Inflammatory Myofibroblastic Tumor of the Esophagus and Stomach Successfully Treated With ALK Inhibitor in a Pediatric Patient: A Case Report and Concise Review of Literature.

An inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm of borderline malignant potential. Nearly half of all IMTs have rearrangement of anaplastic lymphoma kinase (ALK) locus on chromosome 2p23 which can be treated with targeted therapy. Herein, we describe an unusual presentation of IMT involving an anatomical region rarely implicated in this disease process. A 15-year-old male patient came to the ER with dysphagia and coffee ground emesis. On esophagogastroscopy, a nodular luminal obstructing 30 × 50 mm mass in the lower esophagus was found, which was continuous with a large, partially circumferential gastric mass extending from the mid-body to the proximal antrum. Biopsies from esophageal and gastric masses revealed submucosal lesions composed of cytologically bland spindle and epithelioid cells, intermingled with inflammatory infiltrate, for which several immunohistochemical (IHC) stains were performed. The molecular study demonstrated ATIC::ALK fusion. Based on morphological, IHC, and molecular study findings, the diagnosis of ALK-positive IMT was rendered. Because surgical excision was deemed infeasible, the patient was started on ALK-inhibiting therapy with crizotinib. The patient responded well with no evidence of residual or recurrent disease on follow-up imaging or surveillance esophagogastroduodenoscopy. Crizotinib was ultimately discontinued after 10 months of therapy, and the patient continues to undergo surveillance imaging for monitoring of disease burden.

Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis.

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal disease characterized by progressive expansion of kidney cysts. To better understand the cell types and states driving ADPKD progression, we analyze eight ADPKD and five healthy human kidney samples, generating single cell multiomic atlas consisting of ~100,000 single nucleus transcriptomes and ~50,000 single nucleus epigenomes. Activation of proinflammatory, profibrotic signaling pathways are driven by proximal tubular cells with a failed repair transcriptomic signature, proinflammatory fibroblasts and collecting duct cells. We identify GPRC5A as a marker for cyst-lining collecting duct cells that exhibits increased transcription factor binding motif availability for NF-κB, TEAD, CREB and retinoic acid receptors. We identify and validate a distal enhancer regulating GPRC5A expression containing these motifs. This single cell multiomic analysis of human ADPKD reveals previously unrecognized cellular heterogeneity and provides a foundation to develop better diagnostic and therapeutic approaches.

Case Report of an Interprofessional Intervention to Improve Quality of Life for a Fluid-Limited Patient.

This was a case of an 81-year-old female, an amputee, who presented at hospital with a fractured neck of femur after a fall in the nursing home. The patient was being treated for several complex chronic conditions for which 30 regular medicines were prescribed and 100 tablets were being taken per day. The patient was fluid limited to 1500 mL per day but the need to swallow such a high number of tablets meant that there was no fluid allowance available for any other drinks, not even a cup of tea. In the nursing home, the patient had multiple prescribers, not all from the one surgery. The pharmacist conducted a multifaceted review of the patient's medication and lifestyle factors. Working collaboratively with the wider health care team, the intervention was able to reduce the number of medications and improve the patient's quality of life through improving the effectiveness of other lifestyle factors. This case not only showcases pharmacist interventions but also the synergistic benefit of interprofessional working with patients with chronic and complex conditions. This is arguably more critical in rural or remote areas where there is commonly a paucity of most health practitioners, health assistants and technicians.

Impact of COVID-19 Pandemic on Timing of Childhood Cancer Diagnoses.

The COVID-19 pandemic impacted the health care system in unprecedented ways. We reviewed the registry of new cancer patients who presented to the Children's of Mississippi Center for Cancer and Blood Disorders and showed the average number of new pediatric cancer diagnoses dropped during the initial COVID-19 months and rose significantly in June 2020. We must encourage families to seek health care when needed and keep scheduled appointments for routine vaccinations and health maintenance as we know the long-term sequela of delaying health maintenance far outweighs risks at present.

