Otology & Neurotology

Preclinical Validation of a Novel Device Designed to Reduce Biofilms on Percutaneous Osseointegrated Abutments Aim: To assess the efficacy of a prototype cleaning device in removing biofilm from skin-penetrating abutments. Background: Adverse skin reactions around percutaneous osseointegrated implants have been linked to poor hygiene and infection. A cleaning device made from open-cell polyfoam has been developed to facilitate manual cleaning of abutments by the patient. Methods: Serratia biofilm was grown on clean and sterile conical bone-anchored hearing system abutments including both pre-2007 (straight sided) and post-2007 (conical-sided) designs. Eighteen were photographed and then subjected to cleaning using a toothbrush or the cleaning device soaked in water or a proprietary mouthwash. Biofilm on a further group of 10 conical abutments was recorded using a scanning electron microscope before and after cleaning with the test device soaked in water. Quantitative analysis of the efficiency of the cleaning was made using image analysis. Results: Removal of biofilm using a dry or wet toothbrush was not as effective as cleaning with the device. In 10 cases subjected to image analysis, approximately 90% of the biofilm was removed from the top third of the abutments, 85% from the middle third, and 48% from the basal third. Conclusion: The cleaning device is effective in removing most biofilm from the test abutments and represents a significant improvement in comparison with traditional methods such as a toothbrush. Address correspondence and reprint requests to Rachel Sammons, Ph.D., School of Dentistry, University of Birmingham, 5, Mill Pool Way, Birmingham B5 7EG, UK; E-mail: r.l.sammons@bham.ac.uk This study was funded by Sapere Systems Ltd. UK. The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Histopathology of Inner Ear Malformations: Potential Pitfalls for Cochlear Implantation Hypothesis: The presence of bony inner ear malformations may associate with a number of anatomical abnormalities affecting the middle ear structures. Those malformations may create pitfalls and complications for cochlear implantation. Background: Inner ear malformations associate with varying degrees of hearing loss, and frequently require cochlear implantation for hearing rehabilitation. Therefore, the abnormalities affecting the middle- and inner-ear structures may increase the risk of surgical complications. Methods: We examined 38 human temporal bones from donors with bony inner ear malformations. Using light microscopy, we analyzed the presence of abnormalities in the structures of the middle- and inner-ear. Results: Our collection comprises of 38 specimens with inner-ear malformations (cochlear aplasia, n = 3; cochlear hypoplasia, n = 30; incomplete partition, n = 3; isolated vestibular malformation, n = 2). The anatomy of the middle ear was abnormal in most temporal bones with cochlear aplasia, cochlear hypoplasia, and incomplete partition type I (40%–100%). Some of those abnormalities (hypoplastic or obliterated mastoid, 55.2%; aplastic or obliterated round window, 71.0%; aberrant course of the facial nerve, 36.8%) may hinder the access to the round window using the conventional facial recess approach for cochlear implantation. The cochlear nerve and associated bony structures (internal auditory canal and bony canal for cochlear nerve) were normal in 71.0% of all temporal bones with inner ear malformations. Conclusion: Each different type of malformation may create specific surgical challenges to surgeons. Comprehensive preoperative imaging is fundamental toward the surgical success of cochlear implants in patients with malformations. Alternatives to circumvent those middle- and inner-ear abnormalities and potential complications are further discussed. Address correspondence and reprint requests to Rafael da Costa Monsanto, M.D., Ph.D., Department of Otolaryngology, Head and Neck Surgery – University of Minnesota, Lions Research Building, Room 210 – 2001 6th St. SE, Minneapolis, MN 55455, U.S.A. E-mail: rafaelmonsanto@hotmail.com The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. R.d.C.M. received a scholarship from the "Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES)" (Finance Code 001). The research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the NIH (UG3NS107688), the International Hearing Foundation, the 5 M Lions International, the Starkey Foundation, and the "Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil. (CAPES). The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Osteonecrosis of the External Auditory Canal Associated With Oral Sorafenib Therapy: Sorafenib and Temporal Bone Osteonecrosis Objective: To present the first case of osteonecrosis of the external auditory canal associated with sorafenib treatment. Patient: 58-year-old patient with right-sided otorrhea and otalgia was treated for otitis externa for 1 month without improvement. Otoscopic examination revealed a large defect in the inferior wall of the tympanic bone filled with skin debris and bony fragments. Previous medical history included treatment with sorafenib for metastatic renal cell cancer; he had never been exposed to radiotherapy. Computed tomography of the temporal bone showed a large right external auditory canal bony erosion with involvement of the tympanic bone and bony sequestra extending to the mastoid cells and temporomandibular joint. Histologic examination revealed necrotic bone and inflammatory changes with no signs of malignancy. A diagnosis of osteonecrosis of external auditory canal was made. Intervention: Right subtotal petrosectomy with obliteration of surgical cavity with abdominal fat was performed. Results: Final histological report revealed avascular necrosis of the bone with perivascular lymphocitic infiltration of the soft tissues. Diagnosis of medication-related external auditory canal osteonecrosis was confirmed. Conclusion: Medication-related osteonecrosis of the temporal bone is not a well-known entity among otolaryngologists and could therefore be misclassified as another diagnosis. In patients with othorrea and earache following sorafenib treatment, temporal bone osteonecrosis should be suspected. Address correspondence and reprint requests to Dr. Federica Canzano, M.D., University Hospital of Parma, Parma, Italy; E-mail: Federica.canzano@gmail.com The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Effect of Vestibular Exercises Associated With Repositioning Maneuvers in Patients With Benign Paroxysmal Positional Vertigo: A Randomized Controlled Clinical Trial In addition to positional vertigo, it is quite common for patients with benign paroxysmal positional vertigo (BPPV) to present complaints associated with balance problems and a feeling of dizziness even after repositioning maneuvers. Objective: It was to evaluate the additional effects of vestibular rehabilitation exercises as a therapeutic resource in the treatment of BPPV, to improve symptoms and reduce recurrence. Study Design: This was an experimental, prospective, randomized, controlled study. Setting: Instituto Brasiliense de Otorrinolaringologia (IBORL) from August 2016 to September 2017. Patients: Thirty-two individuals, both men and women, over 18 years of age with BPPV. Intervention: They were randomly assigned to two groups: the control group (n = 15) performing only the maneuver technique as treatment and the experimental group (n = 17) performing the maneuvers and vestibular rehabilitation exercises. Patients underwent treatment and responded to the dizziness handicap inventory (DHI) and visual analog scale (VAS) questionnaires for comparison between groups. Participants were followed up for 6 months to observe recurrence of symptoms. Main Outcome Measures: To investigate the additional effects of vestibular exercises in the treatment of BPPV. Results: The experimental group had a lower level of dizziness in the posttreatment period (p < 0.05) and a lower incidence of recurrences (p = 0.038) than the control group. Conclusions: Vestibular exercises performed after repositioning treatments for BPPV increased the overall efficacy of treatment by improving symptoms with a lower rate of recurrence. Address correspondence and reprint requests to Fayez Bahmad, Jr, M.D., Ph.D., Setor Médico Hospitalar Norte Quadra 02, Bloco C, Ed. Dr. Crispim, Sala 515 - Asa Norte, Brasília - DF, 70710-149, Brazil; E-mail: fayezbjr@gmail.com There are no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Speech Perception Outcomes in Transcutaneous Versus Percutaneous Bone Conduction Stimulation in Individuals With Single-Sided Deafness Objective(s): To investigate the differences in percutaneous versus passive transcutaneous bone-conduction stimulation in individuals with single-sided deafness. Study Design: Prospective, single-subject. Setting: Tertiary academic referral center. Patients: Adult bone-anchored implant listeners with single-sided deafness using a percutaneous implant system. Interventions: Experienced percutaneous bone anchored implant recipients were tested in the percutaneous and transcutaneous conditions using a BAHA 5 (Cochlear Corp., Cochlear Bone-Anchored Solutions, Mölnlycke, Sweden) sound processor on the patient's own abutment and on a softband. Main Outcome Measures: Phoneme recognition was assessed using Consonant-Nucleus-Consonant (CNC) words for soft (47 dB SPL) and average (62 dB SPL) speech inputs. Speech perception in noise performance was also assessed for soft (47 dB SPL) and average (62 dB SPL) speech inputs using sentences presented in multi-talker babble. Aided free-field thresholds were obtained in both conditions using warble tone