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Background Suppurative intracranial complications of sinusitis are rare events in children and can lead to harmful neurologic sequelae and significant morbidity. We sought to review the presentation and management of patients admitted at our hospital with these conditions. Methods This was a retrospective study of pediatric patients admitted to a quaternary children’s hospital from 2007 to 2019 for operative management of sinusitis with intracranial extension. Clinical characteristics, including surgical and microbiological data, were collected and analyzed. Results Fifty-four patients were included; the median age was 11.0 years, and there was a male predominance. Eighty-nine percent of patients had prior healthcare visits for the current episode of sinusitis; 46% of patients had an abnormal neurologic exam on admission. Epidural abscess and subdural empyema were the most common complications, and subdural empyema was associated with repeat surgical intervention. The dominant pathogens were Streptococcus anginosus group organisms (74%). The majority of patients completed treatment parenterally, with a median duration of therapy of 35 days. Neurological sequelae, including epilepsy or ongoing focal deficits, occurred in 22% of patients. History of seizure or an abnormal neurological exam at admission were associated with neurological sequelae. Conclusions Clinicians should consider intracranial complications of sinusitis in patients with symptoms of sinusitis for >1 week. Patients should undergo urgent neuroimaging, as neurosurgical intervention is essential for these patients. Subdural empyema was associated with repeat neurosurgical intervention. Neurological sequelae occurred in 22% of patients, and new onset seizure or an abnormal neurological exam at admission were associated with neurological sequelae.

BACKGROUND Exhaled nitric oxide (eNO) is a known biomarker for the diagnosis and monitoring of bronchial hyperreactivity in adults and children. AIMS To investigate the potential role of eNO measurement for predicting perioperative respiratory adverse events in children, we sought to determine its feasibility and acceptability before adenotonsillectomy. METHODS We attempted eNO testing in children, 4-12 years of age, immediately prior to admission for outpatient adenotonsillectomy. We used correlations between eNO levels and postoperative adverse respiratory events to make sample size predictions for future studies that address the predictability of the device. RESULTS One hundred and three (53%) of 192 children were able to provide an eNO sample. The success rate increased with age from 23% (9%-38%) at age 4 to over 85% (54%-98%) after age 9. Using the eNO normal value (

Background. The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC. Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied. Results. Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1–98). ORR was 56.7% (95% CI, 44.1–68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3–4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt. Conclusions. Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment., Highlights • Combination of chemotherapy plus anti HER-2 agents is the standard treatment of HER-2 positive breast cancer. • Combination of trastuzumab and metronomic chemotherapy is an alternative therapeutic approach. • Metronomic therapy allows long-term administration of drugs. • Mild toxicity in advanced breast cancer is desirable.

Choosing the correct target behavior to teach is fundamental for parents, teachers, therapists and other professionals working with people with autism and other intellectual disabilities. While early intensive behavioral intervention (EIBI) for young children diagnosed with autism can produce large gains in social, cognitive, and language development, choosing the appropriate curriculum for adolescents and adults warrants some further reflections. Starting from puberty and adolescence, the focus of teaching should move from what the student is missing with respect to typically development peers to what the student needs to become an effective adult, with the final outcome of “making a life”. Applied Behavior Analysis is effective in teaching functional skills, adaptive skills, daily living skills, safety skills, sexuality, physical exercise, self-advocacy and other often overlooked skills that can contribute to the improvement of the quality of life of people with or without disabilities. Research suggests that working on functional skills provided through a meaningful curriculum leads to a more independent life. During this presentation the contribution ABA can offer in developing a meaningful curriculum for adolescents will be reviewed. Particular focus will be placed on using Behavior Skills Training (BST) and other environmental manipulations to teach safety skills to adolescents and young adults with autism spectrum disorders. Examples of safety skills include abduction prevention, seeking help if lost, inappropriate physical contact and information disclosure. The use of technology in teaching safety skills to students with a poor repertoire of verbal behavior will be discussed.

Background: There is a paucity of data comparing 30-day morbidity and mortality of sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and one anastomosis gastric bypass (OAGB). This study aimed to compare the 30-day safety of SG, RYGB, and OAGB in propensity score-matched cohorts. Materials and methods: This analysis utilised data collected from the GENEVA study which was a multicentre observational cohort study of bariatric and metabolic surgery (BMS) in 185 centres across 42 countries between 01/05/2022 and 31/10/2020 during the Coronavirus Disease-2019 (COVID-19) pandemic. 30-day complications were categorised according to the Clavien–Dindo classification. Patients receiving SG, RYGB, or OAGB were propensity-matched according to baseline characteristics and 30-day complications were compared between groups. Results: In total, 6770 patients (SG 3983; OAGB 702; RYGB 2085) were included in this analysis. Prior to matching, RYGB was associated with highest 30-day complication rate (SG 5.8%; OAGB 7.5%; RYGB 8.0% (p = 0.006)). On multivariate regression modelling, Insulin-dependent type 2 diabetes mellitus and hypercholesterolaemia were associated with increased 30-day complications. Being a non-smoker was associated with reduced complication rates. When compared to SG as a reference category, RYGB, but not OAGB, was associated with an increased rate of 30-day complications. A total of 702 pairs of SG and OAGB were propensity score-matched. The complication rate in the SG group was 7.3% (n = 51) as compared to 7.5% (n = 53) in the OAGB group (p = 0.68). Similarly, 2085 pairs of SG and RYGB were propensity score-matched. The complication rate in the SG group was 6.1% (n = 127) as compared to 7.9% (n = 166) in the RYGB group (p = 0.09). And, 702 pairs of OAGB and RYGB were matched. The complication rate in both groups was the same at 7.5 % (n = 53; p = 0.07). Conclusions: This global study found no significant difference in the 30-day morbidity and mortality of SG, RYGB, and OAGB in propensity score-matched cohorts. © 2021, The Author(s).