Preoperative Intravenous Versus Oral Acetaminophen in Outpatient Surgery: A Double-Blinded, Randomized Control Trial.

PURPOSE: Preoperative acetaminophen is recognized as an effective part of the multimodal approach to perioperative pain management. The present study, conducted between April 12, 2018 and February 14, 2019, examined whether there are differences in patient-reported pain, postoperative opioid consumption, negative opioid effects, length of postanesthesia care unit stay, and patient satisfaction with pain control between patients who receive intravenous (IV) acetaminophen and patients who receive oral acetaminophen. DESIGN: This double-blinded, randomized controlled trial was conducted among 120 patients undergoing outpatient surgery. METHODS: Patients were randomized to receive preoperatively either intravenous (IV) acetaminophen (and oral placebo) or oral acetaminophen (and IV placebo). Results were analyzed using SPSS statistical software; statistical analyses consisted of Mann-Whitney U test, independent samples t test, and χ2 test. In all analyses, a P value less than .05 was considered significant. FINDINGS: There were no significant differences in any outcome measures based on the route of acetaminophen administration. CONCLUSIONS: The findings of the present study support the practice of administering oral acetaminophen, as opposed to IV acetaminophen, preoperatively as part of the multimodal approach to manage postoperative pain in patients able to tolerate preoperative oral medications.

Analysis of Cardiac Amyloidosis Progression Using Model-Based Markers.

Deposition of amyloid in the heart can lead to cardiac dilation and impair its pumping ability. This ultimately leads to heart failure with worsening symptoms of breathlessness and fatigue due to the progressive loss of elasticity of the myocardium. Biomarkers linked to the clinical deterioration can be crucial in developing effective treatments. However, to date the progression of cardiac amyloidosis is poorly characterized. There is an urgent need to identify key predictors for disease progression and cardiac tissue function. In this proof of concept study, we estimate a group of new markers based on mathematical models of the left ventricle derived from routine clinical magnetic resonance imaging and follow-up scans from the National Amyloidosis Center at the Royal Free in London. Using mechanical modeling and statistical classification, we show that it is possible to predict disease progression. Our predictions agree with clinical assessments in a double-blind test in six out of the seven sample cases studied. Importantly, we find that multiple factors need to be used in the classification, which includes mechanical, geometrical and shape features. No single marker can yield reliable prediction given the complexity of the growth and remodeling process of diseased hearts undergoing high-dimensional shape changes. Our approach is promising in terms of clinical translation but the results presented should be interpreted with caution due to the small sample size.

Enablers and barriers to treatment adherence in heterozygous familial hypercholesterolaemia: a qualitative evidence synthesis.

OBJECTIVES: Individuals with heterozygous familial hypercholesterolaemia (FH) are at high risk of developing cardiovascular disease (CVD). This risk can be substantially reduced with lifelong pharmacological and lifestyle treatment; however, research suggests adherence is poor. We synthesised the qualitative research to identify enablers and barriers to treatment adherence. DESIGN: This study conducted a thematic synthesis of qualitative studies. DATA SOURCES: MEDLINE, Embase, PsycINFO via OVID, Cochrane library and CINAHL databases and grey literature sources were searched through September 2018. ELIGIBILITY CRITERIA: We included studies conducted in individuals with FH, and their family members, which reported primary qualitative data regarding their experiences of and beliefs about their condition and its treatment. DATA EXTRACTION AND SYNTHESIS: Quality assessment was undertaken using the Critical Appraisal Skills Programme for qualitative studies. A thematic synthesis was conducted to uncover descriptive and generate analytical themes. These findings were then used to identify enablers and barriers to treatment adherence for application in clinical practice. RESULTS: 24 papers reporting the findings of 15 population samples (264 individuals with FH and 13 of their family members) across 8 countries were included. Data captured within 20 descriptive themes were considered in relation to treatment adherence and 6 analytical themes were generated: risk assessment; perceived personal control of health; disease identity; family influence; informed decision-making; and incorporating treatment into daily life. These findings were used to identify seven enablers (eg, 'commencement of treatment from a young age') and six barriers (eg, 'incorrect and/or inadequate knowledge of treatment advice') to treatment adherence. There were insufficient data to explore if the findings differed between adults and children. CONCLUSIONS: The findings reveal several enablers and barriers to treatment adherence in individuals with FH. These could be used in clinical practice to facilitate optimal adherence to lifelong treatment thereby minimising the risk of CVD in this vulnerable population. PROSPERO REGISTRATION NUMBER: CRD42018085946.

