Otolaryngology

1. Research articleAbstract only

   Aberrant expressed long non-coding RNAs in laryngeal squamous-cell carcinoma

   Hu Li, Fu-Ling Wang, Wei Li, Yong-Hua Fei, ... Mei Zhang

   In Press, Accepted Manuscript, Available online 9 May 2019

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   Abstract

   Purpose

   Laryngeal squamous-cell carcinoma (LSCC) is the second most common malignant tumor of head and neck squamous cell carcinoma. The study was aimed to identify key long non-coding RNAs (lncRNAs) biomarkers for LSCC.

   Methods

   Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between LSCC and adjacent tissues were obtained based on The Cancer Genome Atlas. DElncRNA-DEmRNAs co-expression and DElncRNA-nearby-target DEmRNA interaction networks were constructed. Receiver operating characteristic and survival analysis were performed. A published dataset were as used to validate the result of bioinformatics analysis.

   Results

   We obtained 1103 DEmRNAs and 306 DElncRNAs between LSCC and adjacent tissues. A total of 338 DElncRNA-DEmRNA co-expression pairs and 229 DElncRNA-nearby-target DEmRNA pairs were obtained. Ten DElncRNAs and six DEmRNAs has great diagnostic value for LSCC. HOXB9 has potential prognostic value for LSCC. The results of GSE84957 validation were generally consistent with our results.

   Conclusion

   Our study provided clues for understanding the mechanism and developing potential biomarkers for LSCC.

2. select article Impact of payer status on survival in parotid malignancy

   Research articleAbstract only

   Impact of payer status on survival in parotid malignancy

   Vanessa Stubbs, Karthik Rajasekaran, Jinbo Chen, Steven Cannady, ... Jason Newman

   In Press, Accepted Manuscript, Available online 9 May 2019

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   Abstract

   Objective

   In the setting of current national healthcare reform, it becomes especially relevant to understand the current state of healthcare disparities with regards to insurance status. To determine the impact of payer status on survival in parotid malignancy, we utilized the National Cancer Database (NCDB).

   Study design

   Retrospective database review.

   Setting

   National Cancer Database (2004–2012).

   Subjects and methods

   The NCDB was queried for cases of primary malignancy of the parotid gland between 2004 and 2012. The impact of payer status on overall survival was evaluated, as well as the relationship of insurance status with patient and tumor variables.

   Results

   15,815 cases met inclusion criteria. A majority had private insurance (47.8%), followed by Medicare (40.9%), Medicaid (5.0%), uninsured (3.2%) and other government sources (1.3%). Medicare patients had the lowest 5 and 10-year survival rates (50.7% (95% CI [49.3–52.1]) and 27.8% (95% CI [25.0–30.9]), respectively). On multivariable analysis, uninsured, Medicare, and Medicaid patients had worse overall survival than the privately insured (HR 1.42, 95% CI [1.17–1.74]; HR 1.29, 95% CI [1.17–1.42]; HR 1.36, 95% CI [1.13–1.62], respectively). Uninsured and Medicaid patients were more likely than the privately insured to present with advanced stage disease, nodal metastasis and longer times to treatment following diagnosis.

   Conclusion

   In parotid malignancy, uninsured, Medicaid, and Medicare patients have worse survival outcomes compared to those with private insurance. Uninsured and Medicaid patients also present with more advanced stage disease and have increased wait times before definitive treatment is initiated.

3. select article Clinicopathological features of papillary thyroid microcarcinoma with a diameter less than or equal to 5 mm

   Research articleAbstract only

   Clinicopathological features of papillary thyroid microcarcinoma with a diameter less than or equal to 5 mm

   Lei Yan, Jayjay Blanco, Vijaya Reddy, Samer Al-Khudari, ... Paolo Gattuso

   In Press, Accepted Manuscript, Available online 8 May 2019

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   Abstract

   Purpose

   This retrospective study was conducted to assess the epidemiological, clinical and histologic characteristics of incidentally identified and presurgically diagnosed papillary thyroid microcarcinomas less than or equal to 5 mm in size (small PTMC).

   Materials and methods

   Cases from October 2003 to February 2018 were retrieved from pathology databases, and their clinicopathological features were reviewed.

   Results

   There were a total of 182 cases of small PTMCs, 141 women and 41 men. The mean age at diagnosis was 53.5. Most of the small PTMCs were not detected on clinical examination and workup and were diagnosed incidentally during pathologic examination. 21.4% of small PTMCs showed multifocality, with 21 cases of unilateral multifocal lesions and 18 cases with bilateral multifocal tumors. Small PTMCs were most often follicular variant (51.9%) followed by classic type (47.5%). The average size of follicular variants appeared to be larger than that of the classic type PTMCs (2.84 ± 1.43 mm vs 2.26 ± 1.51 mm, P = 0.01). A total of 66 cases (36.3%) had regional lymph node sampling or selective neck dissection and 15 of these cases identified lymph node metastasis (22.7%). 46.7% of patients with node positive microcarcinomas were male compared with 16% male in group with negative lymph nodes (P = 0.03).

