Orthopedic Disorders

Poncet's disease (tubercular rheumatism): a narrative review Ganesh Singh Dharmshaktu Clinical Trials in Orthopedic Disorders 2020 5(4):23-27 Poncet's disease or tubercular rheumatism is uncommon, and there are not many related studies. No consensus has been achieved with respect to its etiopathogenesis. The low prevalence of this Poncet's disease even in endemic regions suggests hidden mechanisms that require further research to fully comprehend this enigmatic disorder. Careful identification of primary focus of tubercular infection, clinical suspicion and knowledge of this disorder is crucial for prompt identification and treatment. This article aims to provide an overview of the recently published articles about Poncet's disease. The article attempts to highlight key features of the disease for better understanding of this peculiar disorder.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Telephone consultation 11855 int 1193,

Anesthesia & Analgesia

Clinical Outcomes of Pregnant and Postpartum Extracorporeal Membrane Oxygenation Patients BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) as a rescue therapy for cardiopulmonary failure is expanding in critical care medicine. In this case series, we describe the clinical outcomes of 21 consecutive pregnant or postpartum patients that required venovenous (VV) or venoarterial (VA) ECMO. Our objective was to characterize maternal and fetal survival in peripartum ECMO and better understand ECMO-related complications that occur in this unique patient population. METHODS: Between January 2009 and June 2019, all pregnant and postpartum patients treated with ECMO for respiratory or circulatory failure at a single quaternary referral center were identified. For all patients, indications for ECMO, maternal and neonatal outcomes, details of ECMO support, and anticoagulation and bleeding complications were collected. RESULTS: Twenty-one obstetric patients were treated with ECMO over 10 years. Thirteen patients were treated with VV ECMO and 8 patients were treated with VA ECMO. Six patients were pregnant at the time of cannulation and 3 patients delivered while on ECMO; all 6 maternal and infant dyads survived to hospital discharge. The median gestational age at cannulation was 28 weeks (interquartile range [IQR], 24–31). In the postpartum cohort, ECMO initiation ranged from immediately after delivery up to 46 days postpartum. Fifteen women survived (72%). Major bleeding complications requiring surgical intervention were observed in 7 patients (33.3%). Two patients on VV ECMO required bilateral orthotopic lung transplantation and 1 patient on VA ECMO required orthotopic heart transplantation to wean from ECMO. CONCLUSIONS: Survival for mother and neonate are excellent with peripartum ECMO in a high-volume ECMO center. Neonatal and maternal survival was 100% when ECMO was used in the late second or early third trimester. Based on these results, ECMO remains an important treatment option for peripartum patients with cardiopulmonary failure.

Efficiency Metrics at an Academic Freestanding Ambulatory Surgery Center: Analysis of the Impact on Scheduled End-Times BACKGROUND: Understanding the impact of key metrics on operating room (OR) efficiency is important to optimize utilization and reduce costs, particularly in freestanding ambulatory surgery centers. The aim of this study was to assess the association between commonly used efficiency metrics and scheduled end-time accuracy. METHODS: Data from patients who underwent surgery from May 2018 to June 2019 at an academic freestanding ambulatory surgery center was extracted from the medical record. Unique operating room days (ORDs) were analyzed to determine (1) duration of first case delays, (2) turnover times (TOT), and (3) scheduled case duration accuracies. Spearman's correlation coefficients and mixed-effects multivariable linear regression were used to assess the association of each metric with scheduled end-time accuracy. RESULTS: There were 1378 cases performed over 300 unique ORDs. There were 86 (28.7%) ORDs with a first case delay, mean (standard deviation [SD]) 11.2 minutes (15.1 minutes), range of 2–101 minutes; the overall mean (SD) TOT was 28.1 minutes (19.9 minutes), range of 6–83 minutes; there were 640 (46.4%) TOT >20 minutes; the overall mean (SD) case duration accuracy was −6.6 minutes (30.3 minutes), range of −114 to 176; and there were 389 (28.2%) case duration accuracies ≥30 minutes. The mean (SD) scheduled end-time accuracy was 6.9 minutes (68.3 minutes), range of −173 to 229 minutes; 48 (15.9%) ORDs ended ≥1 hour before scheduled end-time and 56 (18.6%) ORDs ended ≥1 hour after scheduled end-time. The total case duration accuracy was strongly correlated with the scheduled end-time accuracy (r = 0.87, 95% confidence interval [CI], 0.84-0.89, P < .0001), while the total first case delay minutes (r = 0.12, 95% CI, 0.01-0.21, P = .04) and total turnover time (r = −0.16, 95% CI, 0.21-0.05, P = .005) were less relevant. Case duration accuracy had the highest association with the dependent variable (0.95 minutes changed in the difference between actual and schedule end time per minute increase in case duration accuracy, 95% CI, 0.90-0.99, P < .0001), compared to turnover time (estimate = 0.87, 95% CI, 0.75-0.99, P < .0001) and first case delay time (estimate = 0.83, 95% CI, 0.56-1.11, P < .0001). CONCLUSIONS: Standard efficiency metrics are similarly associated with scheduled end-time accuracy, and addressing problems in each is requisite to having an efficient ambulatory surgery center. Pursuing methods to narrow the gap between scheduled and actual case duration may result in a more productive enterprise.

Postoperative Morbidity and Mortality in Diabetic Patients After Fast-Track Hip and Knee Arthroplasty: A Prospective Follow-up Cohort of 36,762 Procedures BACKGROUND: Diabetes increases the risk of adverse outcomes in surgical procedures, including total hip and knee arthroplasty (THA/TKA), and the prevalence of diabetic patients undergoing these procedures is high, ranging from approximately 8% to 20%. However, there is still a need to clarify the role of diabetes and antihyperglycemic treatment in a fast-track THA/TKA setting, which otherwise may decrease morbidity. Consequently, we investigated the association between diabetes and antihyperglycemic treatment on length of stay (LOS) and complications following fast-track THA/TKA within a multicenter fast-track collaboration. METHODS: We used an observational study design on data from a prospective multicenter fast-track collaboration on unselected elective primary THA/TKA from 2010 to 2017. Complete follow-up (>99%) was achieved through The Danish National Patient Registry, antihyperglycemic treatment established through the Danish National Database of Reimbursed Prescriptions and types of complications leading to LOS >4 days, 90-day readmission or mortality obtained by scrutinizing health records and discharge summaries. Patients were categorized as nondiabetic and if diabetic into insulin-, orally, and dietary-treated diabetic patients. RESULTS: A total of 36,762 procedures were included, of which 837 (2.3%) had insulin-treated diabetes, 2615 (7.1%) orally treated diabetes, and 566 (1.5%) dietary-treated diabetes. Overall median LOS was 2 (interquartile range [IQR]: 1–3) days, and mean LOS was 2.4 (standard deviation [SD], 2.5) days. The proportion of patients with LOS >4 days was 6.0% for nondiabetic patients, 14.7% for insulin-treated, 9.4% for orally treated, and 9.5% for dietary-treated diabetic patients. Pharmacologically treated diabetes (versus nondiabetes) was independently associated with increased odds of LOS >4 days (insulin-treated: odds ratio [OR], 2.2 [99.6% confidence interval {CI}, 1.3–3.7], P < .001; orally treated: OR, 1.5 [99.6% CI, 1.0-2.1]; P = .002). Insulin-treated diabetes was independently associated with increased odds of "diabetes-related" morbidity (OR, 2.3 [99.6% CI, 1.2-4.2]; P < .001). Diabetic patients had increased renal complications regardless of antihyperglycemic treatment, but only insulin-treated patients suffered significantly more cardiac complications than nondiabetic patients. There was no increase in periprosthetic joint infections or mortality associated with diabetes. CONCLUSIONS: Patients with pharmacologically treated diabetes undergoing fast-track THA/TKA were at increased odds of LOS >4 days. Although complication rates were low, patients with insulin-treated diabetes were at increased odds of postoperative complications compared to nondiabetic patients and to their orally treated counterparts. Further investigation into the pathogenesis of postoperative complications differentiated by antihyperglycemic treatment is needed.

Intermittent Hypoxia and Effects on Early Learning/Memory: Exploring the Hippocampal Cellular Effects of Pediatric Obstructive Sleep Apnea This review provides an update on the neurocognitive phenotype of pediatric obstructive sleep apnea (OSA). Pediatric OSA is associated with neurocognitive deficits involving memory, learning, and executive functioning. Adenotonsillectomy (AT) is presently accepted as the first-line surgical treatment for pediatric OSA, but the executive function deficits do not resolve postsurgery, and the timeline for recovery remains unknown. This finding suggests that pediatric OSA potentially causes irreversible damage to multiple areas of the brain. The focus of this review is the hippocampus, 1 of the 2 major sites of postnatal neurogenesis, where new neurons are formed and integrated into existing circuitry and the mammalian center of learning/memory functions. Here, we review the clinical phenotype of pediatric OSA, and then discuss existing studies of OSA on different cell types in the hippocampus during critical periods of development. This will set the stage for future study using preclinical models to understand the pathogenesis of persistent neurocognitive dysfunction in pediatric OSA.