Quality Improvement Interventions across a Network of Pediatric Hematology-Oncology Clinics.

INTRODUCTION: Achieving improvement in quality among different institutions is challenging. Immunocompromised children with febrile neutropenia are at high risk of severe infection. Pediatric hematology-oncology patients frequently experience central line-associated bloodstream infections (CLABSIs) associated with implanted catheters. A network of 8 pediatric hematology-oncology clinics affiliated with St. Jude Children's Research Hospital launched 2 initiatives designed to reduce the incidence of infections and improve infection treatment. METHODS: We reviewed the timing of antibiotic administration for immunocompromised patients with a fever before and after a quality improvement intervention tailored to each affiliate clinic. We also reviewed the frequency of CLABSIs before and after implementing a central line care bundle for implanted catheters in ambulatory patients. RESULTS: Across the affiliate clinic network, the timing of antibiotic administration improved from the preintervention period (23% of patients received antibiotics within 60 min of registration) to 53% and 73%, in successive postintervention periods. Implementing a central line bundle for implanted catheters was associated with increased compliance and a trend toward increased time between CLABSIs. CONCLUSION: We describe an approach to quality improvement utilizing a system of monitoring with annual clinical audits, development of joint quality improvement initiatives, ongoing education, and focused training of staff for effecting change that improves patient healthcare across multiple institutions.

Age-based versus Risk-based Mammography Screening in Women 40-49 Years Old: A Cross-sectional Study.

Background Risk-based screening in women 40-49 years old has not been evaluated in routine screening mammography practice. Purpose To use a cross-sectional study design to compare the trade-offs of risk-based and age-based screening for women 45 years of age or older to determine short-term outcomes. Materials and Methods A retrospective cross-sectional study was performed by using a database of 20 539 prospectively interpreted consecutive digital screening mammograms in 10 280 average-risk women aged 40-49 years who were screened at an academic medical center between January 1, 2006, and December 31, 2013. Two hypothetical screening scenarios were compared: an age-based (≥45 years) scenario versus a risk-based (a 5-year risk of breast cancer greater than that of an average 50-year-old) scenario. Risk factors for risk-based screening included family history, race, age, prior breast biopsy, and breast density. Outcomes included breast cancers detected at mammography, false-positive mammograms, and benign biopsy findings. Short-term outcomes were compared by using the χ2 test. Results The screening population included 71 148 screening mammograms in 24 928 women with a mean age of 55.5 years ± 8.9 (standard deviation) (age range, 40-74 years). In women 40-49 years old, usual care included 50 screening-detected cancers, 1787 false-positive mammograms, and 384 benign biopsy results. The age-based (≥45 years) screening strategy revealed more cancers than did the risk-based strategy (34 [68%] vs 13 [26%] of 50; P < .001), while prompting more false-positive mammograms (899 [50.3%] vs 216 [12.1%] of 1787; P < .001) and benign biopsy results (175 [45.6%] vs 49 [12.8%] of 384; P < .001). The risk-based strategy demonstrated low levels of eligibility (few screenings) in the 40-44-year age group. Differences in outcomes in the 45-49-year age group explained the overall hypothetical screening strategy differences. Conclusion Risk-based screening for women 40-49 years old includes few women in the 40-44-year age range. Significant trade-offs in the 45-49-year age group explain the overall difference between hypothetical screening scenarios, both of which reduce the benefits as well as the harms of mammography for women 40-49 years old. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Joe and Hayward in this issue.

