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Background Weak alar cartilage and lack of soft tissue on the cleft side are considered to be the main critical factors leading to the asymmetry of bilateral nostrils. The costal cartilage can provide strong structural support and can be used to maintain long-term stability of nostril shape after surgical correction. With the advancement in rhinoplasty techniques, the application and understanding of costal cartilage in cleft lip nasal deformity is still on going. Herein, we present our technique of applying costal cartilage to provide nostril support and correct asymmetry in Asian patients with unilateral secondary cleft lip nasal deformity. Methods Ninety-seven patients who underwent nostril asymmetry correction from January 1, 2013, to October 31, 2018, were analyzed retrospectively. Modified integrative alar cartilage strut and diced nostril augmentation with costal cartilage were implemented to improve the collapsed and flat cleft-side nostril. The release and restoration of muscle and bone were also performed when required. Surgical outcomes were analyzed based on the comparison of nostril parameters, the shape and contour, and symmetry of bilateral nostrils after surgery. During postoperative follow-up, the patients' satisfactions with the corrective outcomes were also investigated. Results All patients received the corrective operations with complete survival of all implanted cartilages. The nostril width was narrower in postoperative group (P < 0.05). The nostril height and long axis angle were higher postoperatively (P < 0.05). After correction, the proportion of moderate type increased from 13.4% to 80.4%, whereas the proportion of horizontal type decreased from 86.6% to 17.5%. The symmetry score on the nostril parameters manifested the rate of high score (AS >3) in postoperative groups were 84.5%, 93.8%, and 87.6% for width, height, and angle of the long axis, respectively. They were higher compared with those of preoperative group (0%). More than 95% of the patients were satisfied with the overall aesthetic outcome of the surgery. Conclusions Through ameliorating its constructive technology and optimizing its filling form, the modified use of costal cartilage displayed excellent correction effects in the width, height, and long axis angle asymmetry of Asian patients' nostril. Precise and comprehensive rhinoplasty technique is the cornerstone for achieving satisfactory long-term aesthetic outcomes, especially in severe cases, such as secondary cleft lip nasal deformity.

Microglial calcium signaling underlies a number of key physiological and pathological processes in situ, but has not been studied in vivo in awake mice. Using multiple GCaMP6 variants targeted to microglia, we assessed how microglial calcium signaling responds to alterations in neuronal activity across a wide range. We find that only a small subset of microglial somata and processes exhibited spontaneous calcium transients in a chronic window preparation. However, hyperactive shifts in neuronal activity (kainate status epilepticus and CaMKIIa Gq DREADD activation) triggered increased microglial process calcium signaling, often concomitant with process extension. Additionally, hypoactive shifts in neuronal activity (isoflurane anesthesia and CaMKIIa Gi DREADD activation) also increased microglial process calcium signaling. Under hypoactive neuronal conditions, microglia also exhibited process extension and outgrowth with greater calcium signaling. Our work reveals that microglia have highly distinct microdomain signaling, and that processes specifically respond to bi-directional shifts in neuronal activity through increased calcium signaling.

Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.

Aim/Objectives/Background: The goal of therapy with unsealed radiopharmaceutical sources is to provide either cure or significant prolongation of disease-specific survival, and effective reduction and/or prevention of adverse disease-related symptoms or untoward events while minimizing treatment-associated side effects and complications. Radium-223 dichloride (radium-223) is an alpha particle–emitting isotope used for targeted bone therapy. This practice parameter is intended to guide appropriately trained and licensed physicians performing therapy with radium-223. Such therapy requires close cooperation and communication between the physicians who are responsible for the clinical management of the patient and those who administer radiopharmaceutical therapy and manage the attendant side effects. Adherence to this parameter should help to maximize the efficacious use of radium-223, maintain safe conditions, and ensure compliance with applicable regulations. Methods: This practice parameter was developed according to the process described on the American College of Radiology (ACR) website (“The Process for Developing ACR Practice Parameters and Technical Standards,” www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the American College of Nuclear Medicine (ACNM), the American Society for Radiation Oncology (ASTRO), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). All these societies contributed to the development of the practice parameter and approved the final document. Results: This practice parameter addresses the many factors which contribute to appropriate, safe, and effective clinical use of radium-223. Topics addressed include qualifications and responsibilities of personnel, specifications of patient examination and treatment; documentation, radiation safety, quality control/improvement, infection control, and patient education. Conclusions: This practice parameter is intended as a tool to guide clinical use of radium-223 with the goal of facilitating safe and effective medical care based on current knowledge, available resources and patient needs. The sole purpose of this document is to assist practitioners in achieving this objective.