stimuli. Results: Compared with percutaneous bone-conduction stimulation, transcutaneous stimulation demonstrated reduced effective gain for high frequency stimulation. Transcutaneous stimulation required higher signal to noise ratios to achieve comparable performance to the percutaneous condition. Phoneme recognition was poorer in transcutaneous versus percutaneous stimulation with the most significant impact observed for soft speech inputs. Conclusion: A significant performance gap in speech recognition is observed between percutaneous and transcutaneous bone-conduction stimulation in individuals with single-sided deafness at the same signal to noise ratios. Compared with percutaneous bone-conduction stimulation, transcutaneous stimulation demonstrated reduced effective gain, decreased phoneme recognition, word recognition, and performance in noise, with the most significant impact observed for soft speech inputs. Address correspondence and reprint requests to Hillary A. Snapp, Au.D., Ph.D., 1120 NW 14th Street, 5th Floor, Miami, FL 33136; E-mail: hsnapp@med.miami.edu This research was presented in part at the 6th International Congress on Bone Conduction Hearing and Related Technologies, May 2017, Nijmegen, The Netherlands. The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Outcomes of Primary Pediatric Stapedotomy Objective: To review a single institution experience with pediatric stapedotomy for juvenile otosclerosis (JO), congenital stapes footplate fixation (CSFF), or tympanosclerosis. Study Design: Retrospective chart review. Setting: Tertiary referral center. Patients: Pediatric patients undergoing surgery for stapes fixation from 2001 to 2017. Main Outcome Measures: Hearing result based on preoperative, first postoperative, and final postoperative pure-tone average air-bone gap (PTA-ABG). Age, sex, diagnosis, procedure performed, prosthesis, and ossicular anomalies were considered. Results: A total of 59 children (4–16 years of age) underwent surgery for stapes fixation (67 ears), with an average postoperative audiogram out to 2.88 years. Final postoperative ABG for tympanosclerosis (30.4 dB ± 10.9 dB) showed some improvement but the outcome was significantly worse than in CSFF (21.0 dB ± 11.4 dB) (p = 0.020) and JO (22.8 dB ± 14.9 dB). Conclusion: Our data suggest, that in our clinic, surgery for stapes fixation is safe to perform in children. While we achieved desirable results for JO and CSFF, patients with tympanosclerosis showed a statistically worse hearing outcome. Tympanosclerosis deserves special consideration and may be better served with a malleovestibulopexy, total ossicular replacement prosthesis (TORP), or amplification in lieu of traditional stapes surgery. Address correspondence and reprint requests to Joshua Cody Page, M.D., Department of Otolaryngology–Head and Neck Surgery, University of Arkansas for Medical Sciences, 4301 W. Markham #543, Little Rock, AR 72205; E-mail: jcpage@uams.edu Funding is not received for this work. The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Management of Traumatic Injury and Osseointegration Failure in Children With Percutaneous Bone Conduction Implants Objective: This study examines the incidence and management of traumatic loss or osseointegration failure of percutaneous bone conduction implants in children. Study Design: Case series. Setting: Pediatric tertiary care institution. Patients: Children who underwent percutaneous osseointegrated implant placement from 1996 to 2016. Interventions: Clinical evaluation and revision surgery after implant loss. Main Outcome Measures: This study compares the characteristics of children who experienced traumatic loss of implant to those who did not to calculate odds ratios (ORs) describing the risk of injury and investigate device utilization after implant failure. Results: One hundred forty-seven children received percutaneous bone conduction devices; 129 were followed for at least 1 year. Trauma occurred in 19 of 129 cases (15%). Among children with traumatic injury, mean age at initial surgery was 5 years (SD = ±3.3), and 42% had a developmental delay. Among children without traumatic injury, mean age at initial surgery was 6.5 years (SD = ±4.4), and 28% had a developmental delay. Multivariate logistic regression found no significant differences in age, sex, or developmental delay associated with implant loss. In five of 19 traumatic cases (26%), the implant remained in situ due to either skull fracture or abutment loss. In the remaining 14 of 19 cases (74%), there was osseointegration failure with extrusion of the implant. Seventeen children underwent revision surgery utilizing previously placed "sleeper," or backup, osseointegrated implant, and 14 (82%) of these continued to use their device. Two patients with extruded implants did not undergo revision surgery. Conclusion: Traumatic injury or osseointegration failure leads to loss of percutaneous bone conduction implants in approximately 15% of children. Revision surgery is often successful. Address correspondence and reprint requests to Patricia L. Purcell, M.D., M.P.H., Department of Otolaryngology, Head & Neck Surgery, 555 University Avenue, 6th floor Burton Wing, Toronto, ON M5G1X8, Canada; E-mail: patricia.purcell@sickkids.ca Financial Disclosures: S.L.C., B.C.P., and K.A.G. hold sponsored research agreements with Cochlear Americas. B.C.P. and K.A.G. receive speaking fees from Cochlear Americas. S.L.C. receives speaking fees for Interacoustics. S.L.C. earns royalties from the book, Balance Disorders in the Pediatric Population. S.L.C. and B.C.P. are Patent Holders for Patents #: 7041-0: Systems and Methods for Balance Stabilization. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Physical and Emotional Burden of the Epley Maneuver in the Elderly Objective: To analyze and compare experiences of anxiety and discomfort caused by the Epley maneuver and the willingness for a potential retreatment between younger (≤70 yr) and older (>70 yr) patients. Study Design: Prospective, observational cohort study. Setting: Tertiary referral center. Methods: Dutch adults, diagnosed with posterior canal benign paroxysmal positional vertigo, were included. Patients with dementia or subjected to an Epley maneuver ≤4 months before the hospital visit were excluded. Patients were asked about their experiences with the Epley maneuver directly after the maneuver, after 2 weeks and after 2 months. Differences in experiences between the age groups were tested with the Fisher's exact test and subgroup analyses were performed using multivariable logistic regression. Results: Out of 179 included patients, 115 (64%) were aged ≤70 and 134 (75%) were female. In both groups, 25% reported anxiety directly after the Epley maneuver. Two weeks later, 19 and 27%, respectively (p = 0.26) reported anxiety. In the young group, 30% expressed discomfort directly after treatment compared with 45% in the elderly (OR 1.98, 95% CI 1.05–3.75, p = 0.04). Two weeks later, this was 36 and 38%, respectively (p = 0.87). This decreased to 24 and 33%, respectively (p = 0.37), after 2 months. There was no significant difference in willingness for potential retreatment between both groups after 2 weeks (93 and 95%, respectively, p = 0.75) nor after 2 months (97 and 92%, respectively, p = 0.13). Conclusion: The Epley maneuver results in little anxiety and discomfort both in young and in elderly patients. Most patients show willingness for potential retreatment in case symptoms recur. Address correspondence and reprint requests to Britta D.P.J. Maas, M.D., Apeldoorn Dizziness Centre, Gelre Hospital, Albert Schweitzerlaan 31, 7334 DZ, Apeldoorn, the Netherlands; E-mail: b.maas@gelre.nl This work was supported solely from institutional and/or departmental sources from the Apeldoorn Dizziness Centre, Gelre Hospital, Apeldoorn. The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Meta-analysis of Delayed Facial Palsy Following Middle Ear Surgery Objective: Delayed facial palsy has been reported following various types of otologic surgery. However, the exact characteristics of this disease have not been fully elucidated because of its low incidence. This study analyzed case series studies on delayed facial palsy to increase the sample size and outline credible disease characteristics. Data Sources: PubMed, Embase, and Cochrane Library databases were searched on October 10, 2018. Study Selection: Delayed facial palsy case series covered in English in which the intervention was typical tympanoplasty, mastoidectomy, stapedectomy, or cochlear implantation including a statement of sample size. Data Extraction: Evaluated according to the Joanna Briggs Institute Critical Appraisal Checklist for Case Series. Data Synthesis: Fourteen case series studies were included. Incidence rate, onset time, prognosis were evaluated with meta-analysis. Etiology and treatment were discussed with systematic review. Conclusions: The overall incidence rate of delayed facial palsy after middle ear surgery was 0.65%; however, it differed depending on the type of surgery. The mean onset time of facial palsy was 8.47 ± 3.98 days after surgery, and 95.3% of the patients completely recovered. The disease seems to have multiple etiologies. Facial palsy occurring 2 to 20 days after surgery is suggested to be considered delayed facial palsy. Address correspondence and reprint requests to Jinsei Jung, M.D., Ph.D., Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea; E-mail: jsjung@yuhs.ac The authors disclose no conflicts of interest. Supplemental digital content is available in the text. 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 © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