Background The extent of surgery required in the management of pediatric non-medial subperiosteal orbital abscess (SPOA) due to medically refractory complicated acute sinusitis is unknown. Objectives The primary objective is to compare operative outcomes of children treated with combined endoscopic sinus surgery (ESS) and external orbital drainage (EOD) versus those treated with EOD alone. Methods Retrospective case series from a tertiary children’s hospital analyzing outcomes in children requiring surgical management for acute sinusitis complicated by non-medial SPOA between November 2007 and September 2019. Results Sixteen children with a mean age of 9.4 years (95% CI: 7.3–11.4) met inclusion. Eleven (68.8%) underwent combined EOD and ESS, while five (31.2%) underwent EOD alone. Groups were similar in age, symptom duration, white blood cell count, C-reactive protein level, intraocular pressure, Lund-Mackay score, and abscess volume. There was no significant difference in median length of stay between patients treated with a combined approach versus those treated by EOD alone. Cultures identified non-beta-hemolytic Streptococcus species in 56.3% of patients, with Streptococcus intermedius representing the most common organism in 37.5%. In one case, ESS identified a pathogen not acquired via concomitant EOD, which did influence management. No child required a subsequent surgical procedure and there were no operative complications. Conclusions The addition of ESS in the management of pediatric non-medial SPOA was not associated with a statistically different duration of hospitalization. Cultures from concomitant ESS rarely aided in diagnosis or antibiotic therapy. Further study should delineate the indications for ESS in these cases.

The coronavirus disease 2019 (COVID-19) pandemic requires clinicians to explore alternatives to routine patient management. Otolaryngologists caring for children commonly depend on physical examination, laboratory data, and ambulatory surgical procedures. Limiting patient care, mindful allocation of resources, and concern for safety have challenged all aspects of our health care system. This evidence-based clinical consensus is designed to guide practitioners of pediatric otolaryngology for common scenarios during this time.Peer-reviewed literature, published reports, institutional guidelines, and expert consensus.A clinical consensus on 6 common scenarios in pediatric otolaryngology developed with evidence-based strategies.Providers should suspend all in-person nonessential office visits and elective surgical procedures. An emphasis on medical management and caregiver education will provide reasonable approaches to many of the common outpatient concerns. Surgery for chronic otitis media, obstructive sleep apnea, and acute rhinosinusitis should occur only in response to severe complications or failure of medical regimens. The approach to the pediatric neck mass focuses on timely management for oncologic etiologies and cautious surgical intervention for abscess drainage or tissue sampling. Finally, epistaxis and otorrhea must be triaged and addressed without the usual ambulatory procedures.Adaptation of practice patterns during this unprecedented moment for our health care system requires thoughtful planning. The strategies described allow for safe handling of common pediatric otolaryngology diagnoses. Ultimately, otolaryngologists must be stewards of our global health community while advocating for the care of individual pediatric patients.

Introduction Invasive fungal sinusitis (IFS) is a rare but deadly clinical entity that occurs in immunocompromised patients. Diagnosis in children typically requires operative biopsies under general anesthesia, which has associated risks. Findings on bedside nasal endoscopy (BNE) can be used with history, exam, and imaging to determine the need for surgery, however, the accuracy of this tool has not been established among pediatric patients. Methods Patients who underwent BNE for evaluation of IFS from 2008 to 2016 at the Children's Hospital of Philadelphia were identified using Current Procedural Terminology (CPT) codes. Retrospective chart analysis was performed and included underlying diagnoses, presenting signs and symptoms, imaging findings, endoscopic findings and outcomes. Results Nineteen patients were identified who underwent evaluation for IFS using BNE during the period studied. Eight patients had exam findings that were concerning for IFS, including debris or crusting, darkened or pale mucosa, or copious, thick and/or purulent secretions. Immediate operative biopsies and debridement revealed IFS in six of eight patients. Eleven patients had exam findings deemed not concerning for IFS including mucosal edema, mucous without purulence, or normal findings. Six of eleven patients underwent operative biopsy despite negative endoscopy, and five were observed clinically. None of the 11 patients with negative bedside endoscopy developed IFS. Conclusions All patients with IFS had concerning exam findings on endoscopy and were treated with immediate biopsies and debridement. No patient with normal or non-concerning findings on BNE progressed to have invasive fungal sinusitis. While suspicion for IFS in immunocompromised children must remain high, BNE is feasible and useful in its assessment.

