The Alzheimer's Knowledge Base: A Knowledge Graph for Alzheimer Disease Research.

BACKGROUND: As global populations age and become susceptible to neurodegenerative illnesses, new therapies for Alzheimer disease (AD) are urgently needed. Existing data resources for drug discovery and repurposing fail to capture relationships central to the disease's etiology and response to drugs. OBJECTIVE: We designed the Alzheimer's Knowledge Base (AlzKB) to alleviate this need by providing a comprehensive knowledge representation of AD etiology and candidate therapeutics. METHODS: We designed the AlzKB as a large, heterogeneous graph knowledge base assembled using 22 diverse external data sources describing biological and pharmaceutical entities at different levels of organization (eg, chemicals, genes, anatomy, and diseases). AlzKB uses a Web Ontology Language 2 ontology to enforce semantic consistency and allow for ontological inference. We provide a public version of AlzKB and allow users to run and modify local versions of the knowledge base. RESULTS: AlzKB is freely available on the web and currently contains 118,902 entities with 1,309,527 relationships between those entities. To demonstrate its value, we used graph data science and machine learning to (1) propose new therapeutic targets based on similarities of AD to Parkinson disease and (2) repurpose existing drugs that may treat AD. For each use case, AlzKB recovers known therapeutic associations while proposing biologically plausible new ones. CONCLUSIONS: AlzKB is a new, publicly available knowledge resource that enables researchers to discover complex translational associations for AD drug discovery. Through 2 use cases, we show that it is a valuable tool for proposing novel therapeutic hypotheses based on public biomedical knowledge.

American Radium Society Appropriate Use Criteria for the use of liver-directed therapies for nonsurgical management of liver metastases: Systematic review and guidelines.

The liver is a common site of cancer metastases. Systemic therapy is widely accepted as the standard treatment for liver metastases (LM), although select patients with liver oligometastases may be candidates for potentially curative liver resection. Recent data support the role of nonsurgical local therapies such as ablation, external beam radiotherapy, embolization, and hepatic artery infusion therapy for management of LM. Additionally, for patients with advanced, symptomatic LM, local therapies may provide palliative benefit. The American Radium Society gastrointestinal expert panel, including members representing radiation oncology, interventional radiology, surgical oncology, and medical oncology, performed a systemic review and developed Appropriate Use Criteria for the use of nonsurgical local therapies for LM. Preferred Reporting Items for Systematic reviews and Meta-Analyses methodology was used. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in seven representative clinical scenarios through a well-established consensus methodology (modified Delphi). A summary of recommendations is outlined to guide practitioners on the use of nonsurgical local therapies for patients with LM.

Environmental enrichment leads to behavioral circadian shifts enhancing brain-wide functional connectivity between sensory cortices and eliciting increased hippocampal spiking.

Environmental enrichment induces widespread neuronal changes, but the initiation of the cascade is unknown. We ascertained the critical period of divergence between environmental enriched (EE) and standard environment (SE) mice using continuous infrared (IR) videography, functional magnetic resonance imaging (fMRI), and neuron level calcium imaging. Naïve adult male mice (n = 285, C57BL/6J, postnatal day 60) were divided into SE and EE groups. We assessed the linear time-series of motion activity using a novel structural break test which examined the dataset for change in circadian and day-by-day motion activity. fMRI was used to map brain-wide response using a functional connectome analysis pipeline. Awake calcium imaging was performed on the dorsal CA1 pyramidal layer. We found the preeminent behavioral feature in EE was a forward shift in the circadian rhythm, prolongation of activity in the dark photoperiod, and overall decreased motion activity. The crepuscular period of dusk was seen as the critical period of divergence between EE and SE mice. The functional processes at dusk in EE included increased functional connectivity in the visual cortex, motor cortex, retrosplenial granular cortex, and cingulate cortex using seed-based analysis. Network based statistics found a modulated functional connectome in EE concentrated in two hubs: the hippocampal formation and isocortical network. These hubs experienced a higher node degree and significant enhanced edge connectivity. Calcium imaging revealed increased spikes per second and maximum firing rate in the dorsal CA1 pyramidal layer, in addition to location (anterior-posterior and medial-lateral) effect size differences between EE and SE. The emergence of functional-neuronal changes due to enrichment consisted of enhanced hippocampal-isocortex functional connectivity and CA1 neuronal increased spiking linked to a circadian shift during the dusk period. Future studies should explore the molecular consequences of enrichment inducing shifts in the circadian period.

