Factors Associated with Severe Late Toxicity After Concurrent Chemoradiation for Locally Advanced Head and Neck Cancer: An RTOG Analysis

Purpose Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases both local tumor control and toxicity. This study evaluates clinical factors that are associated with and might predict severe late toxicity after CCRT. Methods Patients were analyzed from a subset of three previously reported RTOG trials of concurrent chemoradiotherapy for locally advanced SCCHN (RTOG 91-11; 97-03; and 99-14). Severe late toxicity was defined in this secondary analysis as chronic Grade 3-4 pharyngeal/laryngeal toxicity (RTOG/EORTC late toxicity scoring system) and/or requirement for a feeding tube ≥2 years after registration and/or potential treatment-related death (e.g. pneumonia) within 3 years. Case-control analysis was performed, with a multivariable logistic regression model that included pre-treatment and treatment potential factors. Results A total of 230 patients were evaluable for this analysis, 99 cases (patients with severe late toxicities) and 131 controls; thus 43% of evaluable patients had a severe late toxicity. On multivariable analysis, significant variables correlated with the development of severe late toxicity were older age (odds ratio 1.05 per year; p = 0.001); advanced T-stage (odds ratio 3.07; p=0.0036); larynx/hypopharynx primary site (odds ratio 4.17; p=0.0041); and neck dissection after chemo-RT (odds ratio 2.39; p=0.018). Conclusions Severe late toxicity following CCRT is common. Older age, advanced T-stage, and larynx/ hypopharynx primary site were strong independent risk American Society of Clinical Oncology. Machtay, M. et al: J. Clin. Oncol. 26 (21), 2008:3582-3589

Efficacy and safety of Vilobelimab (IFX-1), a novel monoclonal anti-C5a antibody, in patients with early severe sepsis or septic shock — a randomized, placebo-controlled, double-blind, multicenter, phase IIa Trial (SCIENS Study)

IMPORTANCE:. Anaphylatoxin C5a, a proinflammatory complement split product, plays a central role in mediating organ dysfunction. OBJECTIVES:. This phase II clinical trial was conducted to study safety, tolerability, pharmacokinetics, and pharmacodynamics of vilobelimab, a recombinant monoclonal antibody against C5a, in patients with severe sepsis or septic shock. DESIGN:. Multicenter, randomized, and placebo-controlled study. SETTING AND PARTICIPANTS:. Eleven multidisciplinary ICUs across Germany. Adult patients with severe sepsis or septic shock and with early onset of infection-associated organ dysfunction. MAIN OUTCOMES AND MEASURES:. Patients were randomly assigned in a ratio of 2:1 to three subsequent dosing cohorts for IV vilobelimab or placebo receiving either 2 × 2 mg/kg (0 and 12 hr), 2 × 4 mg/kg (0 and 24 hr), and 3 × 4 mg/kg (0, 24, and 72 hr). Co-primary endpoints were pharmacodynamics (assessed by C5a concentrations), pharmacokinetics (assessed by vilobelimab concentrations), and safety of vilobelimab. Preliminary efficacy was evaluated by secondary objectives. RESULTS:. Seventy-two patients were randomized (16 patients for each vilobelimab dosing cohort and eight patients for each placebo dosing cohort). Vilobelimab application was associated with dosing dependent decrease in C5a compared with baseline (p < 0.001). Duration of C5a decrease increased with more frequent dosing. Membrane attack complex lysis capacity measured by 50% hemolytic complement was not affected. Vilobelimab was well tolerated with similar safety findings in all dose cohorts. No vilobelimab-specific adverse events emerged. For vilobelimab-treated patients, investigators attributed less treatment-emergent adverse events as related compared with placebo. Dosing cohorts 2 and 3 had the highest ICU-free and ventilator-free days. There was no difference in mortality, vasopressor-free days, or renal replacement therapy-free days between the groups. CONCLUSIONS AND RELEVANCE:. Administration of vilobelimab in patients with severe sepsis and septic shock selectively neutralizes C5a in a dose-dependent manner without blocking formation of the membrane attack complex and without resulting in detected safety issues. The data warrant further investigation of C5a inhibition in sepsis