Mindfulness-based relapse prevention for alcohol dependence: Findings from a randomized controlled trial.

OBJECTIVES: To assess the effects of mindfulness-based relapse prevention for alcohol dependence (MBRP-A) intervention on drinking and related consequences. METHODS: 123 alcohol-dependent adults in early recovery, recruited from outpatient treatment programs, were randomly assigned to MBRP-A (intervention plus usual-care; N = 64) or Control (usual-care-alone; N = 59) group. MBRP-A consisted of eight-weekly sessions and home practice. Outcomes were assessed at baseline, 8 weeks and 26 weeks (18 weeks post-intervention), and compared between groups using repeated measures analysis. RESULTS: Outcome analysis included 112 participants (57 MBRP-A; 55 Control) who provided follow-up data. Participants were 41.0 ±â€¯12.2 years old, 56.2% male, and 91% white. Prior to "quit date," they reported drinking on 59.4 ±â€¯34.8% (averaging 6.1 ±â€¯5.0 drinks/day) and heavy drinking (HD) on 50.4 ±â€¯35.5% of days. Their drinking reduced after the "quit date" (before enrollment) to 0.4 ±â€¯1.7% (HD: 0.1 ±â€¯0.7%) of days. At 26 weeks, the MBRP-A and control groups reported any drinking on 11.5 ±â€¯22.5% and 5.9 ±â€¯11.6% of days and HD on 4.5 ±â€¯9.3% and 3.2 ±â€¯8.7% of days, respectively, without between-group differences (ps ≥ 0.05) in drinking or related consequences during the follow-up period. Three MBRP-A participants reported "relapse," defined as three-consecutive HD days, during the study. Subgroup analysis indicated that greater adherence to session attendance and weekly home practice minutes were associated with improved outcomes. CONCLUSIONS: MBRP-A as an adjunct to usual-care did not show to improve outcomes in alcohol-dependent adults in early recovery compared to usual-care-alone; a return to drinking and relapse to HD were rare in both groups. However, greater adherence to MBRP-A intervention may improve long-term drinking-related outcomes.

Complexities of genetic diagnosis illustrated by an atypical case of congenital hypoplastic anemia.

Diamond-Blackfan Anemia (DBA) is a rare polygenic disorder defined by congenital hypoplastic anemia with marked decrease or absence of bone marrow erythroid precursors. Identifying the specific genetic etiology is important for counseling and clinical management. A 6-yr-old boy with a clinical diagnosis of DBA has been followed by our pediatric hematology team since birth. His clinical course includes transfusion-dependent hypoplastic anemia and progressive autoimmune cytopenias. Genetic testing failed to identify a causative mutation in any of the classical DBA-associated genes. He and his parents underwent trio whole-exome sequencing (WES) with no genetic etiology identified initially. Clinical persistence and suspicion led to testing for adenosine deaminase 2 (ADA2) activity and whole-genome sequencing (WGS) that identified compound heterozygous pathogenic mutations in the ADA2-encoding CECR1 gene, a recently appreciated etiology for congenital hypoplastic anemia. This case illustrates current challenges in genetic testing and how they can be overcome by multidisciplinary expertise in clinical medicine and genomics.

Quantifying predictive capability of electronic health records for the most harmful breast cancer.