Introduction Biweekly schedule of XELOX-2 (capecitabine plus oxaliplatin) showed interesting results in first-line therapy of patients with metastatic colorectal cancer (mCRC). Bevacizumab plus FOLFOX-4 (oxaliplatin, folinic acid, and infusional 5-fluorouracil) is among standard first-line treatment options in this setting. We performed a phase II randomized trial in order to evaluate the activity of bevacizumab plus either FOLFOX-4 or XELOX-2 in first-line therapy of patients with mCRC. Materials and Methods Patients with mCRC were randomized, in a 1:2 ratio, to first-line bevacizumab plus either FOLFOX-4 (Arm A), as calibration arm, or XELOX-2 (Arm B), up to 12 cycles. Patients without progression were further randomized to maintenance bevacizumab alone or with the same induction fluoropyrimidine. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival, overall survival, and toxicity. The study design was formally non-comparative, but exploratory comparison was performed. Results Forty-five patients were randomized in arm A and 87 in arm B with an ORR of 55.6% versus 48.3% (P = .43), respectively. After a median follow-up of 47.2 months, progression-free survival was 10.0 versus 9.9 months (hazard ratio, 0.96; 95% confidence interval, 0.65-1.41; P = .84) and overall survival was 29.8 versus 25.0 months (hazard ratio, 1.21; 95% confidence interval, 0.77-1.92; P = .41), respectively. The main grade 3 to 4 toxicities (% A/B) were: neutropenia 15/3 and nausea 9/5. Conclusion This exploratory analysis showed that biweekly XELOX-2 plus bevacizumab has a comparable ORR with FOLFOX-4 plus bevacizumab in patients with mCRC.

Objective To provide recommendations to otolaryngologists and allied physicians for the comprehensive management of young infants who present with signs or symptoms of choanal atresia. Methods A two-iterative delphi method questionnaire was used to establish expert recommendations by the members of the International Otolaryngology Group (IPOG), on the diagnostic, intra-operative, post-operative and revision surgery considerations. Results Twenty-eight members completed the survey, in 22 tertiary-care center departments representing 8 countries. The main consensual recommendations were: nasal endoscopy or fiberscopy and CT imaging are recommended for diagnosis; unilateral choanal atresia repair should be delayed after at least age 6 months whenever possible; transnasal endoscopic repair is the preferred technique; long term follow-up is recommended (minimum one year) using nasal nasofiberscopy or rigid endoscopy, without systematic imaging. Conclusion Choanal atresia care consensus recommendations are aimed at improving patient-centered care in neonates, infants and children with choanal atresia.

Vascular malformations presenting in the nasal cavity and paranasal sinuses are rare. Differentiating benign vascular malformations of the sinonasal cavity from other pathologic entities can be challenging and the role of preoperative angiography and embolization is not well defined. We present two unique cases of large pediatric sinonasal vascular malformations and describe their presentation, diagnosis and subsequent management. Both patients underwent embolization of the ipsilateral arterial supply followed by successful and complete endonasal surgical excision. This report provides description of management of the very rare occurrence of sinonasal vascular malformation in two adolescents.

Purpose Surgeons resuming elective procedures during the COVID-19 pandemic should consider strategies to mitigate risk of exposure. For otolaryngologists performing surgery on children, unique vulnerability to SARS-CoV-2 results from a regular interface with the upper respiratory tract mucosa. A growing interest in perioperative application of povidone‑iodine (PVP-I) to the nasopharynx and oropharynx has emerged. The purpose of this review is to provide an evidence-based assessment of PVP-I in pediatric oral, nasal and pharyngeal surgery. Methods A contemporary literature review with algorithmic approach to the potential use of PVP-I in pediatric mucosal surgery. Results Several formulations of PVP-I have shown rapid in vitro virucidal activity against SARS-CoV-2. Antisepsis using 1.0% PVP-I mouthwash and 0.45% PVP-I throat spray can occur after 30 seconds of contact time. To date, in vivo effectiveness of PVP-I against SARS-CoV-2 has yet to be established and possible risks of its direct use on upper aerodigestive mucosa of children must be weighed. Conclusion Further research is required prior to strongly recommending PVP-I use in preparation for nasal, oral or pharyngeal surgery in children.

The microbiology of pediatric complicated acute rhinosinusitis (ARS) has evolved, and our current understanding of pathogenic organisms is limited. The objectives of this study are to describe the incidence of pathogens causing complicated ARS requiring surgical intervention at our institution over a 10-year period as well as their associated treatment outcomes.Retrospective cohort study.A single tertiary care children's hospital.Data were reviewed from all patients who underwent surgery for complicated ARS and had positive culture data from 2006 to 2016. Associations among pathogens, complications, and outcomes were analyzed with Pearson χEighty-nine patients met criteria. Complications included orbital infections (78%), intracranial infections (48%), Pott's puffy tumor (13%), and cavernous sinus thrombosis (9.0%). Bacterial isolates were majority polymicrobial (55%) and included Streptococcus species (58%), Staphylococcus species (49%; including methicillin-resistant S aureus [MRSA], 11%), and anaerobic bacteria (35%). S pneumoniae (9.0%), Haemophilus species (4.5%), and Moraxella catarrhalis (1.1%) were relatively uncommon. Bacterial isolates were similar among patients with all types of complications.Among a large cohort of pediatric patients with complicated ARS, most bacterial isolates were polymicrobial, with Streptococcus and Staphylococcus species contributing to the majority of cases. S aureus species, including MRSA and anaerobic pathogens, were common. The pattern of bacterial isolates was similar among patients with all types of complications of ARS. We suggest treatment for complicated ARS with broad-spectrum antibiotics with coverage for Streptococcus species, Staphylococcus species including MRSA, and anaerobic bacteria.