   Conclusions

   Small PTMCs (≤5 mm) are often multifocal and bilateral and histology is commonly both the classical and follicular variant of PTC. While often diagnosed incidentally small PTMC can lead to regional lymph node involvement in a significant portion of cases and evaluation of the regional lymph nodes should be considered in the clinical management of these patients.

4. select article An unusual case of sudden sensorineural hearing loss after cycling class

   Case reportAbstract only

   An unusual case of sudden sensorineural hearing loss after cycling class

   Vivian F. Kaul, Sarah Kidwai, Adam Lupicki, Maura Cosetti

   In Press, Corrected Proof, Available online 25 April 2019

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   Abstract

   In this case report, our patient developed sudden sensorineural hearing loss (SSNHL) after loud noise exposure during a popular cardiovascular group exercise cycling class. To increase awareness among all healthcare professionals of the effects of these modern-day group fitness classes on hearing loss, we describe this case and review the current literature on SSNHL and its management. A 35-year old man developed SSNHL in the setting of loud noise exposure during a high intensity aerobic exercise class. After a short course of oral steroids with no improvement, intratympanic steroids were administered weekly for three weeks. The patient showed minimal improvement; thus, hyperbaric oxygen therapy was conducted. Serial audiograms continued to show severe to profound mixed hearing loss in the right ear. In conclusion, individuals who participate in loud, high-intensity aerobic group-exercise classes should be careful of the potential for noise-induced hearing loss. Aerobic exercise may make these individuals more susceptible to noise-induced hearing loss. Early intervention is critical for any chance of recovery.

5. select article Practice patterns and knowledge among California pediatricians regarding human papillomavirus and its relation to head and neck cancer

   Research articleAbstract only

   Practice patterns and knowledge among California pediatricians regarding human papillomavirus and its relation to head and neck cancer

   Michael H. Berger, Yarah M. Haidar, Benjamin Bitner, Monica Trent, Tjoson Tjoa

   In Press, Corrected Proof, Available online 25 April 2019

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   Abstract

   Objective

   To identify practice patterns regarding human papillomavirus (HPV) vaccination efforts and vaccination rates in context of head and neck cancer prevention, identify barriers to vaccination, and identify gaps in knowledge regarding the link between HPV and head and neck cancer in the pediatrician population.

   Study design/Methods

   A 27-question cross-sectional survey was distributed to members of the four California chapters of the American Academy of Pediatrics.

   Results

   Of the completed responses, 89.4% identified as "always" recommending the HPV vaccine to patients, but only 19.5% of pediatricians estimated that >75% of their eligible patients had completed the HPV vaccination series. 71.5% of respondents felt that further education about HPV's link to head and neck cancer them more comfortable discussing vaccination. Physicians who were in practice longer were less likely to respond that additional education about HPV and its link to head and neck cancer would make them more comfortable discussing vaccination with patients (p = 0.043). Physicians who were in practice longer were more likely to correctly respond that HPV type 16 is the most common strain linked to head and neck cancer (p = 0.021).

   Conclusion

   There is need to improve both the knowledge base and comfort level of pediatricians in counseling their patients during vaccine recommendations. Otolaryngologists have a critical role in providing education to physicians, trainees, and the general public in the effort to combat the epidemic of HPV-associated head and neck cancer.

6. select article The molecular differences between human papillomavirus-positive and -negative oropharyngeal squamous cell carcinoma: A bioinformatics study

   Research articleAbstract only

   The molecular differences between human papillomavirus-positive and -negative oropharyngeal squamous cell carcinoma: A bioinformatics study

   Jiaming Wang, Xiaoxi Xi, Wei Shang, Aneesha Acharya, ... Xianda Hu

   In Press, Corrected Proof, Available online 23 April 2019

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   Abstract

   Objective

   To investigate the genetic and epigenetic differences between human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) and HPV-negative OPSCC.

   Methods

   Microarray data of HPV-positive and -negative OPSCC were retrieved from NCBI GEO datasets. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DE-miRNAs) were identified by performing differential expression analysis. A functional enrichment analysis was performed to explore the biological processes and signaling pathways that DEGs and DE-miRNAs were involved in, respectively. A protein-protein interaction (PPI) network of DEGs was constructed to identify hub genes. miRNA-target network and miRNA-miRNA functional synergistic network were each constructed in order to identify risk-marker miRNAs. An miRNA-target-pathway network was constructed in order to explore the function of identified risk-marker miRNAs.

