Breast Cryoablation, From the AJR "How We Do It" Special Series.

Breast cryoablation is a minimally invasive image-guided percutaneous procedure to treat fibroadenomas and early-stage breast cancer utilizing liquid nitrogen or argon gas to create extremely cold temperatures that devitalize targeted tissue. Although more long term data are needed, this outpatient procedure is well tolerated and carries minimal risks, including non-target thermal injury that can be mitigated by careful planning and proper technique. Building a sustainable breast cryoablation service in a radiology practice poses several practical considerations, such as training proceduralists, purchasing equipment, recruiting patients, and understanding the revenue cycle. This article describes aspects of the radiologist's role in this procedure, including implementation of a breast ablation program, patient selection, technical details related to intervention, and expected postprocedural outcomes.

Cholangiocarcinoma: Epidemiology and Imaging-Based Review.

Cholangiocarcinoma (CCA) is a rare cancer of the bile duct epithelium, and in the last few decades its incidence rate has been increasing. It is associated with a high mortality rate due to late diagnosis and its aggressive nature. Many risk factors have been identified; some are more common in certain regions than others. CCA can be classified according to its anatomical location or macroscopic growth pattern, the latter being most helpful for imaging interpretation. Clinical features can vary from obstructive-like symptoms to nonspecific symptoms, such as weight loss and malaise. Imaging, specifically MRI/MRCP, is crucial in diagnosing CCA, staging, and treatment planning. Surgery with chemotherapy is the mainstay treatment option, and other palliative treatment options exist for those who have unresectable disease.

The Establishment of Incidental Bidirectional Naming through Multiple Exemplar Instruction: a Systematic Replication.

Although many neurotypical children acquire untaught word-object relations incidentally from naturally occurring environmental experiences, many children with and without developmental disabilities require specific intervention. This study examined the effects of rotating listener (match and point) and speaker (tact and intraverbal-tact) responses with added echoics during multiple exemplar instruction (MEI) with training sets of stimuli on the acquisition of Incidental Bidirectional Naming (Inc-BiN). Listener-speaker MEI procedures reported in Hawkins et al. European Journal of Behavior Analysis, 10(2), 265-273, (2009) were replicated with procedural modification, new instructors, and new participants (four preschoolers with and without disabilities). The listener-speaker MEI with added echoics consisted of rotating across four response operants: match-with-echoics, point-with-echoics, tact, and intraverbal-tact responses. We measured the establishment of Inc-BiN through the number of the correct untaught listener (point) and untaught speaker (intraverbal-tact) responses for untaught stimuli during the listener-speaker MEI with added echoics. We found that listener-speaker MEI with added echoics was effective in establishing Inc-BiN for 3 of 4 participants.

Glucagon-like peptide 1 receptor agonist, exendin-4, reduces alcohol-associated fatty liver disease.

Fatty liver is the earliest response to excessive ethanol consumption, which increases the susceptibility of the liver to develop advanced stage of liver disease. Our previous studies have revealed that chronic alcohol administration alters metabolic hormone levels and their functions. Of current interest to our laboratory is glucagon-like peptide 1 (GLP-1), a widely studied hormone known to reduce insulin resistance and hepatic fat accumulation in patients with metabolic-associated fatty liver disease. In this study, we examined the beneficial effects of exendin-4 (a GLP-1 receptor agonist) in an experimental rat model of ALD. Male Wistar rats were pair-fed the Lieber-DeCarli control or ethanol diet. After 4 weeks of this feeding regimen, a subset of rats in each group were intraperitoneally injected every other day with either saline or exendin-4 at a dose of 3 nmol/kg/day (total 13 doses) while still being fed their respective diet. At the end of the treatment, rats were fasted for 6 h and glucose tolerance test was conducted. The following day, the rats were euthanized, and the blood and tissue samples collected for subsequent analysis. We found that exendin-4 treatment had no significant effect on body weight gain among the experimental groups. Exendin-4-treated ethanol rats exhibited improved alcohol-induced alterations in liver/body weight and adipose/body weight ratio, serum ALT, NEFA, insulin, adiponectin and hepatic triglyceride levels. Reduction in indices of hepatic steatosis in exendin-4 treated ethanol-fed rats was attributed to improved insulin signaling and fat metabolism. These results strongly suggest that exendin-4 mitigates alcohol-associated hepatic steatosis by regulating fat metabolism.

