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Dermatofibrosarcoma protuberance represents less than 0.1% of all tumors, treatment of which requires wide local excision (≥5cm) but recurrence is not rare. Here we present a 32-year male presented with a swelling of 15 x 6cm over the left lumbar region for which he underwent excision three years ago, the histopathological examination of the swelling, showed a malignant mesenchymal tumor and Immunohistochemistry features were suggestive of Dermatofibrosarcoma protuberance. After three years of interval, he again presented with complaints of swelling in the previously operated site for nine months and underwent excision of the mass with Split Thickness Skin Graft. Although the tumor was confined to the skin and subcutaneous tissue in the present case, the patient didn’t undergo any adjuvant radiotherapy to avoid a possible relapse that would infiltrate deeper structures for the first time. Being a recurrent tumor, long-term follow-up is strongly recommended.

The present research work done with an objective of preparation and evaluation of floating tablets of Febuxostat drug with Hydroxypropylenemethyl cellulose (HPMC), Polyox N-60K, Carbopol 934 P and Guar gum polymers. Floating tablets were based on effervescent approach using sodium bicarbonate a gas releasing agent. Direct compression method was used in present study for preparation of tablets. Effect of polymers was evaluated by studying drug release and floating time. In-vitro drug release profile indicates that sustained nature increased by increasing the concentration of polymer. The formulation containing Polyox N-60K and Carbopol 934 P in combination was optimized as it showed drug release up to 12hrs. Optimized formulation F18 was found stable during stability condition up to 1 month.

Background: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Funding: Takeda and Zinfandel.

Celiac disease (CD) is not commonly associated with obesity; however, many patients are overweight or obese at time of diagnosis. As the number of people in the United States with obesity continues to rise, it is not known if the prevalence of obesity among patients with CD has also increased. This study utilized an electronic health record database incorporating over 360 individual hospitals in the United States (Explorys Incorporated, Cleveland, OH). Adult patients who had an esophagogastroduodenoscopy at least 1 day prior to reporting of CD from the years 2014 to 2018 formed the study population. From 2014 to 2018, 13,410 patients had a diagnosis of CD. The prevalence of obesity was 45,000/100,000 persons in this CD population. Prevalence of class I (BMI 30–34.9), II (BMI 35–39.9), and III (BMI > 40) obesity in patients with CD continued to rise over the 5-year span. Class I obesity had the highest prevalence and Class II the highest prevalence increase when obesity classes were compared. Clinicians should be aware of obesity as a comorbidity of increasing prevalence when providing longitudinal care for patients with CD.

Despite the growing trend of obesity, the utilization of anti-obesity therapeutic interventions is not robust in the USA. We aimed to analyze the trends of anti-obesity pharmacotherapy using a population level database. We used an electronic health record-derived database (Explorys, IBM Watson Health) to identify adults with obesity (body mass index ≥ 30 kg/m2), 2010–2019. Annual rates of anti-obesity pharmacotherapy were analyzed. To assess post-bariatric utilization of these medications, the trend of adults with morbid obesity (BMI ≥ 40 kg/m 2) who were newly started on anti-obesity medications after sleeve gastrectomy was also analyzed. Among 11,195,020 adults with obesity, 274,160 (2.4%) were prescribed anti-obesity medications during the study period with an increase from 1.1% in 2010 to 2.9% in 2019 (p

Background Accidental awareness during general anaesthesia (AAGA) is a complex and rare outcome to investigate in surgical patient populations, particularly obstetric patients. We report the protocol of the Direct Reporting of Awareness in Maternity patients (DREAMY) study, illustrating how the research was designed to address practical and methodological challenges for investigating AAGA in an obstetric cohort. Methods This is the trial protocol of a prospective, multicentre cohort study of patients undergoing obstetric surgery under general anaesthesia. Accidental awareness during general anaesthesia will be detected using three repetitions of standardised direct questioning over 30 days, with responses indicating memories during general anaesthesia verified using structured interviews. Reports will be adjudicated, then classified, in accordance with pre-defined and pre-validated structures, including the Michigan Awareness Classification tool. Quantitative data will be collected on general anaesthesia conduct for all participants. This descriptive study is being conducted in England and aims to recruit a minimum of 2015 patients. Results The DREAMY study was prospectively registered (ClinicalTrials.gov Identifier: NCT03100396) and ethical approval granted. Participant recruitment began in May 2017 and one year follow up concluded in August 2019. Publication of the results is anticipated in 2020. Conclusions The DREAMY study will provide data on incidence, experience and implications of AAGA for obstetric patients, using a robust methodology that will reliably detect and translate subjective AAGA reports into objective outcomes. In addition, the study is expected to improve vigilance for AAGA in participating hospitals and encourage adoption of recommendations for support of patients experiencing AAGA.

These practice recommendations for the management of moderate-to-severe UC were developed using the GRADE framework and in adherence to the standards established by the Institute of Medicine for the development of trustworthy guidelines12, 13. The goal of this guideline is to promote high quality, high value evidence-based care for patients with moderate-to-severe UC. Current evidence supports use of infliximab, adalimumab, golimumab, vedolizumab, and tofacitinib for the induction and maintenance of remission in moderate-severe UC. Thiopurine monotherapy should not be used for induction of remission but may be considered for maintenance of remission; in contrast, methotrexate monotherapy, orally or subcutaneously, should not be used for induction or maintenance of remission. Network meta-analysis suggests that infliximab and vedolizumab may be preferred first-line therapy in biologic-naive patients, rather than standard-dose adalimumab or golimumab, with limited evidence to inform appropriate positioning of tofacitinib. In patients with prior exposure to infliximab, particularly those with primary non-response to induction therapy, vedolizumab or tofacitinib may be preferred over adalimumab or golimumab. Combination therapy of a biologic agent with an immunomodulator is more effective than monotherapy with either agent, though patients, particularly those with less severe disease and those averse to side effects from medications, may opt for monotherapy. In patients with moderate-severe disease activity, at high risk of colectomy, biologic agents with or without an immunomodulator, or tofacitinib, should be used early rather than gradual step up therapy after failure of 5-aminosalicylates. Patients in remission with biologic agents and/or immunomodulators or tofacitinib after prior failure of 5-ASA, may discontinue 5-aminosalicylates. Among hospitalized patients with ASUC, after excluding alternative etiologies, intravenous methylprednisolone doses of 40–60mg/day or equivalent are mainstay of therapy. Routine use of adjunctive antibiotics in patients without infections is not recommended. Patients who are refractory to 3–5 days trial of intravenous corticosteroids, who prefer ongoing medical management, may be treated with either infliximab or cyclosporine. In patients being treated with infliximab, no recommendation can be made regarding routine use of intensive vs. standard infliximab dosing.