The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as a potential resistance marker to the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer. We studied activation of EPHA2 in a panel of human colorectal cancer cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (an EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild-type (WT) metastatic colorectal cancer patients treated with FOLFIRI + cetuximab as first-line therapy in the CAPRI-GOIM trial were assessed for EPHA2 expression by immunohistochemistry and correlated with treatment efficacy. EPHA2 was differentially activated in colorectal cancer cell lines. Combined treatment with ALW-II-41-27 plus cetuximab reverted primary and acquired resistance to cetuximab, causing cell growth inhibition, inducing apoptosis and cell-cycle G1–G2 arrest. In tumor xenograft models, upon progression to cetuximab, ALW-II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55 of 82 tumor samples, frequently expressed in less-differentiated and left-sided tumors. High levels of EPHA2 significantly correlated with worse progression-free survival [8.6 months; confidence interval (CI) 95%, 6.4–10.8; vs. 12.3 months; CI 95%, 10.4–14.2; P = 0.03] and with increased progression rate (29% vs. 9%, P = 0.02). A specific EPHA2 inhibitor reverts in vitro and in vivo primary and acquired resistance to anti-EGFR therapy. EPHA2 levels are significantly associated with worse outcome in patients treated with FOLFIRI + cetuximab. These results highlight EPHA2 as a potential therapeutic target in metastatic colorectal cancer.

Fatigue life assessment of turbine rotating components is usually performed taking into account the presence of potential defects and their propagation, together with an accurate description of the stress/strain fields acting at components critical regions. In this work, such an approach was applied on a radial outflow turbine: the component investigated in this paper is the tie-rod. An axisymmetric FEM model of the whole turbine was implemented to evaluate the stress field acting at the root of tie-rod thread, the component most critical region. Three different preload procedures were investigated, in order to evaluate the effects of plastic strains on fatigue cycles. It was found that an initial overtightening, performed before machine assembly, induces a larger plastic zone at the root of the thread, which lowers the peak stress and lessens the stress ratio of the fatigue cycle. Stress gradients for the three different preloading conditions were the starting point of a crack propagation model, which calculated crack advancement as a function of service time. The model, which considered crack closure and stress ratio effects, allowed structural integrity assessment and showed that the initial overtightening had also the effect of crack growth rates reduction.

Background National guidelines for the prevention of surgical site infections (SSI) recommend against antibiotic prophylaxis following wound closure for clean and clean-contaminated surgical procedures. Prolonged antibiotic prophylaxis can lead to antibiotic resistance and adverse drug events without reducing SSI rates. The objective was to reduce the rate of antibiotic prophylaxis following surgical incision closure for specified procedures in the Divisions of Neurosurgery (NRS), Otolaryngology (OTO), and General Surgery (GS) at Children’s Hospital of Philadelphia (CHOP). Methods We identified all NRS, OTO, and GS procedures conducted at CHOP from July 1, 2016 to June 20, 2017. Collaborative meetings between surgical quality improvement team leads and the antimicrobial stewardship program (ASP) were convened to identify procedures most suitable for the intervention, including Chiari decompressions and tethered cord repair (NRS); tympanoplasty and tracheostomy (OTO); and laparoscopic and thoracoscopic procedures (GS). The intervention, started in March 2018, included (1) education of surgeons on perioperative prescribing guidelines, (2) order set modification, and (3) individualized monthly audit with feedback reports of inappropriate postoperative prescribing (via email copying all surgeons within the division). We monitored rates utilizing SPC charts of postoperative antibiotic use (defined as administration within 24 hours of procedure end) and evaluated SSI rates pre and post-intervention with a Poisson regression. Results Following the intervention, postoperative antibiotic use reached special cause resulting in a mean decline for laparoscopy (19.6% to 11.7%), thoracoscopy (35.6% to 17.9%), tympanoplasty (90.5% to 11.4%), tethered cord repair (95% to 25.5%), and Chiari decompression (97% to 45.9%). There was no mean shift in postoperative antibiotic use for tracheostomy (25.5%). 30-day SSI rates did not change pre- and post-intervention (P = 0.36). Conclusion A quality improvement initiative conducted to implement national guidelines recommending against postoperative antibiotic prophylaxis showed a significant reduction in postoperative antibiotic prophylaxis without a concomitant rise in SSI rates. Disclosures All authors: No reported disclosures.

