints of interventions on a regional basis to evaluate the impact of mitigation strategies on net greenhouse gas emissions. Economically affordable enteric CH4 mitigation solutions are urgently needed. Successful implementation of safe and effective antimethanogenic strategies will also require delivery mechanisms and adequate technical support for producers, as well as consumer involvement and acceptance. The most appropriate metrics should be used in quantifying the overall climate outcomes associated with mitigation of enteric CH4 emissions. A holistic approach is required, and buy-in is needed at all levels of the supply chain.

Socio-ecological drivers of vertebrate biodiversity and human-animal interfaces across an urban landscape.

Urbanization can have profound impacts on the distributional ecology of wildlife and livestock, with implications for biodiversity conservation, ecosystem services and human health. A wealth of studies have assessed biotic responses to urbanization in North America and Europe, but there is little empirical evidence that directly links human activities to urban biodiversity in the tropics. Results from a large-scale field study conducted in Nairobi, Kenya, are used to explore the impact of human activities on the biodiversity of wildlife and livestock with which humans co-exist across the city. The structure of sympatric wildlife, livestock and human populations are characterized using unsupervised machine learning, and statistical modelling is used to relate compositional variation in these communities to socio-ecological drivers occurring across the city. By characterizing landscape-scale drivers acting on these interfaces, we demonstrate that socioeconomics, elevation and subsequent changes in habitat have measurable impacts upon the diversity, density and species assemblage of wildlife, livestock and humans. Restructuring of wildlife and livestock assemblages (both in terms of species diversity and composition) has important implications for the emergence of novel diseases at urban interfaces, and we therefore use our results to generate a set of testable hypotheses that explore the influence of urban change on microbial communities. These results provide novel insight into the impact of urbanization on biodiversity in the tropics. An understanding of associations between urban processes and the structure of human and animal populations is required to link urban development to conservation efforts and risks posed by disease emergence to human health, ultimately informing sustainable urban development policy.

Trastuzumab Emtansine (T-DM1) and stereotactic radiation in the management of HER2+ breast cancer brain metastases.

BACKGROUND: Due to recent concerns about the toxicity of trastuzumab emtansine (T-DM1) with stereotactic radiation, we assessed our institutional outcomes treating HER2-positive breast cancer brain metastases (BCBM) with T-DM1 and stereotactic radiation. METHODS: This is a single institution series of 16 patients with HER2-positive breast cancer who underwent 18 stereotactic sessions to 40 BCBM from 2013 to 2019 with T-DM1 delivered within 6 months. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), distant intracranial control (DIC), and systemic progression-free survival (sPFS) from the date of SRS. A neuro-radiologist independently reviewed follow-up imaging. RESULTS: One patient had invasive lobular carcinoma, and 15 patients had invasive ductal carcinoma. All cases were HER2-positive, while 10 were hormone receptor (HR) positive. Twenty-four lesions were treated with stereotactic radiosurgery (SRS) to a median dose of 21 Gy (14-24 Gy). Sixteen lesions were treated with fractionated stereotactic radiation (FSRT) with a median dose of 25 Gy (20-30Gy) delivered in 3 to 5 fractions. Stereotactic radiation was delivered concurrently with T-DM1 in 19 lesions (48%). Median follow up time was 13.2 months from stereotactic radiation. The 1-year LC, DIC, sPFS, and OS were 75, 50, 30, and 67%, respectively. There was 1 case of leptomeningeal progression and 1 case (3%) of symptomatic radionecrosis. CONCLUSIONS: We demonstrate that stereotactic radiation and T-DM1 is well-tolerated and effective for patients with HER2-positive BCBM. An increased risk for symptomatic radiation necrosis was not noted in our series.

Capecitabine and stereotactic radiation in the management of breast cancer brain metastases.

BACKGROUND: Little is known about the safety and efficacy of concurrent capecitabine and stereotactic radiotherapy in the setting of breast cancer brain metastases (BCBM). METHODS: Twenty-three patients with BCBM underwent 31 stereotactic sessions to 90 lesions from 2005 to 2019 with receipt of capecitabine. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of stereotactic radiation. Imaging was independently reviewed by a neuro-radiologist. RESULTS: Median follow-up from stereotactic radiation was 9.2 months. Receptor types of patients treated included triple negative (n = 7), hormone receptor (HR)+/HER2- (n = 7), HR+/HER2+ (n = 6), and HR-/HER2+ (n = 3). Fourteen patients had stage IV disease prior to BCBM diagnosis. The median number of brain metastases treated per patient was 3 (1 to 12). The median dose of stereotactic radiosurgery (SRS) was 21 Gy (range: 15-24 Gy) treated in a single fraction and for lesions treated with fractionated stereotactic radiation therapy (FSRT) 25 Gy (24-30 Gy) in a median of 5 fractions (range: 3-5). Of the 31 stereotactic sessions, 71% occurred within 1 month of capecitabine. No increased toxicity was noted in our series with no cases of radionecrosis. The 1-year OS, LC, and DIC were 46, 88, and 30%, respectively. CONCLUSIONS: In our single institution experience, we demonstrate stereotactic radiation and capecitabine to be a safe treatment for patients with BCBM with adequate LC. Further study is needed to determine the potential synergy between stereotactic radiation and capecitabine in the management of BCBM.