Background: Juvenile polyps (JPs) are the most common gastrointestinal polyps diagnosed in children. There is paucity of evidence differentiating polyp burden groups and the presence and significance of neoplastic changes. Methods: A retrospective chart review of patients, ages birth through 18 years with nonsyndromic JPs was performed from 2003 to 2017. Abstracted data included basic demographics, age, clinical presentation, colonoscopy findings, and pathology report. Slides of polyps with neoplasia were reviewed by a pathologist. Results: A total of 213 subjects underwent 326 procedures and 435 polypectomies. Subjects with positive family history, positive gene mutations, or numerous (>10) polyps were excluded. Groups were defined by polyp number (1, 2–4, 5–10). Polyp recurrence on repeat colonoscopy was significantly related to polyp burden (1 polyp: 1.5%/2–4 polyps 19.2%/5–10 polyps 82.6%: P

Introduction Teduglutide, a glucagon-like peptide-2 analog, is a novel therapy for intestinal failure that reduces need for parenteral support, especially in patients without a functional terminal ileum or colon. It can also predispose patients to accelerated progression of gastrointestinal (GI) malignancy and fluid overload. We demographically and clinically characterized American patients prescribed teduglutide. Methods The Explorys database is an aggregate of deidentified patient data from dozens of US healthcare systems. We used SNOMED classification to identify patients prescribed teduglutide from 2015 to 2019. Through the browse cohort feature we determined the demographics, postsurgical anatomy, comorbidities, and indication for teduglutide use among these patients. Results Of approximately 72 million patients, 170 were prescribed teduglutide. A large majority were female (70.6%). Most common etiologies of short-bowel syndrome were intestinal obstruction (52.9%) and Crohn's disease (41.2%). Common postsurgical anatomy included total colectomy (41.2%) and ileostomy. Common incident symptoms included abdominal pain (41.2%) and nausea (23.5%). Thirty (17.6%) patients were prescribed teduglutide despite comorbid heart failure, and 5.9% despite prior GI malignancy. A total of 11.8% of patients had a history of benign GI neoplasms before starting teduglutide. A total of 5.9% of patients had posttreatment formation of colon polyps. Conclusion In a large American database, the teduglutide prescription is rare. Only a minority have postsurgical anatomy associated with the most robust response to teduglutide. Serious adverse events appear rare, but a substantial number of patients are at risk for adverse effects because of the presence of comorbid heart failure or GI neoplasm.

A 63-year-old man with nonalcoholic steatohepatitis cirrhosis who underwent orthotopic liver transplant presented 1 year later with obstructive jaundice because of a biliary stricture. This anastomotic stricture was initially believed to be ischemic, but further investigation revealed malignant biliary obstruction because of encasement of the bile duct by a mass arising from liver segment VII, later determined to be post-transplant lymphoproliferative disorder with widespread metastasis. After reduction of immunosuppression and systemic chemotherapy, he experienced complete remission. This case illustrates the need to consider post-transplantation lymphoproliferative disorder–related biliary stricture in any postorthotopic liver transplantation transplant patient presenting with obstructive jaundice.

We performed a systematic review using 'consensus-based standards for the selection of health measurement instruments' (COSMIN) criteria to identify and evaluate the quality of patient-reported outcome measures (PROM) instruments that have been utilised to assess functional recovery following caesarean section, and determine the optimal instrument for use in this setting. A literature search was performed using five databases. Studies were included if a psychometrically validated instrument was used to assess functional recovery following caesarean section. The COSMIN appraisal checklist was utilised to: assess the quality of included studies reporting PROMs; determine psychometric quality of instruments; and identify the most promising instruments for use after caesarean section. We identified 13 PROMs used to assess the quality of recovery after caesarean section in 20 studies that included 9214 patients. All PROMs contained between two and seven domains. Five out of the 13 PROMs were specific to postpartum recovery. Only two of these PROM instruments were specifically designed for use after caesarean section (Obstetric Quality of Recovery-11 and Recovery from Caesarean Section Scale). We found very few adequate measures of functional recovery following caesarean section. Overall, the Obstetric Quality of Recovery-11 achieved the highest COSMIN standards for any PROM. Future development of PROMs for use after caesarean section should include multiple domains, and undergo validation as outlined by the COSMIN criteria.

Synovial fluids are complex fluids responsible for the exceptional lubrication present in synovial joints. These fluids consist of various constituents, including hyaluronic acid, surface-active proteins (i.e., lubricin), surface-active phospholipids, as well as various other proteins such as human serum albumin and γ -globulin seric proteins, each of them playing an essential role in lubrication. Being the key to the most efficient biotribological systems, this article is intended to review the current understanding of the underlying lubrication mechanisms of the synovial fluids enables prospective usage in numerous applications, especially as a lubricant for hip and knee prosthetics in combatting osteoarthritis. Current research focuses on the determination of the role of proteins in prosthetic lubrication, optimal material combinations for prosthesis, and the effects of relevant physical variables in prosthetic lubrication. The characterization of prosthetic lubrication and wear mechanisms by synovial fluids represents a prominent challenge in tribological research, yet also an important hurdle to overcome towards optimal lubrication of articular prosthetics.

Melanoma, a cancer of the skin, arises from transformed melanocytes. Melanoma has the highest mutational burden of any cancer partially attributed to UV induced DNA damage. Localized melanoma is “curable” by surgical resection and is followed by radiation therapy to eliminate any remaining cancer cells. Targeted therapies against components of the MAPK signaling cascade and immunotherapies which block immune checkpoints have shown remarkable clinical responses, however with the onset of resistance in most patients, and, disease relapse, these patients eventually become refractory to treatments. Although great advances have been made in our understanding of the metastatic process in cancers including melanoma, therapy failure suggests that much remains to be learned and understood about the multi-step process of tumor metastasis. In this review we provide an overview of melanocytic transformation into malignant melanoma and key molecular events that occur during this evolution. A better understanding of the complex processes entailing cancer cell dissemination will improve the mechanistic driven design of therapies that target specific steps involved in cancer metastasis to improve clinical response rates and overall survival in all cancer patients.