Mutations in the transcription factor FOXC2 are predominately associated with lymphedema. Herein, we demonstrate a key role for related factor FOXC1, in addition to FOXC2, in regulating cytoskeletal activity in lymphatic valves. FOXC1 is induced by laminar, but not oscillatory, shear and inducible, endothelial-specific deletion impaired postnatal lymphatic valve maturation in mice. However, deletion of Foxc2 induced valve degeneration, which is exacerbated in Foxc1; Foxc2 mutants. FOXC1 knockdown (KD) in human lymphatic endothelial cells increased focal adhesions and actin stress fibers whereas FOXC2-KD increased focal adherens and disrupted cell junctions, mediated by increased ROCK activation. ROCK inhibition rescued cytoskeletal or junctional integrity changes induced by inactivation of FOXC1 and FOXC2 invitro and vivo respectively, but only ameliorated valve degeneration in Foxc2 mutants. These results identify both FOXC1 and FOXC2 as mediators of mechanotransduction in the postnatal lymphatic vasculature and posit cytoskeletal signaling as a therapeutic target in lymphatic pathologies.

Objective: Laser acupuncture has become increasingly attractive in clinical practice, especially for patients with needle phobias well as elderly people and children. However, literature concerning the safety of laser acupuncture has been limited. This systematic review synthesizes the current available literature on the safety of laser acupuncture. Methods: Ovid MEDLINE, ® Epub Ahead of Print, In-Process & Other Non-Indexed Citations Daily, Ovid Embase, Scopus, and EBM Reviews—Cochrane Central Register of Controlled Trials databases were searched for available randomized controlled trials (RCTs) on laser acupuncture. Safety data were extracted from the included studies. Adverse events (AEs) data were extracted and assessed in terms of severity and causality. Results: Of 737 articles, 21 RCTs were included. The majority of these RCTs reported that laser acupuncture was safe, without AEs; 6 trials reported AEs (including tingling, pain flare-ups, and transient fatigue). All AEs were mild and resolved spontaneously within 24 hours. The causal relationship between AEs and laser acupuncture was felt to be “certain” in 4 studies, “probable” in 1 study, and “possible” in 1 study. AEs were collected and monitored by evaluation methods in 7 trials: 5 with AE questionnaires, 1 with a checklist, and 1 with oral reports. Conclusions: Laser acupuncture appears to be a safe therapy associated with few mild and transient AEs. However, given the heterogeneity of current studies, large, well-designed placebo-controlled RCTs with rigorous evaluation methods are needed to assess the safety of laser acupuncture more completely.

Abstract Introduction Post-traumatic stress disorder (PTSD) is characterized by persistent mental and emotional stress following one or more significant physical or psychological traumatic incidents earlier in life. Vivid recall of the events, including traumatic nightmares, and prominent sleep disturbance are usual in PTSD. Previous studies have suggested that PTSD may share some clinical features with idiopathic REM sleep behavior disorder (iRBD) including altered REM sleep without atonia (RSWA) levels. Our group has previously found evidence for altered RSWA control in patients with psychiatric disease, including a pilot sample of PTSD patients with iRBD. We aimed to comparatively analyze RSWA levels between patients with PTSD, PTSD and RBD (PTSD+RBD), iRBD, and controls. Methods We selected 18 PTSD, 18 PTSD+RBD, 15 iRBD, and 51 healthy control patients matched for age and sex from the Mayo Clinic Center for Sleep Medicine’s polysomnography database for RSWA quantification. RSWA amounts in the submentalis (SM) and anterior tibialis (AT) were quantitatively analyzed as a percentage of REM sleep duration, in accordance with previously published methods. Non-parametric analyses were performed to compare RSWA, patient demographics, and PSG data across groups. Significance was set at p &lt; 0.016. Results Patients with PTSD had significantly higher RSWA than controls in all RSWA density measures (p &lt; 0.016 for all). All measures of RSWA, excluding average SM duration, were significantly greater in PTSD+RBD patients compared with controls (p &lt; 0.016 for all). Within the PTSD group, patients on antidepressants did not have significantly higher RSWA in any of the measures. PTSD+RBD patients had significantly higher SM Phasic, AT Any, SM+AT Any, and Tonic RSWA measures than PTSD patients (p &lt; 0.016 for all). Conclusion PTSD patients have significantly higher RSWA than controls, with PTSD+RBD patients having higher RSWA levels than PTSD patients. These data provide the first evidence for abnormal RSWA control in patients with chronic PTSD. This provides evidence of a unique biology in PTSD that could imply a future risk for neurodegenerative disease in PTSD similar to RBD patients. Further prospective studying will need to be performed on patients with PTSD to understand the unique biology. Support

