Single-Cell Transcriptomics of Human and Mouse Lung Cancers Reveals Conserved Myeloid Populations across Individuals and Species.

Tumor-infiltrating myeloid cells (TIMs) comprise monocytes, macrophages, dendritic cells, and neutrophils, and have emerged as key regulators of cancer growth. These cells can diversify into a spectrum of states, which might promote or limit tumor outgrowth but remain poorly understood. Here, we used single-cell RNA sequencing (scRNA-seq) to map TIMs in non-small-cell lung cancer patients. We uncovered 25 TIM states, most of which were reproducibly found across patients. To facilitate translational research of these populations, we also profiled TIMs in mice. In comparing TIMs across species, we identified a near-complete congruence of population structures among dendritic cells and monocytes; conserved neutrophil subsets; and species differences among macrophages. By contrast, myeloid cell population structures in patients' blood showed limited overlap with those of TIMs. This study determines the lung TIM landscape and sets the stage for future investigations into the potential of TIMs as immunotherapy targets.

Psilocybin-assisted group therapy in patients with cancer diagnosed with a major depressive disorder.

BACKGROUND: Depression is common in patients with cancer and is associated with lower treatment adherence and reduced quality of life. Antidepressants and psychotherapy have limited success in improving depression among patients with cancer. This study explored the safety, feasibility, and efficacy of psilocybin-assisted therapy in patients with cancer and major depressive disorder. METHODS: This phase 2, open-label trial enrolled patients with curable and noncurable cancer and major depressive disorder at a single community oncology practice site. A single 25-mg dose of psilocybin was administered simultaneously to cohorts of three to four participants with individual (4.25 hours in 1:1 therapist-to-patient ratio) and group therapeutic support (3.75 hours) before, during, and after psilocybin administration. Outcomes included depression severity, anxiety, pain, demoralization, and disability. RESULTS: Thirty participants completed the study. No psilocybin-related serious adverse events occurred; treatment-related adverse events (e.g., nausea, headache) were generally mild and expected. There were no laboratory or electrocardiogram abnormalities. No suicidality was reported. Efficacy was suggested with a robust reduction in depression severity scores from baseline to posttreatment of 19.1 points (95% CI, 22.3 to -16.0; p < .0001) by week 8. Eighty percent of participants demonstrated a sustained response to psilocybin treatment; 50% showed full remission of depressive symptoms at week 1, which was sustained for 8 weeks. CONCLUSIONS: Psilocybin-assisted therapy in group cohort administration was safe and feasible in patients with cancer and depression. Efficacy was suggested based on clinically meaningful reductions in depressive symptoms. The novel, group-oriented format, compact delivery time, community cancer center setting, and one-to-one therapist-to-patient ratio could also add to therapeutic gains and efficiency of administration. TRIAL REGISTRATION: NCT04593563. PLAIN LANGUAGE SUMMARY: Depression is common in patients with cancer and associated with lower treatment adherence, reduced quality of life, and limited response to antidepressants and psychotherapy. We conducted a phase 2 trial to study a single dose of psilocybin administered in a group therapy setting with one-to-one therapist-to-participant psychological support to patients with curable and noncurable cancer and major depressive disorder. Findings of the study showed safety (no treatment-related serious adverse events or suicidality) with psilocybin and suggested efficacy, with a significant reduction in depression severity scores from baseline to posttreatment. Further investigation is warranted.

mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.

N6-methyladenosine (m6A) modification of mRNA is emerging as an important regulator of gene expression that affects different developmental and biological processes, and altered m6A homeostasis is linked to cancer1-5. m6A modification is catalysed by METTL3 and enriched in the 3' untranslated region of a large subset of mRNAs at sites close to the stop codon5. METTL3 can promote translation but the mechanism and relevance of this process remain unknown1. Here we show that METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop codon, supporting a mechanism of mRNA looping for ribosome recycling and translational control. Electron microscopy reveals the topology of individual polyribosomes with single METTL3 foci in close proximity to 5' cap-binding proteins. We identify a direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit h (eIF3h). METTL3 promotes translation of a large subset of oncogenic mRNAs-including bromodomain-containing protein 4-that is also m6A-modified in human primary lung tumours. The METTL3-eIF3h interaction is required for enhanced translation, formation of densely packed polyribosomes and oncogenic transformation. METTL3 depletion inhibits tumorigenicity and sensitizes lung cancer cells to BRD4 inhibition. These findings uncover a mechanism of translation control that is based on mRNA looping and identify METTL3-eIF3h as a potential therapeutic target for patients with cancer.