Background and Objectives Family caregivers will grow in number as dementia prevalence increases, underscoring the continued importance of equipping these individuals for their new roles and ameliorating the adverse effects of caregiving. Research Design and Methods A three-armed, waitlist, randomized trial design tested Tele-Savvy, an online adaptation of a successful in-person psychoeducation program, the Savvy Caregiver. Tele-Savvy is delivered over 43 days to groups of 6–8 caregivers in 7 weekly synchronous sessions accompanied by 36 brief asynchronous video lessons. We enrolled 23 cohorts of 15 eligible caregivers (N = 261), randomized 2:2:1 to active, attention control, and usual care arms. We assessed caregiver psychological well-being and caregiving mastery at baseline and 3, 6, 9, and 12 months. Multilevel linear models assessed outcomes over the 3 time points examined. The trial was slightly truncated, with Data and Safety Monitoring Board approval, because of the apparent confounding psychological effects of coronavirus disease 2019 restrictions. Results Study findings indicate statistically and clinically significant benefits to Tele-Savvy arm caregivers (with moderate to large effect sizes) in the areas of depression, perceived stress, reaction to care recipients’ behaviors, and enhancement of caregiver mastery. Expected benefits for caregiver burden and anxiety were not found. Discussion and Implications Findings attest to program efficacy and the viability of employing distance means to improve family caregivers’ emotional well-being and sense of mastery in the caregiving role over a 6-month period. Next steps entail finding alternate ways to deliver the program to those with connectivity and/or time constraint problems.

Objective Traditional gauze dressings, occlusive, and transparent film dressings for treating burns cause discomfort to patients either due to sepsis formation or by undesirable skin adherence. This study focuses on fabricating and evaluating a biocompatible patch for the treatment of burn wounds which can promote re-epithelization, reduce healing time, prevent scarring and eschar formation, avoid septicemia, and reduce patient’s discomfort. Methods The proposed patch is bi-layered. The top layer made of polydimethylsiloxane acts as the mechanical support and the bottom layer is a drug matrix with antibacterial drug silver (I) sulfadiazine incorporated in it. Results The fabricated patch is evaluated for various parameters related to wound healing such as the release of the drug, swelling index, bio-adhesion, and ability to kill pathogens. Conclusion The evaluated parameters depicted that the patch was quite efficient for treatment and its design has an advantage over the current treatments available. Significance The unique design of the patch and ease of application can make it popular for use among patients.

Background & Aims Weight loss via lifestyle intervention remains the mainstay of treatment for nonalcoholic fatty liver disease (NAFLD). Endoscopic bariatric and metabolic therapies (EBMTs) have recently been developed as an alternative treatment option for obesity. This study aimed to assess the effect of FDA-approved EBMTs on NAFLD. Methods We searched MEDLINE, EMBASE, Web of Science and Cochrane Central through December 2020 for studies that assessed changes in liver outcomes following EBMT. Primary Outcomes: Liver fibrosis. Secondary Outcomes: Liver biochemistry, steatosis, NAFLD histological changes and insulin sensitivity. The Grading of Recommendations, Assessment, Development, and Evidence (GRADE) approach was conducted to assess quality of evidence. Results Of 4994 potential studies, 18 studies with 863 patients were included. Average weight loss was 14.5% of initial weight at a 6-month follow-up. Primary outcomes: Following EBMT, liver fibrosis significantly reduced by standardized mean difference (SMD) of 0.7 (95% CI, 0.1, 1.3; P = .02). Secondary outcomes: There were significant improvements in other NAFLD surrogates including alanine aminotransferase (-9.0 U/L; 95% CI, -11.6, -6.4; P Conclusions EBMTs appear effective at treating NAFLD with significant improvement in liver fibrosis. Given the worsening NAFLD pandemic and limitations of currently available therapies, EBMTs should be further investigated as a potential treatment option for this patient population.

Background Much progress has been made in understanding melanoma pathogenesis within the last few years through targeted therapies and immunotherapies. However, resistance to small molecule inhibitors remains an obstacle. Immunotherapies such as checkpoint inhibitors against PD-1/PD-L1 lead to durable responses but only in a subset of melanoma patients. Mouse models reflecting human cancers provide invaluable tools towards the translation of basic science discoveries to clinical therapies, but many of these in vivo studies are short-term and do not accurately mimic patient circumstances. Our lab has a melanoma-prone transgenic mouse model which is driven by ectopic expression of a normal neuronal receptor, metabotropic glutamate receptor 1 (GRM1). This mouse model recapitulates melanoma development and progression frequently associated with melanoma patients, where aberrant GRM1 expression is detected. We have shown that in >90% of late-stage melanoma patients, there is atypical GRM1 mediated signaling and expression. Methods In this study, we are using these mice, TGS, to determine the long-term, 18-week, therapeutic consequences of troriluzole, a prodrug for riluzole, which is an inhibitor of glutamatergic signaling plus anti-PD-1, an immune-checkpoint inhibitor. Tumor burden is monitored every 6 weeks for 18 weeks using a small imaging system, IVIS and tumor burden is quantified using ImageJ software. Blood, lymphoid, and tumor samples were collected at several time points during the study for molecular, and immune analyses. Results Preliminary results suggest a gender-biased treatment response and that the combination of troriluzole and anti-PD-1 is more efficacious than either agent alone. In males, a 43.9% reduction in tumor burden was observed while in females there was a 29.6% increase in tumor burden in the combination group compared to vehicle. In concordance, after the removal of the treatment modality, the male mice in the combinatorial group survived 42 days longer compared to vehicle controls with sustained tumor reduction by 68.3%. In female mice no significant advantage in survival or reduction in tumor burden was noted. Conclusions N/A