Development and Evaluation of a Risk-Adjusted Measure of Intraoperative Hypotension in Patients Having Nonemergent, Noncardiac Surgery BACKGROUND: Intraoperative hypotension is common and associated with organ injury and death, although randomized data showing a causal relationship remain sparse. A risk-adjusted measure of intraoperative hypotension may therefore contribute to quality improvement efforts. METHODS: The measure we developed defines hypotension as a mean arterial pressure <65 mm Hg sustained for at least 15 cumulative minutes. Comparisons are based on whether clinicians have more or fewer cases of hypotension than expected over 12 months, given their patient mix. The measure was developed and evaluated with data from 225,389 surgeries in 5 hospitals. We assessed discrimination and calibration of the risk adjustment model, then calculated the distribution of clinician-level measure scores, and finally estimated the signal-to-noise reliability and predictive validity of the measure. RESULTS: The risk adjustment model showed acceptable calibration and discrimination (area under the curve was 0.72 and 0.73 in different validation samples). Clinician-level, risk-adjusted scores varied widely, and 36% of clinicians had significantly more cases of intraoperative hypotension than predicted. Clinician-level score distributions differed across hospitals, indicating substantial hospital-level variation. The mean signal-to-noise reliability estimate was 0.87 among all clinicians and 0.94 among clinicians with >30 cases during the 12-month measurement period. Kidney injury and in-hospital mortality were most common in patients whose anesthesia providers had worse scores. However, a sensitivity analysis in 1 hospital showed that score distributions differed markedly between anesthesiology fellows and attending anesthesiologists or certified registered nurse anesthetists; score distributions also varied as a function of the fraction of cases that were inpatients. CONCLUSIONS: Intraoperative hypotension was common and was associated with acute kidney injury and in-hospital mortality. There were substantial variations in clinician-level scores, and the measure score distribution suggests that there may be opportunity to reduce hypotension which may improve patient safety and outcomes. However, sensitivity analyses suggest that some portion of the variation results from limitations of risk adjustment. Future versions of the measure should risk adjust for important patient and procedural factors including comorbidities and surgical complexity, although this will require more consistent structured data capture in anesthesia information management systems. Including structured data on additional risk factors may improve hypotension risk prediction which is integral to the measure's validity.

Do Elderly Patients With Diastolic Dysfunction Require Higher Doses of Norepinephrine During General Anesthesia for Noncardiac Surgeries? A Prospective Observational Study BACKGROUND: Diastolic dysfunction is a risk factor for postoperative major cardiovascular events. During anesthesia, patients with diastolic dysfunction might experience impaired hemodynamic function and worsening of diastolic function, which in turn, might be associated with a higher incidence of postoperative complications. We aimed to investigate whether patients with diastolic dysfunction require higher doses of norepinephrine during general anesthesia. Furthermore, we aimed to examine the association between the grade of diastolic dysfunction and the E/e' ratio during anesthesia. A high E/e' ratio corresponds to elevated filling pressures and is an important measure of impaired diastolic function. METHODS: We conducted a prospective observational cohort study at a German university hospital from February 2017 to September 2018. Patients aged ≥60 years and undergoing general anesthesia (ie, propofol and sevoflurane) for elective noncardiac surgery were enrolled. Exclusion: mitral valve disease, atrial fibrillation, and implanted mechanical device. The primary outcome parameter was the administered dose of norepinephrine within 30 minutes after anesthesia induction (μg·kg−1 30 min−1). The secondary outcome parameter was the change of Doppler echocardiographic E/e' from ECHO1 (baseline) to ECHO2 (anesthesia). Linear models and linear mixed models were used for statistical evaluation. RESULTS: A total of 247 patients were enrolled, and 200 patients (75 female) were included in the final analysis. Diastolic dysfunction at baseline was not associated with a higher dose of norepinephrine during anesthesia (P = .6953). The grade of diastolic dysfunction at baseline was associated with a decrease of the E/e' ratio during anesthesia (P < .001). CONCLUSIONS: We did not find evidence for an association between diastolic dysfunction and impaired hemodynamic function, as expressed by high vasopressor support during anesthesia. Additionally, our findings suggest that diastolic function, as expressed by the E/e' ratio, does not worsen during anesthesia.

Fiber-Needle Swept-Source Optical Coherence Tomography for the Real-Time Visualization of the Transversus Abdominis Plane Block Procedure in a Swine Model BACKGROUND: Fascia blocks (eg, the transversus abdominis plane [TAP] block) target the intermuscular fascia layers. Ultrasound techniques have allowed peripheral blocks to be performed with accuracy and safety, however, with limitations. Optical coherence tomography (OCT) is based on low-coherence interferometry. In this study, we examined the ability of OCT to identify the TAP. METHODS: A swept-source OCT probe was placed in a 17-gauge needle to obtain imaging. The needle was inserted within 2 different angle ranges (0°–30° and 30°–60°) on a slice of pork belly to assess imaging characteristics. A series of real-time OCT imaging of the muscle, fascia, and interfascial space was obtained. The tissue location of the needle tip was identified using near-infrared (NIR) imaging. In vivo OCT imaging was further done on 3 female 6-month-old native Chinese Landrance Duroc pigs. Real-time images of tissue layers were obtained with needle insertion. Ultrasound imaging of the OCT needle probe was also performed at the same time for needle trajectory guidance. After imaging, the OCT probe was removed, and 5 mL of normal saline was injected via the needle to confirm correct fascia plane identification. RESULTS: In and ex vivo studies showed clear visual distinction of muscle, fascia, and interfascial layer with OCT, with limitations. Independent validation of OCT criteria for the muscle/fascia differentiation by 20 OCT readers for the in vivo data demonstrated the sensitivity = 0.91, specificity = 0.90, and accuracy = 0.89. Although the angle of needle entry affected the depth of OCT penetration in the muscle, the attenuation coefficient values of the fascia and muscle tissue were statistically different (P < .001) and with high area under the receiver operating characteristics (ROC) curve (AUC) (AUC = 0.93 in 0°–30° and AUC = 1 in 30°–60°) for fascia identification. CONCLUSIONS: This study introduced a novel needle imaging probe method to identify the transversus abdominis fascia plane in real-time. Quantitative calculation of the attenuation coefficients can further aid objective identification by providing direct confirmation of the tip position, increasing the first-pass success rate, and decreasing the need for needle repositioning. Combining OCT and ultrasound may improve the accuracy of anesthetics placement.

Incidence, Mortality, and Characteristics of 18 Pediatric Perioperative Cardiac Arrests: An Observational Trial From 22,650 Pediatric Anesthesias in a German Tertiary Care Hospital BACKGROUND: Recently, a very low incidence of 3 per 10,000 and a mortality of 30% were reported for pediatric perioperative cardiac arrest (POCA). However, high-risk patients, namely children already anesthetized on the intensive care unit (ICU), were excluded. This study investigates the incidence and mortality of POCA in children in whom anesthesia was induced in the ICU or in the operating room using real-world data. In addition, different classifications of POCA were compared with respect to outcome relevance. METHODS: This is a retrospective observational study conducted at a German level 1 perinatal center and tertiary care hospital between 2008 and 2018. Children ≤15 years who underwent an anesthetic procedure and suffered from POCA (defined as any condition requiring chest compressions and/or defibrillation) from the beginning of care provided by an anesthesiologist to 60 minutes after anesthesia or sedation were included. Primary end points were incidence and mortality of POCA in children with anesthesia induced in the ICU versus in the operating room. Secondary end points included incidences and outcomes with respect to the pathophysiological cause (respiratory versus circulatory associated). RESULTS: There were 18 POCA during 22,650 anesthetic procedures (incidence 7.9 per 10,000; 95% confidence interval [CI], 4.7-12.5). Thirty-day mortality was 3.5 per 10,000 (95% CI, 1.5-6.9). Incidence and mortality were higher in children in whom anesthesia was induced in the ICU versus in the operating room (incidence: 131.6; 95% CI, 57 to 257.6 versus 4.5; 95% CI, 2.2-8.3; P < .001; and mortality: 82.2; 95% CI, 26.7-190.8 versus 1.4; 95% CI, 0.3-3.9; P < .001). Mortality in circulatory-induced POCA (n = 8; 44%) was 100%, in respiratory-induced POCA (n = 9; 50%) 0% (P < .001). CONCLUSIONS: Children with anesthesia induction in the ICU represent a high-risk population for POCA and POCA-associated mortality. POCA classification should be based on the individual cause (respiratory versus circulatory) rather than on the perioperative phase or the responsible specialty.

A Bayesian Comparison of Frailty Instruments in Noncardiac Surgery: A Cohort Study BACKGROUND: Frailty—a multidimensional syndrome related to age- and disease-related deficits—is a key risk factor for older surgical patients. However, it is unknown which frailty instrument most accurately predicts postoperative outcomes. Our objectives were to quantify the probability of association and relative predictive performance of 2 frailty instruments (ie, the risk analysis index-administrative [RAI-A] and 5-item modified frailty index [mFI-5]) with postoperative outcomes in National Surgical Quality Improvement Program (NSQIP) data. METHODS: Retrospective cohort study using Bayesian analysis of NSQIP hospitals. Adults having inpatient small or large bowel surgery 2010–2015 (derivation cohort) or intermediate to high risk mixed noncardiac surgery in 2016 (validation cohort) had preoperative frailty assigned using 2 unique approaches (RAI-A and mFI-5). Probabilities of association were calculated based on posterior distributions and relative predictive performance using posterior predictive distributions and Bayes factors for 30-day mortality (primary outcome) and serious complications (secondary outcome). RESULTS: Of 50,630 participants, 7630 (14.0%) died and 19,545 (38.6%) had a serious complication. Without adjustment, the RAI-A and mFI-5 had >99% probability being associated with mortality with a ≥2.0 odds ratio (ie, large effect size). After adjustment for NSQIP risk calculator variables, only the RAI-A had ≥95% probability of a nonzero association with mortality. Similar results arose when predicting postoperative complications. The RAI-A provided better predictive accuracy for mortality than the mFI-5 (minimum Bayes factor 3.25 × 1014), and only the RAI-A improved predictive accuracy beyond that of the NSQIP risk calculator (minimum Bayes factor = 4.27 × 1013). Results were consistent in leave-one-out cross-validation. CONCLUSIONS: Translation of frailty-related findings from research and quality improvement studies to clinical care and surgical planning will be aided by a consistent approach to measuring frailty with a multidimensional instrument like RAI-A, which appears to be superior to the mFI-5 when predicting outcomes for inpatient noncardiac surgery.