Loom: A Modular Open-Source Approach to Rapidly Produce Sensor, Actuator, Datalogger Systems.

In the face of rising population, erratic climate, resource depletion, and increased exposure to natural hazards, environmental monitoring is increasingly important. Satellite data form most of our observations of Earth. On-the-ground observations based on in situ sensor systems are crucial for these remote measurements to be dependable. Providing open-source options to rapidly prototype environmental datalogging systems allows quick advancement of research and monitoring programs. This paper introduces Loom, a development environment for low-power Arduino-programmable microcontrollers. Loom accommodates a range of integrated components including sensors, various datalogging formats, internet connectivity (including Wi-Fi and 4G Long Term Evolution (LTE)), radio telemetry, timing mechanisms, debugging information, and power conservation functions. Additionally, Loom includes unique applications for science, technology, engineering, and mathematics (STEM) education. By establishing modular, reconfigurable, and extensible functionality across components, Loom reduces development time for prototyping new systems. Bug fixes and optimizations achieved in one project benefit all projects that use Loom, enhancing efficiency. Although not a one-size-fits-all solution, this approach has empowered a small group of developers to support larger multidisciplinary teams designing diverse environmental sensing applications for water, soil, atmosphere, agriculture, environmental hazards, scientific monitoring, and education. This paper not only outlines the system design but also discusses alternative approaches explored and key decision points in Loom's development.

Generation and Aerobic Oxidation of Azavinyl Captodative Radicals.

We describe a cascade reaction that selectively incorporates oxygen into the carbon-carbon backbone of alkynes using air as the source. The process starts by lithiating readily available, electron-deficient 1,2,3-triazoles, resulting in an amphoteric lithium ketenimine intermediate. This intermediate can react with both electrophiles and nucleophiles. Under the conditions outlined in this study, we generate azavinyl radicals, which are a rare subset of captodative radicals. When exposed to atmospheric oxygen, these radicals efficiently transform into α-oxygenated amidines─a class of compounds that has not been extensively studied. This process uniquely utilizes molecular oxygen without requiring metal or photocatalysts, and it occurs under mild conditions. Our mechanistic studies provide insights into the intricate sequence involved in the formation and selective capture of azavinyl captodative radicals.

Evaluation of High-Interval Education to Improve Outcomes for Bariatric Patients With Health Disparities.

A correlation of health disparities, socioeconomic barriers, and health literacy were hypothesized as causative factors of poor weight loss, weight regain, and loss to clinical follow-up in postbariatric patients. This study explored nurse practitioner-led interventions to address health disparities and improve outcomes. This pilot project evaluated 3-month weights of an intervention cohort as compared with a retrospective cohort. The intervention cohort received a weekly educational phone call from the clinical nurse practitioner. Quantitative data based on 3-month weights reveal an average excess body weight percentage lost at the 3-month postoperative clinical visit (36.54 ± 0.11, p = .2929) in the retrospective cohort ( n = 30) as compared with the intervention cohort ( n = 30; 33.46 ± 0.11, p = .2929). Participants responding to the barriers screening tool did not correspond with the actual needs represented by the population. Food access and transportation were leading factors affecting weight loss. This project revealed implications including the need for development of bariatric-specific social needs assessments, the need to explore telehealth as a modality to improve patient education, the need to modify education to overcome deficits in health literacy. Findings also validate the role of the nurse practitioner as a leader of multidisciplinary care teams.

Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer.

BACKGROUND: Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence. METHODS: In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life. RESULTS: Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group. CONCLUSIONS: Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.).