Introduction Cisplatin with pemetrexed (CP) and carboplatin with paclitaxel and bevacizumab (CbTB) are standard first-line treatments for patients with advanced nonsquamous (NS) non–small-cell lung cancer (NSCLC). Quality of life (QoL) is a key objective in the management of advanced NSCLC. Thus, effect on QoL could be an additional factor in the choice of treatment. Patients and Methods Patients with untreated stage IIIB/IV NS-NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomized to receive first-line chemotherapy with cisplatin 75 mg/m 2 and pemetrexed 500 mg/m 2 , every 3 weeks, for 6 cycles followed by maintenance pemetrexed; or carboplatin area under the curve 6, paclitaxel 200 mg/m 2 , and bevacizumab 15 mg/kg, every 3 weeks, for 6 cycles followed by maintenance bevacizumab. The primary end point was the difference in QoL between the 2 treatment arms after 12 weeks of maintenance, measured using the EuroQoL 5 Dimensions-Index (EQ5D-I) and EQ5D-visual analogue scale (EQ5D-VAS). Results One hundred eighteen patients were randomized to CP (n = 60) or CbTB (n = 58). Baseline characteristics were well balanced. The proportion of patients evaluable for the primary end point was lower than planned. After 12 weeks of maintenance, the difference between mean changes in EQ5D-I was 0.137, favoring CP (95% confidence interval [CI], −0.02 to 0.29, Wilcoxon P = .078), although not statistically significant; and the difference between mean changes in EQ5D-VAS was 0.97 (95% CI, −9.37 to 11.31, Wilcoxon P = .41). Conclusion Although the study was underpowered because of a small number of patients evaluable for the primary end point, QoL did not differ between treatment arms. Other factors such as comorbidities and schedule should be used when deciding on first-line treatment.

Objectives/Hypothesis To determine the pediatric age groups viable for nasoseptal flap (NSF) reconstruction of endoscopic endonasal approaches (EEA) to intracranial pathology of suprasella neoplasms. Study Design Retrospective cohort study. Methods Retrospective review of 16 pediatric patients who underwent EEA with NSF reconstruction for a suprasellar defect from 2012 to 2014. Radioanatomic analysis was utilized to assess feasibility of NSF reconstruction of suprasellar neoplasms approached via EEA. Computed tomography (CT) measurements for defect size and potential flap coverage were measured by preoperative maxillofacial CT. Radiographic measurements and surgical outcomes were compared to determine if flap size would be sufficient to cover said defects in two pediatric age groups: those >10 years of age (mean age 14 years) and those 10 years of age population, and this was not due to insufficient flap coverage. Average potential flap length and width are sufficient to cover average suprasellar defect length and width in both age groups (P

The proximity that the nasal cavity, nasopharynx, and paranasal sinuses share with the orbit results in many pathological processes overlapping to involve these regions simultaneously. The thin, partially perforated boundaries that separate these regions render the orbit violable to spread from infections and masses that emanate from the nose. Similarly, primary orbital processes can extend into the nose and present initially with nasal symptoms. This chapter addresses sinonasal pathology that may threaten the orbit and is thus germane to both otolaryngologists and ophthalmological specialists. Methods of diagnosis and intervention, including endoscopic and endonasal surgery, will be reviewed.

Background Liquid biopsy is an alternative to tissue for RAS testing in metastatic colorectal carcinoma (mCRC) patients. Little information is available on the predictive role of liquid biopsy RAS testing in patients treated with first-line anti-EGFR monoclonal antibody-based therapy. Patients and methods In the CAPRI-GOIM trial, 340 KRAS exon-2 wild-type mCRC patients received first-line cetuximab plus FOLFIRI. Tumor samples were retrospectively assessed by next generation sequencing (NGS). Baseline plasma samples were analyzed for KRAS and NRAS mutations using beads, emulsion, amplification, and magnetics digital PCR (BEAMing). Discordant cases were solved by droplet digital PCR (ddPCR) or deep-sequencing. Results A subgroup of 92 patients with available both NGS data on tumor samples and baseline plasma samples were included in this study. Both NGS analysis of tumor tissue and plasma testing with BEAMing identified RAS mutations in 33/92 patients (35.9%). However, 10 cases were RAS tissue mutant and plasma wild-type, and additional 10 cases were tissue wild-type and plasma mutant, resulting in a concordance rate of 78.3%. Analysis of plasma samples with ddPCR detected RAS mutations in 2/10 tissue mutant, plasma wild-type patients. In contrast, in all tissue wild-type and plasma mutant cases, ddPCR or deep-sequencing analysis of tumor tissue confirmed the presence of RAS mutations at allelic frequencies ranging between 0.15% and 1.15%. The median progression-free survival of RAS mutant and wild-type patients according to tissue (7.9 versus 12.6 months; P = 0.004) and liquid biopsy testing (7.8 versus 13.8 moths; P

In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups. Background: In the cetuximab after progression in KRAS wild-type colorectal cancer patients ( CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups.Methods: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by agegroups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (>= 65; >= 70 and >= 75 years).Results: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were > 65 years, 86 > 70 years and 35 > 75 years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were > 65 years, 46 > 70 and 17 > 75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were >= 65 years; 29 were >= 70; 9 were >= 75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade >= 3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients >= 75 years and grade >= 3 fatigue (31% vs 20%, p=0.01) in patients < 75 years.Conclusions: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade >= 3 diarrhoea and neutropaenia in patients >= 75 years and grade >= 3 fatigue in patients < 75 years.

