Search

Cholangiocarcinoma (CCA) is a malignancy that originates from the epithelial cells of the biliary system. Despite advancements in medical diagnostic techniques, CCAs remain a challenge to detect due to their silent clinical progression, making it difficult to diagnose these diseases. There are several well-established risk factors for CCA, including biliary tract infection and inflammation. However, there is also growing evidence that community and occupational exposures play a significant role in the development of bile duct cancers. This review examines the geographical distribution of these risk factors and the importance of surveillance in individuals exposed to these toxins who are more prone to developing CCA.

Several life-prolonging therapies with diverse mechanisms of action (MoA) are available for the treatment of metastatic hormone-sensitive/castration-resistant prostate cancer, with many patients requiring multiple lines of therapy. Nevertheless, treatment optimization to further delay disease progression and improve overall survival remains an unmet need. Despite the number of agents with differing MoAs approved for advanced prostate cancer, many patients receive only one or two life-prolonging therapies. One strategy for enhancing the benefit of treatment for this aggressive disease is combining therapies with different MoAs (treatment intensification) early in the disease course, which may be more effective than administering therapies sequentially, yet still allow for subsequent sequential use of individual therapies to optimize patient outcomes. In this narrative review we discuss the rationale for combining 223radium dichloride (223Ra; an alpha-emitting radionuclide) with enzalutamide (an androgen receptor inhibitor) for treatment intensification, including their differing MoAs, their individual efficacy in this setting, and their largely non-overlapping tolerability profiles. We also summarize the preclinical and clinical data available for this combination to date, including interim safety data from the phase 3 EORTC 1333/PEACE III study which highlight the low fracture risk of 223Ra plus enzalutamide when administered concomitantly with bone health agents. Relevant data were sourced from clinical studies published by the authors and via searches of PubMed, clinical trial registries and congress abstracts.

Abstract Context Second‐generation androgen receptor inhibitors (ARIs) extend metastasis‐free survival, prolong overall survival, and delay symptoms when added to androgen deprivation therapy for the treatment of castration‐sensitive or castration‐resistant prostate cancer (CRPC). However, ARIs may adversely impact physical and cognitive function, thereby decreasing quality of life and prognosis. Objective To evaluate the evidence regarding the potential effects of ARIs on physical and cognitive function and to contextualize how drug‐related adverse effects may influence treatment decisions in CRPC. Evidence acquisition We performed a literature search using MEDLINE from January 1998 to June 2020 using terms relating to prostate cancer, androgen deprivation, and physical and cognitive function. We selected 61 publications for analysis. Evidence synthesis Treatment‐induced deterioration in physical and cognitive function may impair the independence and well‐being of patients with CRPC. Patient‐reported outcomes from clinical trials of ARIs provide quantitative evidence of their impact on these domains, which appears to vary between ARIs, reflecting the different adverse event profiles of these agents. Thus, the risk of physical or cognitive dysfunction may be managed or mitigated by appropriate selection of treatment options. Studies in patients with CRPC have assessed the cognitive effects of ARIs with validated instruments, whereas quantitative analysis of the impact on physical function has been limited. Conclusion Several validated instruments utilized for the assessment of physical and cognitive function in clinical studies have been adapted for clinical practice; however, consensus on the standardization of these assessments is required. Future clinical studies employing validated tools may generate data on the impact of ARIs and guide treatment decisions for patients with CRPC. Patient summary We review the hormonal therapies used to treat men with prostate cancer and the effects they have on physical and cognitive function. We discuss how to measure these effects and how this may assist when choosing treatment.

Using hybridized [18F]-fluorodeoxyglucose positron emission tomography with cardiac magnetic resonance, we identify active myocardial inflammation and demonstrate its relationship with late gadolinium enhancement, in Fabry disease. We demonstrate that late gadolinium enhancement represents, at least in part, active myocardial inflammation and identify an early inflammatory phenotype that may represent a therapeutic window before irreversible tissue injury and adaptation occur. (Level of Difficulty: Intermediate.)

Introduction: The effect of the lipidosterolic extract derived from Serenoa repens (commonly known as “saw palmetto extract” or LSESr) berries on benign prostatic hyperplasia (BPH) and male lower urinary tract symptoms (LUTS) has been extensively studied in the global literature. However, a lack of global consensus with regard to its effectiveness remains, resulting in differing recommendations on the role of LSESr in the BPH/LUTS treatment paradigm. Here, we describe the consensus reached by an international panel of urology experts. Methods: In an independent meeting on 24 April 2021, an international panel of urology experts convened with the goal of developing consensus statements to address the following: the differences between the AUA and EAU guidance regarding the use of LSESr for the treatment of BPH/LUTS, the proposed mechanism of action of LSESr, and data examining the efficacy and safety of LSESr. These consensus statements were developed over the course of several months after an extensive review of the global literature and a discussion thereof. Results: A total of seven consensus statements were agreed upon by the panel. These statements addressed the proposed mechanism of action of LSESr, LSESr quality, and the results from clinical trials examining the efficacy and safety of various LSESrs. Conclusion: Based on the reviewed evidence, the panel recommends that LSESr should be considered as a treatment option for men with mild-to-moderate BPH/LUTS as an alternative to watchful waiting.