Patient reported outcomes for cisplatin and radiation followed by carboplatin/paclitaxel versus carboplatin/paclitaxel for locally advanced endometrial carcinoma: An NRG oncology study.

INTRODUCTION: Chemotherapy plus radiation (Cis-RT + CP) did not demonstrate superiority in prolonging relapse-free survival compared to chemotherapy alone in patients with stage III or IVA endometrial carcinoma. The impact of treatment on quality of life (QOL), neurotoxicity (NTX) and psychometric properties of the gastrointestinal (GI) symptoms subscale during treatment and up to 1 year are described herein. METHODS: QOL assessments were scheduled at baseline, 6 weeks (post completion of RT (Cis-RT + CP) or prior to cycle 3 (CP)), then 18 weeks (end of treatment) and 70 weeks (1 year after the end of treatment) after starting treatment. QOL instruments included the FACT-En TOI, FACT/GOG-neurotoxicity (Ntx) subscale (short), and the gastrointestinal (GI) symptoms subscale. RESULTS: At the end of treatment, patients receiving Cis-RT + CP reported a statistically significant decreased QOL when compared to CP. The decline in QOL was reflected in physical well-being, functional well-being, and endometrial cancer specific concerns, but the minimally important differences (MID) were not considered clinically meaningful. Patients in both groups reported increased chemotherapy-induced Ntx symptoms with the CP group having worse scores and reaching peak symptoms at the time of chemotherapy completion. Patients on Cis-RT + CP reported statistically significantly worse GI symptoms after radiation therapy compared to patients on CP, this occurred across assessment intervals, though the MID was not meaningful. Psychometric evaluations indicated that the GI symptom scale is reliable, valid, and responsive to change. CONCLUSIONS: PROs indicate that the chemoradiotherapy group experienced worse HRQoL and GI toxicity compared to patients randomized to chemotherapy alone for locally advanced endometrial cancer though based on the MID, these were not clinically meaningful differences. The GI symptom subscale was a reliable and valid scale that has value for future trials. TRIAL REGISTRATION: NCT00942357.

Large-scale analysis of BAP1 expression reveals novel associations with clinical and molecular features of malignant pleural mesothelioma.

BRCA1-associated protein-1 (BAP1) expression is commonly lost in several tumors including malignant pleural mesothelioma (MPM). Presence or absence of immunohistochemical BAP1 nuclear staining in tumor cells is currently used for differential diagnosis of MPM. In this study, a large cohort of 596 MPM tumors with available clinical data was analyzed to examine associations of BAP1 staining pattern with clinical and molecular features that may reflect the impact of BAP1 mutation on MPM biology. Cases were classified according to the BAP1 staining pattern of tumor cells. Exome and RNA-sequencing data were available for subsets of cases. Levels of mRNA encoding claudin 15 (CLDN15) and vimentin (VIM) were determined using RT-qPCR on 483 cases to estimate the relative proportions of epithelial-like and mesenchymal-like components in each tumor. Four BAP1 staining patterns were observed: single-pattern nuclear staining (36%), single-pattern cytoplasmic staining (25%), single-pattern absent staining (12%), and combinations of these staining patterns (27%). This study confirmed prior reports that nuclear BAP1 is more frequently associated with wild-type BAP1 and sarcomatoid histology. However, no associations between BAP1 staining pattern(s) and mutations in specific protein domains and/or mutation type were observed. BAP1 staining patterns were significantly associated (p < 0.001) with BAP1 gene expression, MPM histologic subtypes, molecular clusters, and markers of epithelial-to-mesenchymal transition. Frequent observation of combinations of BAP1 staining patterns in MPM tumors indicated intra-tumoral heterogeneity of BAP1 status. Cytoplasmic BAP1 staining was identified as a putative indicator of favorable prognosis in non-epithelioid MPM. In conclusion, novel significant associations among different BAP1 staining patterns and subgroups of MPM tumors were observed, suggesting that the role of BAP1 in tumor progression may be more complex than its presumed tumor suppressor function. Cytoplasmic staining was identified as a putative indicator of favorable prognosis in non-epithelioid MPM, potentially addressing a critical need in clinical decision-making in this disease. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

GOG 244 - The Lymphedema and Gynecologic cancer (LeG) study: The impact of lower-extremity lymphedema on quality of life, psychological adjustment, physical disability, and function.