In-situ tumor vaccination by percutaneous ablative therapy and its synergy with immunotherapeutics: An update on combination therapy.

Percutaneous tumor ablation is now a widely accepted minimally invasive local treatment option offered by interventional radiology and applied to various organs and tumor histology types. It utilizes extreme temperatures to achieve irreversible cellular injury, where ablated tumor interacts with surrounding tissue and host via tissue remodeling and inflammation, clinically manifesting as post-ablation syndrome. During this process, in-situ tumor vaccination occurs, in which tumor neoantigens are released from ablated tissue and can prime one's immune system which would favorably affect both local and remote site disease control. Although successful in priming the immune system, this rarely turns into clinical benefits for local and systemic tumor control due to intrinsic negative immune modulation of the tumor microenvironment. A combination of ablation and immunotherapy has been employed to overcome these and has shown promising preliminary results of synergistic effect without significantly increased risk profiles. The aim of this article is to review the evidence on post-ablation immune response and its synergy with systemic immunotherapies.

Barriers and facilitators for accessing and prescribing hormone therapy in primary care for transgender adults: a scoping review protocol.

OBJECTIVE: The objective of this scoping review is to understand the extent and type of evidence in relation to barriers and facilitators experienced by transgender adults in accessing hormone therapy. It will also explore the experiences of primary care practitioners in prescribing hormone therapy in primary care. INTRODUCTION: Providing care to transgender patients is a rapidly growing area of primary care. Despite the existence of clinical practice guidelines that support the prescription of gender-affirming hormone therapy in primary care, only a small number of primary care providers are offering this care. This review will seek to advance research on this topic by examining the barriers and facilitators of hormone prescription for transgender adults in primary care. INCLUSION CRITERIA: This review will consider research on primary care practitioners who prescribe hormone therapy to transgender adults. It will also focus on transgender adults who seek hormone therapy in primary care. Only studies that examine barriers and facilitators in primary care will be included. The review will include qualitative, quantitative, and mixed methods studies, in addition to systematic reviews and meta-analyses. METHODS: The search will include MEDLINE, CINAHL, EmCare, and Nursing and Allied Health Premium. No date limits will be applied to the search. Only articles written in English will be eligible for inclusion. Articles will be reviewed and data extracted by 2 independent reviewers. The results of the extracted data will be presented in a narrative summary with accompanying tables.

The Shigella Spp. Type III Effector Protein OspB Is a Cysteine Protease.

The type III secretion system is required for virulence of many pathogenic bacteria. Bacterial effector proteins delivered into target host cells by this system modulate host signaling pathways and processes in a manner that promotes infection. Here, we define the activity of the effector protein OspB of the human pathogen Shigella spp., the etiological agent of shigellosis and bacillary dysentery. Using the yeast Saccharomyces cerevisiae as a model organism, we show that OspB sensitizes cells to inhibition of TORC1, the central regulator of growth and metabolism. In silico analyses reveal that OspB bears structural homology to bacterial cysteine proteases that target mammalian cell processes, and we define a conserved cysteine-histidine catalytic dyad required for OspB function. Using yeast genetic screens, we identify a crucial role for the arginine N-degron pathway in the yeast growth inhibition phenotype and show that inositol hexakisphosphate is an OspB cofactor. We find that a yeast substrate for OspB is the TORC1 component Tco89p, proteolytic cleavage of which generates a C-terminal fragment that is targeted for degradation via the arginine N-degron pathway; processing and degradation of Tco89p is required for the OspB phenotype. In all, we demonstrate that the Shigella T3SS effector OspB is a cysteine protease and decipher its interplay with eukaryotic cell processes. IMPORTANCEShigella spp. are important human pathogens and among the leading causes of diarrheal mortality worldwide, especially in children. Virulence depends on the Shigella type III secretion system (T3SS). Definition of the roles of the bacterial effector proteins secreted by the T3SS is key to understanding Shigella pathogenesis. The effector protein OspB contributes to a range of phenotypes during infection, yet the mechanism of action is unknown. Here, we show that S. flexneri OspB possesses cysteine protease activity in both yeast and mammalian cells, and that enzymatic activity of OspB depends on a conserved cysteine-histidine catalytic dyad. We determine how its protease activity sensitizes cells to TORC1 inhibition in yeast, finding that OspB cleaves a component of yeast TORC1, and that the degradation of the C-terminal cleavage product is responsible for OspB-mediated hypersensitivity to TORC1 inhibitors. Thus, OspB is a cysteine protease that depends on a conserved cysteine-histidine catalytic dyad.