Surgical Pulmonary Embolectomy Outcomes for Acute Pulmonary Embolism

Introduction: Acute pulmonary embolism (PE) is associated with significant mortality. Surgical embolectomy is a viable treatment option; however, it remains controversial due to variable outcomes. This review investigates patient outcomes following surgical embolectomy for acute PE. Methods: Electronic search was performed to identify articles reporting surgical embolectomy for treatment of PE. 32 studies were included comprising 936 patients. Demographic, perioperative, and outcome data were extracted and pooled for systematic review. Results: Mean patient age was 56.3 [95% CI 52.5; 60.1] years and 50% [46; 55] were male. 82% had right ventricular dysfunction [62; 93], 80% [67; 89] had unstable hemodynamics, and 9% [5; 16] experienced cardiac arrest. Massive PE and submassive PE were present in 83% of patients [43; 97] and 13% [2; 56], respectively. Before embolectomy, 33% of patients [14; 60] underwent systemic thrombolysis and 14% [8; 24] catheter embolectomy. Preoperatively, 47% of patients were ventilated [26; 70] and 36% had percutaneous cardiopulmonary support [11; 71]. Mean operative time and mean cardiopulmonary bypass time were 170 [101; 239] and 56 [42; 70] minutes, respectively. Intraoperative mortality was 4% [2; 8]. Mean hospital and ICU stay were 10 [6; 14] and 2 [1; 3] days, respectively. Mean postoperative systolic pulmonary artery pressure (sPAP) was significantly decreased from preoperative (sPAP 57.8 mmHg [53; 62.7]) to postoperative period (sPAP 31.3 mmHg [24.9; 37.8]), p \u3c0.01). In-hospital mortality was 16% [12; 21]. Overall survival at five years was 73% [64; 81]. Discussion: Surgical embolectomy is an acceptable treatment option with favorable outcomes

JeffCHAT: A Novel Student-led Extracurricular IPE Experience Increases Humanistic Approach to Care

Presentation Overview • Overview of JeffCHAT mission, design and implementation strategy • Presentation of Evaluation Methods and Results • Interactive Student Panel Discussio

Cell death mechanism in an isolated wood smoke inhalation induced-ARDS large animal model

Acute respiratory distress syndrome (ARDS) is a lethal disease condition in critically ill patients with a reported mortality rate reaching 45%. The current treatment modalities available for severe ARDS are invasive and carry significant risk for patients. Most published studies involving smoke inhalation utilize another simultaneous injury (such as cutaneous burn) to increase pathology burden of their animal models. This introduces confounding variables to investigations which aim to concentrate on inhalation injury. In this study, we evaluated the potential molecular targets associated with isolated smoke inhalation-induced ARDS. We observed an increase in lung injury score and wet/dry ratio 48h post smoke inhalation together with upregulation of inflammatory markers, IL-1βand IL-6 levels. Furthermore, there was a decrease in phosphorylation of cell survival marker Akt and an increase in pro-apoptotic protein BAX at 48h post smoke inhalation. These results indicate that smoke inhalation induced inflammatory processes resulting in increased apoptosis and decreased cell survival in lung parenchymal cells. Use of this unique model may be of benefit in studying the pathophysiology of inhalation injury and for the development of novel therapeutic strategies.https://digitalcommons.unmc.edu/surp2021/1045/thumbnail.jp

Pencil Beam Scanning Proton Therapy for Adolescents and Young Adults with Head and Neck Sarcomas

Purpose: To assess clinical outcomes of adolescents and young adults (AYAs) with head and neck sarcomas (HNSs) treated with pencil beam scanning proton therapy (PBSPT) and to report quality of life (QoL). Materials and Methods: Twenty-eight AYAs (aged 15 to 39 years) with HNS treated between January 2001 and July 2022 at our institution were included. The median age was 21.6 years. Rhabdomyosarcoma (39.3%), Ewing sarcoma (17.9%), chondrosarcoma (14.3%), and osteosarcoma (14.3%) were the most frequent diagnoses. Three (10.7%) patients were metastatic before PBSPT and 13 (46.4%) patients had a tumor with intracranial extension. The median total radiation dose was 63 GyRBE (range, 45 to 74 GyRBE). Thirteen (46.4%) patients received concomitant chemotherapy. Toxicity was reported according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (US National Institutes of Health, Bethesda, Maryland). Survival was estimated using the Kaplan-Meier method. QoL was assessed using a PEDQOL (Pediatric Quality of Life Questionnaire) questionnaire. Self-reported outcomes were assessed using institutional questionnaires. Results: With a median follow-up of 57 months (range, 3.7 to 243 months), 5 patients (17.8%) had local failure (LF) only, 2 (7.1%) experienced distant failure (DF) only, and 2 (7.1%) had LF and DF. The estimated 5-year local control (LC) and distant control (DC) rates were 71.8% and 80.5%, respectively. The median times to LF and DF were 13.4 and 22.2 months, respectively. Four (14.3%) patients died, all but one from their HNS. Estimated 5-year overall survival was 90.7%. Six (21.4%) patients developed nonocular grade ≥3 toxicity, which consisted of otitis media (n = 2), hearing impairment (n = 2), osteoradionecrosis (n = 1), and sinusitis (n = 1). Four (14.3%) patients developed cataracts that required surgery. The 5-year freedom from nonocular grade 3 toxicity was 91.1%. No grade 4 or higher toxicity was observed. Adolescents rated their quality of life before treatment worse than their parents did. Conclusion: Excellent outcomes with acceptable late-toxicity rates were observed for AYAs with HNS after PBSPT