Hearing loss impacts gray and white matter across the lifespan: Systematic review, meta-analysis and meta-regression.

Hearing loss is a heterogeneous disorder thought to affect brain reorganization across the lifespan. Here, structural alterations of the brain due to hearing loss are assessed by using unique effect size metrics based on Cohen's d and Hedges' g. These metrics are used to map coordinates of gray matter (GM) and white matter (WM) alterations from bilateral congenital and acquired hearing loss populations. A systematic review and meta-analysis revealed m = 72 studies with structural alterations measured with magnetic resonance imaging (MRI) (bilateral = 64, unilateral = 8). The bilateral studies categorized hearing loss into congenital and acquired cases (n = 7,445) and control cases (n = 2,924), containing 66,545 datapoint metrics. Hearing loss was found to affect GM and underlying WM in nearly every region of the brain. In congenital hearing loss, GM decreased most in the frontal lobe. Similarly, acquired hearing loss had a decrease in frontal lobe GM, albeit the insula was most decreased. In congenital, WM underlying the frontal lobe GM was most decreased. In congenital, the right hemisphere was more negatively impacted than the left hemisphere; however, in acquired, this was the opposite. The WM alterations most frequently underlined GM alterations in congenital hearing loss, while acquired hearing loss studies did not frequently assess the WM metric. Future studies should use the endophenotype of hearing loss as a prognostic template for discerning clinical outcomes.

Contemporary prostate cancer treatment choices in multidisciplinary clinics referenced to national trends.

BACKGROUND: The purpose of this study was to assess treatment choices among men with prostate cancer who presented at The University of Texas MD Anderson Cancer Center multidisciplinary (MultiD) clinic compared with nationwide trends. METHODS: In total, 4451 men with prostate cancer who presented at the MultiD clinic from 2004 to 2016 were analyzed. To assess nationwide trends, the authors analyzed 392,710 men with prostate cancer who were diagnosed between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. The primary endpoint was treatment choice as a function of pretreatment demographics. RESULTS: Univariate analyses revealed similar treatment trends in the MultiD and SEER cohorts. The use of procedural forms of definitive therapy decreased with age, including brachytherapy and prostatectomy (all P < .05). Later year of diagnosis/clinic visit was associated with decreased use of definitive treatments, whereas higher risk grouping was associated with increased use (all P < .001). Patients with low-risk disease treated at the MultiD clinic were more likely to receive nondefinitive therapy than patients in SEER, whereas the opposite trend was observed for patients with high-risk disease, with a substantial portion of high-risk patients in SEER not receiving definitive therapy. In the MultiD clinic, African American men with intermediate-risk and high-risk disease were more likely to receive definitive therapy than white men, but for SEER the opposite was true. CONCLUSIONS: Presentation at a MultiD clinic facilitates the appropriate disposition of patients with low-risk disease to nondefinitive strategies of patients with high-risk disease to definitive treatment, and it may obviate the influence of race.

One-Year Swallowing Outcomes in Patients Treated with Prophylactic Gabapentin During Radiation-Based Treatment for Oropharyngeal Cancer.

Recent investigations by our study team have demonstrated patients using gabapentin for pain management during chemoradiotherapy (CRT) do well maintaining swallowing during treatment with less need for narcotic pain medication, PEG dependence, weight loss, and short-term swallowing morbidity. The purpose of this investigation was to characterize the long-term swallowing function of these patients 1-year following treatment. Sequential patients receiving CRT for oropharyngeal cancer and concurrent gabapentin were evaluated 1-year following treatment for swallowing outcomes. Functional Oral Intake Scores (FOIS) were utilized to assess diet level. The MD Anderson Dysphagia Inventory (MDADI) was chosen to evaluate patient perception of swallowing function. Videofluoroscopic swallowing studies were completed approximately 1 year after treatment to assess physiologic outcomes as well as Penetration Aspiration Scores (PAS). Data from 26 consecutive participants were available for analysis. The majority of patients had advanced stage disease (Stage 3-4). No patients had a PEG tube 1-year following treatment, and the mean FOIS score was 6.83. Pharyngeal deficits were infrequent with reduced pharyngeal constriction and prominence/early closure of cricopharyngeus predominating. Mean PAS score was 1.5, indicating that the majority of patients had either no laryngeal penetration/aspiration, or transient penetration that was fully cleared. Mean MDADI score was 85.52, indicating that, in general, patients perceived their swallowing to be minimally impaired. Patients receiving gabapentin pain management as part of a comprehensive dysphagia prevention protocol during CRT have excellent long-term swallowing outcomes as reflected in diet levels, physiologic functioning, and patient-perceived quality of life.