Assessment of Anesthesia Capacity in Public Surgical Hospitals in Guatemala BACKGROUND: International standards for safe anesthetic care have been developed by the World Federation of Societies of Anaesthesiologists (WFSA) and the World Health Organization (WHO). Whether these standards are met is unknown in many nations, including Guatemala, a country with universal health coverage. We aimed to establish an overview of anesthesia care capacity in public surgical hospitals in Guatemala to help guide public sector health care development. METHODS: In partnership with the Guatemalan Ministry of Public Health and Social Assistance (MSPAS), a national survey of all public hospitals providing surgical care was conducted using the WFSA anesthesia facility assessment tool (AFAT) in 2018. Each facility was assessed for infrastructure, service delivery, workforce, medications, equipment, and monitoring practices. Descriptive statistics were calculated and presented. RESULTS: Of the 46 public hospitals in Guatemala in 2018, 36 (78%) were found to provide surgical care, including 20 district, 14 regional, and 2 national referral hospitals. We identified 573 full-time physician surgeons, anesthesiologists, and obstetricians (SAO) in the public sector, with an estimated SAO density of 3.3/100,000 population. There were 300 full-time anesthesia providers working at public hospitals. Physician anesthesiologists made up 47% of these providers, with an estimated physician anesthesiologist density of 0.8/100,000 population. Only 10% of district hospitals reported having an anesthesia provider continuously present intraoperatively during general or neuraxial anesthesia cases. No hospitals reported assessing pain in the immediate postoperative period. While the availability of some medications such as benzodiazepines and local anesthetics was robust (100% availability across all hospitals), not all hospitals had essential medications such as ketamine, epinephrine, or atropine. There were deficiencies in the availability of essential equipment and basic intraoperative monitors, such as end-tidal carbon dioxide detectors (17% availability across all hospitals). Postoperative care and access to resuscitative equipment, such as defibrillators, were also lacking. CONCLUSIONS: This first countrywide, MSPAS-led assessment of anesthesia capacity at public facilities in Guatemala revealed a lack of essential materials and personnel to provide safe anesthesia and surgery. Hospitals surveyed often did not have resources regardless of hospital size or level, which may suggest multiple factors preventing availability and use. Local and national policy initiatives are needed to address these deficiencies.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Telephone consultation 11855 int 1193,

Medicine

Editorial Rajendra N Srivastava Apollo Medicine 2020 17(4):239-239

Cytological evaluation of p16Ink4a in precancerous lesions of the cervix: Conventional papanicolaou smears Seema Singhal, Vinod Kumar Arora Apollo Medicine 2020 17(4):240-245 Background: Cancer of the uterine cervix is the second most common cancer among women worldwide. More than three fourths of these patients are diagnosed at advanced stages, leading to poor prospects of long term survival and cure. Introduction of Papanicolaou (Pap test) cytological screening for cervical precancerous lesions has significantly reduced the incidence and mortality of cervical cancer. Human papillomavirus (HPV) DNA testing has been recently demonstrated to be efficient to be integrated into screening programs, so it can be used to triage women with equivocal cytological abnormalities and also identifies women at risk of residual or recurrent disease after treatment of cervical intraepithelial neoplasia. However, it fails into triage low grade lesions. HPV DNA test confirms infection by the virus, present in 99% of cases. However, it does not discriminate between transient and persistent infection as it is crucial because it is the persistent infection which progresses to neoplasia. Histological assessment of cervical biopsy that is considered as “gold standard” can be hampered by intra and inter observer variability. A more specific triage marker is required to identify women who would need colposcopy. Hence, p16INK4a has emerged as a new diagnostic and prognostic biomarker. Aims and objectives: This study was conducted to evaluate the utility of staining of p16INK4a on conventional Pap smears and its comparison with corresponding biopsies. Material and Methods: 50 cases of conventional Papanicolaou stained cervical smears cases were randomly selected from the archive of cytopathology laboratory. The cervical smears were re-evaluated for adequacy, preservation of cells, cytomorphology and various lesions were categorized according to The Bethesda system 2001 (TBS) classification. Consecutive such cases were selected for which both cytological and histological material were available. Immunostaining of cervical cytological specimens for p16 was performed using monoclonal murine antibody, clone 16P04, JC2. Ready to use antibody was used for immunostaining as per manufacturer's protocol. Results: Out of the 50 smears of preneoplastic and invasive lesions, ASCUS was seen in 5 cases, LSIL in 10 cases, HSIL in 20 cases, SCC in 20 cases and AGUS in 5 cases. Of the 5 cases of ASCUS, histopathology showed 3 chronic cervicitis and 1 each in CIN-1 and CIN-2. Histopathological diagnosis of 10 cases of LSIL showed 6 CIN-1 and 2 each in CIN-2 and chronic cervicitis. Similarly, for 10 cases of HSIL, 3 were CIN-2, 5 CIN-3 and 2 SCC. All 20 cases of carcinoma showed SCC while 5 cases of AGUS showed 4 chronic cervicitis and one adenocarcinoma. Immunohistochemical staining of p16INK4A showed weak positivity in 3 cases of chronic cervicitis and 4 cases of CIN-1. In CIN-2 cases, 66.67% showed strong positivity, CIN-3 showed 80% while both carcinoma and adenocarcinoma showed 100% strong positivity. The sensitivity of immunohistochemical staining of p16INK4A was 77.5%, specificity was 100%, PPV 100% and NPV 52.6%. The relation between histological and cytological immunostaining of p16INK4A. Conclusion: p16INK4A is a reliable marker for dysplastic squamous and glandular cervical cells both in tissue sections and in cervical smears. p16 immunostaining can be easily performed on CPS, and there is high concordance of positivity on smears and tissue sections.

Intraoperative ultrasound in neurosurgical procedures V A Kiran Kumar, N A Sai Kiran, B Girija Kumari, Ranabir Pal, V Umamaheswar Reddy, Amit Agrawal Apollo Medicine 2020 17(4):246-251 Introduction: The objective of the present study was to study the utility and the effectiveness of intraoperative ultrasound in neurosurgical procedures and to assess the outcome. Material and Methods: In this prospective study, operative procedures by a single surgeon under intraoperative ultrasound localization for basal ganglia/thalamic haematoma or traumatic brain contusions or brain tumours were included. Ultrasound scanning of the brain was performed before and after the excision of the lesion and during the procedure to verify the extent of removal of the lesion. Results: 74 patients underwent surgery for brain tumor/basal ganglia bleed/head injury with hemorrhagic contusion with the help of intraoperative ultrasound. Gross tumor resection was noted in 25 out of 36 cases of brain tumors (69.44%), complete evacuation of hematoma was noted in 14 out of 34 cases(41.2%) of basal ganglia bleed and in 2 out of 4 cases (50%) of intracerebral contusion. As per Modified Rankin scale (MRS)score, among the brain tumor cases, all patients had fared well in recovery and had better MRS scores except in one patient who expired during postoperative period. Conclusions: IoUS is a widely accessible, cheap, portable and less space occupying and reliable imaging tool to follow and modify the surgical plan in real time, and is more accurate and helpful in complete tumor resection, evacuation of intracerebral bleeds and contusions, and biopsy of deep seated lesions. It is easy and safe to handle with no risk of radiation.

Prevalence of Side Effects of Propofol Anesthesia among Adult and Pediatric Patients Undergoing Surgery Khaled D Alsaeiti, Fathi M Elbraky, Salem A Ibkhatra, Khawla A Al-Zoubi, Ghada A Alagoury, Fatima F Al-Farajani, Hawa Al-Kharaz, Fatima A Al-Megrahi Apollo Medicine 2020 17(4):252-255 Introduction: Propofol is a short-acting medication that lowers awareness and causes a transient memory loss. It is given intravenously. The aim of this study was to assess the prevalence of various side effects of the use of propofol as an anesthetic in various surgical procedures and to compare their prevalence among adults and children. Materials and Methods: One hundred patients were included in the study, fifty adults and fifty of children, who underwent various types of surgery and received propofol anesthesia, at Pediatrics Hospital, Benghazi Medical Center (BMC) and Al-Hawari hospital, from September to November 2019. Results: The mean age was 6.37 ± 4.18 years in the pediatric group (ranging from 1 to 15 years) and 40.0 ± 17.03 years in the adult group (range from 16 to 97 years). The indication of surgery among the adult group was cholecystectomy (14 patients, 28%), followed by ENT operations (12 patients, 24%), while the indication of surgery among the pediatric group was tonsillectomy (20 patients, 40%), followed by hernia repair (15 patients, 30%). Thirty-five adults (70%) and 40 children (80%) suffered different types of complications during the study. Pain at the site of propofol injection was the most common complication. It was observed in 21 adult patients (42%) and 23 children (46%). Bronchospasm developed among 11 children who underwent tonsillectomy. Low blood pressure was more prevalent among adult patients (14 patients, 28%). An arrhythmia was developed in nine patients (six adults and three children). Two adults and five children experienced delayed recovery from anesthesia. The recovery time was 14.67 ± 8.37 min (5â€"45 min), Conclusion: Burning at site of propofol injection is the most common side effect of propofol anesthesia; other complications need further evaluation by more detailed studies.