A Transcutaneous Active Middle Ear Implant (AMEI) in Children and Adolescents: Long-term, Multicenter Results Objective: Evaluation of the long-term safety and performance of an active middle ear implant (AMEI) in the treatment of hearing loss in children and adolescents with a primary focus on improvement in speech discrimination. Study Design: Prospective, multicentric, single-subject repeated-measures design in which each subject serves as his or her own control. Subjects: Thirty-one pediatric subjects aged 5 to 17 years. Intervention: Implantation of an active middle ear implant. Methods: Improvement in word recognition scores, speech reception thresholds (SRT) in quiet and noise, in addition to air conduction, bone conduction, and sound field thresholds were evaluated in two age groups. Results: Residual hearing did not change over time and speech intelligibility significantly improved and remained stable after 36 months. Children aged 5 to 9 improved in WRS from 21.92 to 95.38% and in SRT in quiet and in noise respectively from 62.45 dB SPL (sound pressure level) and +1.14 dB SNR to 42.07 dB SPL and −4.45 dB SNR. Adolescents aged 10 to 17 improved in WRS from 12.78 to 84.71% and in SRT in quiet and in noise respectively from 63.96 dB SPL and +3.32 dB SNR to 35.31 dB SPL and −4.55 dB SNR. Conclusions: The AMEI, under investigation, is a safe treatment for children and adolescents, and significantly improved audiological performance that remains stable on the long-term scale (up to 36 mo postimplantation). In general, all adult-related issues and questions regarding safety and performance can also be applied to the pediatric population, as no apparent specific issues developed. Address correspondence and reprint requests to John-Martin Hempel, Priv.-Doz. Dr. med., Clinic and Policlinic for ENT Treatment, Ludwig-Maximilians-University (LMU) Clinic Grosshadern, Marchioninistr. 15, 81377 München, Germany; E-mail: John-Martin.Hempel@med.uni-muenchen.de MED-EL, Innsbruck, Austria, initiated, organized, and monitored this study and gave support for statistical analysis and manuscript preparation. There was no external financial funding for this project (National Institutes of Health [NIH], Wellcome Trust, Howard Hughes Medical Institute [HHMI], or others). None of the authors has any financial interest (consultancies, stock ownership, or other equity interests, patent licensing arrangements, or payments for conducting or publicizing a study) in the used and mentioned products or companies. The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Clinical and Translational Gastroenterology

Primer on Precision Medicine for Complex Chronic Disorders Precision medicine promises patients with complex disorders the right treatment for the right patient at the right dose at the right time with expectation of better health at a lower cost. The demand for precision medicine highlights the limitations of modern Western medicine. Modern Western medicine is a population-based, top-down approach that uses pathology to define disease. Precision medicine is a bottom-up approach that identifies predisease disorders using genetics, biomarkers, and modeling to prevent disease. This primer demonstrates the contrasting strengths and limitations of each paradigm and why precision medicine will eventually deliver on the promises.

Blunted Evoked Prouroguanylin Endocrine Secretion in Chronic Constipation OBJECTIVES: Prouroguanylin (ProUGN) in the intestine is cleaved to form uroguanylin (UGN), which stimulates guanylate cyclase C (GUCY2C), inducing cyclic guanosine monophosphate signaling. Paracrine release regulates fluid secretion, contributing to bowel function, whereas endocrine secretion evoked by eating forms a gut-brain axis, controlling appetite. Whereas hormone insufficiency contributes to hyperphagia in obesity, its contribution to the pathophysiology of constipation syndromes remains unexplored. Here, we compared circulating ProUGN and UGN in healthy subjects and in patients with chronic idiopathic constipation (CIC) and patients with irritable bowel syndrome with constipation (IBS-C). METHODS: Circulating ProUGN and UGN levels were measured in 60 healthy subjects, 53 patients with CIC, and 54 patients with IBS-C. After an overnight fast, the participants ingested a standardized meal; blood samples were drawn at fasting and at 30, 60, and 90 minutes thereafter, and hormone levels were quantified by enzyme-linked immunosorbent assay. RESULTS: Fasting ProUGN levels were >30% lower in patients with CIC and those with IBS-C compared with healthy subjects regardless of age, sex, or disease state. After eating, ProUGN levels increased compared with fasting levels, although the rate of change was slower and maximum levels were lower in patients with CIC and those with IBS-C. Similarly, fasting UGN levels were lower in patients with CIC and those with IBS-C compared with healthy subjects. However, unlike ProUGN levels, UGN levels did not increase after eating. DISCUSSION: These observations support a novel pathophysiologic model in which CIC and IBS-C reflect a contribution of ProUGN insufficiency dysregulating intestinal fluid and electrolyte secretion. TRANSLATIONAL IMPACT: This study suggests that CIC and IBS-C can be treated by oral GUCY2C hormone replacement. Indeed, these observations provide a mechanistic framework for the clinical utility of oral GUCY2C ligands like plecanatide (Trulance) and linaclotide (Linzess) to treat CIC and IBS-C.

Immunologic Features of Patients With Advanced Hepatocellular Carcinoma Before and During Sorafenib or Anti-programmed Death-1/Programmed Death-L1 Treatment INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Today, a promising treatment strategy is focused on the enhancement of antitumor immune responses by immune checkpoint modification. However, as only 20% of patients with HCC are responders, identification of predictive factors is urgently required. Therefore, for the first time, the features of the intrahepatic and circulating immune system in patients with advanced-stage HCC, before and during the treatment, were analyzed. METHODS: We collected fresh HCC biopsies, along with adjacent tumor-free liver tissues and peripheral blood samples, from 21 patients with advanced HCC. Furthermore, we performed an extensive immunomonitoring of patients with HCC treated with sorafenib or programmed death (PD)-1/PD-L1 pathway blockade using multiparametric flow cytometry. RESULTS: We observed that regardless of the treatment, low baseline intratumoral CD4+/CD8+ T-cell ratio was associated with better overall survival (P = 0.0002). The baseline frequency of intratumoral PD-1high CD8+ T cells was significantly lower in patients responding to sorafenib treatment than in the nonresponders (P = 0.0117), and the frequency of circulating PD-1high T cells increased with tumor progression (P = 0.0329). By contrast, responders to PD-1/PD-L1 pathway blockade showed a trend of high baseline frequency of intratumoral PD-1high CD8+ T cells. Moreover, we observed a trend of LAG3 and TIM3 upregulation on circulating T cells in nonresponding patients to PD-1/PD-L1 pathway blockade. DISCUSSION: Immunosuppressive state, characterized by an enhanced intratumoral CD4+/CD8+ T-cell ratio, was associated with poor prognosis. Additionally, our results suggest that the frequency of intratumoral PD-1high CD8+ T cells may serve as a biomarker to identify which individuals will benefit from which treatment and support the use of combination strategies.