OBJECTIVE: To assess quality of life (QOL) in patients who developed lower-extremity lymphedema (LLE) after radical gynecologic cancer surgery on prospective clinical trial GOG 244. METHODS: The prospective, national, cooperative group trial GOG-0244 determined the incidence of LLE and risk factors for LLE development, as well as associated impacts on QOL, in newly diagnosed patients undergoing surgery for endometrial, cervical, or vulvar cancer from 6/4/2012-11/17/2014. Patient-reported outcome (PRO) measures of QOL (by the Functional Assessment of Cancer Therapy [FACT]), body image, sexual and vaginal function, limb function, and cancer distress were recorded at baseline (within 14 days before surgery), and at 6, 12, 18, and 24 months after surgery. Assessments of LLE symptoms and disability were completed at the time of lower limb volume measurement. A linear mixed model was applied to examine the association of PROs/QOL with a Gynecologic Cancer Lymphedema Questionnaire (GCLQ) total score incremental change ≥4 (indicative of increased LLE symptoms) from baseline, a formal diagnosis of LLE (per the GCLQ), and limb volume change (LVC) ≥10%. RESULTS: In 768 evaluable patients, those with a GCLQ score change ≥4 from baseline had significantly worse QOL (p < 0.001), body image (p < 0.001), sexual and vaginal function (p < 0.001), limb function (p < 0.001), and cancer distress (p < 0.001). There were no significant differences in sexual activity rates between those with and without LLE symptoms. CONCLUSIONS: LLE is significantly detrimental to QOL, daily function, and body image. Clinical intervention trials to prevent and manage this chronic condition after gynecologic cancer surgery are needed.

Magnetic Sphincter Augmentation Superior to Proton Pump Inhibitors for Regurgitation in a 1-Year Randomized Trial.

BACKGROUND & AIMS: Regurgitative gastroesophageal reflux disease (GERD) refractive to medical treatment is common and caused by mechanical failure of the anti-reflux barrier. We compared the effects of magnetic sphincter augmentation (MSA) with those of proton-pump inhibitors (PPIs) in a randomized trial. METHODS: Patients with moderate to severe regurgitation (assessed by the foregut symptom questionnaire) despite once-daily PPI therapy (n = 152) were randomly assigned to groups given twice-daily PPIs (n = 102) or laparoscopic MSA (n = 50) at 20 sites, from July 2015 through February 2017. Patients answered questions from the foregut-specific reflux disease questionnaire and GERD health-related quality of life survey about regurgitation, heartburn, dysphagia, bloating, diarrhea, flatulence, and medication use, at baseline and 6 and 12 months after treatment. Six months after PPI therapy, MSA was offered to patients with persistent moderate to severe regurgitation and excess reflux episodes during impedance or pH testing on medication. Regurgitation, foregut scores, esophageal acid exposure, and adverse events were evaluated at 1 year. RESULTS: Patients in the MSA group and those who crossed over to the MSA group after PPI therapy (n = 75) had similar outcomes. MSA resulted in control of regurgitation in 72/75 patients (96%); regurgitation control was independent of preoperative response to PPIs. Only 8/43 patients receiving PPIs (19%) reported control of regurgitation. Among the 75 patients who received MSA, 61 (81%) had improvements in GERD health-related quality of life improvement scores (greater than 50%) and 68 patients (91%) discontinued daily PPI use. Proportions of patients with dysphagia decreased from 15% to 7% (P < .005), bloating decreased from 55% to 25%, and esophageal acid exposure time decreased from 10.7% to 1.3% (P < .001) from study entry to 1-year after MSA (Combined P < .001). Seventy percent (48/69) of patients had pH normalization at study completion. MSA was not associated with any peri-operative events, device explants, erosions, or migrations. CONCLUSIONS: In a prospective study, we found MSA to reduce regurgitation in 95% of patients with moderate to severe regurgitation despite once-daily PPI therapy. MSA is superior to twice-daily PPIs therapy in reducing regurgitation. Relief of regurgitation is sustained over 12 months. ClinicalTrials.gov no: NCT02505945.