Distinct Regulatory Programs Control the Latent Regenerative Potential of Dermal Fibroblasts during Wound Healing.

Dermal fibroblasts exhibit considerable heterogeneity during homeostasis and in response to injury. Defining lineage origins of reparative fibroblasts and regulatory programs that drive fibrosis or, conversely, promote regeneration will be essential for improving healing outcomes. Using complementary fate-mapping approaches, we show that hair follicle mesenchymal progenitors make limited contributions to wound repair. In contrast, extrafollicular progenitors marked by the quiescence-associated factor Hic1 generated the bulk of reparative fibroblasts and exhibited functional divergence, mediating regeneration in the center of the wound neodermis and scar formation in the periphery. Single-cell RNA-seq revealed unique transcriptional, regulatory, and epithelial-mesenchymal crosstalk signatures that enabled mesenchymal competence for regeneration. Integration with scATAC-seq highlighted changes in chromatin accessibility within regeneration-associated loci. Finally, pharmacological modulation of RUNX1 and retinoic acid signaling or genetic deletion of Hic1 within wound-activated fibroblasts was sufficient to modulate healing outcomes, suggesting that reparative fibroblasts have latent but modifiable regenerative capacity.

Transcriptional Profiling of the Adult Hair Follicle Mesenchyme Reveals R-spondin as a Novel Regulator of Dermal Progenitor Function.

The adult hair follicle (HF) undergoes successive regeneration driven by resident epithelial stem cells and neighboring mesenchyme. Recent work described the existence of HF dermal stem cells (hfDSCs), but the genetic regulation of hfDSCs and their daughter cell lineages in HF regeneration remains unknown. Here we prospectively isolate functionally distinct mesenchymal compartment in the HF (dermal cup [DC; includes hfDSCs] and dermal papilla) and define the transcriptional programs involved in hfDSC function and acquisition of divergent mesenchymal fates. From this, we demonstrate cross-compartment mesenchymal signaling within the HF niche, whereby DP-derived R-spondins act to stimulate proliferation of both hfDSCs and epithelial progenitors during HF regeneration. Our findings describe unique transcriptional programs that underlie the functional heterogeneity among specialized fibroblasts within the adult HF and identify a novel regulator of mesenchymal progenitor function during tissue regeneration.

Macrophages Promote Wound-Induced Hair Follicle Regeneration in a CX3CR1- and TGF-ß1-Dependent Manner.

Hair follicle stem cells are regulated by intrafollicular and extrafollicular niche signals. Appropriate hair follicle regeneration relies on the coordinated release and integration of these signals. How immune cells, particularly cutaneous macrophages, influence the hair follicle stem cell niche and regeneration is not well understood. We took advantage of wound-induced hair growth (WIHG) to explore the relationship between wound macrophages and hair follicle regeneration. First, we showed that WIHG is dependent on CD11b+F4/80+ macrophages at 7-11 days after injury. Next, using CX3CR1gfp/+:CCR2rfp/+ mice to capture the dynamic spectrum of macrophage phenotypes during wound healing, we showed that wound macrophages transition from a CX3CR1lo/med to a CX3CR1hi phenotype at the onset of WIHG. Finally, WIHG is abolished in mice deficient for CX3CR1, delayed with pharmacological inhibition of transforming growth factor-ß receptor type 1, and rescued with exogenous transforming growth factor-ß1. Overall, we propose a model in which transforming growth factor-ß1 and CX3CR1 are critical for recruiting and maintaining the CCR2+CX3CR1hiLy6CloTNFα+ macrophages critical for stimulating WIHG.

Benign Metastasizing Leiomyomas Following Myomectomy and Uterine Artery Embolization.