Clinicopathologic and Racial/Ethnic Differences of Colorectal Cancer Among Adolescents and Young Adults OBJECTIVES: Despite overall reductions in colorectal cancer burden, incidence rates continue to rise among younger patients, and causes remain unknown. We examined differences in clinicopathologic and racial/ethnic characteristics within the adolescent and young adult (AYA) population diagnosed with colorectal cancer in the United States. METHODS: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results program data, we identified individuals diagnosed with first primary colorectal cancer between ages 15 and 39 years from 2010 to 2015. Adjusted multivariable logistic regression models were used to quantify clinicopathologic and racial/ethnic differences across age at onset subgroups (15–19, 20–24, 25–29, 30–34, and 35–39 years). RESULTS: We identified 5,350 AYA patients diagnosed with colorectal cancer. Of note, 28.6% of AYA cases were diagnosed with right-sided tumors (cecum to transverse colon). The proportion of right-sided colorectal cancers differed significantly by age group at diagnosis (38.3% vs 27.3% of AYAs aged 15–19 vs 35–39 years, respectively; P trend = 0.01). Proportions of cases with mucinous adenocarcinoma and signet ring cell carcinoma histopathologic subtypes significantly increased with younger age at onset (P trends = 0.01 and 0.03, respectively). Differences in clinical stage were observed across AYA age groups, with stage II disease increasing with younger age (P trend = 0.01). The proportion of Hispanic AYAs was higher within younger patients, accounting for 21.0% of the AYA population aged 35–39 years up to 28.3% of 15–19-year-old individuals (P trend = 0.003). DISCUSSION: Within the AYA population, colorectal cancers differ by clinicopathologic and racial/ethnic characteristics. Further investigation of the clinical and biologic diversity of colorectal cancers that partially underlie age- and race-related differences in cancer susceptibility and outcomes is warranted.

Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A OBJECTIVES: Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited. METHODS: We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A. We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis. RESULTS: Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS. DISCUSSION: The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.

Transjugular Liver Biopsy: Safe Even in Patients With Severe Coagulopathies and Multiple Biopsies OBJECTIVES: To investigate the safety profile and diagnostic efficacy of transjugular liver biopsy (TJLB), with a focus on patients with severe coagulopathies and with multiple biopsies. METHODS: Clinical, laboratory, and demographic information was collected on 1,321 TJLBs in 932 patients (mean age 43.5 ± 23.2 years) performed between January 2009 and May 2017 to determine the diagnostic success rate and incidence of both major and minor complications in the 3-day and 30-day period post-biopsies. These outcomes were also analyzed for severely coagulopathic patients and a subgroup of patients who underwent multiple biopsies. RESULTS: The overall success rate (diagnostic yield) of the TJLB procedure was 97.7% (1,291/1,321). Overall, the major and minor complication rates were 1.0% (13/1,321) and 9.5% (126/1,321), respectively. In patients with multiple biopsies, the overall complication rate was similar to the entire study cohort, which was 10.4% (57/550). Patients were also stratified according to the platelet counts of 0–50, 51–100, 101–200, 201–300 and >300 × 103 platelets/μL. The overall complication rates were 8.0% (10/124), 11.6% (36/310), 9.9% (54/547), 11.9% (28/235), and 14.3% (11/77), respectively, and these were not statistically significant from each other. Patients were also stratified by international normalized ratio into 0–1, 1.1–2, 2.1–3, and >3. The overall complication rates of these patients were 8.0% (19/237), 11.8% (113/954), 16.3% (7/43), and 0% (0/9), respectively, and were not statistically significant from each other. DISCUSSION: TJLB is a highly efficacious, well-tolerated and safe procedure. It can be safely performed multiple times in the same patient or in critically ill, severely coagulopathic patients with no significant increase in the rate of complication while maintaining an extremely favorable diagnostic yield.

Clinical Potential of Circulating Tumor Cells in Colorectal Cancer: A Prospective Study OBJECTIVES: Circulating tumor cells (CTCs) in the blood have been used as diagnostic markers in patients with colorectal cancer (CRC). In this study, we evaluated a CTC detection system based on cell size to assess CTCs and their potential as early diagnostic and prognostic biomarkers for CRC. METHODS: From 2014 to 2015, 88 patients with newly diagnosed CRC, who were scheduled for surgery, and 31 healthy volunteers were enrolled and followed up in Pusan National University Hospital. CTCs were enriched using a centrifugal microfluidic system with a new fluid-assisted separation technique (FAST) and detected by cytomorphological evaluation using fluorescence microscopy. RESULTS: Two or more CTCs were detected using FAST in 74 patients and 3 healthy volunteers. The number of CTCs in the CRC group was significantly higher than that in the healthy volunteers (P < 0.001). When a receiver operating characteristic curve was created to differentiate patients with CRC from healthy volunteers, the sensitivity and specificity were almost optimized when the critical CTC value was 5/7.5 mL of blood. When this value was used, the sensitivity and specificity in differentiating patients with CRC from the healthy controls were 75% and 100%, respectively. In patients with CRC with ≥5 CTCs, vascular invasion was frequently identified (P = 0.035). All patients with stage IV were positive for CTCs. Patients with ≥5 CTCs showed a trend toward poor overall and progression-free survival. DISCUSSION: Our study demonstrated promising results with the use of FAST-based CTC detection for the early diagnosis and prognosis of CRC.

A Phase 2 Study of Galunisertib (TGF-β1 Receptor Type I Inhibitor) and Sorafenib in Patients With Advanced Hepatocellular Carcinoma INTRODUCTION: Inhibition of tumor growth factor-β (TGF-β) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-β1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment. METHODS: The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-β1, safety, overall survival (OS), response rate, and pharmacokinetics (PK). RESULTS: Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-β1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038). DISCUSSION: The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.

Genetic Risk Score in Diabetes Associated With Chronic Pancreatitis Versus Type 2 Diabetes Mellitus Introduction: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM. We approached this question from a unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. Methods: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. Results: The mean GRS was identical between 321 subjects with CP-DM and 423 subjects with T2DM (66.53 vs 66.42, P = 0.95), and the GRS of both diabetic groups was significantly higher than that of nondiabetic controls (n = 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreas-specific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. Discussion: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.