Among the turbine technologies for medium to large size Organic Rankine Cycle (ORC) systems, the radial outflow turbine represents the most recent development. This chapter gives an overview of the technology in terms of history, theoretical basis, and technical solutions. A brief history of the radial outflow turbine is presented. Starting from the radial outflow single-rotating steam turbine designed and applied in 1884 by Sir. Charles Parsons, the chapter then looks at the development of this technology by Birger and Fredrik Ljungstrom, who patented their turbine in 1908. In respect to other turbines their configuration had a unique feature; a multi-stage counter-rotating centrifugal steam turbine, in which two discs facing each other are connected with two independent shafts, with crowns of blades installed alternately on both of them. Thanks to this unique design, the turbine was used mainly for power generation but it also found application in railway engineering because of its favorable mass-to-power ratio and is the basis of designs used today. A detailed description of the Radial Outflow Turbine (ROT) basics is carried out in comparison to the more common axial and radial inflow arrangements, describing the main features of the ORC radial outflow turbine through mechanical, thermodynamic, and fluid-dynamic fundamentals. A comparison of the presented ROT with an axial ORC turbine in an overhung configuration directly coupled with a generator is presented. This analysis highlights differences in fluid-dynamic losses and can explain the higher efficiency of ROTs compared with the axial overhung turbines. Finally, the typical configurations allowed by the radial outflow technology are presented.

Cystic fibrosis (CF) is the most common inherited disease of Caucasians. Sinus disease affects 90 % of patients with CF making it a common indication for otolaryngology referral and surgical intervention. Aggressive medical management for sinus disease in CF may help delay or avoid surgical intervention and improve patient outcomes. Judicious use of antimicrobials in the management of sinus disease is necessary to avoid development of multi-drug resistant organisms and treat refractory disease. When surgery is required, a variety of surgical techniques may be employed depending on the patient’s anatomy and other concomitant sinonasal issues such as nasal polyps.

Background Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. Patients and methods We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progression-free survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. Results Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7–8.0] versus 4.5 months (95% CI 3.3–5.7); [hazard ratio (HR), 0.81; 95% CI 0.58–1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5–8.2) versus 5.3 months (95% CI 3.7–6.9); HR, 0.56 (95% CI 0.33–0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4–28.0) versus 19.8 months (95% CI 14.9–24.7); HR, 0.57 (95% CI 0.32–1.02); P = 0.056]. Conclusions Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials.

3542Background: B plus bi-weekly FOLFOX4 or three-weekly XELOX represents a standard 1-line therapy for mCRC pts. In our previous phase II study (Fedele P et al, ASCO 2009) we demonstrated a simila...

TPS405 Background: The most significant morbidity of prostate cancer (PC) is bone metastasis (BM). More than 90% of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) have radiologic evidence of BM, which are a major cause of death, disability, decreased QoL, and increased treatment cost. Unlike deaths from many other types of cancer, deaths from PC are often due to bone disease and its complications. In vitro data demonstrate a role for taxanes in the regulation of osteoclast formation and function, with a decreased resorption activity. ÊSTAMPEDE study has shown a strong clinical benefit, in term of OS, PFS and skeletal related events (SREs) delay compared with ADT alone, in metastatic hormone-sensitive pts treated with docetaxel (DOC) and ADT. TROPIC Study has shown that cabazitaxel (CBZ) prolongs OS regardless of DOC response in responder, resistant and refractory pts. Some data are available on pain progression, pain response and ECOG PS deterioration but in a unselected ITT population with a low prevalence of only BM disease at baseline, 25% of men had visceral metastasis. No data are available on effects of CBZ on BM and his direct impact on quality of life, bone turnover markers and time to the first SRE events. The aim of CaBone phase II study is to investigate, specifically, the effects on bone disease, bone turnover and on the bone related quality of life of CBZ in mCRPC pts with skeletal involvement without visceral disease. Methods: CaBone is a single arm, prospective, open label, multi center, phase II - GOIM - cooperative study of CBZ 25 mg/m2 q21 plus daily PDN (10 mg) in mCRPC pts with bone mets without visceral disease progressed during or after DOC treatment. Primary endpoint is Bone PFS according to PCWG2 while the Secondary are related on Evaluation of bone disease: Time to SRE, Time to Bone Pain Progression, Bone Pain Response, Time to opiate use for cancer-related pain, Time to deterioration in ECOG PS, Evaluation of Quality of Life and Functional status, Safety and centralized bone turnover markers: ALP, Bone ALP , LDHÊ, Serum CTx, iPTH, 1.25 (OH)2ÊD3. 107 subjects will be enrolled in CaBone study. CaBone is partially supported by Sanofi Genzyme. Clinical trial information: 2016-001253-41.

Objective To describe our outcomes after laryngotracheal reconstruction that required posterior costal cartilage grafting focused on decannulation rates and complications. Study Design Case series with chart review. Subjects and Methods Charts were reviewed on 58 patients. Operation specific and overall decannulation rates were determined. Complications were reviewed and correlated with technique of graft placement. Available voice outcomes were reviewed. Results Forty-eight patients were included. There was no statistically significant correlation between degree of stenosis and rate of decannulation. The overall decannulation rate, regardless of number of surgeries performed, was 96 percent. The relative risk for complications was higher among children who had a sutured versus a sutureless flanged posterior graft (RR = 2.5, P Conclusions Operation-specific decannulation rates are not significantly different with increasing disease severity, although the power to detect small differences in this study is low. Sutureless graft placement is associated with a lower complication rate. Supraglottic compression is a common postoperative compensatory vocal behavior and may correlate with disease severity.