Abstract Despite the increased usage of post-transplant cyclophosphamide (PTCy) in allogeneic hematopoietic stem cell transplantation (allo-HSCT), our knowledge of immune reconstitution post-allo-HSCT in the setting of PTCy is limited. Adequate immune reconstitution is the key to a successful transplant. In this study, we aim to investigate the effect of PTCy on the reconstitution of each immune component; more focus was placed on the immunophenotype and functions of T cells. Using blood samples from patients who underwent allo-HSCT under regimens containing PTCy (n = 23) versus those who received no PTCy (n = 14), we examined the impact of PTCy on the post-transplant immune response. We demonstrated a distinct T cell immune signature between PTCy versus non-PTCy group. PTCy significantly delayed T cell reconstitution and affected the T cell subsets by increasing regulatory T cells (Treg) while reducing naïve T cells. In addition, we observed remarkable enhancement of multiple inhibitory receptors (TIGIT, PD-1, TIM-3, CD38, CD39) on both CD4+ and CD8+ T cells on day 30 post-transplantation in patients who received PTCy. Importantly, upregulation of PD-1 on CD8 T cells was persistent through day 180 and these T cells were less functional, manifested by reduced cytokine production upon anti-CD3/CD28 stimulation. Furthermore, we found a significant correlation of T cell immune phenotypes to clinical outcome (disease relapse and GVHD) in patients who received PTCy. Our novel findings provide critical information to understand the mechanism of how PTCy impacts immune reconstitution in allo-HSCT and may subsequently lead to optimization of our clinical practice using this treatment.

ObjectiveMicro-ultrasound is an imaging modality used to visualize and target prostate cancer during transrectal or transperineal biopsy. We evaluated the effectiveness of a micro-ultrasound training program and estimated the learning curve for prostate biopsy. MethodsA training program registry was assessed for the rate of clinically significant prostate cancer (csPCa, grade group ≥ 2), negative predictive value, and specificity at each stage of the program. Nine metrics of biopsy quality were evaluated in 4 stages for each practitioner. Non-linear fitting and logistic regression models were used to evaluate the time-course of these metrics over training. ResultsThirteen practitioners from 8 institutions completed stages 1 to 3 of the program, and 9 completed all 4 stages. Over 1190 micro-ultrasound biopsy procedures were performed. Detection of csPCa increased from 40% to 57% from stage 1 to stage 4 (P < 0.01). Stage 4 “expert” level was independently associated with higher detection of csPCa when correcting for overall risk factors (OR 1.95; P = 0.03). Limitations include the retrospective analysis and variation in biopsy protocols. ConclusionThe micro-ultrasound training program was effective in improving biopsy quality and rate of csPCa detection. The presented learning curve provides an initial guide for acquiring expertise with real-time micro-ultrasound image-guided biopsy.

The treatment landscape for metastatic hormone-sensitive prostate cancer (mHSPC) has dramatically evolved. Monotherapy androgen deprivation therapy (ADT) with testosterone suppression alone is no longer the standard of care as multiple global phase 3 trials of different combinatorial strategies have been clinically and statistically successful and the combinations have been incorporated into guidelines on advanced prostate cancer. For appropriate patients, clinicians should consider combining ADT with docetaxel or an androgen receptor pathway inhibitor, or possibly with both. Shared patient-physician decision-making mandates a review of the level 1 evidence supporting the optimization and intensification of combination therapy for patients with mHSPC. Here we discuss the evidence underscoring intensification strategies as the standard of care for low-volume, low-risk mHSPC. Patient summary: We discuss treatment strategies for men with metastatic prostate cancer. Combinations of androgen deprivation therapy (ADT) and drugs that inhibit the androgen receptor pathway are superior to ADT alone and prolong survival in patients with metastatic hormone-sensitive prostate cancer.