For years, the endoscopic management of the disorder formerly known as Type III Sphincter of Oddi Dysfunction (SOD) had been controversial. In 2013, the results of the Evaluating Predictors and Interventions in Sphincter of Oddi Dysfunction (EPISOD) trial demonstrated that there was no benefit associated with endoscopic sphincterotomy for patients with Type III SOD. We aimed to assess the utilization of endoscopic sphincterotomy for patients with SOD in a large population database from 2010-2019.We searched a large electronic health record (EHR)-based dataset incorporating over 300 individual hospitals in the United States (Explorys, IBM Watson health, Armonk, NY). Using Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT) we identified patients with a first-ever diagnosis of "disorder of Sphincter of Oddi" annually from 2010-2019. Subclassification of SOD types was not feasible using SNOMED-CT codes. Stratified by year, we identified the proportion of patients with newly-diagnosed SOD undergoing endoscopic sphincterotomy and those receiving newly-prescribed medical therapy.A total of 39,950,800 individual patients were active in the database with 7,750 index diagnoses of SOD during the study period. The incidence rates of SOD increased from 2.4 to 12.8 per 100,000 persons from 2010-2019 (P.001). In parallel, there were reductions in the rates of biliary (34.3% to 24.5%) and pancreatic sphincterotomy (25% to 16.4%), respectively (P.001). Sphincter of Oddi manometry (SOM) was infrequently utilized,20 times in any given year, throughout the study duration. There were no significant increases in new prescriptions for TCAs, nifedipine, or vasodilatory nitrates.Among a wide range of practice settings which do not utilize routine SOM, a sudden and sustained decrease in rates of endoscopic sphincterotomy for newly-diagnosed SOD was observed beginning in 2013. These findings highlight the critical importance of high-quality, multi-center, randomized controlled trials in endoscopy to drive evidence-based changes in real-world clinical practice.

Key Points Question Which patient-reported outcome measures have been used to evaluate global and individual domains of postpartum recovery? Findings In this systematic review, 573 studies were included that used 233 patient-reported outcome measures (201 specific to outpatient studies) to assess postpartum recovery. Meaning Patient-reported outcome measure use among studies assessing postpartum recovery is heterogeneous, which highlights the need to psychometrically evaluate the quality of available patient-reported outcome measures to formulate recommendations regarding which instruments to use., Importance Despite the global delivery rate being approximately 259 deliveries per minute in 2018, postpartum recovery remains poorly defined. Objectives To identify validated patient-reported outcome measures (PROMs) used to assess outpatient and inpatient postpartum recovery, evaluate frequency of PROM use, report the proportion of identified PROMs used within each recovery domain, report the number of published studies within each recovery domain, summarize descriptive data (country of origin, year of study, and journal specialty) for published studies using PROMs to evaluate postpartum recovery, and report PROMs used to evaluate global postpartum recovery. Evidence Review This study followed PRISMA-ScR guidelines. A literature search of 4 databases (MEDLINE through PubMed, Embase, Web of Science, and CINAHL) was performed on July 1, 2019, to identify PROMs used to evaluate 12 author-defined domains of postpartum recovery. All psychometrically evaluated PROMs used to evaluate inpatient or outpatient postpartum recovery after all delivery modes were included. Findings From 8008 screened titles and abstracts, 573 studies (515 outpatient and 58 inpatient) were identified in this review. A total of 201 PROMs were used to assess recovery for outpatient studies and 73 PROMs were used to assess recovery for inpatient studies. The top 5 domains (with highest to lowest numbers of PROMs) used to assess outpatient recovery were psychosocial distress (77 PROMs), surgical complications (26 PROMs), psychosocial support (27 PROMs), motherhood experience (16 PROMs), and sexual function (13 PROMs). Among inpatient studies, the top 5 domains were psychosocial distress (32 PROMs), motherhood experience (7 PROMs), psychosocial support (5 PROMs), fatigue (5 PROMs), and cognition (3 PROMs). The 3 most frequently used PROMs were the Edinburgh Postnatal Depression Scale (267 studies), Short-Form 36 Health Questionnaire (global recovery assessment; 40 studies), and Female Sexual Function Index (35 studies). A total of 24 global recovery PROMs were identified among all included studies. Most studies were undertaken in the United States within the last decade and were published in psychiatry and obstetrics and gynecology journals. Conclusions and Relevance Most PROMs identified in this review evaluated a single domain of recovery. Future research should focus on determining the psychometric properties of individual and global recovery PROMs identified in this review to provide recommendations regarding optimum measures of postpartum recovery., This systematic review identifies patient-reported outcome measures (PROMs) used to evaluate global and individual domains of postpartum recovery.

Background This evidence review was conducted to inform the accompanying clinical practice guideline on the management of cyclic vomiting syndrome (CVS) in adults. Methods We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and focused on interventions aimed at prophylactic management and abortive treatment of adults with CVS. Specifically, this evidence review addresses the following clinical questions: (a) Should the following pharmacologic agents be used for prophylaxis of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, or mitochondrial supplements? (b) Should the following pharmacologic agents be used for abortive treatment: triptans or aprepitant? Results We found very low‐quality evidence to support the use of the following agents for prophylactic and abortive treatment of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, and mitochondrial supplements. We have moderate certainty of evidence for the use of triptans as abortive therapy. We found limited evidence to support the use of ondansetron and the treatment of co‐morbid conditions and complementary therapies. Conclusions This evidence review helps inform the accompanying guideline for the management of adults with CVS which is aimed at helping clinicians, patients, and policymakers, and should improve patient outcomes.

Aberrant glutamatergic signaling has been implicated in altered metabolic activity in many cancer types, including malignant melanoma. Previously, we have illustrated the role of metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous metastatic melanoma in vivo. In this study, we showed that autocrine stimulation constitutively activates the GRM1 receptor and its downstream mitogenic signaling. GRM1-activated (GRM1+) melanomas exhibited significantly increased expression of glutaminase (GLS), which catalyzes the first step in the conversion of glutamine to glutamate. In cultured GRM1+ melanoma cell lines, CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, suppressed cell proliferation, while riluzole, an inhibitor of glutamate release, promoted apoptotic cell death in vitro and in vivo. Combined treatment with CB-839 and riluzole treatment proved to be superior to single-agent treatment, restricting glutamate bioavailability and leading to effective suppression of tumor cell proliferation in vitro and tumor progression in vivo. Hyperactivation of GRM1 in malignant melanoma is an oncogenic driver, which acts independently of canonical melanoma proto-oncogenes, BRAF or NRAS. Overall, these results indicate that expression of GRM1 promotes a metabolic phenotype that supports increased glutamate production and autocrine glutamatergic signaling, which can be pharmacologically targeted by decreasing glutamate bioavailability and the GLS-dependent glutamine to glutamate conversion.Significance:These findings demonstrate that targeting glutaminolytic glutamate bioavailability is an effective therapeutic strategy for GRM1-activated tumors.