Breast cancer subtype predicts clinical outcomes after stereotactic radiation for brain metastases.

PURPOSE: We investigated the prognostic ability of tumor subtype for patients with breast cancer brain metastases (BCBM) treated with stereotactic radiation (SRT). METHODS: This is a retrospective review of 181 patients who underwent SRT to 664 BCBM from 2004 to 2019. Patients were stratified by subtype: hormone receptor (HR)-positive, HER2-negative (HR+/HER2-), HR-positive, HER2-positive (HR+/HER2+), HR-negative, HER2-positive (HR-/HER2+), and triple negative (TN). The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of SRT. Multivariate analysis (MVA) was conducted using the Cox proportional hazards model. RESULTS: Median follow up from SRT was 11.4 months. Of the 181 patients, 47 (26%) were HR+/HER2+, 30 (17%) were HR-/HER2+, 60 (33%) were HR+/HER2-, and 44 (24%) were TN. Of the 664 BCBMs, 534 (80%) received single fraction stereotactic radiosurgery (SRS) with a median dose of 21 Gy (range 12-24 Gy), and 130 (20%) received fractionated stereotactic radiation therapy (FSRT), with a median dose of 25 Gy (range 12.5-35 Gy) delivered in 3 to 5 fractions. One-year LC was 90%. Two-year DIC was 35%, 23%, 27%, and 16% (log rank, p = 0.0003) and 2-year OS was 54%, 47%, 24%, and 12% (log rank, p < 0.0001) for HR+/HER2+, HR-/HER2+, HR+/HER2-, and TN subtypes, respectively. On MVA, the TN subtype predicted for inferior DIC (HR 1.62, 95% CI 1.00-2.60, p = 0.049). The modified breast-Graded Prognostic Assessment (GPA) significantly predicted DIC and OS (both p < 0.001). CONCLUSIONS: Subtype is prognostic for OS and DIC for patients with BCBM treated with SRT.

Gonadal-sparing total body irradiation with the use of helical tomotherapy for nonmalignant indications.

BACKGROUND: The aim was to demonstrate the feasibility and technique of gonadal sparing total body irradiation (TBI) with helical tomotherapy. Total body irradiation is a common part of the conditioning regimen prior to allogeneic stem cell transplantation. Shielding or dose-reduction to the gonads is often desired to preserve fertility, particularly in young patients undergoing transplant for non-malignant indications. Helical tomotherapy (HT) has been shown to be superior to traditional TBI delivery for organ at risk (OA R) doses and dose homogeneity. MATERIALS AND METHODS: We present two representative cases (one male and one female) to illustrate the feasibility of this technique, each of whom received 3Gy in a single fraction prior to allogeneic stem cell transplant for benign indications. The planning target volume (PTV) included the whole body with a subtraction of OA Rs including the lungs, heart, and brain (each contracted by 1cm) as well as the gonads (testicles expanded by 5 cm and ovaries expanded by 0.5 cm). RESULTS: For the male patient we achieved a homogeneity index of 1.35 with a maximum and median planned dose to the testes of 0.53 Gy and 0.35 Gy, respectively. In-vivo dosimetry demonstrated an actual received dose of 0.48 Gy. For the female patient we achieved a homogeneity index of 1.13 with a maximum and median planned dose to the ovaries of 1.66 Gy and 0.86 Gy, respectively. CONCLUSION: Gonadal sparing TBI is feasible and deliverable using HT in patients with non-malignant diseases requiring TBI as part of a pre-stem cell transplant conditioning regimen.

Mendelian randomisation analysis of circulating adipokines and C-reactive protein on breast cancer risk.