Cochlear implantation is increasingly being performed in children with inner ear malformations. In severe cochleovestibular anomalies, such as severe partitioning defects and common cavity dysplasia, positioning of the electrode array can be hazardous, with inadvertent placement into the internal auditory canal (IAC) or carotid canal being well known. We describe a case in which real-time intraoperative computed tomographic scanning was used to help achieve proper electrode positioning in a child with a severe malformation.Child with common cavity malformations undergoing cochlear implantation.Intraoperative computed tomography used during implantation procedure.Use of technique in determining electrode position.A 10-year-old patient with bilateral common cavity malformations presented with declining performance in a functioning implant placed 7 years earlier. The family elected implantation of the contralateral ear. Via a posterior labyrinthotomy approach, a straight array was placed into the common cavity. Intraoperative computed tomographic scanning was immediately performed on the operating room table, showing that the array was in the IAC. A second attempt with a different insertion angle also resulted in IAC placement. In a third attempt, the electrode was advanced as a loop, grasping the tip through an adjacent second labyrinthotomy. Computed tomography confirmed good position against the outer wall of the cavity.Real-time intraoperative computed tomography is a new technology with many potential applications in surgery. In our patient, it allowed rapid and accurate determination of electrode position and helped achieve ideal placement in a severely malformed inner ear.

More than 500,000 children undergo tonsillectomy each year in the United States. Although prior studies suggest that most patients received perioperative antibiotics, practice varies across centers. In 2011, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) published a practice guideline recommending against perioperative antibiotic use for pediatric tonsillectomy. The impact of this recommendation has not been thoroughly examined.To determine the impact of the AAO-HNS guideline on the use of perioperative antibiotics and patient outcomes for pediatric tonsillectomy.This was a quasi-experimental study including 9265 children who underwent routine tonsillectomy from January 2009 through August 2012 within a large pediatric health care network containing hospital-based and ambulatory surgical facilities. Data were collected from a shared electronic health record and validated through manual medical record review. We used an interrupted time series analysis with segmented logistic regression and a nonequivalent dependent variable (tympanoplasty) to assess acute changes and differences in trends over time relative to guideline publication.Publication of the AAO-HNS clinical practice guideline.The primary outcome was antibiotic administration on the day of surgery. Secondary outcomes included otolaryngology clinic encounters, emergency department encounters, hospital admissions, and surgical procedures for bleeding in the 30 days following tonsillectomy.Of 9265 tonsillectomies during the study period, 5359 met inclusion criteria. Immediately after guideline publication, perioperative antibiotic use dropped by 86.5% (P .001) and was sustained throughout the postintervention period. Rates of otolaryngology clinic encounters, emergency department encounters, and hospital admissions did not change significantly over time. There was a small but statistically significant increase in surgical procedures for bleeding following the intervention from 1.35% (95% CI, 0.57%-2.14%) to 3.48% (95% CI, 1.85%-5.10%).AAO-HNS guideline publication decreased perioperative antibiotic use for pediatric tonsillectomy across a large pediatric health care network. Although there were no changes in otolaryngology clinic visits, emergency department visits, or admissions, we found a small but significant increase in surgery for bleeding following guideline publication. Additional studies are necessary to verify this unexpected association.

Background: Evidence suggests that metastatic colorectal carcinoma (mCRC) has a high level of intratumor heterogeneity. We carried out a quantitative assessment of tumor heterogeneity for KRAS, NRAS, BRAF and PIK3CA mutations, in order to assess potential clinical implications. Patients and methods: Tumor samples (n = 182) from the CAPRI-GOIM trial of first-line cetuximab + FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next-generation sequencing that allows quantitative assessment of mutant genes. Mutant allelic frequency was normalized for the neoplastic cell content and, assuming that somatic mutations usually affect one allele, the Heterogeneity Score (HS) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells. Therefore, HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation. Results: The KRAS HS ranged between 12 and 260 with mean value of 87.1 and median value of 84.4, suggesting that in most CRC, the majority of neoplastic cells carry mutant KRAS. Similar findings were observed for NRAS (HS range 35.5-146.7; mean 102.8; median 117.1). In contrast, in BRAF (HS range 17.1-120; mean 54.8; median 54.3) and PIK3CA (HS range 14.3-120; mean 59.5; median 47.3) mutant cases, only a fraction of neoplastic cells seem to carry the mutant allele. The response rate was 70% in KRAS mutant patients with an HS 33 patients (high KRAS; n = 35); median progression-free survival were 7.97 and 8.37 months, respectively. Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA when compared with high-KRAS (6/10 versus 8/35). Conclusions: KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load.