A Low FODMAP Diet May Reduce Symptoms in Patients With Fecal Incontinence INTRODUCTION: Fecal incontinence (FI) is a common complaint and is often associated with diarrhea and urgency. Foods high in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAP) cause symptoms of diarrhea and urgency. Therefore, this study assesses the impact of a low FODMAP diet on the occurrence of FI due to loose stool. METHODS: This study is a retrospective chart review of patients with FI seen in the Michigan Bowel Control Program clinic between August 2012 and December 2017. Patients who had FI with loose stool without red flag signs and who were recommended a low FODMAP diet and underwent formal dietary instruction with a Michigan Medicine dietician were included. RESULTS: Sixty-five patients with FI who underwent formal dietary teaching were included in this study. Eighty-eight percent of the patients were white, and 87% were women with a mean age of 62 years (±14 years). Additionally, the chart review showed that 35% of the patients had FI daily, 21.5% had FI weekly, and 5% had FI monthly. About 64.6% of the patients (42) had reported a reduction in their FI symptoms with the low FODMAP diet. There was no demographic or clinical characteristic that predicted the response to a low FODMAP diet. DISCUSSION: In this case series, dietary manipulation with a low FODMAP diet was a useful tool to treat patients who suffer from FI due to loose stool. Further confirmatory, prospective randomized controlled trials are required to see the true efficacy of a low FODMAP diet in patients who suffer with FI.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Anaesthesia

Intraoperative Placement of Paravertebral Catheters to Manage Postoperative Pain in Opioid-Dependent Patients After Thoracolumbar Spine Fusion Surgery: A Case Report We introduce a regional technique that involves the intraoperative placement of bilateral paravertebral catheters under direct visualization. The patient had stage IV lung cancer and was on chronic oxycodone therapy. He presented with a T10 metastatic lesion, and underwent spinal decompression with T7–L1 fusion and T10 corpectomy. Before fascial closure, catheters were advanced into the T10 paravertebral space under direct visualization by the surgeon bilaterally. Postoperatively, his pain was well controlled, and narcotic requirements were decreased. Our case report demonstrates that for patients undergoing posterior spine surgery, intraoperative placement of bilateral paravertebral catheters can be used to help manage postoperative pain. Accepted for publication June 17, 2019. Funding: None. The authors declare no conflicts of interest. The authors declare no conflicts of interest., Address correspondence to Kelly Y. Chen, MD, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, 55 Fruit St, Gray-Bigelow 444, Boston, MA 02114. Address e-mail to kychen1@mgh.harvard.edu. © 2019 International Anesthesia Research Society

A Guide for Submitting a Manuscript That Is Aligned With the Mission of Anesthesia & Analgesia Practice Anesthesia & Analgesia (A&A) Practice is a journal for clinicians worldwide. It is aligned with the educational mission of its parent organization, the International Anesthesia Research Society. A&A Practice is an online-only companion journal of A&A. A&A Practice seeks to publish short yet informative, peer-reviewed, PubMed indexed articles that offer a solution to a perioperative care or patient safety conundrum or a health management issue, which is communicated as one of the several manuscript types. We herein provide authors with a guide to assist them toward a successfully published manuscript in A&A Practice. Accepted for publication June 5, 2019. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Address correspondence to BobbieJean Sweitzer, MD, FACP, Department of Anesthesiology, Northwestern University, Chicago, IL. Address e-mail to bobbiejean.sweitzer@nm.org. © 2019 International Anesthesia Research Society

Abdominal Surgery With Bilateral Rectus Sheath Block: A Case Report A 44-year-old man, American Society of Anesthesiologists physical status class IV, presented for fulguration of anal condyloma and diverting colostomy. The patient's medical history includes World Health Organization (WHO) class I pulmonary hypertension (PH), right heart failure, and bilateral lower extremity paralysis due to Pott's disease. The patient was not a candidate for neuraxial anesthesia due to sacral decubitus ulcers, and alternative options to general anesthesia (GA) were considered to avoid the high risk of right ventricular (RV) failure and ensuing complications. The case was successfully performed under sedation with dexmedetomidine infusion and bilateral rectus sheath blocks for surgical anesthesia. Accepted for publication May 16, 2019. Funding: None. The authors declare no conflicts of interest. Address correspondence to Elizabeth W. Duggan, MD, Department of Anesthesiology, Emory University Hospital, 1364 Clifton Rd, Office C-238, Atlanta, GA 30322. Address e-mail to ewdugga@emory.edu. © 2019 International Anesthesia Research Society

Neuropathic Pain due to Neurofibromatosis Treated With Transcutaneous Electrical Nerve Stimulation in a Pregnant Patient: A Case Report A patient with neurofibromatosis type 1 presented to the pain clinic with neuropathic pain. Thoracolumbar magnetic resonance imagining revealed meningocele T12–L2 with cauda equina distortion. After becoming pregnant, the patient interrupted opioid treatment, refusing pharmacological treatment until the pain became unbearable. Transcutaneous electrical nerve stimulation (TENS) was proposed. The patient used this treatment from the first trimester until month 6 postpartum, achieving good analgesia without any adverse effects for the mother or child. TENS may be a viable treatment for neuropathic pain (NP) during pregnancy. However, more data are needed due to the difficulty of conducting clinical trials in this population. Accepted for publication June 20, 2019. Funding: None. The authors declare no conflicts of interest. Address correspondence to Victor Caño Silva, MD, Department of Anesthesiology, Critical Care and Pain Clinics, L'Hospitalet de Llobregat, Av Feixa Llarga s/n, Barcelona 08907, Spain. Address e-mail to victorc@bellvitgehospital.cat. © 2019 International Anesthesia Research Society

Continuous Intravenous Lidocaine as an Effective Pain Adjunct for Opioid-Induced Bowel Dysfunction: A Case Report This case study describes a patient with suspected opioid-induced bowel dysfunction who had improved pain control when treated with intravenous (IV) lidocaine. An 80-year-old man with failed back surgery syndrome managed with an intrathecal (IT) pump presented with protracted abdominal pain. The acute pain service initiated a lidocaine infusion at 1 mg·min−1, and the patient reported significant pain relief. The patient experienced refractory abdominal pain with 3 attempts to wean the lidocaine infusion. Eventually, a successful transitional regimen was achieved with methylnaltrexone and transdermal lidocaine patches. Lidocaine infusions may be an effective and underutilized multimodal adjunct for nonsurgical pain conditions. Accepted for publication June 17, 2019. Funding: None. The authors declare no conflicts of interest. Address correspondence to Bryant W. Tran, MD, Department of Anesthesiology, Virginia Commonwealth University Medical Center, 1200 E Broad St, Box 980695, Richmond, VA 23298. Address e-mail to bryant.tran@vcuhealth.org. © 2019 International Anesthesia Research Society

Erector Spinae Plane Blocks in Major Hepatopancreaticobiliary Surgery: A Case Series Hepatopancreaticobiliary (HPB) surgery is major upper abdominal surgery with considerable risk of pulmonary complications related to postoperative pain. While epidural analgesia remains an effective analgesic technique for upper abdominal surgery, HPB surgery poses challenges to its use due to coagulopathy. Erector spinae plane (ESP) blocks are a promising alternative to epidurals. Injection of local anesthetic deep to the erector spinae muscle plane and placement of a catheter for prolonged effect provide both somatic and visceral analgesia for both thoracic and abdominal surgery. We describe a series of 3 cases that illustrate the efficacy of ESP blocks after major HPB surgery. Accepted for publication June 20, 2019. Funding: None. The authors declare no conflicts of interest. Address correspondence to Shrijit Nair, FCAI, Department of Anesthesia and Intensive Care Medicine, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland. Address e-mail to drshrijitnair@yahoo.com. © 2019 International Anesthesia Research Society

Total Hip Replacement in a Patient With a Fontan Circulation: A Case Report Anesthetic management of the adult patient with a Fontan circulation is complex and requires understanding of the specific physiology of the individual patient. Long-term survival in this cohort has increased to the point where patients are presenting for noncardiac surgery related to degenerative diseases of aging. We describe the perioperative management of a patient with a Fontan circulation undergoing total hip arthroplasty using combined spinal–epidural anesthesia and discuss the issues requiring special consideration for this surgical procedure in this group of patients. Accepted for publication June 9, 2019. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Address correspondence to Nicholas D. Black, MBBCh, BAO (Hons), Department of Anesthesia, Toronto Western Hospital, 399 Bathurst St, Toronto, ON, Canada. Address e-mail to nicholasdavidblack@hotmail.com. © 2019 International Anesthesia Research Society