A biparatopic agonistic antibody that mimics fibroblast growth factor 21 ligand activity.

Bispecific antibodies have become important formats for therapeutic discovery. They allow for potential synergy by simultaneously engaging two separate targets and enable new functions that are not possible to achieve by using a combination of two monospecific antibodies. Antagonistic antibodies dominate drug discovery today, but only a limited number of agonistic antibodies (i.e. those that activate receptor signaling) have been described. For receptors formed by two components, engaging both of these components simultaneously may be required for agonistic signaling. As such, bispecific antibodies may be particularly useful in activating multicomponent receptor complexes. Here, we describe a biparatopic (i.e. targeting two different epitopes on the same target) format that can activate the endocrine fibroblast growth factor (FGF) 21 receptor (FGFR) complex containing ß-Klotho and FGFR1c. This format was constructed by grafting two different antigen-specific VH domains onto the VH and VL positions of an IgG, yielding a tetravalent binder with two potential geometries, a close and a distant, between the two paratopes. Our results revealed that the biparatopic molecule provides activities that are not observed with each paratope alone. Our approach could help address the challenges with heterogeneity inherent in other bispecific formats and could provide the means to adjust intramolecular distances of the antibody domains to drive optimal activity in a bispecific format. In conclusion, this format is versatile, is easy to construct and produce, and opens a new avenue for agonistic antibody discovery and development.

Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration.

Calcimimetics decrease parathyroid hormone (PTH) secretion in patients with secondary hyperparathyroidism. The decrease in PTH should cause a reduction in bone turnover; however, the direct effect of calcimimetics on bone cells, which express the calcium-sensing receptor (CaSR), has not been defined. In this study, we evaluated the direct bone effects of CaSR activation by a calcimimetic (AMG 641) in vitro and in vivo. To create a PTH "clamp," total parathyroidectomy was performed in rats with and without uremia induced by 5/6 nephrectomy, followed by a continuous subcutaneous infusion of PTH. Animals were then treated with either the calcimimetic or vehicle. Calcimimetic administration increased osteoblast number and osteoid volume in normal rats under a PTH clamp. In uremic rats, the elevated PTH concentration led to reduced bone volume and increased bone turnover, and calcimimetic administration decreased plasma PTH. In uremic rats exposed to PTH at 6-fold the usual replacement dose, calcimimetic administration increased osteoblast number, osteoid surface, and bone formation. A 9-fold higher dose of PTH caused an increase in bone turnover that was not altered by the administration of calcimimetic. In an osteosarcoma cell line, the calcimimetic induced Erk1/2 phosphorylation and the expression of osteoblast genes. The addition of a calcilytic resulted in the opposite effect. Moreover, the calcimimetic promoted the osteogenic differentiation and mineralization of human bone marrow mesenchymal stem cells in vitro. Thus, calcimimetic administration has a direct anabolic effect on bone that counteracts the decrease in PTH levels.

Diagnostic value of biopsy sampling in predicting histology in patients with diffuse malignant pleural mesothelioma.