Benign metastasizing leiomyomas (BMLs) are rare sequelae of common uterine leiomyomas and most frequently found in the lungs. Most cases of BMLs occur with a history of prior gynecologic procedures; however, none have yet been reported in association with uterine artery embolization (UAE). This case report highlights the disease course for a 48-yo female with a history of both myomectomy and UAE for uterine fibroids who presented later with bilateral pulmonary BMLs. Though the pathophysiology of BMLs is poorly understood and this case is confounded by prior myomectomy, it does bring into question whether UAE has a role in BML development. Regardless, UAEs have become a routine procedure and interventionalists should be aware of the possibility of BMLs in post-fibroid treatment patient populations.

Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD.

BACKGROUND: The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine (AZA), remain as a mainstay therapy in inflammatory bowel disease (IBD). Differences in metabolism of these drugs lead to individual variation in thiopurine metabolite levels that can determine its therapeutic efficacy and development of adverse reactions. In this update, we will review thiopurine metabolic pathway along with the up-to-date approaches in administering thiopurine medications based on the current literature. METHODS: A search of the PubMed database by 2 independent reviewers identifying 98 articles evaluating thiopurine metabolism and IBD management. RESULTS: Monitoring thiopurine metabolites can assist physicians in optimizing 6-MP and AZA therapy in treating patients with IBD. Of the dosing strategies reviewed, we found evidence for monitoring thiopurine metabolite level, use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of AZA or 6-MP to optimize thiopurine therapy and minimize adverse effects in IBD. CONCLUSIONS: Based on the currently available literature, various dosing strategies to improve therapeutic response and reduce adverse reactions can be considered, including use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of thiopurine.

Low uptake of colorectal cancer screening among African Americans in an integrated Veterans Affairs health care network.

BACKGROUND: African Americans have the highest incidence and mortality from colorectal cancer (CRC). Despite guidelines to initiate screening with colonoscopy at age 45 in African Americans, the CRC incidence remains high in this group. OBJECTIVE: To examine the rates and predictors of CRC screening uptake as well as time to screening in a population of African Americans and non-African Americans in a health care system that minimizes variations in insurance and access. DESIGN: Retrospective cohort study. SETTING: Greater Los Angeles Veterans Affairs (VA) Healthcare System. PATIENTS: Random sample (N = 357) of patients eligible for initial CRC screening. MAIN OUTCOME MEASUREMENTS: Uptake of any screening method; uptake of colonoscopy, in particular; predictors of screening; and time to screening in African Americans and non-African Americans. RESULTS: The overall screening rate by any method was 50%. Adjusted rates for any screening were lower among African Americans than non-African Americans (42% vs 58%; odds ratio [OR] 0.49; 95% confidence interval [CI], 0.31-0.77). Colonoscopic screening was also lower in African Americans (11% vs 23%; adjusted OR 0.43; 95% CI, 0.24-0.77). In addition to race, homelessness, lower service connectedness, taking more prescription drugs, and not seeing a primary care provider within 2 years of screening eligibility predicted lower uptake of screening. Time to screening colonoscopy was longer in African Americans (adjusted hazard ratio 0.43; 95% CI, 0.25-0.75). LIMITATIONS: The sample may not be generalizable. CONCLUSIONS: We found marked disparities in CRC screening despite similar access to care across races. Despite current guidelines aimed at increasing CRC screening in African Americans, participation in screening remained low, and use of colonoscopy was infrequent.

Lower hemoglobin levels in first time mothers from Cebu, Philippines.

OBJECTIVES: The association between parity and hemoglobin status in mothers is unclear. Closely spaced pregnancies may predict decreased hemoglobin in women, as these shorter intervals may limit the time available for iron repletion, or maternal age may be associated with general declines in hemoglobin. This study investigated the association between parity and hemoglobin status in a 1-year birth cohort of mothers from Cebu, Philippines, with variable parities. It was hypothesized that maternal parity would be inversely associated with hemoglobin status and that among multiparous mothers, interbirth interval, and prior breastfeeding duration would be positively associated with hemoglobin level. METHODS: The study design was cross-section with participants (n = 125) recruited from the Cebu Longitudinal Health and Nutrition Survey; all mothers were 24-25 years of age at the time of the study and currently breastfeeding infants less than 3 years of age. Hemoglobin was measured using B-Hemocue Analyzer. Detailed dietary information, health recalls, anthropometrics, and reproductive histories were available on all mothers. RESULTS: Maternal parity ranged from 1 to 6 with an average of 2.2 (1.0) births. In this cross section of parity among similarly aged women, hemoglobin levels were significantly lower for primiparous (12.1 ± 1.8) compared to multiparous mothers (13.2 ± 1.5; P = 0.03), despite similar antianemic usage during gestation. There was no significant association between prior interbirth interval, prior, or current breastfeeding duration and hemoglobin in multiparas. CONCLUSIONS: Low hemoglobin levels of primiparous women in this sample might indicate increased nutritional stress associated with first pregnancy.