Osteopontin (OPN) is produced by tumor cells as well as by myeloid cells and is enriched in the tumor microenvironment (TME) of many cancers. Given the roles of OPN in tumor progression and immune suppression, we hypothesized that targeting OPN with aptamers that have high affinity and specificity could be a promising therapeutic strategy. Bi-specific aptamers targeting ligands for cellular internalization were conjugated to siRNAs to suppress OPN were created, and therapeutic leads were selected based on target engagement and in vivo activity. Aptamers as carriers for siRNA approaches were created including a cancer targeting nucleolin aptamer Ncl-OPN siRNA and a myeloid targeting CpG oligodeoxynucleotide (ODN)-OPN siRNA conjugate. These aptamers were selected as therapeutic leads based on 70–90% OPN inhibition in cancer (GL261, 344SQ, 4T1B2b) and myeloid (DC2.4) cells relative to scramble controls. In established immune competent 344SQ lung cancer and 4T1B2b breast cancer models, these aptamers, including in combination, demonstrate therapeutic activity by inhibiting tumor growth. The Ncl-OPN siRNA aptamer demonstrated efficacy in an immune competent orthotopic glioma model administered systemically secondary to the ability of the aptamer to access the glioma TME. Therapeutic activity was demonstrated using both aptamers in a breast cancer brain metastasis model. Targeted inhibition of OPN in tumor cells and myeloid cells using bifunctional aptamers that are internalized by specific cell types and suppress OPN expression once internalized may have clinical potential in cancer treatment.

Radium-223 dichloride (223Ra) is an α-emitter approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with bone metastases, but without visceral involvement. Despite being a life-prolonging therapy (LPT), 223Ra remains underutilized. A large body of real-world evidence (RWE) for 223Ra has been published in the decade since the pivotal phase 3 ALSYMPCA study, a period during which the treatment landscape has continued to evolve. How to optimize 223Ra use, including how to integrate it into the mCRPC management pathway amongst other current LPTs (i.e., with respect to timing and concurrent, layered, or sequential use), is therefore of considerable interest. RWE studies lack the conventional restraints of clinical trials and can therefore help to build an understanding of how treatments may be best used in routine practice. Here we review RWE studies investigating the efficacy and safety of 223Ra in mCRPC [including in sequence with the recently approved 177-Lutetium conjugated to the ligand prostate-specific membrane antigen (177Lu-PSMA)], as well as response marker development, imaging techniques, and current clinical practice recommendations.

Antibiotic resistance among gram-negative bacteria continues to rise globally at an alarming rate. New vaccines that prevent bacterial infections and reduce antibiotic use could provide a potential solution to these problems. This study focused on development of an investigational vaccine to prevent recurrent urinary traction infections (UTI) caused by gram-negative bacteria that use type 1 pili to adhere to, invade, and colonize human bladders. The vaccine antigen is FimH, an adhesin protein on the tip of type 1 pili with a lectin binding domain that enables attachment to glycoproteins on mammalian bladders. This was a phase 1, open-label, dose escalation study evaluating the vaccine in 67 healthy women with and without histories of recurrent UTI. The objectives of the study were to evaluate the safety, tolerability, and immunogenicity of different dosages of the antigen and adjuvant of the vaccine. All dosages were well-tolerated and a low incidence of systemic reactions occurred. No serious adverse events related to the vaccine were reported. The vaccine induced both binding and functional antibodies. The women with histories of recurrent UTI demonstrated greater than 150-fold increases in antibodies against the N-terminal region of FimH. Based on the results of this phase 1 study, this vaccine is proceeding to a double-blind, randomized, placebo-controlled phase 2 study. If this vaccine is successful in future studies, it could potentially prevent millions of recurrent UTI globally and reduce the development of antibiotic resistance.

Abstract Angiogenesis is a critical component of breast cancer development, and identification of imaging-based angiogenesis assays has prognostic and treatment implications. We evaluated the association of semi-quantitative kinetic and radiomic breast cancer features on dynamic contrast-enhanced (DCE)-MRI with microvessel density (MVD), a marker for angiogenesis. Invasive breast cancer kinetic features (initial peak percent enhancement [PE], signal enhancement ratio [SER], functional tumor volume [FTV], and washout fraction [WF]), radiomics features (108 total features reflecting tumor morphology, signal intensity, and texture), and MVD (by histologic CD31 immunostaining) were measured in 27 patients (1/2016–7/2017). Lesions with high MVD levels demonstrated higher peak SER than lesions with low MVD (mean: 1.94 vs. 1.61, area under the receiver operating characteristic curve [AUC] = 0.79, p = 0.009) and higher WF (mean: 50.6% vs. 22.5%, AUC = 0.87, p = 0.001). Several radiomics texture features were also promising for predicting increased MVD (maximum AUC = 0.84, p = 0.002). Our study suggests DCE-MRI can non-invasively assess breast cancer angiogenesis, which could stratify biology and optimize treatments.

Abstract Background Cancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~ 30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy. Methods Human metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and 14C-Aminoisobutyric acid followed by an indocyanine green vascular washout. Tracer accumulation was determined by quantitative fluorescent microscopy and quantitative autoradiography. Survival was tracked and tumor burden was monitored via bioluminescent imaging. Extent of mutation differences and acquired resistance was measured in-vitro through half-maximal inhibitory assays and qRT-PCR analysis. Results A PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50 > 2.5 μM at 48 h and 0.1 μM at 72 h) compared with parental PC-9 (IC50: 0.75 μM at 48 h and 0.027 μM at 72 h). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither a T790M mutation nor amplifications of MET and HER2 compared with parental PC-9. Conclusion Our study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.