BACKGROUND: The classification of diffuse malignant mesothelioma into epithelioid, biphasic, and sarcomatoid types is based on histologic patterns. The diagnosis is made on biopsies, and because of intratumoral heterogeneity, they may not be representative of the entire tumor. The number and volume of biopsies needed to reach diagnostic accuracy in diffuse malignant mesothelioma and their prognostic value remain unclear. METHODS: This study examined 759 consecutive patients with pleural diffuse malignant mesothelioma treated by pleurectomy/decortication or extrapleural pneumonectomy for the presence of epithelioid and/or sarcomatoid histology and classified both the presurgery biopsies (core-needle or thoracoscopic) and surgical resection specimens. The number and volume of biopsies were correlated with pre- and postsurgery histologies and overall survival. RESULTS: Diffuse malignant mesothelioma was classified as epithelioid (76%), biphasic (18%), sarcomatoid (5%), or indeterminate (1%) in biopsies and as epithelioid (64%), biphasic (32%), and sarcomatoid (4%) in surgical resection specimens (overall concordance, 80.6%). The positive likelihood ratios were 2.4, 13.6, and 90.1 for biopsies with epithelioid, biphasic, and sarcomatoid histologies, respectively. Concordant histologies between biopsies and resections were associated with a higher number of biopsies (median tissue blocks for concordant histologies vs discordant histologies, 3 vs 2; P < .002) but were less associated with a higher volume (median, 1.2 vs 1.1 cm3 ; P = .06). In a multivariate analysis, overall survival was independently predicted by histology in the resection specimen (P < .0001) but not in the biopsy (P = .09). CONCLUSIONS: In contrast to epithelioid histology, sarcomatoid histology in biopsies is highly accurate. Despite intratumoral heterogeneity, the accuracy of histologic classification increases with the number of tissue blocks examined, emphasizing the diagnostic value of extensive sampling by presurgery biopsies.

Autophagy facilitates the release of immunogenic signals following chemotherapy in 3D models of mesothelioma.

We have previously shown that nearly half of mesothelioma patients have tumors with low autophagy and that these patients have a significantly worse outcome than those with high autophagy. We hypothesized that autophagy may be beneficial by facilitating immunogenic cell death (ICD) of tumor cells following chemotherapy. An important hallmark of ICD is that death of tumor cells is preceded or accompanied by the release of damage-associated molecular pattern molecules (DAMPs), which then can stimulate an antitumor immune response. Therefore, we measured how autophagy affected the release of three major DAMPs: high mobility group box 1 (HMGB1), ATP, and calreticulin following chemotherapy. We found that autophagy in three-dimensional (3D) models with low autophagy at baseline could be upregulated with the cell-permeant Tat-BECN1 peptide and confirmed that autophagy in 3D models with high autophagy at baseline could be inhibited with MRT 68921 or ATG7 RNAi, as we have previously shown. In in vitro 3D spheroids, we found that, when autophagy was high or upregulated, DAMPs were released following chemotherapy; however, when autophagy was low or inhibited, DAMPs release was significantly impaired. Similarly, in ex vivo tumors, when autophagy was high or upregulated, HMGB1 was released following chemotherapy but, when autophagy was low, HMGB1 release was not seen. We conclude that autophagy can be upregulated in at least some tumors with low autophagy and that upregulation of autophagy can restore the release of DAMPs following chemotherapy. Autophagy may be necessary for ICD in this tumor.

Laparoscopic magnetic sphincter augmentation versus double-dose proton pump inhibitors for management of moderate-to-severe regurgitation in GERD: a randomized controlled trial.