Total skin electron beam therapy may be associated with improvement of peripheral blood disease in Sézary syndrome.

Total skin electron beam radiation is an effective therapy for palliation of the cutaneous symptoms of the most common types of cutaneous T-cell lymphomas, mycosis fungoides and Sézary syndrome. We report 4 cases of patients with Sézary syndrome who had significant improvement in their blood burden of malignant cells in addition to complete cutaneous responses to total skin electron beam therapy. The data from these 4 patients illustrate the potential for total skin electron beam to be used as both a skin and blood tumor debulking agent, and not merely as a palliation for skin symptoms.

IL-21 enhances antitumor responses without stimulating proliferation of malignant T cells of patients with Sézary syndrome.

IL-21, a common gamma-chain cytokine secreted by activated CD4+ T cells, influences both humoral and cell-mediated immune responses through the regulation of T, B, dendritic, and natural killer (NK) cells. Sézary syndrome is an advanced form of cutaneous T-cell lymphoma, a clonally derived malignancy of CD4+ T cells that is characterized by profound defects in host cellular immune function. As a modulator of both innate and adaptive immune responses, IL-21 could play an important role in augmenting cell-mediated immunity in these patients. Normal donor and Sézary syndrome patient peripheral blood mononuclear cells were cultured with IL-21 and tested for CD8+ T- and NK-cell activation, NK-cell cytotoxicity, and tumor cell proliferation and apoptosis. IL-21 resulted in a modest increase in CD8+ T- and NK-cell activation, associated with a marked increase in cytolytic activity against both K562 and malignant CD4+ T-cell targets. Although IL-21 failed to demonstrate pro-apoptotic effects on the malignant CD4+ T cells, it is noteworthy that it had no demonstrable proliferative effects on these cells. Thus, IL-21 may play an important role in enhancing the host immune response of Sézary syndrome patients through the increased cytolytic activity of T and NK cells.

Bexarotene blunts malignant T-cell chemotaxis in Sezary syndrome: reduction of chemokine receptor 4-positive lymphocytes and decreased chemotaxis to thymus and activation-regulated chemokine.

The malignant cells in Sezary syndrome express the skin trafficking molecules' cutaneous lymphocyte associated antigen (CLA) and chemokine receptor 4 (CCR4). High levels of the CCR4 ligand, thymus, and activation-regulated chemokine (TARC), have been reported in the blood and skin of patients. The rexinoid X-receptor specific retinoid, bexarotene, has contributed to the resolution of cutaneous disease among patients. To evaluate the effects of bexarotene on skin trafficking molecule expression and chemotaxis, peripheral blood mononuclear cells from Sezary syndrome patients and healthy controls were treated with bexarotene in vitro. CCR4 and CLA expression levels and chemotaxis in response to TARC (6.25 ng/ml) were evaluated among lymphocytes before and after treatment with bexarotene (10 microM). Flow cytometric analysis was performed to evaluate CD4, CD26, CLA, and CCR4 cell surface expression. Transwell migration assays were performed to evaluate chemotaxis to TARC. Prior to treatment, malignant cells exhibited higher CCR4 expression (45-90%) and greater than four times more chemotaxis to TARC compared with healthy controls. After treatment with bexarotene for 36-96 hr, a 28% reduction in CCR4 expression was noted (P < 0.05) among the malignant population with an associated 9% decrease in chemotaxis to TARC (P < 0.05). Our results show that bexarotene may inhibit malignant cell trafficking to the skin through an ability to suppress CCR4 expression among Sezary syndrome lymphocytes.