Improved prediction of the "most harmful" breast cancers that cause the most substantive morbidity and mortality would enable physicians to target more intense screening and preventive measures at those women who have the highest risk; however, such prediction models for the "most harmful" breast cancers have rarely been developed. Electronic health records (EHRs) represent an underused data source that has great research and clinical potential. Our goal was to quantify the value of EHR variables in the "most harmful" breast cancer risk prediction. We identified 794 subjects who had breast cancer with primary non-benign tumors with their earliest diagnosis on or after 1/1/2004 from an existing personalized medicine data repository, including 395 "most harmful" breast cancer cases and 399 "least harmful" breast cancer cases. For these subjects, we collected EHR data comprised of 6 components: demographics, diagnoses, symptoms, procedures, medications, and laboratory results. We developed two regularized prediction models, Ridge Logistic Regression (Ridge-LR) and Lasso Logistic Regression (Lasso-LR), to predict the "most harmful" breast cancer one year in advance. The area under the ROC curve (AUC) was used to assess model performance. We observed that the AUCs of Ridge-LR and Lasso-LR models were 0.818 and 0.839 respectively. For both the Ridge-LR and Lasso-LR models, the predictive performance of the whole EHR variables was significantly higher than that of each individual component (p<0.001). In conclusion, EHR variables can be used to predict the "most harmful" breast cancer, providing the possibility to personalize care for those women at the highest risk in clinical practice.

Improving breast cancer risk prediction by using demographic risk factors, abnormality features on mammograms and genetic variants.

The predictive capability of combining demographic risk factors, germline genetic variants, and mammogram abnormality features for breast cancer risk prediction is poorly understood. We evaluated the predictive performance of combinations of demographic risk factors, high risk single nucleotide polymorphisms (SNPs), and mammography features for women recommended for breast biopsy in a retrospective case-control study (n = 768) with four logistic regression models. The AUC of the baseline demographic features model was 0.580. Both genetic variants and mammography abnormality features augmented the performance of the baseline model: demographics + SNP (AUC =0.668), demographics + mammography (AUC =0.702). Finally, we found that the demographics + SNP + mammography model (AUC = 0.753) had the greatest predictive power, with a significant performance improvement over the other models. The combination of demographic risk factors, genetic variants and imaging features improves breast cancer risk prediction over prior methods utilizing only a subset of these features.

Hemodynamic effects of the Abdominal Aortic and Junctional Tourniquet in a hemorrhagic swine model.

BACKGROUND: Torso hemorrhage constitutes a leading cause of battlefield mortality. The Abdominal Aortic and Junctional Tourniquet (AAJT) uses a pneumatic bladder to compress the aorta reducing pelvic and lower extremity perfusion; however, concern exists over the risk of caval compression exacerbating hypotension after application. METHODS: Male swine (70-90 kg) were randomized into four groups of 10: presence or absence of hemorrhage and AAJT placement. After a 40% hemorrhage, a 15-min period of hypovolemia was observed before the AAJT application. All animals received two 500 mL boluses of Hextend separated by 30 min. Cardiovascular, pulmonary, and oxygenation values were compared among groups. RESULTS: The AAJT was effective in reducing blood flow to the femoral arteries in both hemorrhaged and nonhemorrhaged animals (P < 0.001 for both groups). Hemorrhage resulted in significant decrease in mean arterial pressure compared with sham controls (23.5 ± 2.4 versus 61.6 ± 7.8 mm Hg, respectively, P < 0.001). AAJT application, compared with untreated controls, resulted in a significant increase in mean arterial pressure and systemic vascular resistance but not in cardiac output, oxygenation, and central venous pressure. Furthermore, no indication of overresuscitation injury was present as evidenced by pulmonary artery pressure and pulmonary histology. CONCLUSIONS: AAJT application in an animal model of severe shock results in a favorable hemodynamic profile because of afterload support. The present study did not demonstrate any adverse consequences because of caval compression, bowel injury, or pulmonary dysfunction. In addition, there does not appear to be any particular intravenous fluid economy achieved by AAJT application.

Mindfulness Meditation and Cognitive Behavioral Therapy Intervention Reduces Pain Severity and Sensitivity in Opioid-Treated Chronic Low Back Pain: Pilot Findings from a Randomized Controlled Trial.