Retained Perineural Catheter: A Sentinel Case Report We report the rare complication of a retained peripheral nerve block catheter (PNBC). A 45-year-old man with intractable postamputation phantom limb pain was treated with continuous infusions via femoral and sciatic peripheral nerve catheters. The catheters were removed by an emergency department physician 2 days after placement. Five months later, the patient presented with a discharging sinus from the sciatic nerve catheter site. Magnetic resonance imaging (MRI) was inconclusive. Surgical exploration showed 15 cm of retained peripheral nerve catheter, which was removed. Accepted for publication June 12, 2019. Funding: None. The authors declare no conflicts of interest. Address correspondence to Alparslan Turan, MD, Outcomes Research Department, Cleveland Clinic, Cleveland, OH 44195. Address e-mail to turana@ccf.org. © 2019 International Anesthesia Research Society

Intravenous Ketamine as an Adjunct for Pachyonychia Congenita–Associated Pain: A Case Report Pachyonychia congenita (PC) is a rare, inherited disorder of keratin filaments characterized by palmoplantar hyperkeratosis, keratoderma, and extreme pain. Management is largely symptomatic and typically involves multimodal pain control strategies. Here, we report the treatment of one 21-year-old man's refractory neuropathic PC pain with a 4-day inpatient ketamine infusion. Within 1 night of beginning treatment, his pain diminished to a 0/10 without any adverse effects, with effects lasting 2 weeks. No reported PC pain regimens have made use of intravenous ketamine; thus, we suggest recurrent ketamine infusions as an additional option in the multimodal pain regimen for patients with PC. Accepted for publication June 17, 2019. Funding: None. The authors declare no conflicts of interest. Address correspondence to Xiang Qian, MD, PhD, Stanford University School of Medicine, Pain Management Center, 450 Broadway St, Pavilion A, 1st Floor MC5340, Redwood City, CA 94063. Address e-mail to xqian@stanford.edu. © 2019 International Anesthesia Research Society

A Case Report of Surgical Entrapment and Catheter Embolization: A Rare Complication of Peripherally Inserted Central Catheters Peripherally inserted central catheters (PICCs) are a feasible alternative to conventional central venous access. PICCs are often used perioperatively for central venous pressure monitoring and administration of vasoactive drugs especially in cancer patients. Catheter breakage and embolization are rare but potentially fatal complications, and most of the reported literature pertains to pediatric patients after medium- to long-term use. In this report, we describe a rare scenario of catheter breakage, entrapment, and embolization in a patient caused by inadvertent surgical clip and suture placement. Accepted for publication May 30, 2019. Funding: None. The authors declare no conflicts of interest. Address correspondence to Seema Mishra, MD, Department of Onco-Anaesthesia and Palliative Medicine, Dr BRAIRCH, All India Institute of Medical Sciences, New Delhi 110029, New Delhi. Address e-mail to seemamishra2003@gmail.com. © 2019 International Anesthesia Research Society

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Menopause

Sexual pain in the menopausal patient: individualizing treatment still best No abstract available

Understanding the unmet sexual health needs of women with breast cancer No abstract available

Vaginal laser treatment—first, do no harm No abstract available

Sexual frequency and pain in a randomized clinical trial of vaginal estradiol tablets, moisturizer, and placebo in postmenopausal women Objective: To evaluate the efficacy of two common interventions for bothersome postmenopausal vaginal symptoms on improving sexual frequency and pain. Methods: This is a post-hoc analysis of data from a 12-week double-blind placebo-controlled trial that randomized postmenopausal women (ages 45-70 years) with moderate-severe genitourinary discomfort to vaginal 10 μg estradiol tablet plus placebo gel (n = 102), placebo tablet plus vaginal moisturizer (n = 100), or dual placebo (n = 100). Outcomes were proportion of sexually active women at 12 weeks, frequency of sexual activity, and pain severity with sexual activity (0-3 scale). Consistent with the original study design, comparisons were made between each active arm and the dual placebo arm. Results: Most women enrolled in the trial, 294/302 (97%), had sufficient data to be included in this analysis. Mean age of participants was 61 years, most were white (88%), college educated (66%), and most reported sexual activity in the month before enrollment (81%). After 12 weeks of treatment, a similar proportion of women in the vaginal estrogen and dual placebo groups reported sexual activity in the past week (50% and 40%; P = 0.10) and the past month (78% and 84%, P = 0.52). Mean (standard deviation) pain with sexual activity scores at 12 weeks were similar between vaginal estrogen (1.0 [1.0]) and placebo (0.9 [0.9], P = 0.52] groups. The proportion sexually active at 12 weeks (35%) and mean (standard deviation) pain severity in the vaginal moisturizer group (1.1 [0.9]) did not differ from placebo (P = 0.36). Conclusions: Compared to placebo, neither low-dose vaginal estradiol nor vaginal moisturizer treatment over 12 weeks resulted in significantly greater increases in the proportions of women reporting sexual activity or improvement in pain scores with sexual activity. Trial registration: Clinical trials.gov: NCT02516202.

Partner status moderates the relationships between sexual problems and self-efficacy for managing sexual problems and psychosocial quality-of-life for postmenopausal breast cancer survivors taking adjuvant endocrine therapy Objective: Past studies indicate that >90% of breast cancer survivors taking adjuvant endocrine therapy (AET) experience menopausal symptoms including sexual problems (eg, vaginal dryness, dyspareunia); however, research examining the impact of these problems on quality-of-life is limited. This cross-sectional study examined (1) the impact of sexual problems and self-efficacy for coping with sexual problems (sexual self-efficacy) on quality-of-life (ie, psychosocial quality-of-life and sexual satisfaction), and (2) partner status as a moderator of these relationships. Methods: Postmenopausal breast cancer survivors taking AET completed measures of sexual problems (Menopause-Specific Quality-of-Life [MENQOL] sexual subscale], sexual self-efficacy, psychosocial quality-of-life (MENQOL psychosocial subscale), and sexual satisfaction (Functional Assessment of Cancer Therapy-General item). Results: Bivariate analyses showed that women reporting greater sexual problems and lower sexual self-efficacy had poorer quality-of-life and less sexual satisfaction (all P-values < 0.05). Partner status moderated the relationship between sexual problems and psychosocial quality-of-life (P = 0.02); at high levels of sexual problems, unpartnered women experienced poorer psychosocial quality-of-life than partnered women. Partner status also moderated the relationship between self-efficacy and psychosocial quality-of-life (P = 0.01). Self-efficacy was unrelated to psychosocial quality-of-life for partnered women; for unpartnered women, low self-efficacy was associated with poorer quality-of-life. Partner status did not moderate the relationships between sexual problems or self-efficacy with sexual satisfaction. Conclusions: Greater sexual problems and lower sexual self-efficacy were associated with poorer psychosocial quality-of-life and sexual satisfaction among postmenopausal breast cancer survivors taking AET. Interventions to address sexual problems and sexual self-efficacy, particularly among unpartnered women, may be beneficial for improving the well-being of postmenopausal breast cancer survivors on AET.

Fractional CO2 laser versus promestriene and lubricant in genitourinary syndrome of menopause: a randomized clinical trial Objective: The aim of this study was to compare the effects of fractional CO2 laser therapy, promestriene, and vaginal lubricants on genitourinary syndrome treatment and sexual function in postmenopausal women. Methods: We performed a randomized clinical trial including 72 postmenopausal women over the age of 50 years. The women were randomized into three intervention groups to receive one of the following treatments: three sessions of intravaginal fractional CO2 laser therapy; 10 mg of intravaginal promestriene cream 3 times a week; and vaginal lubricant application alone. Vaginal maturation, Vaginal Health Index (VHI) score, and Female Sexual Function Index (FSFI) were evaluated at baseline and after 14 weeks of therapy. Results: We observed an improvement in the vaginal elasticity, volume, moisture, and pH in the CO2 laser and promestriene groups. The VHI score at 14 weeks was higher in the CO2 laser group (mean score 18.68) than in the promestriene (15.11) and lubricant (10.44) groups (P < 0.001). Regarding vaginal maturation, basal cells were reduced and superficial cells were increased after treatment. This improvement was more significant in the CO2 laser group (P <0.001). The FSFI score only showed improvement in the desire and lubrication domains in the CO2 laser group. There were no differences in total FSFI score among the three treatment groups. There were no adverse effects associated with any of the treatments. Conclusions: The use of fractional CO2 laser therapy to treat genitourinary syndrome resulted in better short-term effects than those of promestriene or lubricant with respect to improving the vaginal health in postmenopausal women.