The glutamate metabotropic receptor 1 (GRM1) drives oncogenesis when aberrantly activated in melanoma and several other cancers. Metabolomics reveals that patient-derived xenografts with GRM1-positive melanoma tumors exhibit elevated plasma glutamate levels associated with metastatic melanoma in vivo. Stable isotope tracing and GCMS analysis determined that cells expressing GRM1 fuel a substantial fraction of glutamate from glycolytic carbon. Stimulation of GRM1 by glutamate leads to activation of mitogenic signaling pathways, which in turn increases the production of glutamate, fueling autocrine feedback. Implementing a rational drug-targeting strategy, we critically evaluate metabolic bottlenecks in vitro and in vivo. Combined inhibition of glutamate secretion and biosynthesis is an effective rational drug targeting strategy suppressing tumor growth and restricting tumor bioavailability of glutamate., Comment: 6 figures

Anaesthesia is required for surgical procedures to be performed. A thorough knowledge of the principles of anaesthesia, and when each type of anaesthesia is appropriate to use is important.

Simple Summary Within the last few years, accumulating evidences suggest the involvement of altered metabolisms in human diseases including cancer. Metabolism is defined as the sum of biochemical processes in living organisms that produce and consume energy. Tumor growth requires restructuring of cellular metabolism to meet the increasing demand for building blocks to support the ever-increasing cancer cell numbers. The principle of perturbed metabolism in tumors is known for 50–60 years, it regains greater appreciation within the last few years with the realization that there is interdependency between metabolism and all aspects of cellular function including regulation and control of cell growth. Tumor cells do not need stimulation signals from the surrounding environment to promote cell proliferation; in some cases, the tumor cells can generate their own growth signals. In order to support the continuous tumor cell growth even under stressful conditions, a change in metabolism is necessary to fulfill the continuous demand for energy and building blocks. A better understanding of the relationship between tumor environment and altered cell metabolisms will provide valuable insights to design innovative approaches to limit the supply of energy and macromolecules for the treatment of cancer including melanoma. Abstract Aberrant glutamatergic signaling has been implicated in altered metabolic activity and the demand to synthesize biomass in several types of cancer including melanoma. In the last decade, there has been a significant contribution to our understanding of metabolic pathways. An increasing number of studies are now emphasizing the importance of glutamate functioning as a signaling molecule and a building block for cancer progression. To that end, our group has previously illustrated the role of glutamatergic signaling mediated by metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous development of metastatic melanoma in vivo. Glutamate, the natural ligand of GRM1, is one of the most abundant amino acids in humans and the predominant excitatory neurotransmitter in the central nervous system. Elevated levels of glutaminolytic mitochondrial tricarboxylic acid (TCA) cycle intermediates, especially glutamate, have been reported in numerous cancer cells. Herein, we highlight and critically review metabolic bottlenecks that are prevalent during tumor evolution along with therapeutic implications of limiting glutamate bioavailability in tumors.

Ascending aortic pseudoaneurysms pose a difficult therapeutic dilemma. Surgical repair carries high morbidity and mortality risk and may be challenging in patients with unfavorable anatomy or prior aortic surgery. Endovascular repair is difficult due to short landing zones, need for precise delivery, and the lack of adequately sized commercially available devices. This report describes a case of back-table modification of a thoracic aortic stent graft successfully deployed using an "innominate bounce" technique.

Raj Shah,1 Cameron Johnstone,2 Douglas Rappaport,3 Leslie A Bilello,4 William Adamas-Rappaport5 1University of Arizona College of Medicine, Tucson, AZ, USA; 2University of Arizona College of Medicine, Tucson, AZ, USA; 3Department of Emergency Medicine, Mayo Clinic Hospital, Phoenix, AZ, USA; 4Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA; 5Department of Surgery, University of Arizona College of Medicine, Tucson, AZ, USA Background: This study investigates whether students with pre-matriculation, formalized, clinical experience performed better in Step 1 and Step 2 of the United States Medical Licensing Exams (USMLE) compared to students without formal pre-matriculation clinical experience.Methods: This research investigation was a retrospective cohort study conducted at the University of Arizona College of Medicine in Tucson, Arizona, USA, and analyzed students in the Class of 2017 and Class of 2018. Formal clinical experience was defined as registered nurses, physician assistants, nurse practitioners, paramedics, emergency medical technicians, or licensed practical nurses for any amount of time prior to matriculation, as well as scribing for at least 6 months prior to matriculation. Students with any amount of shadowing experience were not considered to have clinical experience. The authors performed multiple regression analyses to investigate the effects of formal clinical experience on USMLE exam performance. Statistical significance was defined as P

OBJECTIVE: To perform a systematic review of randomized trials comparing oral versus intravenous iron therapy to treat postpartum anemia. DATA SOURCES: Data sources were: PubMed (1972–2017); Cochrane Central Register of Controlled Trials, CENTRAL (1972–2017); CINAHL (1972–2017); Web of Science; Excerpta Medica Database, and EMBASE (1972–2017). STUDY ELIGIBILITY CRITERIA: We included randomized trials comparing oral versus intravenous iron monotherapy to treat postpartum anemia (classified as a hemoglobin

Guidelines often use the term expert opinion (EO) to qualify recommendations. We sought to identify the rationale and evidence type in EO recommendations. We searched multiple databases and websites for contemporary guidelines published in the last decade that used the term EO. We identified 1106 references, of which 69 guidelines were included (2390 recommendations, of which 907 were qualified as EO). A rationale for using EO designation was not provided in most (91%) recommendations. The most commonly cited evidence type was extrapolated from studies that did not answer guideline question (40% from randomised trials, 38% from observational studies and 2% from case reports or series). Evidence extrapolated from populations that were different from those addressed in the guideline was found in 2.5% of EO recommendations. We judged 5.6% of EO recommendations as ones that could have been potentially labelled as good practice statements. None of the EO recommendations were explicitly described as being solely dependent on the clinical experience of the panel. The use of EO as a level of evidence in guidelines remains common. A rationale for such use is not explicitly provided in most instances. Most of the time, evidence labelled as EO was indirect evidence and occasionally was very low-quality evidence derived from case series. We posit that the explicit description of evidence type, as opposed to using the label EO, may add clarity and transparency and may ultimately improve uptake of recommendations.