BACKGROUND AND AIMS: GERD patients frequently complain of regurgitation of gastric contents. Medical therapy with proton-pump inhibitors (PPIs) is frequently ineffective in alleviating regurgitation symptoms, because PPIs do nothing to restore a weak lower esophageal sphincter. Our aim was to compare effectiveness of increased PPI dosing with laparoscopic magnetic sphincter augmentation (MSA) in patients with moderate-to-severe regurgitation despite once-daily PPI therapy. METHODS: One hundred fifty-two patients with GERD, aged ≥21 years with moderate-to-severe regurgitation despite 8 weeks of once-daily PPI therapy, were prospectively enrolled at 21 U.S. sites. Participants were randomized 2:1 to treatment with twice-daily (BID) PPIs (N = 102) or to laparoscopic MSA (N = 50). Standardized foregut symptom questionnaires and ambulatory esophageal reflux monitoring were performed at baseline and at 6 months. Relief of regurgitation, improvement in foregut questionnaire scores, decrease in esophageal acid exposure and reflux events, discontinuation of PPIs, and adverse events were the measures of efficacy. RESULTS: Per protocol, 89% (42/47) of treated patients with MSA reported relief of regurgitation compared with 10% (10/101) of the BID PPI group (P < .001) at the 6-month primary endpoint. By intention-to-treat analysis, 84% (42/50) of patients in the MSA group and 10% (10/102) in the BID PPI group met this primary endpoint (P < .001). Eighty-one percent (38/47) of patients with MSA versus 8% (7/87) of patients with BID PPI had ≥50% improvement in GERD-health-related quality of life scores (P < .001), and 91% (43/47) remained off of PPI therapy. A normal number of reflux episodes and acid exposures was observed in 91% (40/44) and 89% (39/44) of MSA patients, respectively, compared with 58% (46/79) (P < .001) and 75% (59/79) (P = .065) of BID PPI patients at 6 months. No significant safety issues were observed. In MSA patients, 28% reported transient dysphagia; 4% reported ongoing dysphagia. CONCLUSION: Patients with GERD with moderate-to-severe regurgitation, especially despite once-daily PPI treatment, should be considered for minimally invasive treatment with MSA rather than increased PPI therapy. (Clinical trial registration number: NCT02505945.).

GOG 244 - The LymphEdema and Gynecologic cancer (LEG) study: The association between the gynecologic cancer lymphedema questionnaire (GCLQ) and lymphedema of the lower extremity (LLE).

OBJECTIVE: To explore whether patient-reported lymphedema-related symptoms, as measured by the Gynecologic Cancer Lymphedema Questionnaire (GCLQ), are associated with a patient-reported diagnosis of lymphedema of the lower extremity (LLE) and limb volume change (LVC) in patients who have undergone radical surgery, including lymphadenectomy, for endometrial, cervical, or vulvar cancer on Gynecologic Oncology Group (GOG) study 244. METHODS: Patients completed the baseline and at least one post-surgery GCLQ and LVC assessment. The 20-item GCLQ measures seven symptom clusters-aching, heaviness, infection-related, numbness, physical functioning, general swelling, and limb swelling. LLE was defined as a patient self-reported LLE diagnosis on the GCLQ. LVC was measured by volume calculations based on circumferential measurements. A linear mixed model was fitted for change in symptom cluster scores and GCLQ total score and adjusted for disease sites and assessment time. RESULTS: Of 987 eligible patients, 894 were evaluable (endometrial, 719; cervical, 136; vulvar, 39). Of these, 14% reported an LLE diagnosis (endometrial, 11%; cervical, 18%; vulvar, 38%). Significantly more patients diagnosed versus not diagnosed with LLE reported ≥4-point increase from baseline on the GCLQ total score (p < 0.001). Changes from baseline were significantly larger on all GCLQ symptom cluster scores in patients with LLE compared to those without LLE. An LVC increment of >10% was significantly associated with reported general swelling (p < 0.001), heaviness (p = 0.005), infection-related symptoms (p = 0.002), and physical function (p = 0.006). CONCLUSIONS: Patient-reported symptoms, as measured by the GCLQ, discerned those with and without a patient-reported LLE diagnosis and demonstrated predictive value. The GCLQ combined with LVC may enhance our ability to identify LLE.

Magnetoenterography for the Detection of Partial Mesenteric Ischemia.