Women's Health Initiative clinical trials: potential interactive effect of calcium and vitamin D supplementation with hormonal therapy on cardiovascular disease Objective: Data in humans and nonhuman primates have suggested a possible synergistic effect of vitamin D and calcium (CaD) and estrogen on the cardiovascular disease (CVD) risk factors. Using randomized trial data we explored whether the effect of menopausal hormone therapy (HT) on CVD events is modified by CaD supplementation. Methods: A prospective, randomized, double-blind, placebo-controlled trial was implemented among postmenopausal women in the Women's Health Initiative. A total of 27,347 women were randomized to the HT trials (0.625 mg/d of conjugated equine estrogens [CEE] alone for women without a uterus vs placebo; or 0.625 mg of CEE in addition to 2.5 mg of medroxyprogesterone acetate daily [CEE + MPA] for women with a uterus vs placebo). After 1 year, 16,089 women in the HT trial were randomized to the CaD trial and received either 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D3 daily or placebo. The mean (SD) duration of follow-up after CaD randomization was 6.2 (1.3) years for the CEE trial and 4.6 (1.1) years for the CEE + MPA trial. CVD and venous thromboembolism events evaluated in this subgroup analysis included coronary heart disease, stroke, pulmonary embolism, all-cause mortality, plus select secondary endpoints (total myocardial infarction, coronary revascularization, deep venous thrombosis, cardiovascular death, and all CVD events). Time-to-event methods were used and models were fit with a Cox proportional hazards regression model. Results: In the CEE trial, CaD significantly modified the effect of CEE on stroke (P interaction = 0.04). In the CaD-placebo group, CEE's effect on stroke was harmful (hazard ratio [95% confidence interval] = 2.19[1.34-3.58]); however, it was neutral in the CaD-supplement group (hazard ratio [95% confidence interval] = 1.07[0.66-1.73]). We did not observe significant CEE-CaD interactions for coronary heart disease, total CVD events, or any of the remaining endpoints. In the CEE + MPA trial, there was no evidence that the effect of CEE + MPA on any of CVD endpoints was modified by CaD supplementation. Conclusions: CaD did not consistently modify the effect of CEE therapy or CEE + MPA therapy on CVD events. However, the increased risk of stroke due to CEE therapy appears to be mitigated by CaD supplementation. In contrast, CaD supplementation did not influence the risk of stroke due to CEE + MPA.

Confirmatory factor analysis of the Insomnia Severity Index (ISI) and invariance across race: a pooled analysis of MsFLASH data Objective: Women's sleep at menopause is widely reported to be problematic. The Insomnia Severity Index (ISI) is a commonly used tool for quantifying sleep problems in clinical and research settings, but psychometric properties in postmenopausal women have not been reported. Our study aim was to examine the factor structure of the ISI in a large and diverse sample of midlife women with hot flashes. Methods: Baseline data were from 899 women enrolled in one of the three clinical trials using similar entry criteria conducted by the Menopause Strategies Finding Lasting Answers to Symptoms and Health research network. We conducted confirmatory factor analyses for the total sample and within strata defined by race/ethnicity (black and white women). Results: The ISI had two factors in the total sample. The two-factor structure was consistent across black and white women, with the exception of one item "difficulty falling asleep." Conclusions: The ISI in midlife women with hot flashes is composed of two factors that capture dimensions of the insomnia severity and daytime impact. The instrument is a psychometrically sound scale appropriate for use in research and clinical practice to capture the severity and daytime impact of insomnia symptoms in diverse samples of midlife women with hot flashes. An abbreviated screening of two items could be considered to determine if further evaluation is needed of sleep complaints.

Accuracy of the Menopause Rating Scale and the Menopause Quality of Life Questionnaire to discriminate menopausal women with anxiety and depression Objective: The aim of the study was to evaluate the accuracy of the Menopause Rating Scale (MRS) and the Menopause Quality of Life Questionnaire (MENQOL) to discriminate women suffering from anxiety (AD) and depression disorder (DD). Methods: A cohort of 416 women aged 45 to 65 years (51.7 ± 3.8) completed the MRS, MENQOL and Hospital Anxiety and Depression Scale, plotting receiver operator curves to assess the diagnostic accuracy of the MRS and MENQOL items related to anxiety and depression. Results: Both the MRS6 (area under the ROC curve [AUC] 0.773, 95% confidence interval [CI] 0.721-0.824) and MENQOL5 (AUC: 0.772, 95% CI 0.723-0.822) proved to be accurate tools to identify individuals with anxiety or with a likelihood to develop AD. Likewise, the items MRS4 (AUC: 0.771, 95% CI 0.625-0.797) and MENQOL8 (AUC: 0.744, 95% CI 0.668-0.821) appeared to be suitable to discriminate individuals with DD. Two cut-off points were established for each item in the different scales to optimize their capacity to detect and discriminate problems of anxiety and depression. Lower cut-off values (MRS ≥ 1; MENQOL ≥ 2) were established to detect AD and DD, the sensitivity of which varied between 76.0% and 84.6%% and a negative predictive value varying between 86.7% and 95.3%. A more specific cut-off was established for the discrimination of AD and DD (MRS ≥ 2; MENQOL ≥ 7), with a specificity ranging from 86.2% to 99.4% and a positive predictive value varying between 68.6% and 92.6%. Conclusions: The MRS and MENQOL display moderate accuracy in discriminating menopausal women with symptoms of anxiety and depression. The intensity of the symptoms appears to be related to the probability of detecting a probable or definitive disorder.

Tamoxifen use as a malignancy risk factor in postmenopausal women with endometrial polyps Objective: We analyzed tamoxifen use as a malignancy risk factor in women with endometrial polyps. Methods: This retrospective study included 675 women who underwent hysteroscopic polypectomy in 2010 to 2015 at the University of Campinas. Women were divided into tamoxifen use (n = 169) and no tamoxifen use (n = 506) groups. The primary outcome was endometrial cancer prevalence. Dependent variables included age, parity, years since menopause, presence of abnormal uterine bleeding, endometrial pattern on hysteroscopy, and endometrial thickness. Results: There were seven cases of endometrial cancer in the tamoxifen use group (4.14%) and 41 in the no tamoxifen use group (8.1%; P = 0.083). On performing multivariate analysis, tamoxifen use was not a risk factor for endometrial cancer (prevalence ratio 0.51, 95% confidence interval [CI] 0.23-1.14, P = 0.101). The no tamoxifen use group had an increased prevalence of malignancy when women presented with abnormal uterine bleeding (prevalence ratio 3.9, 95% CI 2.08-7.29, P < 0.001), age >60 years (prevalence ratio 2.1, 95% CI 1.12-3.93, P = 0.021), or nulliparous status (prevalence ratio 3.13, 95% CI 1.55-6.35, P = 0.002). The tamoxifen use group had increased prevalence of malignancy when women were >60 years (prevalence ratio 7.85, 95% CI 1.05-58.87, P = 0.006) or nulliparous (prevalence ratio 8.36, 95% CI 2.32-30.11, P < 0.001). Conclusion: Tamoxifen use was not related with a higher prevalence of endometrial cancer in women with endometrial polyps. Abnormal uterine bleeding, age > 60 years, and nulliparous status were associated with malignancy.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Clinical Orthopaedics and Related Research(R)