IntroductionConsumption of a healthy diet improves cardiovascular (CV) risk factors and reduces the development of cardiovascular disease (CVD). Food insecure (FIS) adults often consume an unhealthy diet, which can promote obesity, type 2 diabetes mellitus (T2DM), hypertension (HTN), and hyperlipidemia (HLD). The Supplemental Nutrition Assistance Program (SNAP) is designed to combat food insecurity by increasing access to healthy foods. However, there is a paucity of data on the association of SNAP participation among FIS adults and these CVD risk factors.MethodsThe National Health and Nutrition Examination Survey (NHANES) is a publicly available, ongoing survey administered by the Centers for Disease Control and Prevention and the National Center for Health Statistics. We analyzed five survey cycles (2007–2016) of adult participants who responded to the CVD risk profile questionnaire data. We estimated the burden of select CVD risk factors among the FIS population and the association with participation in SNAP.ResultsAmong 10,449 adult participants of the survey, 3,485 (33.3%) identified themselves as FIS. Food insecurity was more common among those who were younger, female, Hispanic, and Black. Among the FIS, SNAP recipients, when compared to non-SNAP recipients, had a lower prevalence of HLD (36.3 vs. 40.1% p = 0.02), whereas rates of T2DM, HTN, and obesity were similar. Over the 10-year survey period, FIS SNAP recipients demonstrated a reduction in the prevalence of HTN (p < 0.001) and HLD (p < 0.001) which was not evident among those not receiving SNAP. However, obesity decreased only among those not receiving SNAP. The prevalence of T2DM did not change over the study period in either group.ConclusionOver a 10-year period, FIS adults who received SNAP demonstrated a reduction in the prevalence of HTN and HLD, which was not seen among those not receiving SNAP. However, the prevalence of obesity and T2DM did not decline among SNAP recipients, suggesting that additional approaches are required to impact these important CVD risk factors.

BackgroundThe number of colleges and universities with smoke- or tobacco-free campus policies has been increasing. The effects of campus smoking policies on overall sentiment, particularly among young adult populations, are more difficult to assess owing to the changing tobacco and e-cigarette product landscape and differential attitudes toward policy implementation and enforcement. ObjectiveThe goal of the study was to retrospectively assess the campus climate toward tobacco use by comparing tweets from California universities with and those without smoke- or tobacco-free campus policies. MethodsGeolocated Twitter posts from 2015 were collected using the Twitter public application programming interface in combination with cloud computing services on Amazon Web Services. Posts were filtered for tobacco products and behavior-related keywords. A total of 42,877,339 posts were collected from 2015, with 2837 originating from a University of California or California State University system campus, and 758 of these manually verified as being about smoking. Chi-square tests were conducted to determine if there were significant differences in tweet user sentiments between campuses that were smoke- or tobacco-free (all University of California campuses and California State University, Fullerton) compared to those that were not. A separate content analysis of tweets included in chi-square tests was conducted to identify major themes by campus smoking policy status. ResultsThe percentage of positive sentiment tweets toward tobacco use was higher on campuses without a smoke- or tobacco-free campus policy than on campuses with a smoke- or tobacco-free campus policy (76.7% vs 66.4%, P=.03). Higher positive sentiment on campuses without a smoke- or tobacco-free campus policy may have been driven by general comments about one’s own smoking behavior and comments about smoking as a general behavior. Positive sentiment tweets originating from campuses without a smoke- or tobacco-free policy had greater variation in tweet type, which may have also contributed to differences in sentiment among universities. ConclusionsOur study introduces preliminary data suggesting that campus smoke- and tobacco-free policies are associated with a reduction in positive sentiment toward smoking. However, continued expressions and intentions to smoke and reports of one’s own smoking among Twitter users suggest a need for more research to better understand the dynamics between implementation of smoke- and tobacco-free policies and resulting tobacco behavioral sentiment.

Superparamagnetic iron-oxide nanoparticles are robust contrast agents for magnetic resonance imaging (MRI) used for sensitive structural and functional mapping of the cerebral blood volume (CBV) when administered intravenously. To date, many CBV-MRI studies are conducted with Feraheme, manufactured for the clinical treatment of iron-deficiency. Unfortunately, Feraheme is currently not available outside the United States due to commercial and regulatory constraints, making CBV-MRI methods either inaccessible or very costly to achieve. To address this barrier, we developed a simple, one-pot recipe to synthesize Carboxymethyl-dextran coated Iron Oxide Nanoparticles, namely, “CION”, suitable for preclinical CBV-MRI applications. Here we disseminate a step-by-step instruction of our one-pot synthesis protocol, which allows CION to be produced in laboratories with minimal cost. We also characterized different CION-conjugations by manipulating polymer to metal stoichiometric ratio in terms of their size, surface chemistry, and chemical composition, and shifts in MR relaxivity and pharmacokinetics. We performed several proof-of-concept experiments in vivo, demonstrating the utility of CION for functional and structural MRI applications, including hypercapnic CO2 challenge, visual stimulation, targeted optogenetic stimulation, and microangiography. We also present evidence that CION can serve as a cross-modality research platform by showing concurrent in vivo optical and MRI measurement of CBV using fluorescent-labeled CION. The simplicity and cost-effectiveness of our one-pot synthesis method should allow researchers to reproduce CION and tailor the relaxivity and pharmacokinetics according to their imaging needs. It is our hope that this work makes CBV-MRI more openly available and affordable for a variety of research applications.