A review of chronic relapsing inflammatory optic neuropathy Pushpendra Nath Renjen, Dinesh Mohan Chaudhari, Kamal Ahmad, Shivangi Garg, Anjali Mishra Apollo Medicine 2020 17(4):256-258 Chronic relapsing inflammatory optic neuropathy (CRION), initially described in 2003, is a form of recurrent optic neuritis (ON) that has relatively good response/dependency to steroid treatment. In demyelinating ON, patients present with periorbital ache and pain elicited by eye movement, which usually begins insidiously and worsens, in synchrony with or preceding a reduction in vision, which deteriorates over days. The etiology of CRION is unknown. However, the excellent response to corticosteroids and the need for immunosuppressive therapy to prevent relapse suggests an immunomediated origin.

Recurrent respiratory papillomatosis: A challenging clinical entity Santosh Kumar Swain, Sidharth Mohanty, Bulu Nahak, Mahesh Chandra Sahu Apollo Medicine 2020 17(4):259-263 Recurrent respiratory papillomatosis (RRP) is a benign lesion seen in the respiratory airway caused by human papillomatosis virus (HPV).RRP can affects children to young adults. Most of the childhood RRP occur at birth which contaminated from birth canals of the mother. In adult ages, the infections transmitted via sexual route. The lesions are often seen as exophytic nodules, mostly in the larynx and occasionally at the nasopharynx, tracheobronchial trees and lung parenchyma. This disease is often unpredictable and varies from spontaneous remission to aggressive persistent or recurrence in nature.RRP has chance for malignant transformation to squamous cell carcinoma although it is a rare happening. The diagnosis is confirmed by histopathological study. Presently there is no definite treatment for RRP available. Surgery is the treatment of choice along with several adjuvant therapies available. The aim of this review article is to describe the detail etiology, epidemiology, clinical presentations, investigations and treatment of RRP.

A Reflection on the Use of Additive Manufacturing in Nephrology for Education and Surgical Planning Azhar Equbal, Shahid Akhtar, Md. Asif Equbal Apollo Medicine 2020 17(4):264-266 Additive manufacturing (AM) or three-dimensional printing (3DP) is a new technology known for rapid fabrication of customized or finely detailed parts with decreased cost. The technology uses the principle of layer by layer-based manufacturing of parts following the bottom-up approach. In recent years, AM technologies have seen a rapid development in various fields of engineering, medical, and aeronautics. Development in technology and biomaterials has made AM more novel and approachable techniques for complex medical treatments. In the current work, a reflection on the use of AM technology in the field nephrology has been presented. At present, AM technologies are used in conceptualizing and fabricating urological instruments, planning surgeries, and educating the apprentices and patients. The review primarily aimed to present the use of AM for education and surgical planning in nephrology. The study will also discuss the limitation and future scope of AM in the field of nephrology.

Diabetes Mellitus and Periodontitis: Relevance of the Diabolic Duo in India Sumidha Bansal, Sangeeta Dhir, Subhash Kumar Wangnoo Apollo Medicine 2020 17(4):267-271 Diabetes and periodontitis are highly prevalent diseases. Chronic nature, along with shared risk factors, magnifies the complexity of both the diseases. Periodontal treatment results in clinically relevant reductions in HbA1c, and the presence of diabetes worsens the periodontal health and vice-versa. This paper presents an overview on the pathogenic mechanisms, impact of intervention, and significance of interprofessional collaborations for holistic management in diabetes and periodontitis.

Choleteryl ester storage disease: A rare cause of adrenal calcifications in children Fatiha Benmiloud, Maria Rkain, A El Aouali, A Babakhouya, Noufissa Benajiba Apollo Medicine 2020 17(4):272-274 Cholesteryl ester storage disease (CESD) in children is a rare anatomo-clinical entity, characterized by a secondary lysosomal accumulation and an autosomal recessive mutation in the LIPA gene, which results from a lysosomal acid lipase (LAL) deficiency. The work of this paper is based on our observation of a 25-month-old infant, who had an abdominal distension with a hepatomegaly of 13 cm. The abdomen X-ray has shown some bilateral adrenal calcifications. The results of the biological assessment : the hepatic check showed a slight cytolysis, triglycerides increased to 5.4 g.l with a reduced rate of high density lipoproteins. The blood smear has shown the presence of intracytoplasmic lipid vacuoles in the lymphocytes, with a positive MGG staining and a negative PAS staining. The activity of the LAL enzyme has decreased to 3.6%. This observation joins the rare pediatric cases of the CESD and highlights the interest in a simply available radiological examination to make a guidance diagnosis of a complex metabolic disorder.

Xanthogranulomatous osteomyelitis Seema Singhal, Chander Shekher Apollo Medicine 2020 17(4):275-276 Xanthogranulomatous osteomyelitis (XO) is a type of chronic osteomyelitis characterized by collection of foamy macrophages admixed with mononuclear cells. Xanthogranulomatous inflammation is characterized by the presence of histiocytes, foamy macrophages, activated plasma cells, and presence of suppurative foci and hemorrhage. It has been encountered in various tissues such as gallbladder, kidney, urinary bladder, fallopian tube, ovary, vagina, prostate, testis, epididymis, colon, and appendix. Very rarely, it can affect lungs, brain, or bone. Only three cases of XO have been described previously in the literature till date.

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HNO

S1-Leitlinie: Obstruktive Schlafapnoe im Rahmen von Tonsillenchirurgie mit oder ohne Adenotomie bei Kindern – perioperatives Management Zusammenfassung Operationen aus dem Fachgebiet der Hals-Nasen-Ohren-Heilkunde zählen zu den häufigsten operativen Eingriffen im Kindesalter. Die Tonsillenchirurgie mit oder ohne Adenotomie aufgrund einer adenotonsillären Hyperplasie mit Obstruktion der oberen Atemwege in Kombination mit oder ohne Belüftungsstörung des Mittelohrs ist bei diesen Eingriffen führend. Kinder mit obstruktiver Schlafapnoe (OSA) haben hierbei ein deutlich erhöhtes Risiko, perioperativ respiratorische Komplikationen zu erleiden. Es wurde über Todesfälle und bleibende neurologische Schäden aufgrund von Apnoe und einer erhöhten Opioidsensibilität berichtet. Die vorliegende Leitlinie stellt einen risikoadjustierten pragmatischen Ansatz dar. Patienten mit bestätigter oder vermuteter OSA sollen perioperativ entsprechend ihren individuellen Risiken und Bedürfnissen behandelt und überwacht werden, um schwere bleibende Schäden zu verhindern.

Welche Funktion haben die Nasennebenhöhlen?

Zur Funktion und Physiologie der Kieferhöhle

Navigierte endoskopisch-kontrollierte transtympanale Resektion eines infracochleären Cholesteatomrezidivs Zusammenfassung Ein infracochleär gelegenes Cholesteatom der Felsenbeinspitze, welches direkten Kontakt zur A. carotidea interna (ACI) hat, ist selten anzutreffen. Aufgrund der Gefahr der Eröffnung der Cochlea mit konsekutiver Ertaubung und der Verletzung der ACI erfordert es eine gründliche präoperative Zugangsplanung, ausführliche Aufklärung und Information des Patienten. Der dargestellte Fall zeigt das navigierte endoskopisch kontrollierte transtympanale Vorgehen bei einem solchen infracochleären Cholesteatomrezidiv. Das Hörvermögen des Patienten wurde nicht beeinträchtigt, und es zeigte sich kein Anhalt für ein Rezidiv.

Validierung des Düsseldorfer Screeningtools: ein traitbasierter Ansatz zur Erfassung der psychischen Belastung von Krebspatienten Zusammenfassung Hintergrund Screening von psychischen Belastungen während einer Krebserkrankung ist notwendig, um gezielt die Patienten herauszufiltern, die psychologische Unterstützung benötigen. Derzeit geschieht dies überwiegend über die Abfrage akuter Probleme. Stabile interne und externe Risikofaktoren und präventiv wirkende Merkmale bleiben weitestgehend unberücksichtigt. Das neu entwickelte Düsseldorfer Screeningtool (DST) erfasst psychische Belastung mithilfe stabiler Traits, unter Berücksichtigung der sozialen Unterstützung und des Krankheitsverarbeitungsstils. Zielsetzung ist eine Validierung des DST anhand des Distress-Thermometers (DT) sowie der Psychoonkologischen Basisdokumentation (PO-Bado). Methodik Untersucht wurden 126 Patienten mit Plattenepithelkarzinomen im Bereich Hals und Kopf. Zur Festlegung des Cut-Off-Wertes wurden ROC Kurven (Receiver-Operating-Characteristics) berechnet. Als Maß für die Güte werden Area under Curve Werte (AUC) angegeben. Sensitivität und Spezifität wurden für den jeweils als Goldstandard genutzten Fragebogen festgelegt. Ergebnisse Die Diskriminationsfähigkeit des DST ist sowohl im Vergleich mit dem DT als auch mit der PO-Bado mit AUC-Werten von 0,62 bis 0,80 als gut zu bewerten. Bei einem Cut-Off-Wert des DT von 5 kann eine Sensitivität von 84,2 % bei gleichzeitiger Spezifität von 37,0 % angegeben werden. Im Vergleich zur PO-Bado kann ein Sensitivitätswert von 92,9 % bei gleichzeitiger Spezifität von 43,6 % angegeben werden. Schlussfolgerung Die Ergebnisse zeigen, dass auch ein traitbasierter Ansatz zur Erfassung von psychischer Belastung zielführend und sicher die Belastungssituation von Krebspatienten aufzeigen kann, sodass sich hier ein neuer Ansatz des Screenings in der Psychoonkologie herauskristallisiert hat.