Editorial: What Do You Say When a Patient Says Thank You? No abstract available

Editor's Spotlight/Take 5: What Role Does Positive Psychology Play in Understanding Pain Intensity and Disability Among Patients with Hand and Upper-extremity Conditions? No abstract available

What Role Does Positive Psychology Play in Understanding Pain Intensity and Disability Among Patients with Hand and Upper Extremity Conditions? Background A large body of research shows that psychologic distress and ineffective coping strategies substantially contribute to more severe pain and increased physical limitations among patients with orthopaedic disorders. However, little is known about the relationship between positive psychology (constructs that enable individuals to thrive and adapt to challenges) and pain and physical limitations in this population. Questions/purposes (1) Which positive-psychology factors (satisfaction with life, gratitude, coping through humor, resilience, mindfulness, and optimism) are independently associated with fewer upper-extremity physical limitations after controlling for the other clinical and demographic variables? (2) Which positive-psychology factors are independently associated with pain intensity after controlling for relevant clinical and demographic variables? Methods In a cross-sectional study, we recruited patients presenting for a scheduled appointment with an orthopaedic surgeon at a hand and upper-extremity clinic of a major urban academic medical center. Of 125 approached patients, 119 (44% men; mean age, 50 ± 17 years) met screening criteria and agreed to participate. Patients completed a clinical and demographic questionnaire, the Numerical Rating Scale to assess pain intensity, the Patient-reported Outcomes Measurement Information System (PROMIS) Upper Extremity Physical Function computerized adaptive test to assess physical limitations, and six measures assessing positive-psychology constructs: The Satisfaction with Life Scale, the Gratitude Questionnaire, the Coping Humor Scale, the Brief Resilience Scale, the Cognitive and Affective Mindfulness Scale-Revised, and the Life Orientation Test-Revised. We first examined bivariate associations among physical limitations, pain intensity, and all positive-psychology factors as well as demographic and clinical variables. All variables that demonstrated associations with physical limitations or pain intensity at p < 0.05 were included in two-stage multivariable hierarchical regression models. Results After controlling for the potentially confounding effects of prior surgical treatment and duration since pain onset (step1; R2 total = 0.306; F[7,103] = 6.50), the positive-psychology variables together explained an additional 15% (R2 change = 0.145, F change [5, 103] = 4.297, p = 0.001) of the variance in physical limitations. Among the positive-psychology variables tested, mindfulness was the only one associated with fewer physical limitations (β = 0.228, t = 2.293, p = 0.024, 4% variance explained). No confounding demographic or clinical variables were found for pain intensity in bivariate analyses. All positive-psychology variables together explained 23% of the variance in pain intensity (R2 = 0.23; F[5,106] = 6.38, p < 0.001). Among the positive-psychology variables, satisfaction with life was the sole factor independently associated with higher intensity (β = -0.237, t = -2.16, p = 0.033, 3% variance explained). Conclusions Positive-psychology variables explained 15% of the variance in physical limitations and for 23% of the variance in pain intensity among patients with heterogenous upper extremity disorders within a hand and upper extremity practice. Of all positive-psychology factors, mindfulness and satisfaction with life were most important for physical limitations and pain intensity, respectively. As positive-psychology factors are more easily modifiable through skills-based interventions than pain and physical limitations, results suggest implementation of such interventions to potentially improve outcomes in this population. Skills-based interventions targeting mindfulness and satisfaction with life may be of particular benefit. Level of Evidence Level II, prognostic study.

Value-based Healthcare: Can Artificial Intelligence Provide Value in Orthopaedic Surgery? No abstract available

Clinical Faceoff: Should Routine Histopathological Analysis be Performed on Specimens Obtained During Primary Arthroplasty Surgery? No abstract available

Not the Last Word: Prizes for Cures No abstract available

Equity360: Gender, Race, and Ethnicity—What's in Your Knapsack? No abstract available

From Bench to Bedside: We Can (Still) Do Better—Moving Towards More Thoughtful, "Constructive" Amputations No abstract available

CORR® International – Asia-Pacific: Moving from University to Private Practice No abstract available

CORR® ORS Richard A. Brand Award: Disruption in Peroxisome Proliferator-Activated Receptor-γ (: PPARG: ) Increases Osteonecrosis Risk Through Genetic Variance and Pharmacologic Modulation Background The pathophysiology of osteonecrosis of the femoral head (ONFH) is poorly understood, and the diagnosis is idiopathic in as many as 40% of patients. Genetic and epigenetic etiologies have been postulated, yet no single nucleotide polymorphisms (SNPs) with intuitive biologic implications have been elucidated. Questions/purposes (1) Do individuals with ONFH share common biologically relevant genetic variants associated with disease development? (2) What is the mechanism by which these SNPs may impact the expression or function of the affected gene or protein? Methods This retrospective genome-wide association study (GWAS) evaluated participants from the Mayo Clinic Biobank and Mayo Clinic Genome Consortium between August 2009 and March 2017. We included every patient with atraumatic ONFH in each of these respective registries and every control patient in a previous GWAS with an acceptable platform to perform statistical imputation. The study was performed in two phases, with an initial discovery cohort and a subsequent validation cohort. The initial discovery cohort consisted of 102 patients with ONFH and 4125 controls. A logistic regression analysis was used to evaluate associations between SNPs and the risk of ONFH, adjusted for age and sex. Seven SNPs were identified in a gene of biological interest, peroxisome proliferator-activated receptor gamma (PPARG), which were then evaluated in a subsequent validation cohort of 38 patients with ONFH and 464 controls. Age, sex, race, and previous steroid exposure were similar between patients with ONFH and controls in both the discovery and validation cohorts. Separate from the two-phase genetic investigation, we performed targeted pharmacosurveillance to evaluate the risk association between the use of antidiabetic thiazolidinediones, a class of PPARG agonists, and development of ONFH by referencing 9,638,296 patient records for individuals treated at Mayo Clinic. Results A combined analysis of the discovery and validation cohorts revealed that seven SNPs were tightly clustered adjacent to the 3' end of PPARG, suggesting an association with the risk of ONFH (p = 1.58 x 10-2-5.50 x10-6). PPARG gene-level significance was achieved (p = 3.33 x 10-6) when all seven SNPs were considered. SNP rs980990 had the strongest association with the risk of ONFH (odds ratio [OR], 1.95; 95% CI, 1.46-2.59; p = 5.50 x 10-6). The seven identified SNPs were mapped to a region near the PPARG gene and fell in a highly conserved region consisting of several critical transcription factor binding sites. Nucleotide polymorphisms at these sites may compromise three-dimensional chromatin organization and alter PPARG 3' end interactions with its 5' promoter and transcription start site. Pharmacosurveillance identified that patients who were exposed to thiazolidinediones had an increased relative risk of developing ONFH of 5.6 (95% CI, 4.5-7.1). Conclusions We found that disruption of PPARG regulatory domains is linked to an increased risk of ONFH. Mechanistically, aberrant regulation of PPARG compromises musculoskeletal differentiation because this master regulator creates a proadipogenic and antiosteogenic state. Furthermore, PPARG alters steroid metabolism and vasculogenesis, processes that are inextricably linked with ONFH. Pharmacologically, predisposition to ONFH was further exposed with thiazolidinedione use, which upregulates the expression of PPARG and is known to alter bone metabolism. Collectively, these findings provide a foundation to perform confirmatory studies of our proposed mechanism in preclinical models to develop screening diagnostics and potential therapies in patients with limited options. Level of Evidence Level III, prognostic study.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com