A number of immunotherapies have been developed and adopted for the treatment of urothelial cancer (encompassing cancers arising from the bladder, urethra, or renal pelvis). For these immunotherapies to positively impact patient outcomes, optimal selection of agents and treatment scheduling, especially in conjunction with existing treatment paradigms, is paramount. Immunotherapies also warrant specific and unique considerations regarding patient management, emphasizing both the prompt identification and treatment of potential toxicities. In order to address these issues, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in the field of immunotherapy for urothelial cancer. The expert panel developed this clinical practice guideline (CPG) to inform healthcare professionals on important aspects of immunotherapeutic treatment for urothelial cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with urothelial cancer.

Introduction: College-aged youth are active on social media yet smoking-related social media engagement in these populations has not been thoroughly investigated. We sought to conduct an exploratory infoveillance study focused on geolocated data to characterize smoking-related tweets originating from California 4-year colleges on Twitter.Methods: Tweets from 2015 to 2019 with geospatial coordinates in CA college campuses containing smoking-related keywords were collected from the Twitter API stream and manually annotated for discussions about smoking product type, sentiment, and behavior.Results: Out of all tweets detected with smoking-related behavior, 46.7% related to tobacco use, 50.0% to marijuana, and 7.3% to vaping. Of these tweets, 46.1% reported first-person use or second-hand observation of smoking behavior. Out of 962 tweets with user sentiment, the majority (67.6%) were positive, ranging from 55.0% for California State University, Long Beach to 95.8% for California State University, Los Angeles.Discussion: We detected reporting of first- and second-hand smoking behavior on CA college campuses representing possible violation of campus smoking bans. The majority of tweets expressed positive sentiment about smoking behaviors, though there was appreciable variability between college campuses. This suggests that anti-smoking outreach should be tailored to the unique student populations of these college communities.Conclusion: Among tweets about smoking from California colleges, high levels of positive sentiment suggest that the campus climate may be less receptive to anti-smoking messages or adherence to campus smoking bans. Further research should investigate the degree to which this varies by campuses over time and following implementation of bans including validating using other sources of data.

The Open Payments database reports payments made to physicians by industry. Given the potential for financial conflicts of interest relating to patient outcomes, further scrutiny of these data is valuable. Therefore, the objective of this study was to analyze physician-industry relationships by specialty type, payment type, geospatial trend, and longitudinal trend between 2014-2018. We conducted an observational, retrospective data analysis of payments from the Open Payments database for licensed United States physicians listed in the National Plan & Provider Enumeration System (NPPES). Datasets from 2013-2018 were joined using the Python programming language. Aggregation and sub-setting by characteristics of interest was done in R to calculate means and frequencies of reported general physician payments from industry across different specialties, locations, timeframes, and payment types. Normalization was applied for numbers of physicians or payments. Geospatial statistical hot spot analysis was conducted in ArcGIS. 51.73 million payment records were analyzed. In total, 50,047,930 payments were issued to 771,113 allopathic or osteopathic physicians, representing $8,702,631,264 transferred from industry to physicians over the five-year period between 2014 and 2018. The mean payment amount was $179, with a standard deviation of $12,685. Variability in physicians' financial relationships with industry were apparent across specialties, regions, time, and payment type. A limited match rate between records in the NPPES and Open Payments databases may have resulted in selection bias of trends related to physician characteristics. Further research is necessary, particularly in the context of changing industry payment trends and public perceptions of the appropriateness of these relationships.

Advances in minimally invasive tissue resection techniques now allow for the majority of early colorectal neoplasia to be managed endoscopically. To optimize their respective risk–benefit profiles, and, therefore, appropriately select between endoscopic mucosal resection, endoscopic submucosal dissection, and surgery, the endoscopist must accurately predict the risk of submucosal invasive cancer and estimate depth of invasion. Herein, we discuss the evidence and our approach for optical evaluation of large (⩾ 20 mm) colorectal laterally spreading lesions.