ACR Appropriateness Criteria® Borderline and Unresectable Pancreas Cancer.

The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature and voted on five variants to establish appropriate recommended treatment of borderline and unresectable pancreatic cancer. The guidelines reviewed the use of radiation, chemotherapy, and surgery. Radiation technique, dose, and targets were evaluated, as was the recommended chemotherapy, administered either alone or concurrently with radiation. This report will aid clinicians in determining guidelines for the optimal treatment of borderline and unresectable pancreatic cancer.

Predictive Factors for Prophylactic Percutaneous Endoscopic Gastrostomy (PEG) Tube Placement and Use in Head and Neck Patients Following Intensity-Modulated Radiation Therapy (IMRT) Treatment: Concordance, Discrepancies, and the Role of Gabapentin.

The prophylactic placement of a percutaneous endoscopic gastrostomy (PEG) tube in the head and neck cancer (HNC) patient is controversial. We sought to identify factors associated with prophylactic PEG placement and actual PEG use. Since 2010, data regarding PEG placement and use were prospectively recorded in a departmental database from January 2010 to December 2012. HNC patients treated with intensity-modulated radiation therapy (IMRT) were retrospectively evaluated from 2010 to 2012. Variables potentially associated with patient post-radiation dysphagia from previous literature, and our experience was evaluated. We performed multivariate logistic regression on these variables with PEG placement and PEG use, respectively, to compare the difference of association between the two arms. We identified 192 HNC patients treated with IMRT. Prophylactic PEG placement occurred in 121 (63.0 %) patients, with PEG use in 97 (80.2 %) patients. PEG placement was associated with male gender (p < .01), N stage ≥ N2 (p < .05), pretreatment swallowing difficulties (p < .01), concurrent chemotherapy (p < .01), pretreatment KPS ≥80 (p = .01), and previous surgery (p = .02). Concurrent chemotherapy (p = .03) was positively associated with the use of PEG feeding by the patient, whereas pretreatment KPS ≥80 (p = .03) and prophylactic gabapentin use (p < .01) were negatively associated with PEG use. The analysis suggests there were discrepancies between prophylactic PEG tube placement and actual use. Favorable pretreatment KPS, no pretreatment dysphagia, no concurrent chemotherapy, and the use of gabapentin were significantly associated with reduced PEG use. This analysis may help refine the indications for prophylactic PEG placement.

ACR Appropriateness Criteria® Resectable Stomach Cancer.

For resectable gastric cancer, perioperative chemotherapy or adjuvant chemoradiation with chemotherapy are standards of care. The decision making for adjuvant therapeutic management can depend on the stage of the cancer, lymph node positivity, and extent of surgical resection. After gastric cancer resection, postoperative chemotherapy combined with chemoradiation should be incorporated in cases of D0 lymph node dissection, positive regional lymph nodes, poor clinical response to induction chemotherapy, or positive margins. In the setting of a D2 lymph node dissection, especially those with negative regional lymph nodes, adjuvant chemotherapy alone could be considered. The American College of Radiology (ACR) Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review includes an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

The Effect of Radiation Dose on Swallowing: Evaluation of Aspiration and Kinematics.