Prevalence of brachial plexus injuries in patients with scapular fractures: a national trauma data Bank review

S capular fractures comprise 3% to 5% of all shoulder girdle fractures, while accounting for &lt;1% of all fractures (1). Fracture of the scapula usually occurs after high-energy trauma; thus, approximately 90% of patients have concomitant injuries (2,3). In a previous study investigating scapular fractures, McGahan et al (4) found that at four weeks follow-up after injury, complaints pertaining to the shoulder, such as decreased range of motion and pain, were limited to the subset of patients who experienced neurological deficits in addition to their scapular fracture. That article emphasized the importance of early recognition and treatment of brachial plexus injuries to improving patient outcomes. The purpose of the present investigation was to study a large number of patients with different types of scapular fractures to determine the prevalence of concurrent brachial plexus injuries; to determine how prevalence varies in different regions of the scapula injured; and to assess which specific nerves of the brachial plexus were injured. This information may help to guide clinical suspicion and increase awareness of this often devastating injury. The National Trauma Data Bank (NTDB), currently the largest trauma registry in the United States (US), containing data on &gt;5 million cases from &gt;900 registered US trauma centres, was used to gather the data (5). METHODS The present study was a retrospective review of the NTDB data set from 2007 through 2011. The NTDB is an incident-centred database that uses International Classification of Diseases, Ninth Revision (ICD-9) codes to code for specific diagnoses. Because no patient identifiers exist in the database, patient incidents are represented with unique incident identifier keys. All incidents involving scapular fracture, as assessed according to ICD-9 diagnosis code, were extracted from the database. Specifically, scapular fractures were divided into six anatomical regions according to ICD-9 code: acromial process, coracoid process, body or spine grouped together, glenoid cavity or neck grouped together, multiple region fractures and unspecified region fractures. The scapular fracture data were accompanied by a list of other injuries associated with the given incident. Among these, injuries to the brachial plexus were of interest. Brachial plexus injuries were divided according to ICD-9 codes into injuries to specific nerves: axillary nerve, median nerve, musculocutaneous nerve, radial nerve, ulnar nerve, cutaneous sensory nerve of the upper limb, cervical root injury, other specified nerve injury, multiple nerve injury and unspecified nerve injury. BACKgROUND: Studies investigating the prevalence of brachial plexus injuries associated with scapular fractures are sparse, and are frequently limited by small sample sizes and often restricted to single-centre experience. OBJECTIVE: To determine the prevalence of brachial plexus injuries associated with scapular fractures; to determine how the prevalence varies with the region of the scapula injured; and to assess which specific nerves of the brachial plexus were involved. METHODS: The present study was a retrospective review of data from the National Trauma Data Bank over a five-year period (2007 to 2011). RESULTS: Of 68,118 patients with scapular fractures, brachial plexus injury was present in 1173 (1.72%). In patients with multiple scapular fractures, the prevalence of brachial plexus injury was 3.12%, and ranged from 1.52% to 2.22% in patients with single scapular fractures depending on the specific anatomical location of the fracture. Of the 426 injuries with detailed information on nerve injury, 208 (49%) involved the radial nerve, 113 (26.5%) the ulnar nerve, 65 (15%) the median nerve, 36 (8.5%) the axillary nerve and four (1%) the musculocutaneous nerve. CONCLUSION: The prevalence of brachial plexus injuries in patients with scapular fractures was 1.72%. The prevalence was similar across anatomical regions for single scapular fracture and was higher with multiple fractures. The largest percentage of nerve injuries were to the radial nerve