Ausgeprägte rechtsseitige Zephalgien mit Parese des rechten N. abducens

Erratum zu: Präoperative Coronavirustestung in Deutschland Ein Erratum zu dieser Publikation wurde veröffentlicht: https://doi.org/10.1007/s00106-020-00966-2

Hygiene bei der HNO-Untersuchung Zusammenfassung Das Bewusstsein für die Wichtigkeit eines möglichst keimfreien Arbeitens entstand erst im 19. Jahrhundert. Mittlerweile besteht u. a. laut Infektionsschutzgesetz die Pflicht, der Übertragung und Weiterverbreitung von Krankheitserregern vorzubeugen. Diese können auch auf unbelebten Oberflächen längere Zeit überleben, von dort über die Hände des Personals übertragen werden und so zu Infektionen führen. Studien zeigten, dass auch Kontaminationen von noch unbenutzten Instrumenten nach einer HNO-Untersuchung keine Seltenheit sind. Die Kommission für Krankenhaushygiene und Infektionsprävention (KRINKO) des Robert Koch-Instituts gibt Empfehlungen für allgemeine Hygienemaßnahmen (Basis- oder Standardhygiene). Diese müssen für die HNO-Untersuchung situativ angepasst und umgesetzt werden. Wegen zunehmender Resistenzentwicklung nosokomialer Krankheitserreger und der aktuellen Pandemie ist die konsequente Umsetzung dieser infektionspräventiven Maßnahmen wichtig.

Seltene Diagnose einer knochendestruierenden Läsion der Keilbeinhöhle

Einfluss cochleärer Parameter auf die aktuelle Cochleaimplantatversorgung Zusammenfassung Seit dem Einzug von Cochleaimplantaten in die klinische Routine ist das Interesse an der Messung der cochleären Parameter, insbesondere der cochleären Länge (Länge des Canalis spiralis cochleae, „cochlear duct length", CDL), immer größer geworden, da diese einen Einfluss auf die korrekte Auswahl der Elektrode haben können. Einerseits ist die Abdeckung eines optimalen Frequenzbands für ein gutes audiologisches Ergebnis relevant, andererseits gilt es, ein cochleäres Trauma durch eine zu tiefe Insertion oder Fehllage des Elektrodenträgers zu vermeiden. Cochleaimplantate stimulieren die Spiralganglienzellen (SGZ), deren Anzahl und insbesondere Verteilung auch einen Einfluss auf die Funktion eines Cochleaimplantats haben. Darüber hinaus kann die Frequenzzuordnung jedes Elektrodenkontakts für den postoperativen Erfolg eine entscheidende Rolle einnehmen, da die Frequenzverteilung der menschlichen Cochlea mit variierender CDL substanzielle interindividuelle Unterschiede aufweist. Ziel der vorliegenden Arbeit ist es, einen Überblick über verwendete Methoden zur Bestimmung der cochleären Parameter und über relevante Studien zur CDL, zur Anzahl und Verteilung der SGZ und zur Frequenzzuordnung der Elektrodenkontakte zu geben. Aufbauend darauf wird ein Konzept zur personalisierten Cochleaimplantatversorgung vorgestellt. Zusammenfassend soll die vorliegende Arbeit dabei helfen, die personalisierte Medizin im Bereich der Cochleaimplantatversorgung zukünftig zu fördern, um aktuelle Grenzen zu überwinden und das audiologische Ergebnis zu optimieren.