Radiation oncologists have focused on the pharyngeal constrictors as the primary muscles of concern for dysphagia. However, our prior investigations have demonstrated that radiation dose to the geniohyoid rather than the constrictor muscles was more closely related to penetration aspiration scores (PAS). We examined the relationship between (1) radiation dose and swallowing temporal kinematics, and (2) between PAS and swallowing kinematics in these patients. Videofluoroscopic swallowing studies of 41 patients following radiation therapy for oropharyngeal cancer were analyzed for thin liquid boluses. Timing measures included duration of laryngeal vestibule closure (DLVC), duration to maximum hyoid elevation (DTMHE), duration to cricopharyngeal opening (DTCPO), and pharyngeal transit time (PTT). PAS was extracted for each swallow and considered normal if ≤ 2. As minimum and mean dose to the geniohyoid increased, DTMHE, DTCPO, and PTT increased. Worse PA scores were most strongly correlated with radiation dose received by geniohyoid (r = 0.445, p < 0.0001). Mean DLVC varied according to PAS group (normal PAS mean = 0.67 s, abnormal PAS mean = 0.13 s; p < 0.001). Similarly, DTCPO was significantly different based upon PAS (normal PAS mean = 0.22 s, abnormal PAS mean = 0.37 s, p = 0.016). As PAS increased, DTPCO and PTT increased (r = 0.208, p = 0.04; r = 0.204, p = 0.043). A negative correlation was noted between PAS and DLVC (r = -0.375, p = 0.001). Higher doses of radiation to the geniohyoid muscles are associated with increased severity of dysphagia as measured through both kinematics and PAS. Consideration of dose to the geniohyoid should be considered when planning radiation.

Baseline hemoglobin-A1c impacts clinical outcomes in patients with pancreatic cancer.

An association between diabetes mellitus and pancreatic ductal adenocarcinoma (PDA) has long been recognized. This article assesses the effect of the baseline hemoglobin-A1c (HbA1c) value on the clinical outcomes of patients with PDA. HbA1c values were prospectively collected on 656 consecutive patients presenting to a pancreas multidisciplinary cancer clinic from 2009 to 2012. Patients were diagnosed with benign pancreatic disease (BPD) or biopsy-confirmed resectable (R), borderline/locally advanced (BL), or metastatic (M) PDA. Excluded were those with prior treatment for PDA or a history of chronic diabetes mellitus (>1-year or unknown duration), resulting in a final cohort of 284 patients. Of 284 patients, 44 had benign disease, 62 had R-PDA, 115 had BL-PDA, and 63 had M-PDA. Patients with malignant disease (R-, BL-, and M-PDA) collectively had a higher average HbA1c value than patients with BPD (6.1% vs 5.6%; P<.001). Among patients with PDA (n=240), HbA1c values of 6.5% or greater were significantly associated with inferior overall survival (OS) compared with patients with HbA1c values less than 6.5% (hazard ratio [HR], 1.74; OS, 10.2 vs 13.0 months; P=.007), along with other known prognostic factors, such as age of 65 years or older, ECOG performance status of 1 or greater, carbohydrate antigen 19-9 level greater than 90, tumor size larger than 3 cm, and disease stage. HbA1c values of 6.5% or greater remained in the final predictive model using backward elimination (HR, 1.46; P=.097), indicating that HbA1c values of 6.5% or greater influence OS of patients with PDA even when accounting for other known prognostic factors. HbA1c level at presentation is significantly higher in patients with PDA than patients with BPD and seems to affect survival.

ACR Appropriateness Criteria® rectal cancer: metastatic disease at presentation.

The management of rectal cancer in patients with metastatic disease at presentation is highly variable. There are no phase III trials addressing therapeutic approaches, and the optimal sequencing of chemotherapy, radiation therapy, and surgery remains unresolved. Although chemoradiation is standard for patients with stage II/III rectal cancer, its role in the metastatic setting is controversial. Omitting chemoradiation may not be appropriate in all stage IV patients, particularly those with symptomatic primary tumors. Moreover, outcomes in this setting are vastly different, as some treatments carry the potential for cure in selected patients, while others are purely palliative. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application, by the panel, of a well-established consensus methodology (Modified Delphi) to rate the appropriateness of imaging and treatment procedures. In instances in which evidence is lacking or not definitive, expert opinion may be used as the basis for recommending imaging or treatment.

Effect of gabapentin on swallowing during and after chemoradiation for oropharyngeal squamous cell cancer.