Circulating adipokines and C-reactive protein (CRP) have been linked to breast cancer risk in observational epidemiological studies. The causal nature of these associations is unclear because of the susceptibility of conventional observational designs to residual confounding, reverse causation and other forms of bias. Mendelian randomisation (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational settings. We performed a MR analysis to evaluate the causal relevance of six previously reported circulating adipokines [adiponectin, hepatocyte growth factor (HGF), interleukin-6, leptin receptor, plasminogen activator inhibitor-1 and resistin] and CRP in risk of overall and oestrogen receptor-stratified breast cancer in up to 122,977 cases and 105,974 controls of European ancestry. Genetic instruments were constructed from single-nucleotide polymorphisms robustly (p < 5 × 10-8 ) associated with risk factors in genome-wide association studies. Colocalisation was performed as a sensitivity analysis to examine whether findings reflected shared causal variants or genomic confounding. In MR analyses, there was evidence for an association of HGF with oestrogen receptor-negative cancer (odds ratio per standard deviation increase: 1.17, 95% confidence interval: 1.01-1.35; p = 0.035) but little evidence for associations of other adipokines or CRP with overall or oestrogen receptor-stratified breast cancer. Colocalisation analysis suggested that the association of HGF with oestrogen receptor-negative breast cancer was unlikely to reflect a causal association. Collectively, these findings do not support an important aetiological role of various adipokines or CRP in overall or oestrogen receptor-specific breast cancer risk.

Clinical outcomes of breast leptomeningeal disease treated with intrathecal trastuzumab, intrathecal chemotherapy, or whole brain radiation therapy.

PURPOSE: Leptomeningeal disease is a rare presentation of advanced metastatic breast cancer. The purpose of this study was to evaluate craniospinal progression between intrathecal (IT) trastuzumab, IT chemotherapy, and whole brain radiation therapy (WBRT) in leptomeningeal disease. METHODS: A total of 56 patients were identified with breast cancer leptomeningeal disease at our institution treated with IT trastuzumab (n = 18; 32%), single-agent IT chemotherapy (methotrexate n = 14 or thiotepa n = 1; 27%), or WBRT alone (n = 23; 41%). Patients were treated beginning November 2012 and followed until November 2018. RESULTS: Median time from breast cancer diagnosis to development of leptomeningeal disease was 4.3 years. There were no significant differences noted between IT trastuzumab, IT chemotherapy, or WBRT groups in age (p = 0.4), Karnofsky Performance Status (KPS) (p = 0.07), or receipt of systemic therapy at time of leptomeningeal disease treatment (p = 0.47). Median follow-up of patients from leptomeningeal diagnosis was 5 months (range 0.2-81.1 months). Significant differences were noted in Kaplan-Meier (KM) craniospinal progression-free survival (CS-PFS) with 6-month rates of 44%, 18%, and 26% (p = 0.04) between IT trastuzumab, IT chemotherapy, and WBRT, respectively. Craniospinal control > 10 months was achieved in four patients treated with IT trastuzumab. Twelve-month KM OS rates were 54%, 10%, and 19% (p = 0.01) between IT trastuzumab, IT chemotherapy, and WBRT groups, respectively. IT therapy was adequately tolerated with three patients undergoing treatment-related hospitalizations. CONCLUSIONS: In our institutional series, significant differences were noted in CS-PFS and OS by treatment modality. IT trastuzumab should be considered in the management HER2+ breast leptomeningeal disease.

CDK 4/6 inhibitors and stereotactic radiation in the management of hormone receptor positive breast cancer brain metastases.

PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors are becoming increasingly utilized in the setting of advanced, hormone receptor (HR+) positive breast cancer. Pre-clinical data suggests a potential synergy between radiation therapy (RT) and CDK4/6 inhibitors. We assessed clinical outcomes of patients treated at our institution with the use of CDK4/6 inhibitors and stereotactic radiation in the management of HR+ breast brain metastases. METHODS: A retrospective analysis of patients who received stereotactic radiotherapy for HR+ brain metastases within 6 months of CDK4/6 inhibitor administration was performed. The primary endpoint was neurotoxicity during or after stereotactic radiation. Secondary endpoints were local brain control, distant brain control, and overall survival (OS). RESULTS: A total of 42 lesions treated with stereotactic radiation in 15 patients were identified. Patients received either palbociclib (n = 10; 67%) or abemaciclib (n = 5; 33%). RT was delivered concurrently, before, or after CDK4/6 inhibitors in 18 (43%), 9 (21%), and 15 (36%) lesions, respectively. Median follow-up following stereotactic radiation was 9 months. Two lesions (5%) developed radionecrosis, both of which received four prior RT courses to the affected lesion prior to onset of radionecrosis and subsequently managed with steroids and bevacizumab. Six- and 12-month local control of treated lesions was 88% and 88%, while 6- and 12-month distant brain control was 61% and 39%, respectively. Median OS was 36.7 months from the date of brain metastases diagnosis. CONCLUSIONS: Stereotactic radiation to breast brain metastases was well tolerated alongside CDK4/6 inhibitors. Compared to historical data, brain metastases control rates are similar whereas survival appears prolonged.