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Otology & Neurotology

Treatment Analysis and Overall Survival Outcomes of Patients With Bilateral Vestibular Schwannoma Objectives: To investigate the clinical presentation, treatment breakdown, and overall survival (OS) outcomes of patients with neurofibromatosis type 2 (NF2)-associated bilateral vestibular schwannoma (NVS). Methods: The 2004 to 2016 National Cancer Database was queried for patients with a diagnosis of VS. The "Laterality" code was used to stratify patients into sporadic unilateral vestibular schwannoma (UVS) and NVS. Results: Of the 33,839 patients with VS, 155 (0.46%) were coded for NVS with an average age and tumor size of 37.4 ± 20.5 years and 23.5 ± 18.2 mm. Patients underwent observation (45.3%), surgery (29.3%), and radiotherapy (20.0%), and had a 5.8% 5-year mortality rate. Compared with UVS, NVS was negatively associated with receiving surgery (40.2% versus 29.3%, p = 0.02) while watchful observation was more prevalent (30.1% versus 45.3%, p = 0.001). In NVS, undergoing surgery was associated with larger tumor size (34.5 ± 21.2 versus 17.8 ± 13.3 mm, p = 0.001) and shorter diagnosis-to-treatment time (49.1 ± 60.6 versus 87.0 ± 78.5 d, p = 0.02), radiotherapy was associated with older age (44.4 ± 18.9 versus 35.2 ± 20.6 yr, p = 0.02) and longer diagnosis-to-treatment time (85.9 ± 77.9 versus 53.9 ± 65.5 d, p = 0.04), and observation was associated with smaller tumor size (17.8 ± 15.9 versus 28.0 ± 19.2 mm, p = 0.01). Kaplan–Meier log-rank analysis demonstrated similar 10-year OS between NVS and UVS patients (p = 0.58) without factoring the earlier age of presentation. Furthermore, there were no temporal changes in presentation/management of NVS, and OS was not dependent on the received treatment (p = 0.30). Conclusions: With younger age, larger tumors, and more conservative management, NVS's OS was not treatment-dependent and was similar to sporadic UVS, though the latter should not be interpreted as similar life expectancies due to the much earlier presentation. Address correspondence and reprint requests to Hamid R. Djalilian, M.D., Division of Neurotology and Skull Base Surgery, Department of Otolaryngology–Head and Neck Surgery, University of California Irvine, 19182 Jamboree Road, Otolaryngology-5386, Irvine, CA 92697; E-mail: hdjalili@hs.uci.edu K.G. and M.A. have contributed equally to this work. Presented as a podium at the 2020 Triological Society: Combined Sections Meeting, Coronado, CA, January 23–25, 2020. Financial Disclosure: M.A. is supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant TL1TR001415. The authors disclose no conflicts of interest. Copyright © 2020 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Reliability of Primary Health Care Audiograms by Non-Qualified Examiners—An Analysis of 1,224 Cases Objective: To evaluate the accuracy of primary health care audiograms conducted by non-qualified examiners in a non-standard acoustic environment. Study Design: Retrospective chart review. Setting: Referring primary health care institutions and hospital hearing center. Patients: One thousand two hundred twenty four adult patients evaluated for hearing aid fitting at North Karelia Central hospital in years 2017 and 2018. Main Outcome Measures: Intraclass correlation coefficient (ICC), mean threshold differences, and mean absolute errors were used to assess agreement between primary health care and hospital audiograms. Primary health care audiometry sensitivity, specificity and positive (PPV) and negative (NPV) predictive values were calculated for hearing aid candidacy in general and open ear mold candidacy in particular. Results: ICC for both better ear hearing level (BEHL0.5,1,2,4  kHz) and pure-tone average (PTA0.5,1,2,4  kHz) in frequencies 0.5, 1, 2, and 4 kHz was 0.82, and in individual full octave frequencies from 0.125 to 8 kHz ranged from 0.70 to 0.83. Mean threshold differences in BEHL0.5,1,2,4  kHz and PTA0.5,1,2,4  kHz were 1.8 and 1.6 dB and mean absolute errors 4.9 and 5.3 dB, respectively. Sensitivity for hearing aid candidacy was 0.97, specificity 0.58, PPV 0.92, and NPV 0.79. Conclusions: Primary health care audiometry is reasonably accurate, allowing preselection of patients to adequate hearing care pathways. Address correspondence and reprint requests to Jukka Kokkonen, M.D., Department of Otorhinolaryngology, North Karelia Central Hospital, Tikkamäentie 16, 80210 Joensuu, Finland; E-mail: jukka.kokkonen@siunsote.fi Sources of support or funding received: none. The authors disclose no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.jcraniofacialsurgery.com). Copyright © 2020 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Cochlear Implant Outcomes in Neurofibromatosis Type 2: Implications for Management Objective: To describe our institutional experience with cochlear implantation (CI) for rehabilitation of hearing loss in Neurofibromatosis type 2 (NF2) patients. Study Design: Retrospective review between 1989 and 2019. Setting: Tertiary-care center. Patients: Twenty-four patients (67% female, mean age 45.6years) with NF2. Management of their ipsilateral vestibular schwannoma included microsurgery (n=12), stereotactic radiation (n=5), and observation (n=7). Interventions: Cochlear implantation. Main Outcome Measures: Ability to obtain open-set speech, daily device usage and long-term device benefit. Results: All patients achieved some degree of sound awareness with CI. Nineteen patients (79%) achieved open-set speech understanding with a mean word-recognition score of 43% (range 0-88%). Patients with tumors 1.5 cm or less demonstrated the better speech understanding, without significant differences among treatment modalities. For tumors greater than 1.5 cm, patients who underwent microsurgery had a lower rate of open-set speech understanding compared to those treated with radiation or observation. Regular daily device use in 83% of patients was found. Long-term use (>10years) was observed in several patients, though some ultimately required reimplantation with an auditory brainstem implant due to progressive tumor growth. Mean follow-up duration was 4.1 years (range 0.4-15). Conclusions: Cochlear implantation can be an effective treatment for hearing loss in NF2 patients provided the cochlear nerve is intact, regardless of prior management for the ipsilateral tumor. The degree of benefit varies and is influenced by tumor size. Management strategies that preserve the cochlear nerve maximize the interval during which a CI could be of benefit to NF2 patients. Address correspondence and reprint requests to David R. Friedmann, M.D., M.Sc., Department of Otolaryngology, New York University School of Medicine, 530 1st Avenue Suite 7Q, New York, NY 10016; E-mail: david.friedmann@nyulangone.org The following manuscript was presented in oral form at the Annual North American Skull Base Society Meeting, February 9, 2020 in San Antonio, TX. J.T.R. and W.H.S. are consultants for Cochlear Pty Limited and receive research support. Institutional review board approval: New York University IRB Approval #i19-01139. Copyright © 2020 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Cochlear Implantation in Sporadic Vestibular Schwannoma and Other Retrocochlear Pathology: A Case Series Objective: To describe outcomes with cochlear implantation (CI) for rehabilitation of hearing loss in patients with sporadic vestibular schwannomas (VS) and other retrocochlear pathologies. Study Design: Retrospective review. Setting: Tertiary-care center. Patients: Twenty three cases in 19 patients (53% men, mean age 55.8 yr) with non-neurofibromatosis type 2 related retrocochlear pathology. Interventions: Unilateral or bilateral CI. Main Outcome Measures: Word recognition score, device usage. Results: Etiology of deafness included sporadic VS (n = 9, 39%), radiation after head and neck or central nervous system (CNS) malignancy (n = 8, 35%), superficial siderosis (n = 3, 13%), neurosarcoidosis (n = 2, 9%), and pontine stroke (n = 1, 4%). Mean follow-up duration was 2.3 years (standard deviation [SD] 3.0; range, 0.2–9.4). Auditory perception was achieved in 20 out of 22 patients (91%) who have been activated. Mean WRS in patients with sporadic VS was 18% (SD 20; range, 0–44). Mean WRS in patients with non-VS retrocochlear pathology was 55% (SD 30; range, 0–94). Data logs showed 7.0 h/d of average use (SD 4.3; range, 0–13). Conclusions: Appropriately selected patients with retrocochlear pathology may benefit from CI so long as the patient has a cochlear fluid signal and an intact cochlear nerve. Patients with sporadic VS patients and normal contralateral hearing exhibited guarded outcomes with CI, whereas most patients with non-VS retrocochlear pathologies demonstrated open-set speech understanding scores comparable to or slightly worse than conventional CI candidates. Since variable performance benefit is observed with CI in patients with retrocochlear pathology, counseling is imperative to align patient expectations with realistic outcomes. Address correspondence and reprint requests to John Thomas Roland, M.D., Department of Otolaryngology–Head & Neck Surgery, New York University School of Medicine, 550 1st Avenue, New York, NY 10016; E-mail: J.Thomas.RolandJr@nyulangone.edu Institutional Review Board Approval: New York University IRB Approval #i19-01139. Conflict(s) of Interest to Declare: J.T.R. and S.O.M. are consultants for Cochlear Pty Limited and receive research support. Copyright © 2020 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Increased Radiosurgery Toxicity Associated With Treatment of Vestibular Schwannoma in Multiple Sclerosis Objective: Explore the risk of radiation-induced neurotoxicity in patients with multiple sclerosis (MS) treated with stereotactic radiosurgery (SRS) and better understand the pathophysiology of radiation-induced injury in the central nervous system (CNS). Patients/Intervention: We present the clinical course and magnetic resonance imaging (MRI) findings of a 52-year-old woman with a history of relapsing remitting MS, who developed radiation-induced neurotoxicity following CyberKnife SRS (25 Gy in five fractions) for a left-sided vestibular schwannoma (VS). Main Outcome Measure: Risk of radiation-induced damage following SRS to the CNS, including radiation type and dose, toxicity, and time to symptom onset, in patients with MS. Results: Our patient developed increased imbalance (grade 2 toxicity) 3 months following CyberKnife SRS. Brain MRI showed new fluid-attenuated inversion recovery (FLAIR) hyperintensity in the pons and cerebellum. Neurotoxicity from SRS is rare. However, our literature review showed that 19 patients with MS who underwent intracranial radiation therapy sustained radiation-induced toxicity. The potential mechanisms for increased toxicity in MS could be due to a combination of demyelination, inflammatory, and/or vascular changes. Efficacy of treatments including steroids, bevacizumab, and hyperbaric oxygen therapy is currently unknown. Conclusion: Treatment options of SRS and surgery for VS should be carefully considered as patients with known MS may be at increased risk for radiation-induced damage following SRS to the CNS. Thoughtful radiosurgical planning and dosing accounting for this inherent risk is essential for managing patients with MS and VS. Address correspondence and reprint requests to Katherine Wallerius, M.D., Department of Otolaryngology—Head and Neck Surgery, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Building 1, Washington, DC 20007; E-mail: kpw30@georgetown.edu Conflicts of Interest and Source Funding: No funding organization contributed to the design or conduct of this study; collection, management, analysis, or interpretation of the data; or preparation, review, or decision to submit this article for publication. The authors have no funding, financial relationships, or conflicts of interest to disclose. Copyright © 2020 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Effects of Presentation Level on Spatial Hearing With and Without Bone-Conduction Amplification in Congenital Unilateral Aural Atresia Objective: This study assessed the effect of ipsilateral bone-conduction amplification on spatial hearing abilities in subjects with congenital unilateral aural atresia (CUAA). Patients: Twelve patients with unilateral conductive hearing loss secondary to CUAA and normal hearing in the contralateral ear were tested. Most (75%) had limited experience with a bone-conduction hearing aid (BCHA). Intervention: Performance was evaluated with and without a BCHA fitted acutely on a softband. Main Outcome Measures: Spatial hearing abilities were evaluated in two paradigms. Spatial release from masking was evaluated by comparing masked sentence recognition with a target and two speech maskers either colocated at 0 degree or with the maskers separated at +90 degrees and −90 degrees. Sound source localization was evaluated in a 180 degrees arc of loudspeakers on the horizontal plane. Performance was evaluated at 50 and 75 dB SPL, and results were compared for patients tested with and without a BCHA. Results: Group level results indicate similar spatial release from masking in the aided and unaided conditions at both presentation levels. Localization at 50 dB SPL was similar aided and unaided, but at 75 dB SPL the root mean square error was lower unaided than aided (17.2 degrees vs 41.3 degrees; p = 0.010). Conclusions: Use of a BCHA in patients with CUAA may interfere with auditory cues required for sound source localization when the signal level is intense enough to overcome the patient's conductive hearing loss. These findings have potential clinical implications in fitting of BCHAs to support optimal spatial hearing in patients with CUAA. Address correspondence and reprint requests to Michael W. Canfarotta, M.D., Department of Otolaryngology/Head and Neck Surgery, Houpt Building, Room G-190, 170 Manning Drive, CB 7070, Chapel Hill, NC 27599-7070; E-mail: michael.canfarotta@unchealth.unc.edu M.W.C., S.L.G.K., and E.B. designed experiments, wrote the paper, and contributed significantly to analysis and revisions leading to its final form. This project was funded in part by the NIH through NIDCD (T32 DC005360 and R01 000397). Portions of these data were presented at the 7th International Congress on Bone Conduction Hearing and Related Technologies in December 2019 in Miami, FL. The authors have no conflicts of interest to disclose. Copyright © 2020 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Transcanal Endoscopic Management of Glomus Tympanicum: Multicentric Case Series Objective: The aim of this study was to report a multicentric surgical experience in the exclusive endoscopic management of glomus tympanicum (GT). Study Design: Retrospective case series review at two institutions. Setting: Tertiary referral centers. Patients: The study included 30 patients who underwent exclusive transcanal excision of GT between 2010 and 2017 at the two referral centers. Interventions: Exclusive endoscopic transcanal excision of GT type A1, A2, and B1 (modified Fisch-Mattox classification). All surgical procedures were performed by two senior surgeons (L.P.; M.B.). Main Outcome Measures: For each procedure, intraoperative features of the disease, postoperative complications, and functional outcomes were evaluated. Recurrent or residual diseases were clinically and radiologically assessed during the follow-up period. Results: None of the patients treated with transcanal endoscopic approach (TEA) experienced intraoperative complications, nor required conversion to microscopic approach. Gross total resection (GTR) was obtained in 90% of the cases, while a near total resection was advocated when the residual pathology had a close relationship with the internal carotid artery. Mean hospitalization time was 1.6 (±0.8 SD) days and no postoperative complications were reported. No recurrences were reported in the GTR group after a mean follow-up period of 38.1 (±28.7 SD) months. Conclusions: Middle ear paragangliomas with no mastoid involvement (Class A1, A2, and B1) can be safely managed by means of a transcanal endoscopic approach. Low rate of postoperative complications, short hospitalization, and high rate of gross total resection demonstrate that TEA is a safe and effective procedure. Address correspondence and reprint requests to Matteo Fermi, M.D., Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital of Modena, Modena, Italy; E-mail: matteo.fermi.med@gmail.com Funding Disclosures: No funding is reported for the present study. The authors disclose no conflicts of interest. Copyright © 2020 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Price Differences Between Otic and Ophthalmic Drops Objective: Otic drops are one of the most frequently prescribed medications in otolaryngology. However, some forms of these drops can be very expensive, and ophthalmic formulations are sometimes used by practitioners to decrease the cost for their patients. The goal of this study is to determine the cost differential between otic and ophthalmic drops. Methods: Pharmacies in New York City, Chicago, and Portland were surveyed in the span of 6 weeks by telephone to evaluate the current prices of various otic and ophthalmic drops commonly prescribed by otolaryngologists. Results: A total of 83 pharmacies were surveyed. Surveyed drugs included ciprofloxacin/dexamethasone (cip/dex) otic, neomycin/polymyxin B sulfates/hydrocortisone (neo/poly/HC) otic, acetic acid (AA) otic, acetic acid/hydrocortisone (AA/HC) otic, ofloxacin otic, ofloxacin ophthalmic, and tobramycin/dexamethasone (tob/dex) ophthalmic. Per milliliter, cip/dex otic was consistently the most expensive, with a median price of $38.00 per milliliter. Among the antibiotic drops, neo/poly/HC otic was the least expensive formulation with a median price of $11.60 per milliliter. Ofloxacin ophthalmic was significantly less expensive than the otic formulation, at $11.00 and $31.00 per milliliter, respectively (adjusted p < 0.001). In general, otic and ophthalmic formulations were not significantly different according to manufacturing information, although ophthalmic drops were more often packaged in a sterile fashion and with less abrasive ingredients for use in the more sensitive tissue of the eye. Conclusion: Significant and meaningful price differences exist between otic and ophthalmic drops. Given the safety of ophthalmic drops used in the ears, they may be a more cost-effective alternative to traditionally prescribed otic drops when clinically appropriate. Address correspondence and reprint requests to Lawrence Lustig, M.D., 180 Fort Washington Avenue, New York, NY 10032; E-mail: lrl2125@cumc.columbia.edu Funding: None. The authors disclose no conflicts of interest. Copyright © 2020 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Cool OtOprotective Ear Lumen (COOL) Therapy for Cisplatin-induced Hearing Loss Hypothesis: Localized cooling of the external ear has a protective effect on the susceptibility to cisplatin-induced hearing loss. Background: We previously demonstrated significant protection from cisplatin-induced hearing loss using cool water ear canal irrigation. However, the study was limited to a single bolus injection of cisplatin and an acute time period. Here, we examined the application of localized cooling of the ear canal with repeated doses of cisplatin, over an expanded period of time, and using two methods of cooling. Methods: Twenty-four guinea pigs (12 male and 12 female) underwent auditory physiological testing (auditory brainstem response and distortion product otoacoustic emissions at 8–32 kHz) and pre/postadministration of cisplatin. Cisplatin (4 mg/kg i.p.) was administered in 3 weekly single injections for a total of 12 mg/kg. While anesthetized, the left ears of the guinea pigs were exposed to either cool water (22°C; ICS Water Caloric Irrigator), a cool ear bar (15°C, cooled by a Peltier device; TNM, Scion NeuroStim), or left uncooled as a sham control. The animals were tested 3 days post each dosage and 1 month post the final dose. At the end of the experiment the animals were euthanized for histological evaluation. Results: We found that hearing loss was significantly reduced, and hair cell survival greatly improved, in animals that received cooling treatments compared to cisplatin-only control animals. No significant difference was observed between the two methods of cooling. Conclusion: Localized cooling of the ear canal during administration of cisplatin mitigated loss of auditory function and loss of hair cells. Address correspondence and reprint requests to Christopher Spankovich, University of Mississippi Medical Center, Jackson, MS, 39216; E-mail: cspankovich@umc.edu This work was funded by the University of Mississippi Medical Center, American Otological Society, an ONR N00014-18-1-2716. The authors disclose no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.jcraniofacialsurgery.com). Copyright © 2020 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Failure and Revision Surgery After Cochlear Implantation in the Adult Population: A 10-year Single-institution Retrospective and Systematic Review of the Literature Objective: To characterize failure rate and etiology after cochlear implantation; to identify predictors and describe outcomes after implant failure. Study Design: Retrospective chart review and systematic review of the literature using PubMed and Embase. Setting: Academic Cochlear Implant Center. Subject Population: Four hundred ninety-eight devices in 439 distinct adult patients. Interventions: Unilateral or bilateral cochlear implantation. Main Outcome Measures: Implant failure rate and etiology. Results: A total of 32 devices (5.9%) failed in 31 patients encompassing the following failure types in accordance with the European Consensus Statement of Cochlear Implants: 17 device failures (53.1%), 11 failures due to performance decrement/adverse reactions (34.4%), and 4 medical reasons (12.9%). There was no significant difference in age, sex, or manufacturer between patients with and without failures. Twenty-five percent of patients with failure leading to explantation had childhood onset of deafness compared to 12.1% of patients with adult-onset hearing loss (OR = 2.42; p = 0.04). Performance decrement/adverse reaction patients had an older average age at implantation compared to device failure patients (mean 68.5 yr 95% CI: 59.9–77.1 vs mean 47.6 yr, CI: 39.9–55.3, p < 0.01). There was no significant difference in time to failure, sex, or device manufacturer between the different types of failures. Twenty-nine patients who experienced CI failure underwent a revision surgery, while the remaining two opted for explantation without reimplantation. One patient who underwent revision surgery subsequently presented with a second failure and underwent a second revision, which was successful. In our systematic review, 815 citations were reviewed, and 9 studies were selected for inclusion. Overall failure rate across all studies was 5.5%. Device failure was the leading cause of failure in the majority (6/9) of studies, accounting for 40.8% of all failures. Medical reasons were the second leading cause at 33.6%, followed by performance decrement/adverse reaction (20.9%) and other (4.8%). Conclusions: Cochlear implant failure is a rare phenomenon. Childhood-onset of hearing loss appears to be associated with an increased risk of overall failure. Older patients are at increased risk for performance decrement/adverse reaction. Revision surgery success rates remain very high and patients with failure of any cause should be offered explantation with concurrent reimplantation. Address correspondence and reprint requests to Michael J. Ruckenstein, M.D., Vice Chairman, Department of Otolaryngology-Head and Neck Surgery, Hospital of the University of Pennsylvania, 3400 Spruce Street, Silverstein 5, Philadelphia, PA; E-mail: michael.ruckenstein@pennmedicine.upenn.edu The authors disclose no conflicts of interest. Copyright © 2020 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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Investigational New Drugs

Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma Summary Background Precision medicine and drug repurposing are attractive strategies, especially for tumors with worse prognosis. Glioblastoma is a highly malignant brain tumor with limited treatment options and short survival times. We identified novel BRAF (47-438del) and PIK3R1 (G376R) mutations in a glioblastoma patient by RNA-sequencing. Methods The protein expression of BRAF and PIK3R1 as well as the lack of EGFR expression as analyzed by immunohistochemistry corroborated RNA-sequencing data. The expression of additional markers (AKT, SRC, mTOR, NF-κB, Ki-67) emphasized the aggressiveness of the tumor. Then, we screened a chemical library of > 1500 FDA-approved drugs and > 25,000 novel compounds in the ZINC database to find established drugs targeting BRAF47-438del and PIK3R1-G376R mutated proteins. Results Several compounds (including anthracyclines) bound with higher affinities than the control drugs (sorafenib and vemurafenib for BRAF and PI-103 and LY-294,002 for PIK3R1). Subsequent cytotoxicity analyses showed that anthracyclines might be suitable drug candidates. Aclarubicin revealed higher cytotoxicity than both sorafenib and vemurafenib, whereas idarubicin and daunorubicin revealed higher cytotoxicity than LY-294,002. Liposomal formulations of anthracyclines may be suitable to cross the blood brain barrier. Conclusions In conclusion, we identified novel small molecules via a drug repurposing approach that could be effectively used for personalized glioblastoma therapy especially for patients carrying BRAF47-438del and PIK3R1-G376R mutations.