The aim of this study was to examine the impact of gabapentin (neurontin) on swallowing and feeding tube use during chemoradiation (CRT) for oropharyngeal squamous cell carcinoma (OPSCC), and physiologic swallowing outcomes following completion of treatment. A total of 23 patients treated for OPSCC with concurrent CRT and prophylactically treated for pain using gabapentin were assessed. Historical controls were matched for T stage and primary site of disease. Timing of PEG use and removal were recorded. Video fluoroscopic swallowing studies were completed post-treatment to assess physiologic outcomes as well as penetration-aspiration scores (PAS). Functional oral intake scale (FOIS) scores were determined at the time of swallowing evaluation to assess diet level. Patients treated with gabapentin began using their PEG tubes later (3.7 vs. 2.29 weeks; P = 0.013) and had their PEG tubes removed earlier (7.29 vs. 32.56 weeks; P = 0.039) than the historical controls. A number of physiologic parameters were found to be less impacted in the gabapentin group, including oral bolus control (P = 0.01), epiglottic tilt (P = 0.0007), laryngeal elevation (P = 0.0017), and pharyngeal constriction (P = 0.002). PAS scores were significantly lower in the group treated with gabapentin (1.89 vs. 4; P = 0.0052). Patients receiving gabapentin had more advanced diet levels at the time of the initial swallowing study as evidenced by their FOIS scores (5.4 vs. 3.21; P = 0.0003). We conclude that patients using gabapentin for pain management during CRT appears to do well maintaining swallow function during treatment and have favorable post-treatment physiologic swallowing outcomes. Prospective evaluation is warranted.

SABER: Statistical Identification of Loci of Interest in GWAS Summary Statistics using a Bayesian Gaussian Mixture Model.

Genome-wide association studies (GWAS) remain a popular method for identifying novel genetic associations with human phenotypes and have provided many insights into the etiology of many diseases. However, GWAS provide limited support for how a genetic association might contribute to disease due to inherent limitations, such as linkage disequilibrium. As such, many methods that operate on GWAS summary statistics have been developed to generate evidence for functional pathways or for variants of interest, but they require defining the genomic region bounds for loci of interest. At present, there are limited methods for determining these bounds in a rigorous, reproducible way. We present a novel statistical method, Statistical Analysis for Bayesian Estimation of Regions (SABER), that uses Bayesian Gaussian mixture models to reproducibly generate ratios that quantify whether particular genomic positions represent the bounds of loci of interest and can be used to delineate genomic regions for downstream analyses.

Biomechanical analysis of complications following T10-Pelvis spinal fusion: A population based computational study.

Proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) are challenging complications of long fusion constructs for the treatment of adult spinal deformity. The objective of this study is to understand the biomechanical stresses proximal to the upper instrumentation of a T10-pelvis fusion in a large patient cohort. The pre-fusion models were subject-specific thoracolumbar spine models that incorporate the height, weight, spine curvature, and muscle morphology of 250 individuals from the Framingham Heart Study Multidetector CT Study. To create post-fusion models, the subject-specific models were further modified to eliminate motion between the intervertebral joints from T10 to the pelvis. OpenSim analysis tools were used to calculate the medial lateral shear force, anterior posterior shear force, and compressive force on the T9 vertebra during the static postures. Differences between pre-fusion and post-fusion T9 biomechanics were consistent between increased segmental mobility and unchanged segmental mobility conditions. For all static postures, compression decreased (p < 0. 0005). Anterior-posterior shear force significantly increased (p < 0. 0005) during axial twist and significantly increased (p < 0. 0005) during trunk flexion. Medial lateral shear force significantly increased (p < 0. 0005) during axial twist. This computational study provided the first use of subject-specific models to investigate the biomechanics of long spinal fusions. Patients undergoing T10-Pelvis fusion were predicted to have increased shear forces and decreased compressive force at the T9 vertebra, independent of change in segmental mobility. The computational model shows potential for the investigation of spinal fusion biomechanics to reduce the risk of PJK or PJF.

Sociodemographic factors and research experience impact MD-PhD program acceptance.