Comparison of Anal Versus Rectal Staging in the Prognostication of Rectal Squamous Cell Carcinoma: A Population-Based Analysis.

BACKGROUND: Rectal squamous cell carcinoma is a rare malignancy with limited data regarding management and prognosis. It is also unknown whether a rectal squamous cell cancer staging system should be based on size, as for anal squamous cell carcinoma, or depth of invasion, as for rectal adenocarcinoma. OBJECTIVE: The aims of the current study were to determine the optimal management strategy, prognostic factors, and staging system for rectal squamous cell carcinoma. DESIGN: This was a population-based study. SETTINGS: The Surveillance, Epidemiology, and End Results database was used to identify patents diagnosed between 1988 and 2013. PATIENTS: Patients ≥18 years of age undergoing radiation or local excision alone, radiation with local excision, or radiation with radical resection were included. Patients were then staged according to both the American Joint Committee on Cancer classification for rectal adenocarcinoma (American Joint Committee on Cancer-rectum) and anal cancer (American Joint Committee on Cancer-anus). MAIN OUTCOME MEASURES: The main outcome was 5-year, disease-specific survival. RESULTS: In both univariate and multivariate survival analyses, the addition of local excision or radical resection to radiation resulted in similar-to-worse outcomes across all of the stages. Among patients staged according to American Joint Committee on Cancer-rectum (n = 1646), although a significant difference in 5-year survival was observed for stage I as compared with higher stages, no difference was noted between stages II and III (80% vs 61% and 62%). However, in the American Joint Committee on Cancer-anus classification (n = 1327), a significant difference was observed across all of the stages (87% vs 72% vs 59%; p < 0.001). In multivariate analysis, the prognostic discrimination based on HRs provided by the American Joint Committee on Cancer-anus was superior to that of the American Joint Committee on Cancer-rectum. LIMITATIONS: This study was limited by lack of data on chemotherapy and location of positive nodes. CONCLUSIONS: A treatment approach primarily based on radiation should be considered the optimal management strategy for rectal squamous cell carcinoma. Moreover, a staging system based on size (American Joint Committee on Cancer-anus) rather than on depth of invasion (American Joint Committee on Cancer-rectum) appears to be more accurate in predicting its prognosis. See Video Abstract at http://links.lww.com/DCR/A734.

Changing Geographic Patterns and Risk Factors for Avian Influenza A(H7N9) Infections in Humans, China.

The fifth epidemic wave of avian influenza A(H7N9) virus in China during 2016-2017 demonstrated a geographic range expansion and caused more human cases than any previous wave. The factors that may explain the recent range expansion and surge in incidence remain unknown. We investigated the effect of anthropogenic, poultry, and wetland variables on all epidemic waves. Poultry predictor variables became much more important in the last 2 epidemic waves than they were previously, supporting the assumption of much wider H7N9 transmission in the chicken reservoir. We show that the future range expansion of H7N9 to northern China may increase the risk of H7N9 epidemic peaks coinciding in time and space with those of seasonal influenza, leading to a higher risk of reassortments than before, although the risk is still low so far.

Intrathecal trastuzumab in the management of HER2+ breast leptomeningeal disease: a single institution experience.

PURPOSE: Leptomeningeal disease is a rare and devastating presentation of advanced stage metastatic breast cancer with historically poor overall survival. We assessed the safety and feasibility of intrathecal (IT) trastuzumab in HER2+ leptomeningeal disease. METHODS: A total of 13 patients were treated at our institution with IT trastuzumab beginning November 2012 and followed until November 2017. Outcomes including craniospinal progression as well as overall survival (OS) following initiation of IT trastuzumab were assessed from review of the clinical chart and radiologic examinations. RESULTS: The median age of patients was 48 (range 29-75). Median time from breast cancer diagnosis to development of brain metastases was 87.7 months with a median of 4.6 months from brain metastases diagnosis to the development of leptomeningeal disease. Previous whole brain radiotherapy was received by the majority of patients (92%) and prior surgery for brain metastases was performed in 23%. Median duration of IT trastuzumab treatment was 6.4 months. Median time from IT trastuzumab start to craniospinal progression was 5.7 months with 6- and 12-month Kaplan-Meier rates of 41 and 21%, respectively. Sustained responses > 6 months were achieved in 4 patients. Median survival from the start of IT trastuzumab was 10.6 months with 6- and 12-month OS rates of 68 and 47%, respectively. IT trastuzumab was well tolerated with one patient developing ventriculitis, which resolved with IV antibiotics. CONCLUSIONS: IT trastuzumab was well tolerated with prolongation of OS over historical controls. IT trastuzumab should be considered for management of HER2+ leptomeningeal disease patients.