Depositional age and provenance of high-grade paragneisses from the Mérida Andes, Venezuela: Implications for the Ediacaran–Cambrian tectonic setting of northwestern Gondwana

Isotopic, geochemical, and geochronological data are provided to constrain sedimentary sources and depositional ages of high-grade paragneisses of the Iglesias Complex in the Mérida Andes (Venezuela). U-Pb geochronology of detrital zircons suggests a maximum depositional age of 540–530 Ma, whereas age spectra reveal sources from Pan-African-Brasiliano belts, the Amazon Craton, and Oaxaquia-Putumayo basement. Reworking of such Gondwanan sources is also reflected in whole-rock Nd and Hf crustal residence ages of ~2.0–1.3 Ga. Post-depositional disturbance of the U-Pb system by metamorphism during the early Paleozoic and Permo–Triassic is assessed through in-situ analysis of zircon rims and discordant analyses. Field evidence, geochemical and isotopic signatures are consistent with pelitic-psammitic and volcanic-volcaniclastic compositions for sedimentary protoliths. The former show provenances from continental intermediate sources, whereas the latter are probably sourced in an immature volcanic arc, suggesting the initiation of subduction of the Iapetus oceanic crust beneath northwestern Gondwana around 530 Ma. Sedimentary precursors were likely deposited during the latest Ediacaran–earliest Cambrian in an extensive continental shelf, fed by detritus draining from the topographic highs of the Pan-African-Brasiliano belts, across the Amazon craton and into the Iapetus Ocean. Thus, the main direction of sediment flow was opposite to the present-day transport from the Andes Cordillera by the Pacific Ocean to the Amazon fan in the Atlantic Ocean. Chemical trends in gneisses suggest fluvial sedimentary protoliths and cold-climate weathering at high latitudes. Metasedimentary rocks in the Mérida Andes show similarities with equivalent units in Peri-Gondwanan crustal fragments such as the Acatlán Complex and the Santander Massif, but no correlation with Ediacaran metasedimentary rocks of the Maya Block. Ediacaran–Cambrian fossiliferous sedimentary rocks in the Eastern Venezuela Basin and the Colombian foreland basin are possible equivalents but these units remained unmetamorphosed, as its paleoposition was far from the subduction trench during the Early Ordovician climax of the Famatinian orogeny. © 2021 Elsevier B.V

The Effects of Serotonin Receptor Antagonists on Contraction and Relaxation Responses Induced by Electrical Stimulation in the Rat Small Intestine

Background: The main source of 5-HT in body is in enterchromafin cells of intestine, different studies mentioned different roles for endogenous 5-HT and receptors involved and it is not clearified the mechanism of action of endogenous 5-HT. Objectives: To study the role of endogenous 5-HT on modulation of contraction and relaxation responses induced by electrical field stimulation (EFS) in different regions of the rat intestine. Materials and Methods: Segments taken from the rat duodenum, jejunum, mid and terminal ileum were vertically mounted, connected to a transducer and exposed to EFS with different frequencies in the absence and presence of various inhibitors of enteric mediators i. e. specific 5-HT receptor antagonists. Results: EFS-induced responses were sensitive to TTX and partly to atropine, indicating a major neuronal involvement and a cholinergic system. Pre-treatment with WAY100635 (a 5-HT1A receptor antagonist) and granisetron up to 10.0 µM, GR113808 (a 5-HT4 receptor antagonist), methysergide and ritanserin up to 1.0 µM, failed to modify responses to EFS inall examined tissues. In the presence of SB258585 1.0 µM (a 5-HT6 receptor antagonist) there was a trend to enhance contraction in the proximal part of the intestine and reduce contraction in the distal part. Pre-treatment with SB269970A 1.0 µM (5-HT7 receptor antagonist) induced a greater contractile response to EFS at 0.4 Hz only in the duodenum. Conclusions: The application of 5-HT1A, 5-HT2, 5-HT3, 5-HT4, 5-HT6 and 5-HT7 receptor antagonists, applied at concentrations lower than 1.0 µM did not modify the EFS-induced contraction and relaxation responses, whichsuggests the unlikely involvement of endogenous 5-HT in mediating responses to EFS in the described test conditions. Keywords: Electric Stimulation Therapy; Serotonin 5-HT1 Receptor Antagonists; Intestine, Smal