OBJECTIVE: To assess benefits of mindfulness meditation and cognitive behavioral therapy (CBT)-based intervention for opioid-treated chronic low back pain (CLBP). DESIGN: 26-week parallel-arm pilot randomized controlled trial (Intervention and Usual Care versus Usual Care alone). SETTING: Outpatient. SUBJECTS: Adults with CLBP, prescribed ≥30 mg/day of morphine-equivalent dose (MED) for at least 3 months. METHODS: The intervention comprised eight weekly group sessions (meditation and CLBP-specific CBT components) and 30 minutes/day, 6 days/week of at-home practice. Outcome measures were collected at baseline, 8, and 26 weeks: primary-pain severity (Brief Pain Inventory) and function/disability (Oswestry Disability Index); secondary-pain acceptance, opioid dose, pain sensitivity to thermal stimuli, and serum pain-sensitive biomarkers (Interferon-γ; Tumor Necrosis Factor-α; Interleukins 1ß and 6; C-reactive Protein). RESULTS: Thirty-five (21 experimental, 14 control) participants were enrolled and completed the study. They were 51.8 ± 9.7 years old, 80% female, with severe CLBP-related disability (66.7 ± 11.4), moderate pain severity (5.8 ± 1.4), and taking 148.3 ± 129.2 mg/day of MED. Results of the intention-to-treat analysis showed that, compared with controls, the meditation-CBT group reduced pain severity ratings during the study (P = 0.045), with between-group difference in score change reaching 1 point at 26 weeks (95% Confidence Interval: 0.2,1.9; Cohen's d = 0.86), and decreased pain sensitivity to thermal stimuli (P < 0.05), without adverse events. Exploratory analyses suggested a relationship between the extent of meditation practice and the magnitude of intervention benefits. CONCLUSIONS: Meditation-CBT intervention reduced pain severity and sensitivity to experimental thermal pain stimuli in patients with opioid-treated CLBP.

A clip-based protocol for breast boost radiotherapy provides clear target visualisation and demonstrates significant volume reduction over time.

INTRODUCTION: The clinical target volume (CTV) for early stage breast cancer is difficult to clearly identify on planning computed tomography (CT) scans. Surgical clips inserted around the tumour bed should help to identify the CTV, particularly if the seroma has been reabsorbed, and enable tracking of CTV changes over time. METHODS: A surgical clip-based CTV delineation protocol was introduced. CTV visibility and its post-operative shrinkage pattern were assessed. The subjects were 27 early stage breast cancer patients receiving post-operative radiotherapy alone and 15 receiving post-operative chemotherapy followed by radiotherapy. The radiotherapy alone (RT/alone) group received a CT scan at median 25 days post-operatively (CT1rt) and another at 40 Gy, median 68 days (CT2rt). The chemotherapy/RT group (chemo/RT) received a CT scan at median 18 days post-operatively (CT1ch), a planning CT scan at median 126 days (CT2ch), and another at 40 Gy (CT3ch). RESULTS: There was no significant difference (P = 0.08) between the initial mean CTV for each cohort. The RT/alone cohort showed significant CTV volume reduction of 38.4% (P = 0.01) at 40 Gy. The Chemo/RT cohort had significantly reduced volumes between CT1ch: median 54 cm(3) (4-118) and CT2ch: median 16 cm(3), (2-99), (P = 0.01), but no significant volume reduction thereafter. CONCLUSION: Surgical clips enable localisation of the post-surgical seroma for radiotherapy targeting. Most seroma shrinkage occurs early, enabling CT treatment planning to take place at 7 weeks, which is within the 9 weeks recommended to limit disease recurrence.

Determining optimal planning target volume and image guidance policy for post-prostatectomy intensity modulated radiotherapy.