Bladder perforation, especially when atraumatic, is a rare cause of ascites and is often difficult to differentiate from other causes of abdominal pain and ascites in the acute setting. A 43-year-old Caucasian woman with a history of multiple sclerosis presented with acute abdominal pain. A computed tomography (CT) scan of her abdomen and pelvis without contrast revealed ascites, acute kidney injury (AKI) was noted on laboratory workup, and very little urine was drained by Foley catheter. Over the next several days, the patient's clinical condition deteriorated with no definitive diagnosis. A repeat CT of her abdomen and pelvis without contrast showed worsening ascites. She underwent paracentesis, which revealed a markedly elevated ascitic fluid creatinine consistent with bladder rupture. She then underwent an urgent cystogram to confirm the diagnosis, and the urologic consultant recommended conservative management with a Foley catheter to allow for bladder healing. Conservative treatment failed however, and she underwent a surgical repair with drain placement which was followed by an improvement in her clinical condition. This case illustrates a unique presentation of a young woman with multiple sclerosis whose bladder perforation presented as abdominal pain and ascites. The multidisciplinary approach required here highlights the difficulty in reaching this diagnosis which is often undermined in patients who lack a history of traumatic injury. Such delays led to a complicated hospital course for our patient. Maintaining a broad differential for abdominal pain and ascites is essential.

Ipilimumab is a human monoclonal antibody that functions as a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor that is used to treat malignant melanoma. Due to ipilimumab’s removal of immune regulation, specifically through the inactivation of CTLA-4, it is commonly associated with inflammatory and autoimmune events. Gastrointestinal (GI) related immune-related adverse events such as diarrhea occur in 29% of patients with 7.6% of patients specifically suffering from colitis. We describe a case of colonic perforation with ipilimumab use. Our goal is to raise awareness and alert practicing gastroenterologists of this particular adverse effect.​ A 74-year-old male patient presented to the emergency department with complaints of hematochezia, abdominal pain and decreased appetite. The patient’s past medical history included desmoplastic BRAF mutation negative melanoma with metastatic disease to the face, liver, and trigeminal nerve. He underwent his last treatment of ipilimumab three weeks prior to presentation. In total, the patient received four doses of 3 mg/kg of ipilimumab every three weeks. Since the initiation of ipilimumab, he reported diarrhea as its adverse effect, which was treated with tapering doses of prednisone one month at a time. Colonoscopy revealed mucosal ulceration and erosion in the rectum, sigmoid colon, and remaining descending colon up to the splenic flexure and cecum. After the colonoscopy, the patient became tachycardic, hypotensive and complained of sudden abdominal pain. A computed tomographic (CT) scan of the abdomen showed free intraperitoneal air. He was immediately taken to the operating room (OR) for an emergent laparotomy. In the operating room, perforations were noted at the splenic flexure and the cecum with large amounts of succus spilling from the perforations. The majority of the large bowel appeared cyanotic and dusky; consequently, a sub-total colectomy with terminal ileostomy was performed. After the procedure, the patient was started on antibiotics for severe peritonitis and admitted to the intensive care unit (ICU) with septic shock. His clinical status continued to deteriorate due to acute respiratory failure, nosocomial pneumonia, severe protein calorie malnutrition and coagulopathy from disseminated intravascular coagulation (DIC). The patient did not recover from his illness and died a few days later. It is imperative that physicians caring for patients receiving treatment with CTLA-4 inhibitors frequently monitor for and promptly treat possible immune-related adverse effects. For patients with ipilimumab-related colitis, prompt identification of symptoms and early treatment with steroids are crucial in preventing harmful or possibly fatal immune-related adverse events. Gastroenterologists should be wary of this adverse side effect in this high-risk population when performing colonoscopy and take necessary precautions.

Henoch-Schonlein purpura (HSP) is typically seen as a self-limiting disease in children, but can present more severely in adults, especially when there is renal involvement. Management of HSP in adults also remains a controversial topic with very few studies evaluating available therapies. In this case, HSP presenting as a combination of severe gastrointestinal involvement and a rapid decline in renal function in an adult patient directed our therapy. The patient was a 48-year-old Caucasian male with no known past medical history, who presented with a combination of purpuric rash over the lower extremities, severe abdominal pain with upper gastrointestinal bleeding and a rapidly increasing serum creatinine, with hematuria. He initially underwent a skin biopsy, along with investigation for other possible causes, including autoimmune and infectious etiologies, which were negative. He was started on therapy for presumed HSP with intravenous methylprednisolone. The skin biopsy, however, was not conclusive, and the patient had no improvement in his clinical status. He then underwent a kidney biopsy that was consistent with HSP nephritis (immunoglobulin A (IgA) predominant glomerulonephritis with crescents), and esophagogastroduodenoscopy (EGD) that showed mucosal inflammation, ulcerations, and stigmata of bleeding-findings that were consistent with ischemia. Cyclophosphamide was added to the regimen at this time. However, he had worsening abdominal pain, continued gastrointestinal bleeding, now with hematochezia, and also worsening renal function that required dialysis. Plasmapheresis was then initiated on days alternating with dialysis. This resulted in the improvement of his gastrointestinal symptoms, but no recovery was seen of his renal function, and the patient required outpatient dialysis. This case report exhibits the unique presentation of severe gastrointestinal (GI) manifestations and rapid progression to renal failure in an adult patient with partial resolution of his severe manifestation after therapy was escalated as above. There was no established protocol that guided this therapy, which reflects the need for more studies on adult HSP.