Abstract Background Brain tumor vasculature can be significantly compromised and leakier than that of normal brain blood vessels. Little is known if there are vascular permeability alterations in the brain adjacent to tumor (BAT). Changes in BAT permeability may also lead to increased drug permeation in the BAT, which may exert toxicity on cells of the central nervous system. Herein, we studied permeation changes in BAT using quantitative fluorescent microscopy and autoradiography, while the effect of chemotherapy within the BAT region was determined by staining for activated astrocytes. Methods Human metastatic breast cancer cells (MDA-MB-231Br) were injected into left ventricle of female NuNu mice. Metastases were allowed to grow for 28 days, after which animals were injected fluorescent tracers Texas Red (625 Da) or Texas Red dextran (3 kDa) or a chemotherapeutic agent 14C-paclitaxel. The accumulation of tracers and 14C-paclitaxel in BAT were determined by using quantitative fluorescent microscopy and autoradiography respectively. The effect of chemotherapy in BAT was determined by staining for activated astrocytes. Results The mean permeability of texas Red (625 Da) within BAT region increased 1.0 to 2.5-fold when compared to normal brain, whereas, Texas Red dextran (3 kDa) demonstrated mean permeability increase ranging from 1.0 to 1.8-fold compared to normal brain. The Kin values in the BAT for both Texas Red (625 Da) and Texas Red dextran (3 kDa) were found to be 4.32 ± 0.2 × 105 mL/s/g and 1.6 ± 1.4 × 105 mL/s/g respectively and found to be significantly higher than the normal brain. We also found that there is significant increase in accumulation of 14C-Paclitaxel in BAT compared to the normal brain. We also observed animals treated with chemotherapy (paclitaxel (10 mg/kg), erubilin (1.5 mg/kg) and docetaxel (10 mg/kg)) showed activated astrocytes in BAT. Conclusions Our data showed increased permeation of fluorescent tracers and 14C-paclitaxel in the BAT. This increased permeation lead to elevated levels of activated astrocytes in BAT region in the animals treated with chemotherapy.

In this study, we aimed to predict mechanical ventilation requirement and mortality using computational modeling of chest radiographs (CXRs) for coronavirus disease 2019 (COVID-19) patients. This two-center, retrospective study analyzed 530 deidentified CXRs from 515 COVID-19 patients treated at Stony Brook University Hospital and Newark Beth Israel Medical Center between March and August 2020. Linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), and random forest (RF) machine learning classifiers to predict mechanical ventilation requirement and mortality were trained and evaluated using radiomic features extracted from patients’ CXRs. Deep learning (DL) approaches were also explored for the clinical outcome prediction task and a novel radiomic embedding framework was introduced. All results are compared against radiologist grading of CXRs (zone-wise expert severity scores). Radiomic classification models had mean area under the receiver operating characteristic curve (mAUCs) of 0.78 ± 0.05 (sensitivity = 0.72 ± 0.07, specificity = 0.72 ± 0.06) and 0.78 ± 0.06 (sensitivity = 0.70 ± 0.09, specificity = 0.73 ± 0.09), compared with expert scores mAUCs of 0.75 ± 0.02 (sensitivity = 0.67 ± 0.08, specificity = 0.69 ± 0.07) and 0.79 ± 0.05 (sensitivity = 0.69 ± 0.08, specificity = 0.76 ± 0.08) for mechanical ventilation requirement and mortality prediction, respectively. Classifiers using both expert severity scores and radiomic features for mechanical ventilation (mAUC = 0.79 ± 0.04, sensitivity = 0.71 ± 0.06, specificity = 0.71 ± 0.08) and mortality (mAUC = 0.83 ± 0.04, sensitivity = 0.79 ± 0.07, specificity = 0.74 ± 0.09) demonstrated improvement over either artificial intelligence or radiologist interpretation alone. Our results also suggest instances in which the inclusion of radiomic features in DL improves model predictions over DL alone. The models proposed in this study and the prognostic information they provide might aid physician decision making and efficient resource allocation during the COVID-19 pandemic.