Simvastatin treatment varies the radiation response of human breast cells in 2D or 3D culture Summary Background Statins inhibit the cholesterol biosynthesis and are used as cholesterol-lowering agents in fat-metabolism disorders. Furthermore, several studies state that statins have supportive functions in breast cancer treatment. Therefore, simvastatin (SVA) as a potential radiosensitizer should be investigated on the basis of human breast cells. Methods First, an optimal concentration of SVA for normal (MCF10A) and cancer (MCF-7) cells was identified via growth and cytotoxicity assays that, according to the definition of a radiosensitizer in the narrower sense, enhances the effect of radiation therapy but has no cytotoxic effect. Next, in combination with radiation SVA's influence on DNA repair capacity and clonogenic survival in 2D and 3D was determined. Furthermore cell cycle distribution, expression of survivin and connective tissue growth factor (CTGF) as well as ERK1 map kinase were analysed. Results 1 μM SVA was identified as highest concentration without an influence on cell growth and cytotoxicity and was used for further analyses. In terms of early and residual γH2AX-foci, SVA affected the number of foci in both cell lines with or without irradiation. Different radiation responses were detected in 2D and 3D culture conditions. During the 2D cultivation, a radiosensitizing effect within the clonogenic survival was observable, but not in 3D. Conclusion The present study suggests that SVA may have potential for radiosensitization. Therefore, it is important to further investigate the role of SVA in relation to the extent of radiosensitization and how it could be used to positively influence the therapy of breast cancer or other entities.

Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma Summary Objectives Malignant pleural mesothelioma (MPM) is an occupational disease mainly due to asbestos exposure. Effective therapies for MPM are lacking, making this tumour type a fatal disease. Materials and Methods In order to meet this need and in view of a future "drug repositioning" approach, here we screened five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model, with a library of 1170 FDA-approved drugs. Results Among several potential compounds, we found that fludarabine (F-araA) and, to a lesser extent, risedronic acid (RIS) were cytotoxic in MPM cells, in comparison to the non-malignant Met-5A cells. In particular, F-araA reduced the proliferation and the colony formation ability of the MPM malignant cells, in comparison to the non-malignant control cells, as demonstrated by proliferation and colony formation assays, in addition to measurement of the phospho-ERK/total-ERK ratio. We have shown that the response to F-araA was not dependent upon the expression of DCK and NT5E enzymes, nor upon their functional polymorphisms (rs11544786 and rs2295890, respectively). Conclusion This drug repositioning screening approach has identified that F-araA could be therapeutically active against MPM cells, in addition to other tumour types, by inhibiting STAT1 expression and nucleic acids synthesis. Further experiments are required to fully investigate this.

Correction to: The old CEACAMs find their new role in tumor immunotherapy Correction is needed to the original version of this article.

Correction to: Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer The article Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer, written by Shunsuke Kondo, Masaomi Tajimi, Tomohiko Funai, Koichi Inoue, Hiroya Asou, Vinay Kumar Ranka, Volker Wacheck, Toshihiko Doi, was originally published electronically on the publisher's internet portal on 23 June 2020 without open access.

The pan-Bcl-2 inhibitor obatoclax promotes differentiation and apoptosis of acute myeloid leukemia cells Summary One of the key features of acute myeloid leukemia (AML) is the arrest of differentiation at the early progenitor stage of myelopoiesis. Therefore, the identification of new agents that could overcome this differentiation block and force leukemic cells to enter the apoptotic pathway is essential for the development of new treatment strategies in AML. Regarding this, herein we report the pro-differentiation activity of the pan-Bcl-2 inhibitor, obatoclax. Obatoclax promoted differentiation of human AML HL-60 cells and triggered their apoptosis in a dose- and time-dependent manner. Importantly, obatoclax-induced apoptosis was associated with leukemic cell differentiation. Moreover, decreased expression of Bcl-2 protein was observed in obatoclax-treated HL-60 cells. Furthermore, differentiation of these cells was accompanied by the loss of their proliferative capacity, as shown by G0/G1 cell cycle arrest. Taken together, these findings indicate that the anti-AML effects of obatoclax involve not only the induction of apoptosis but also differentiation of leukemic cells. Therefore, obatoclax represents a promising treatment for AML that warrants further exploration.

A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma Summary Background PF-06840003 is a highly selective indoleamine 2, 3-dioxygenase (IDO1) inhibitor with antitumor effects in preclinical models. This first-in-human phase 1 study evaluated safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy in recurrent malignant glioma to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Methods Patients (N = 17) received oral PF-06840003 in four dose-escalation groups: 125 mg once-daily (QD; n = 2); 250 mg QD (n = 4); 250 mg twice-daily (BID; n = 3); 500 mg BID (n = 8). A modified toxicity probability interval method determined the MTD. Results Four patients experienced serious adverse events (SAEs); one with treatment-related SAEs (grade 4 alanine and aspartate aminotransferase elevations). The dose-limiting toxicity (DLT) rate at 500 mg BID was 12.5% (n = 1/8); the MTD was not reached. Following PF-06840003 dosing, median time to maximum plasma concentration for the active enantiomer PF-06840002 was 1.5–3.0 hr and mean elimination half-life was 2 to 4 hr (Cycle 1 Day 1). Urinary recovery of PF-06840002 was low (< 1%). At 500 mg BID, maximum mean percentage inhibition of 13C10 kynurenine vs endogenous kynurenine was 75% vs 24%. PF-06840002 CSF-to-plasma ratio was 1.00. Disease control occurred in eight patients (47%). Mean duration of stable disease (SD) was 32.1 (12.1–72.3) weeks. Two patients with SD discontinued the study at 450 and 561 days and continued PF-06840003 on compassionate use. Conclusion PF‑06840003 up to 500 mg BID was generally well tolerated with evidence of a pharmacodynamic effect and durable clinical benefit in a subset of patients with recurrent malignant glioma. ClinicalTrials.gov, NCT02764151, registered April 2016.

A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients with advanced solid tumors Summary Purpose Combining small-molecule inhibitors of different targets was shown to be synergistic in preclinical studies. Testing this concept in clinical trials is, however, daunting due to challenges in toxicity management and efficacy assessment. This study attempted to evaluate the safety and efficacy of vatalanib plus everolimus in patients with advanced solid tumors and explore the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies as a predictive biomarker. Patients and Methods This single-center, phase I trial containing 70 evaluable patients consisted of a dose escalation proportion based on the traditional "3 + 3" design (cohort IA and IB) and a dose expansion proportion (cohort IIA and IIB). Toxicity was evaluated using the Common Terminology Criteria of Adverse Events. Antitumor activity was assessed using the Modified Response Evaluation Criteria in Solid Tumors. Results The maximum tolerated doses were determined to be vatalanib 1250 mg once daily or 750 mg twice daily in combination with everolimus 10 mg once daily. No treatment-related death occurred. The most common toxicities were hypertriglyceridemia, hypercholesterolemia, fatigue, vomiting, nausea and diarrhea. There was no complete response. Nine patients (12.9%) had partial response (PR) and 41 (58.6%) had stable disease (SD). Significant antitumor activity was observed in neuroendocrine tumors with a disease-control rate (PR + SD) of 66.7% and other tumor types including renal cancer, melanoma, and non-small-cell lung cancer. Conclusions The combination of vatalanib and everolimus demonstrated reasonable toxicity and clinical activity. Future studies combining targeted therapies and incorporating biomarker analysis are warranted based on this phase I trial.

A randomized, double-blind, placebo-controlled study of B-cell lymphoma 2 homology 3 mimetic gossypol combined with docetaxel and cisplatin for advanced non-small cell lung cancer with high expression of apurinic/apyrimidinic endonuclease 1 Summary Background Overexpression of apurinic/apyrimidinic endonuclease 1 (APE1) is an important cause of poor chemotherapeutic efficacy in advanced non-small cell lung cancer (NSCLC) patients. Gossypol, a new inhibitor of APE1, in combination with docetaxel and cisplatin is believed to improve the efficacy of chemotherapy for advanced NSCLC with high APE1 expression. Methods Sixty-two patients were randomly assigned to two groups. Thirty-one patients in the experimental group received 75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1 with gossypol administered at 20 mg once daily on days 1 to 14 every 21 days. The control group received placebo with the same docetaxel and cisplatin regimen. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), response rate, and toxicity. Results There were no significant differences in PFS and OS between the experimental group and the control group. The median PFS (mPFS) in the experimental and control groups was 7.43 and 4.9 months, respectively (HR = 0.54; p = 0.06), and the median OS (mOS) was 18.37 and 14.7 months, respectively (HR = 0.68; p = 0.27). No significant differences in response rate and serious adverse events were found between the groups. Conclusion The experimental group had a better mPFS and mOS than did the control group, though no significant difference was observed. Because the regimen of gossypol combined with docetaxel and cisplatin was well tolerated, future studies with larger sample sizes should be performed.

The old CEACAMs find their new role in tumor immunotherapy Summary Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) contain 12 family members(CEACAM1、CEACAM3、CEACAM4、CEACAM5、CEACAM6、CEACAM7、CEACAM8、CEACAM16、CEACAM18、CEACAM19、CEACAM20 and CEACAM21)and are expressed diversely in different normal and tumor tissues. CEA (CEACAM5) has been used as a tumor biomarker since 1965. Here we review the latest research and development of the structures, expression, and function of CEACAMs in normal and tumor tissues, and their application in the tumor diagnosis, prognosis, and treatment. We focus on recent clinical studies of CEA targeted cancer immunotherapies, including bispecific antibody (BsAb) for radio-immuno-therapy and imaging, bispecific T cell engager (BiTE) and chimeric antigen receptor T cells (CAR-T). We summarize the promising clinical relevance and challenges of these approaches and give perspective view for future research. This review has important implications in understanding the diversified biology of CEACAMs in normal and tumor tissues, and their new role in tumor immunotherapy.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Telephone consultation 11855 int 1193,