Giardia lamblia (G. lamblia)-filled pancreatic masses are a rarely reported entity. Furthermore, there are only a few case reports in literature on the association of these masses with cancer. We present a case of a G. lamblia-filled pancreatic cystic mass in a patient with a history of T-cell-rich B-cell lymphoma. The authors performed a PubMed search using (Medical Subject Headings) MeSH terms of pancreas, mass, Giardia, and lymphoma. A 53-year-old male with past medical and surgical history of T-cell-rich B-cell lymphoma, status post R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) therapy with positron emission tomography (PET) scan showing no residual disease, essential hypertension, and alcohol use disorder presented to the emergency department (ED) with epigastric pain and nausea for one week. Computed tomography (CT) scan of the abdomen showed a 2.3 cm hypodense pancreatic cystic mass. This was a new finding when compared to his prior abdominal imaging. Fine needle aspiration (FNA) biopsy of the mass showed lymphocytes, reactive atypical epithelial cells, and numerous organisms consistent with Giardia lamblia. He was treated with metronidazole 250 mg by mouth three times a day (TID) for five days. Follow-up magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) showed complete resolution of the pancreatic mass. There are only a few case reports on G. lamblia in the pancreas. The pathologist indicated sheets of numerous Giardia in the sample, making small bowel contamination less likely and G. lamblia aspirate from the pancreas more probable as the source. The authors hypothesize that this patient may have had chronic G. lamblia infection as a potential cause for the T-cell-rich B-cell lymphoma manifestation. The patient reported travel to an area with possible exposure to G. lamblia one year prior to presentation with the lymphoma. During that time he had increasing abdominal pain, intermittent chronic diarrhea, and weight loss. G. lamblia's mechanism of action has been theorized to involve induction of pro-apoptotic factors, intestinal barrier dysfunction, up-regulation of cell-cycle genes, and crypt hyperplasia. The mechanism of action of pancreatic masses filled with G. lamblia and the association of G. lamblia and cancer is not completely understood. Further research is required to better understand these possible phenomena as it can help us better comprehend G. lamblia, its associations, and new cancer etiologies.

Our laboratory previously described the oncogenic properties of metabotropic glutamate receptor 1 (mGluR1) in melanocytes. mGluR1 transformed immortalized mouse melanocytes in vitro and induced vigorous tumor formation in vivo. Subsequently, we observed the activation of PI3K/AKT in mGluR1-mediated melanocytic tumorigenesis in vivo. In particular, we identified AKT2 being the predominant isoform contributing to the activation of AKT. Suppression of Grm1 or AKT2 using an inducible Tet-R siRNA system resulted in a 60 or 30% reduction, respectively, in in vivo tumorigenesis. We show that simultaneous downregulation of Grm1 plus AKT2 results in a reduction of approximately 80% in tumor volumes, suggesting that both mGluR1 and AKT2 contribute to the tumorigenic phenotype in vivo. The discrepancy between the mild in vitro transformation characteristics and the aggressive in vivo tumorigenic phenotypes of these stable mGluR1-melanocytic clones led us to investigate the possible involvement of other growth factors. Here, we highlight a potential crosstalk network between mGluR1 and tyrosine kinase, insulin-like growth factor 1 receptor (IGF-1R).

Aberrant glutamatergic signaling has been implicated in multiple metabolic processes and several types of cancer. Our laboratory has previously illustrated the role of metabotropic glutamate receptor 1 (GRM1), a G-protein coupled receptor, in neoplastic transformation of melanocytes in vitro and spontaneous development of metastatic melanoma in vivo. Here, we demonstrate significant overexpression of glutaminase (GLS) in GRM1 expressing melanoma cells, resulting in excess production of GRM1’s natural ligand, glutamate, and the establishment of autocrine loops. GLS catalyzes the first step in glutamine metabolism–the conversion of glutamine to glutamate before entering the TCA cycle. Comparison of glutamate levels in circulating blood plasma between melanoma prone GRM1-transgenic and wild type mice showed elevated glutamate levels in melanoma prone GRM1-transgenic mice, suggesting that aberrant GRM1 expression also promotes an increase in circulating glutamate, to ensure constitutive activation of the GRM1 receptor and its downstream signaling effecters in vivo. We also discovered that manipulation of GRM1 expression by genetic means led to robust parallel changes in metabolite expression levels and intracellular glutamate concentrations by mass spectrometry analysis, as well as the endogenous levels of GLS in melanoma cells, suggesting a strong association between GRM1 and GLS. Inclusion of CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, resulted in significant inhibition of GRM1+ melanoma cell proliferation compared to GRM1- ones. The sensitivity of GRM1+ melanoma cells to modulation of GLS points to the dependency of these cells to glutamate amounts via GLS activity. We also demonstrated that treatment with Riluzole, an inhibitor of glutamatergic signaling by decreasing the available ligand, glutamate, led to significantly reduced melanoma cell proliferation in vitro and tumor progression in vivo. We found that simultaneous targeting of glutamate production (CB-839) and release (Riluzole) in GRM1+ melanoma cells led to additive suppression of cell proliferation in vitro. Most importantly, disruption of GRM1 signaling through combined actions of CB-839 and Riluzole significantly suppressed tumor growth in two independent xenograft mouse models of melanoma, with no obvious symptoms of toxicity detected in these mice. Taken together, these results describe a novel pathway for GRM1-mediated tumorigenesis through rewiring of cellular metabolic networks. We are continuing to investigate the mechanisms and regulation of GLS in our experimental system, with the goal of developing a rational strategy for the treatment of GRM1-expressing cancers. Citation Format: Raj Shah, Simar Singh, Kevinn Eddy, Fabian Filipp, Suzie Chen. Concurrent inhibition of glutaminase (GLS) and metabotropic receptor 1 (GRM1) reduced glutamate bioavailability and led to a decrease in GRM1-expressing melanoma cell proliferation in vitro and tumor progression in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1839.