The 2014 NIH Physician-Scientist Workforce Working Group predicted a future shortage of physician-scientists. Subsequent studies have highlighted disparities in MD-PhD admissions based on race, income, and education. Our analysis of data from the Association of American Medical Colleges covering 2014-2021 (15,156 applicants and 6,840 acceptees) revealed that acceptance into US MD-PhD programs correlates with research experience, family income, and research publications. The number of research experiences associated with parental education and family income. Applicants were more likely to be accepted with a family income greater than $50,000 or with one or more publications or presentations. Applicants were less likely to be accepted if they had parents without a graduate degree, were Black/African American, were first-generation college students, or were reapplicants, irrespective of the number of research experiences, publications, or presentations. These findings underscore an admissions bias that favors candidates from affluent and highly educated families, while disadvantaging underrepresented minorities.

Executive Summary of the American Radium Society Appropriate Use Criteria for Neoadjuvant Therapy for Nonmetastatic Pancreatic Adenocarcinoma: Systematic Review and Guidelines.

For patients with locoregionally confined pancreatic ductal adenocarcinoma (PDAC), margin-negative surgical resection is the only known curative treatment; however, the majority of patients are not operable candidates at initial diagnosis. Among patients with resectable disease who undergo surgery alone, the 5-year survival remains poor. Adjuvant therapies, including systemic therapy or chemoradiation, are utilized as they improve locoregional control and overall survival. There has been increasing interest in the use of neoadjuvant therapy to obtain early control of occult metastatic disease, allow local tumor response to facilitate margin-negative resection, and provide a test of time and biology to assist with the selection of candidates most likely to benefit from radical surgical resection. However, limited guidance exists regarding the relative effectiveness of treatment options. In this systematic review, the American Radium Society multidisciplinary gastrointestinal expert panel convened to develop Appropriate Use Criteria evaluating the evidence regarding neoadjuvant treatment for patients with PDAC, including surgery, systemic therapy, and radiotherapy, in terms of oncologic outcomes and quality of life. The evidence was assessed using the Population, Intervention, Comparator, Outcome, and Study (PICOS) design framework and "Preferred Reporting Items for Systematic Reviews and Meta-analyses" 2020 methodology. Eligible studies included phases 2 to 3 trials, meta-analyses, and retrospective analyses published between January 1, 2012 and December 30, 2022 in the Ovid Medline database. A summary of recommendations based on the available literature is outlined to guide practitioners in the management of patients with PDAC.

Accelerating Genome- and Phenome-Wide Association Studies using GPUs - A case study using data from the Million Veteran Program.

The expansion of biobanks has significantly propelled genomic discoveries yet the sheer scale of data within these repositories poses formidable computational hurdles, particularly in handling extensive matrix operations required by prevailing statistical frameworks. In this work, we introduce computational optimizations to the SAIGE (Scalable and Accurate Implementation of Generalized Mixed Model) algorithm, notably employing a GPU-based distributed computing approach to tackle these challenges. We applied these optimizations to conduct a large-scale genome-wide association study (GWAS) across 2,068 phenotypes derived from electronic health records of 635,969 diverse participants from the Veterans Affairs (VA) Million Veteran Program (MVP). Our strategies enabled scaling up the analysis to over 6,000 nodes on the Department of Energy (DOE) Oak Ridge Leadership Computing Facility (OLCF) Summit High-Performance Computer (HPC), resulting in a 20-fold acceleration compared to the baseline model. We also provide a Docker container with our optimizations that was successfully used on multiple cloud infrastructures on UK Biobank and All of Us datasets where we showed significant time and cost benefits over the baseline SAIGE model.

American Radium Society (ARS) Appropriate Use Criteria (AUC) for Extrahepatic Cholangiocarcinoma.

Although uncommon, extrahepatic cholangiocarcinoma (EHCC) is a deadly malignancy, and the treatment approaches remain controversial. While surgery remains the only cure, few patients are candidates for resection up front, and there are high rates of both local and distant failure following resection. Herein, we systematically review the available evidence regarding treatment approaches for patients with EHCC, including surgery, radiation, and chemotherapy. The evidence regarding treatment outcomes was assessed using the Population, Intervention, Comparator, Outcome, and Study design (PICOS) framework. A summary of recommendations based on the available literature is outlined for specific clinical scenarios encountered by providers in the clinic to guide the management of these patients.

Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial.

Importance: Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial. Objective: To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone. Design, Setting, Participants: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022. Interventions: Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. Main Outcomes and Measures: The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing. Results: The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm. Conclusions and Relevance: In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals. Trial Registration: ClinicalTrials.gov Identifier: NCT03599765.