BACKGROUND: There is limited information available on the optimal Planning Target Volume (PTV) expansions and image guidance for post-prostatectomy intensity modulated radiotherapy (PP-IMRT). As the prostate bed does not move in a uniform manner, there is a rationale for anisotropic PTV margins with matching to soft tissue. The aim of this study is to find the combination of PTV expansion and image guidance policy for PP-IMRT that provides the best balance of target coverage whilst minimising dose to the organs at risk. METHODS: The Cone Beam CT (CBCT) images (n = 377) of 40 patients who received PP-IMRT with daily online alignment to bony anatomy (BA) were reviewed. Six different PTV expansions were assessed: 3 published PTV expansions (0.5 cm uniform, 1 cm uniform, and 1 + 0.5 cm posterior) and 3 further anisotropic PTV expansions (Northern Sydney Cancer Centre (NSCC), van Herk, and smaller anisotropic). Each was assessed for size, bladder and rectum coverage and geographic miss. Each CBCT was rematched using a superior soft tissue (SST) and averaged soft tissue (AST) match. Potential geographic miss was assessed using all PTV expansions except the van Herk margin. RESULTS: The 0.5 cm uniform expansion yielded the smallest PTV (median volume = 222.3 cc) and the 1 cm uniform expansion yielded the largest (361.7 cc). The Van Herk expansion includes the largest amount of bladder (28.0 %) and rectum (36.0 %) and the 0.5 cm uniform expansion the smallest (17.1 % bladder; 10.2 % rectum). The van Herk PTV expansion had the least geographic miss with BA matching (4.2 %) and the 0.5 cm uniform margin (28.4 %) the greatest. BA matching resulted in the highest geographic miss rate for all PTVs, followed by SST matching and AST matching. Changing from BA to an AST match decreases potential geographic miss by half to two thirds, depending on the PTV expansion, to <10 % for all PTV expansions. When using the smaller anisotropic PTV expansion, AST matching would reduce the geographic miss rate from 21.0 % with BA matching down to 5.6 %. CONCLUSIONS: Our results suggest the optimal PTV expansion and image guidance policy for PP-IMRT is daily average soft tissue matching using CBCT scans with a small anisotropic PTV expansion of 0.5 cm in all directions apart from a 1 cm expansion in the anterior-posterior direction in the upper prostate bed. Care must be taken to ensure adequate training of Radiation Therapists to perform soft tissue matching with CBCT scans.

Pan-viral-microRNA screening identifies interferon inhibition as a common function of diverse viruses.

Diverse viruses encode regulatory RNAs called microRNAs (miRNAs). Despite much progress, the functions of the majority of viral miRNAs remain unknown. Most previous studies have used biochemical methods to uncover targets of viral miRNAs, but it is unclear what fraction of these targets is functionally important. Here, we apply an alternative strategy based on the premise that assorted viral miRNAs will share functionality. Screening a library of >70 human viral miRNAs showed that three unrelated miRNAs from distantly related herpesviruses significantly inhibited IFN signaling. Strikingly, each of these miRNAs directly reduced expression of the cyclic AMP-responsive element-binding protein (CBP), which as part of the p300-CBP complex, mediates IFN signaling. We show that both 5' and 3' derivatives from Epstein-Barr virus (EBV) encoded miR-BART-18 precursor miRNA (pre-miRNA) and the orthologous pre-miRNA from Rhesus lymphocryptovirus contribute to reducing IFN signaling. Thus, through both convergent and divergent evolutionary mechanisms, varied herpesviral miRNAs share the ability to decrease IFN signaling. Restoring miR-BART-18 to cells infected with an EBV miRNA mutant conveyed a cellular growth advantage upon IFN treatment, and relevant miRNAs from other herpesviruses were able to complement this activity. Blocking miR-BART-18 function in an EBV(+) tumor cell line renders cells more susceptible to IFN-mediated effects. These findings provide a mechanism that can at least partially explain the resistance of some EBV-associated tumors to IFN therapy. Our work suggests that similar pan-viral-miRNA functional-based screening strategies are warranted for determining relevant activities of other viral miRNAs.