Aberrant glutamatergic signaling has been implicated in many cancer types. Our laboratory has previously illustrated the role of metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous metastatic melanoma in vivo. Glutamate, the natural ligand of GRM1 is also the predominant excitatory neurotransmitter in the central nervous system. We have demonstrated significant upregulation of glutaminase (GLS) expression in GRM1 expressing melanoma cells, resulting in excess glutamate production and the establishment of autocrine loops in vitro. GLS catalyzes the first step in glutamine metabolism–the conversion of glutamine to glutamate. Comparison of glutamate levels in circulating blood plasma between melanoma prone and wild type mice showed elevated glutamate levels in melanoma prone GRM1-transgenic mice, suggesting that aberrant GRM1 expression also promotes an increase in circulating glutamate, to ensure constitutive activation of the GRM1 receptor and its downstream signaling affecters in vivo. Inclusion of CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, resulted in significant inhibition of GRM1+ melanoma cell proliferation compared to GRM1- ones. We also demonstrated that treatment with Riluzole, an inhibitor of glutamatergic signaling by decreasing the available ligand, glutamate, led to significantly reduced melanoma cell proliferation in vitro and tumor progression in vivo. We found that simultaneous targeting of glutamate production (CB-839) and release (Riluzole) in GRM1+ melanoma cells led to synergistic suppression of cell proliferation in vitro. Furthermore, we found that CB-839 altered the function not the expression of GLS in melanoma cells. Additionally, we also discovered that manipulation of GRM1 expression by genetic means led to robust parallel changes in gene expression levels and intracellular glutamate concentrations by mass spectrometry analysis, as well as the endogenous levels of GLS in melanoma cells, suggesting association between GRM1 and GLS. The sensitivity of GRM1+ melanoma cells to modulation of GLS point to the dependency of these cells to glutamate amounts via GLS activity. We are continuing to investigate the mechanisms and regulation of GLS in our experimental system, with the goal of developing a rational approach for the treatment of GRM1 expressing tumors. Citation Format: Raj Shah, Mengying Zhu, Andrew Boreland, Fabian Filipp, Suzie Chen. Targeted inhibition of glutaminase in GRM1-expressing melanoma cells inhibits cell proliferation by reducing glutamate bioavailability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5493.

Question: A 35-year-old woman presented with a 3-month history of postprandial abdominal discomfort and vomiting. The patient’s history included left jugular foramen schwannoma with involvement of the vagus and spinal accessory nerves (cranial nerves X and XI) treated with left level II/III neck dissection 4 months before presentation; intraoperatively, electromyography (EMG) monitoring confirmed transection of both nerves in the process of tumor resection. Physical examination yielded a soft, nondistended abdomen with bowel sounds present; no guarding, rebound, or bruits were found. The only laboratory abnormality included a mildly elevated leukocyte count of 11.7 10/L (normal range, 3.5-10.5 10/L). Abdominal computed tomographic imaging demonstrated pronounced gallbladder contraction (Figure A [transverse plane] and Figure B [coronal plane]; arrows) without additional intra-abdominal pathology. Subsequent abdominal ultrasound performed in the fasting state also demonstrated gallbladder contraction (Figure C). The patient proceeded to cholecystectomy for diagnostic and therapeutic intent. Postoperative surgical pathology revealed chronic inflammation and thickened muscularis mucosa of the gallbladder (Figure D; star indicates thickened muscularis mucosa). After cholecystectomy, the patient reported complete symptomatic resolution. What are the diagnosis and the likely etiology? Look on page 47 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

122 Background: GRM1 transgenic mice in an immune competent background (C57BL6) develope melanoma with 100% penetrance (TG-3 mice). Ectopic expression of GRM1 in immortalized mouse melanocytes (MelanA) produce cells (MASS20) that are tumorigenic in both SCID and immune competent C57BL6 mice. We have examined the downstream events of GRM1 signaling that allow transformed cells to evade immune destruction. Methods: Cytokine antibody arrays and Western blot were used to examine differences in cytokine expression between MASS20 cells and parental controls. Next, we cultured C57BL6 bone marrow cells in MASS20 conditioned medium for 24 and 48 hours and determined resultant M2 macrophage levels. Finally, we used oral weekly liposome clodronate (LC) treatment to deplete macrophages in murine models to determine the effect on tumor growth. Results: MASS20 cells produce higher levels of M-CSF and CCL2 as compared with control cells. These two cytokines recruit and induce the polarization of tumor associated macrophages (TAM) to increase the M2 fraction resulting in accelerated tumor progression. Culturing C57BL6 bone marrow cells in MASS20 conditioned medium increased expression of the M2 macrophage marker arginase1 at both time points. Weekly oral LC treatment to C57BL6 mice greatly inhibited the growth of MASS20 tumors as compared to growth in control animals. Single-cell suspensions of spleen and tumor cells from these animals were subjected to flow cytometry and showed that LC treatment depleted macrophages by 90% in the spleen, and increased the percentage of cd8+T and cd335+ NK cells in tumors from treated mice as compared to controls. Finally, we treated TG-3 transgenic mice with weekly oral LC and found that treated animals still developed tumors, but progression was greatly slowed, and survival greatly prolonged, compared to untreated animals. Within 1 week of stopping LC in the treated animals there was rapid growth of the tumors. These findings suggest a link between GRM1-signal transduction and TAM-induced suppression of tumor-immunity in melanoma. Conclusions: We conclude that GRM1-induced suppression of tumor immunity occurs through induction of M2 macrophages in the tumor microenvironment.

Metabotropic glutamate receptor 1 (mGluR1/Grm1) is a member of the G-protein-coupled receptor superfamily, which was once thought to only participate in synaptic transmission and neuronal excitability, but has more recently been implicated in non-neuronal tissue functions. We previously described the oncogenic properties of Grm1 in cultured melanocytes in vitro and in spontaneous melanoma development with 100 % penetrance in vivo. Aberrant mGluR1 expression was detected in 60–80 % of human melanoma cell lines and biopsy samples. As most human cancers are of epithelial origin, we utilized immortalized mouse mammary epithelial cells (iMMECs) as a model system to study the transformative properties of Grm1. We introduced Grm1 into iMMECs and isolated several stable mGluR1-expressing clones. Phenotypic alterations in mammary acinar architecture were assessed using three-dimensional morphogenesis assays. We found that mGluR1-expressing iMMECs exhibited delayed lumen formation in association with decreased central acinar cell death, disrupted cell polarity, and a dramatic increase in the activation of the mitogen-activated protein kinase pathway. Orthotopic implantation of mGluR1-expressing iMMEC clones into mammary fat pads of immunodeficient nude mice resulted in mammary tumor formation in vivo. Persistent mGluR1 expression was required for the maintenance of the tumorigenic phenotypes in vitro and in vivo, as demonstrated by an inducible Grm1-silencing RNA system. Furthermore, mGluR1 was found be expressed in human breast cancer cell lines and breast tumor biopsies. Elevated levels of extracellular glutamate were observed in mGluR1-expressing breast cancer cell lines and concurrent treatment of MCF7 xenografts with glutamate release inhibitor, riluzole, and an AKT inhibitor led to suppression of tumor progression. Our results are likely relevant to human breast cancer, highlighting a putative role of mGluR1 in the pathophysiology of breast cancer and the potential of mGluR1 as a novel therapeutic target.