e16771 Background: AbGn-107 is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric (G), colorectal (CRC), pancreatic (PDA), and biliary (BIL) cancers. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a Phase Ia trial in patients with the aforementioned GI malignancies. Methods: Standard 3+3 dose escalation was used. Key eligibility included locally advanced or metastatic G, CRC, PDA, or BIL cancer, previously treated, ECOG PS 0-1; positive AG-7 expression was not required. Two dosing intervals were tested: AbGn-107 administered i.v. Q4 weeks (at doses ranging from 0.1-1.2 mg/kg) and Q2 weeks (at doses from 0.8-1.0 mg/kg). Dose limiting toxicities (DLT) were based on grade 3/4 hematologic and non-heme AEs occurring during the initial 4-week rx window. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments Q8 weeks. 1o objectives: safety and MTD; 2o objectives: PK, immunogenicity, and efficacy defined by ORR (RECIST 1.1). Results: 35 patients were enrolled across 6 dose levels (median age 61.5 yo (range 40 – 81); G (0)/CRC (12)/PDA (20)/BIL (3); median # lines of prior rx = 3 (range 1-7). Safety: 5 patients experienced Grade 3 or 4 neutropenia, all at higher dose levels, inc. 1 episode of febrile neutropenia. Other frequent drug-related AEs, mostly grade 1/2, inc. fatigue (29%), nausea (20%), and diarrhea (14%). DLTs included grade 4 CK elevation (n = 1) at 0.8 mg/kg Q4W and grade 3 arthralgias (n = 1) at 1.2 mg/kg Q4W. Based on safety profile and PK data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase. Efficacy: Median duration of treatment = 56 days (range, 8 – 225 days). Six pts have demonstrated a minor response by RECIST (range, -1.3 to -21.1%); 4 pts (all PDA) have had durable dz control > 180 days. Conclusions: Overall, AbGn-107 appears well-tolerated with encouraging prelim signs of efficacy in unselected pts with heavily pre-treated advanced GI cancers. Updated safety and efficacy data will be provided at the time of the meeting for the cohort expansion phase of this study (currently open across multiple sites in U.S. and Taiwan), in which subjects with G, CRC, PDA, and BIL cancers are pre-screened for high levels of AG-7 tumor expression. Clinical trial information: NCT02908451 .

Management of PD-1 blockade resistance in metastatic melanoma (MM) remains challenging. Immunotherapy or chemotherapy alone provides limited benefit in this setting. Chemo-immunotherapy (CIT) has demonstrated favorable efficacy and safety profiles in lung cancer. Our pre-clinical study showed that in MM patients who have failed PD-1 blockade, the addition of chemotherapy increases CX3CR1+ therapy-responsive CD8+ T-cells with enhanced anti-tumor activity, resulting in improved clinical response. Here, we examined the clinical outcomes of CIT in MM patients after PD-1 blockade failure and the treatment-related changes in CX3CR1+ therapy-responsive CD8+ T-cells. We reviewed MM patients seen between January 2012 and June 2018 who failed anti-PD-1-based therapy and received subsequent CIT, immune checkpoint inhibitors (ICI) or chemotherapy alone. Overall survival (OS), objective response rate (ORR), event-free survival (EFS), and toxicities were assessed. Among 60 patients, 33 received CIT upon disease progression on PD-1 blockade. At a median follow-up of 3.9 years, the CIT group had a median OS of 3.5 years [95% confidence interval (CI) 1.7–NR] vs. 1.8 years (95% CI 0.9–2; P = 0.002) for those who received subsequent ICI (n = 9) or chemotherapy alone (n = 18), with ORR of 59% vs. 15% (P = 0.0003), respectively. The median EFS was 7.6 months (95% CI 6–10) following CIT vs. 3.4 months (95% CI 2.8–4.1; P = 0.0005) following ICI or chemotherapy alone. Therapy-responsive CX3CR1+CD8+ T-cells showed dynamic increase with successful CIT. CIT showed favorable clinical outcomes and acceptable safety profile in PD-1 blockade-resistant patients. CX3CR1+CD8+ therapy-responsive T-cells can be potentially used for monitoring disease response to CIT.