IntroductionFrom late 2014 through 2015, Scott County, Indiana faced an HIV outbreak triggered by opioid abuse and transition to injection drug use. Investigating the origins, risk factors, and responses related to this outbreak is critical to inform future surveillance, interventions, and policymaking. In response, this retrospective infoveillance study identifies and characterizes user-generated messages related to opioid abuse, heroin injection drug use, and HIV status using natural language processing (NLP) among Twitter users in Indiana during the period of this HIV outbreak.Materials and methodsOur study consisted of two phases: data collection and processing, and data analysis. We collected Indiana geolocated tweets from the public Twitter API using Amazon Web Services EC2 instances filtered for geocoded messages in the immediate pre and post period of the outbreak. In the data analysis phase we applied an unsupervised machine learning approach using NLP called the Biterm Topic Model (BTM) to identify tweets related to opioid, heroin/injection, and HIV behavior and then examined these messages for HIV risk-related topics that could be associated with the outbreak.ResultsMore than 10 million geocoded tweets occurring in Indiana during the immediate pre and post period of the outbreak were collected for analysis. Using BTM, we identified 1350 tweets thought to be relevant to the outbreak and then confirmed 358 tweets using human annotation. The most prevalent themes identified were tweets related to self-reported abuse of illicit and prescription drugs, opioid use disorder, self-reported HIV status, and public sentiment regarding the outbreak. Geospatial analysis found that these messages clustered in population dense areas outside of the outbreak, including Indianapolis and neighboring Clark County.DiscussionThis infoveillance study characterized the social media conversations of communities in Indiana in the pre and post period of the 2015 HIV outbreak. Behavioral themes detected reflect discussion about risk factors related to HIV transmission stemming from opioid and heroin abuse for priority populations, and also help identify community attitudes that could have motivated or detracted the use of HIV prevention methods, along with helping identify factors that can impede access to prevention services.ConclusionsInfoveillance approaches, such as the analysis conducted in this study, represent a possibly strategy to detect "signal" of the emergence of risk factors associated with an outbreak though may be limited in their scope and generalizability. Our results, in conjunction with other forms of public health surveillance, can leverage the growing ubiquity of social media platforms to better detect opioid-related HIV risk knowledge, attitudes and behavior, as well as inform future prevention efforts.

Background: Corruption is a significant challenge to the future of human development, economic progress, and population health in the post millennium. Corruption, in its different forms of bribery, fraud, waste, collusion, and illicit financial flows, not only leads to waste but can also erode trust in government and public systems. Corruption is also complex and globalized with different forms of corruption occurring across different countries and multiple industries. One critical tool to leverage in the fight against corruption is the use of innovative technologies such as machine learning. Methods: In this study, we deployed an unsupervised machine learning methodology using natural language processing to collect and analyze data from the popular social media platform Twitter with the aims of detecting self-reported experiences with corruption, including in the health sector. We collected data from the Twitter public API for keywords associated with corruption and used the biterm topic model to extract themes from the entire corpus of Tweets in order to detect user-generated messages reporting or discussing experiences with corruption. Results: We analyzed 22, 180, 425 tweets filtered for corruption-related keywords from January–May 2019. Using a combination of NLP and manual annotation, we detected 2383 tweets from 1556 users that included self-reporting of corruption for two dominant themes: police bribery and healthcare corruption. Overall, we found a small number of users actively reporting experiences with corruption, identified users located in countries that are perceived as having higher levels of corruption by their citizens, and found that the majority of messages included reports of users’ own experiences and/or documentation of corruption. Conclusion: Though technology is not a “silver bullet” that can entirely address the multifaceted nature of global corruption, this study demonstrates its potential utility as a force for good to enable better detection, characterize forms of corruption in different sectors, and hopefully inform future anti-corruption efforts. Additionally, the UN Sustainable Development Goals, with shared goals of fighting corruption, improving population health, encouraging technology adoption, and fostering multistakeholder partnerships, may serve as a critical governance space to catalyze technology-driven anti-corruption approaches.

Introduction After the outbreak of COVID-19 unprecedented changes in the healthcare systems worldwide were necessary resulting in a reduction of urological capacities with postponements of consultations and surgeries. Material and methods An email was sent to 66 urological hospitals with focus on robotic surgery (RS) including a link to a questionnaire (e.g. bed/staff capacity, surgical caseload, protection measures during RS) that covered three time points: a representative baseline week prior to COVID-19, the week of March 16th-22nd and April 20th-26th 2020. The results were evaluated using descriptive analyses. Results 27 out of 66 questionnaires were analyzed (response rate: 41%). We found a decrease of 11% in hospital beds and 25% in OR capacity with equal reductions for endourological, open and robotic procedures. Primary surgical treatment of urolithiasis and benign prostate syndrome (BPS) but also of testicular and penile cancer dropped by at least 50% while the decrease of surgeries for prostate, renal and urothelial cancer (TUR-B and cystectomies) ranged from 15 to 37%. The use of personal protection equipment (PPE), screening of staff and patients and protection during RS was unevenly distributed in the different centers–however, the number of COVID-19 patients and urologists did not reach double digits. Conclusion The German urological landscape has changed since the outbreak of COVID-19 with a significant shift of high priority surgeries but also continuation of elective surgical treatments. While screening and staff protection is employed heterogeneously, the number of infected German urologists stays low.

The blood–brain barrier (BBB) limits movement of solutes from the lumen of the brain microvascular capillary system into the parenchyma. The unidirectional transfer constant, Kin, is the rate at which transport across the BBB occurs for individual molecules. Single and multiple uptake experiments are available for the determination of Kin for new drug candidates using both intravenous and in situ protocols. Additionally, the single uptake method can be used to determine Kin in heterogeneous pathophysiological conditions such as stroke, brain cancers, and Alzheimer’s disease. In this review, we briefly cover the anatomy and physiology of the BBB, discuss the impact of efflux transporters on solute uptake, and provide an overview of the single-timepoint method for determination of Kin values. Lastly, we compare preclinical Kin experimental results with human parallels.