BACKGROUND: Acute mesenteric ischemia represents a life-threatening gastrointestinal condition. A noninvasive diagnostic modality that identifies mesenteric ischemia patients early in the disease process will enable early surgical intervention. Previous studies have identified significant changes in the small-bowel electrical slow-wave parameters during intestinal ischemia caused by total occlusion of the superior mesenteric artery. The purpose of this study was to use noninvasive biomagnetic techniques to assess functional physiological changes in intestinal slow waves in response to partial mesenteric ischemia. METHODS: We induced progressive intestinal ischemia in normal porcine subjects (n = 10) by slowly increasing the occlusion of the superior mesenteric artery at the following percentages of baseline flow: 50%, 75%, 90%, and 100% while simultaneous transabdominal magnetoenterogram (MENG) and serosal electromyogram (EMG) recordings were being obtained. RESULTS: A statistically significant serosal EMG amplitude decrease was observed at 100% occlusion compared with baseline, whereas no significant change was observed for MENG amplitude at any progressive occlusion levels. MENG recordings showed significant changes in the frequency and percentage of power distributed in bradyenteric and normoenteric frequency ranges at 50%, 75%, 90%, and 100% vessel occlusions. In serosal EMG recordings, a similar percent power distribution (PPD) effect was observed at 75%, 90%, and 100% occlusion levels. Serosal EMG showed a statistically significant increase in tachyenteric PPD at 90% and 100% occlusion. We observed significant increase in tachyenteric PPD only at the 100% occlusion level in MENG recordings. CONCLUSIONS: Ischemic changes in the intestinal slow wave can be detected early and noninvasively even with partial vascular occlusion. Our results suggest that noninvasive MENG may be useful for clinical diagnosis of partial mesenteric ischemia.

Endoscopic technique for closure of enterocutaneous fistulas.

BACKGROUND AND OBJECTIVES: Endoscopic over the scope clip (OTSC) closure represents a new technique for endoscopic management of enteric bleeding and tissue defects such as anastomotic leaks and enterocutaneous (EC) fistulas. We aim to describe our technical approach for OTSC closure of EC fistulas and convey our outcomes. METHODS AND PROCEDURES: This retrospective review includes ten patients who underwent OTSC application for EC fistulas by surgical endoscopists at a US tertiary care hospital from July 2015 to October 2017. Demographic data, along with type of defect, location, duration of lesion, success or failure of OTSC, and nutritional status were compiled. The ACS NSQIP surgical risk calculator was used to project the risk of mortality, complications, length of stay, and risk of readmission had our patients undergone surgical correction of their fistula. RESULTS: Overall success for EC fistula closure was 70%. Acute fistulas were closed with a success rate of 86%. Chronic fistulas were closed successfully in only 33% of cases. Of patients successfully closed, NSQIP-predicted rates of mortality, any complication, and median length of stay were 21.1%, 34.5%, and 9.5 days, respectively. With OTSC, these patients experienced 0 mortalities, 0 complications, and had a median length of stay of 4 days. CONCLUSION: OTSC is an effective adjunctive measure to improving rates of successful closure of EC fistulas and compromised anastomosis. OTSC conveys a markedly improved procedural risk profile as compared to standard surgical correction.

In Vitro and in Vivo Analyses Reveal Profound Effects of Fibroblast Growth Factor 16 as a Metabolic Regulator.

The discovery of brown adipose tissue (BAT) as a key regulator of energy expenditure has sparked interest in identifying novel soluble factors capable of activating inducible BAT (iBAT) to combat obesity. Using a high content cell-based screen, we identified fibroblast growth factor 16 (FGF16) as a potent inducer of several physical and transcriptional characteristics analogous to those of both "classical" BAT and iBAT. Overexpression of Fgf16 in vivo recapitulated several of our in vitro findings, specifically the significant induction of the Ucp1 gene and UCP1 protein expression in inguinal white adipose tissue (iWAT), a common site for emergent active iBAT. Despite significant UCP1 up-regulation in iWAT and dramatic weight loss, the metabolic improvements observed due to Fgf16 overexpression in vivo were not the result of increased energy expenditure, as measured by indirect calorimetric assessment. Instead, a pattern of reduced food and water intake, combined with feces replete with lipid and bile acid, indicated a phenotype more akin to that of starvation and intestinal malabsorption. Gene expression analysis of the liver and ileum indicated alterations in several steps of bile acid metabolism, including hepatic synthesis and reabsorption. Histological analysis of intestinal tissue revealed profound abnormalities in support of this conclusion. The in vivo data, together with FGF receptor binding analysis, indicate that the in vivo outcome observed is the likely result of both direct and indirect mechanisms and probably involves multiple receptors. These results highlight the complexity of FGF signaling in the regulation of various metabolic processes.