To describe an interesting clinical and histopathologic case of a neonate presenting with respiratory distress and a laryngeal hamartoma with ectopic thymus and parathyroid tissue. Case report and PubMed review of the English literature. A full term, newborn male who presented immediately after birth with postitional, inspiratory stridor and airway distress. During operative microlaryngoscopy, a well-delineated, non-cystic, stalk-like mass was found in the endolarynx. Biopsy revealed thymic tissue with Hassall's corpuscles, parathyroid tissue and a central core of mature fibroadipose tissue and skeletal muscle. The mass was removed endoscopically with cold instrumentation. At 4 months postoperatively, the patient was doing well, without any respiratory symptoms, feeding difficulties, or endoscopic findings of recurrence. Neonatal laryngeal hamartomas are extremely rare. In general, an excellent prognosis is associated with these lesions, and the treatment of choice is endoscopic, surgical excision. This case is histopathologically unique because it is the first to encounter the presence of thymic and parathyroid tissue within a glandular hamartoma.

Retrospective studies have limitations in predicting perioperative risk following adenotonsillectomy in children with obstructive sleep apnea syndrome (OSAS). Few prospective studies exist. We hypothesized that demographic and polysomnographic (PSG) variables would predict respiratory and general perioperative complications.Prospective, observational cohort study.Pediatric tertiary center.Consecutive children undergoing adenotonsillectomy for OSAS within 12 months of PSG were evaluated for complications occurring within 2 weeks of surgery.There were 329 subjects, with 27%3 years old, 24% obese, 16% preterm, and 29% with comorbidities. In this higher risk population, 28% had respiratory complications (major and/or minor), and 33% had nonrespiratory complications. Significant associations were found between PSG parameters and respiratory complications as follows: apnea hypopnea index (rank-biserial correlation coefficient [r] = 0.174, P = .017), SpO2 nadir (r = -0.332, P.0005), sleep time with SpO290% (r = 0.298, P.0005), peak end-tidal CO2 (r = 0.354, P.0005), and sleep time with end-tidal CO250 mm Hg (r = 0.199, P = .006). Associations were also found between respiratory complications and age3 years (r = -0.174, P = .003) or black race (r = 0.123, P = .039). No significant associations existed between PSG parameters and nonrespiratory complications. A model using age3 years, SpO2 nadir, and peak CO2 predicted respiratory complications better than the American Academy of Pediatrics or American Academy of Otolaryngology-Head and Neck Surgery Foundation guidelines but was imperfect (area under the curve = 0.72).Thus, PSG predicted perioperative respiratory, but not nonrespiratory, complications in children with OSAS. Age3 years or black race are high-risk factors. Present guidelines have limitations in determining the need for postoperative admission.

Treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies has been restricted to metastatic colorectal cancer (mCRC) patients with RAS wild-type tumors. Next-generation sequencing (NGS) allows the assessment in a single analysis of a large number of gene alterations and might provide important predictive and prognostic information.In the CAPRI-GOIM trial, 340 KRAS exon 2 wild-type mCRC patients received first-line FOLFIRI plus cetuximab. Tumor samples (182/340, 53.5%) were assessed by NGS to search for mutations in 22 genes involved in colon cancer.Objective responses in the NGS cohort were observed in 104/182 patients [overall response rate (ORR) 57.1%; 95% confidence interval (95% CI) 52% to 66.4%] with a median progression-free survival (mPFS) of 9.8 (95% CI 8.7-11.5) months. NGS analysis was successfully completed in all 182 samples. One or more gene mutations (up to five) were detected in 124/182 (68.1%) tumors within 14/22 genes for a total of 206 mutations. KRAS exon 2 mutations were identified in 29/182 (15.9%) samples, defined as wild type by local laboratory assessment. Frequently mutated genes were: TP53 (39.6%), KRAS exons 3/4 (8.8%), NRAS exons 2/3 (7.1%), PIK3CA exons 9/20 (13.2%), BRAF (8.2%). FOLFIRI plus cetuximab treatment determined ORR of 62.0% (95% CI 55.5% to 74.6%) with mPFS of 11.1 (95% CI 9.2-12.8) months in patients with KRAS and NRAS wild-type tumors. Conversely, ORR was 46.6% (95% CI 39.9-57.5%) with mPFS of 8.9 (95% CI 7.4-9.6) months in patients with KRAS or NRAS mutations. Similarly, the subgroup of patients carrying KRAS, NRAS, BRAF, or PIK3CA mutations showed a worse outcome, although this might be due to a prognostic effect.This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.

We report an episode of transient, severe hypertension occurring within 2 minutes of injection of 1% lidocaine with 1:100 000 U of epinephrine in a patient taking midodrine for orthostatic hypotension. We hypothesize that the patient's autonomic nervous system was dangerously susceptible to the effect of local anesthetic when combined with the vasoactive systemic effect of midodrine. Surgeons should minimize the use of vasoconstrictors in patients treated with midodrine to avoid hypertensive complications.

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A first level trigger system based on a 40 MHz digital pipeline has been developed for the CERN NA48 experiment, aiming at measuring CP violation in K/sup 0//spl rarr/2/spl pi/ decays. The outputs of the 13340 cells of the 10 m/sup 3/ liquid krypton calorimeter are summed into 64 X and 64 Y projection strips and continuously digitised with 40 MHz FADCs. This information is used to reconstruct at each clock cycle and for the two calorimeter projections, the number of clusters, the impact time of each of them (with a precision of about 3 ns), their total energy and the first and second moments of the energy distribution. Based on the quantities listed above, a programmable look-up table system subsequently computes online the longitudinal position of the kaon decay vertex and performs an event selection. The system is described.