Male lower urinary tract symptoms (LUTS) is an increasingly important problem for the majority of late middle aged and elderly men. Fexapotide triflutate (FT) is a first in-class compound given by local injection via the transrectal intraprostatic route under ultrasound guidance. Data from >1700 FT and control injections in prospective randomized blinded controlled multicenter trials are reviewed and discussed in relation to current developments in the field of treatments for LUTS associated with benign prostatic hyperplasia (BPH). Long-term studies of FT in the United States have shown statistically significant improvement in BPH symptoms and objective outcomes including significant reduction in both spontaneous acute urinary retention as well as the subsequent incidence of BPH surgery. FT has been shown to be well tolerated with an excellent safety profile, and is an efficacious clinic-based treatment for BPH involving an intraprostatic injection that requires only a few minutes to administer, with no catheter nor anesthesia requirements.

Background/Study aim The American Society for Gastrointestinal Endoscopy (ASGE) recommends that trainees complete 150 endoscopic ultrasound (EUS) procedures before assessing competency. However, this recommendation is largely based on limited evidence and expert opinion. With new evidence suggesting that this historical threshold is underestimating training requirements, we evaluated the learning curve for achieving competency in EUS. Patients/Materials and methods Two investigators independently searched MEDLINE for full-text citations assessing the learning curve for achieving competency in EUS in the period 1946 to 25 March 2016. A learning curve was defined as either a tabulated or graphic representation of competency as a function of increasing EUS experience. Results Eight studies assessing 28 trainees and 7051 EUS procedures were included. When stratifying studies based on procedural indication: three studies assessed competency in evaluating mucosal lesions, three studies assessed competency in EUS fine-needle aspiration (EUS-FNA), and two studies assessed comprehensive competency. Among studies assessing mucosal lesion T-staging accuracy, competency was achieved by 65 to 231 procedures. Among studies assessing EUS-FNA, competency was achieved by 30 to 40 procedures. Among the two studies assessing comprehensive competency in EUS, competency was not achieved in either study across all trainees. Only four of 17 trainees reached competency by 225 to 295 EUS procedures. Conclusion As EUS competency assessment has evolved to more closely reflect independent clinical practice, the number of procedures required to achieve competency has risen well above ASGE recommendations. Advanced endoscopy training programs and specialty societies need to re-assess the structure of EUS training.

Vedolizumab, an α4β7-integrin antagonist, is the first gut-selective monoclonal antibody that has been approved for the treatment of moderate-to-severe ulcerative colitis and Crohn’s disease in many countries in the world. However, questions still remain regarding its appropriate use and placement in current treatment algorithms. Therefore, we sought out to evaluate the existing literature on the use of vedolizumab in inflammatory bowel disease. From inception to 21 June 2015 we searched MEDLINE for phase III randomized control trials assessing the utility of vedolizumab in inflammatory bowel disease, of which three were identified. The GEMINI trials demonstrate that vedolizumab is an effective and safe treatment for patients suffering from moderate-to-severe ulcerative colitis (GEMINI I) and Crohn’s disease (GEMINI II and III). However, further studies are needed comparing its efficacy directly with anti-tumor necrosis factor therapies to allow for further delineation of current treatment algorithms as well as ensuring its long-term safety profile.

Background and Aims. The Canadian Partnership Against Cancer (CPAC) recommends a fecal immunochemical test- (FIT-) positive predictive value (PPV) for all adenomas of ≥50%. We sought to assess FIT performance among average-risk participants of the British Columbia Colon Screening Program (BCCSP). Methods. From Nov-2013 to Dec-2014 consecutive participants of the BCCSP were assessed. Data was obtained from a prospectively collected database. A single quantitative FIT (NS-Plus, Alfresa Pharma Corporation, Japan) with a cut-off of ≥10 μg/g (≥50 ng/mL) was used. Results. 20,322 FIT-positive participants underwent CSPY. At a FIT cut-off of ≥10 μg/g (≥50 ng/mL) the PPV for all adenomas was 52.0%. Increasing the FIT cut-off to ≥20 μg/g (≥100 ng/mL) would increase the PPV for colorectal cancer (CRC) by 1.5% and for high-risk adenomas (HRAs) by 6.5% at a cost of missing 13.6% of CRCs and 32.4% of HRAs. Conclusions. As the NS-Plus FIT cut-off rises, the PPV for CRC and HRAs increases but at the cost of missed lesions. A cut-off of ≥10 μg/g (≥50 ng/mL) produces a PPV for all adenomas exceeding national recommendations. Health authorities need to take into consideration endoscopic resources when selecting a FIT positivity threshold.