   Results

   Microarray data from 3 datasets (GSE39366, GSE40774, and GSE55550) was included and analyzed. The PPI network identified 3 hub genes (VCAM1, UBD, and RPA2). MiR-107 and miR-142-3p were found to play the most significant role in both the DE-miRNA-target network as well as in the miRNA-miRNA functional synergistic network. MiR-107 was involved in HPV-induced tumorigenesis by targeting many genes (CAV1, CDK6, MYB, and SERPINB5) and regulating the p53 signaling pathway, the PI3K-Akt signaling pathway, and the autophagy pathway. In addition, miR-142-3p was implicated in HPV-induced tumorigenesis by targeting the PPFIA1 gene and regulating transcriptional dysregulation and other cancerous pathways.

   Conclusion

   Three genes (VCAM1, UBD, and RPA2), two miRNAs (miR-107 and miR-142-3p), and four pathways (p53, PI3K-Akt, autophagy, and transcription dysregulation in cancer) were identified to play critical roles in distinguishing HPV-positive OPSCC from HPV-negative OPSCC.

7. select article Vitamin D deficiency and its relationship to cancer stage in patients who underwent thyroidectomy for papillary thyroid carcinoma.

   Research articleAbstract only

   Vitamin D deficiency and its relationship to cancer stage in patients who underwent thyroidectomy for papillary thyroid carcinoma.

   Anita Sulibhavi, Matthew L. Rohlfing, Scharukh M. Jalisi, David B. McAneny, ... J. Pieter Noordzij

   In Press, Corrected Proof, Available online 22 April 2019

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   Abstract

   Purpose

   As imaging technology improves and more thyroid nodules and malignancies are identified, it is important to recognize factors associated with malignancy and poor prognosis. Vitamin D has proven useful as a prognostic tool for other cancers and may be similarly useful in thyroid cancer. This study explores the relationship of Vitamin D to papillary thyroid carcinoma stage while accounting for socioeconomic covariates.

   Materials and methods

   The medical records of all patients who underwent thyroidectomy at one institution between 2000 and 2015 were reviewed. Subjects with non-papillary thyroid cancer pathology, prior malignancy, and without Vitamin D levels were excluded. The remaining 334 patient records were examined for cancer stage, Vitamin D levels, Vitamin D deficiency listed in history, and demographic and comorbid factors.

   Results

   Vitamin D laboratory values showed no significant relationship to cancer stage (p = 0.871), but patients with Vitamin D deficiency documented in the medical record were more likely to have advanced disease (28.6% versus 14.7%; p = 0.028). The patients with documented Vitamin D deficiency also had lower 25-hydroxyvitamin D nadirs (21.5 ng/mL versus 26.5 ng/mL, p = 0.008) and were more likely to be on Vitamin D supplementation (92.6% versus 41.8%, p < 0.001).

   Conclusions

   The results suggest that Vitamin D deficiency may have value as a negative prognostic indicator in papillary thyroid cancer and that pre-operative laboratory evaluation may be less useful. This is important because Vitamin D deficiency is modifiable. While different racial subgroups had different rates of Vitamin D deficiency, neither race nor socioeconomic status showed correlation with cancer stage.

8. select article Failed larynx preservation and survival in patients with advanced larynx cancer

   Research articleAbstract only

   Failed larynx preservation and survival in patients with advanced larynx cancer

   Cheryl C. Nocon, Jessica Yesensky, Gaurav S. Ajmani, Mihir K. Bhayani

   In Press, Corrected Proof, Available online 22 April 2019

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   Abstract

   Purpose

   To evaluate the survival benefit of total laryngectomy (TL) after induction chemotherapy in locally advanced laryngeal cancer patients.

   Materials and methods

   This is a retrospective study utilizing the National Cancer Database, which captures >80% of newly diagnosed head and neck squamous cell carcinoma cases in the United States. We included patients diagnosed with advanced stage laryngeal squamous cell carcinoma between 2004 and 2013 (n = 5649) who received either TL (n = 4113; 72.8%) or induction chemotherapy followed by either radiation therapy (n = 1431) or TL (n = 105). Kaplan-Meier curves and Cox proportional hazards regression were used to evaluate overall survival. A Cox regression model was computed to examine how the prognostic impact of treatment differed by clinical stage.

   Results

   In multivariable analysis, when compared to patients receiving TL alone, those receiving induction chemotherapy followed by TL experienced no significant difference in survival (HR 0.85, 95% CI 0.63–1.13), while those receiving induction chemotherapy followed by radiation experienced poorer survival (HR 1.15, 95% CI 1.06–1.26). Induction chemotherapy followed by TL was associated with improved survival compared to induction chemotherapy and radiation (P = .042). Among patients with T4a tumors, TL (P < .001) and induction chemotherapy followed by TL (P = .002) were both associated with improved survival compared to induction chemotherapy and radiation. There were no survival differences between TL and induction chemotherapy followed by TL (HR 0.76, 95% CI 0.52–1.10).

   Conclusions

   Larynx preservation may be attempted without compromising survival in patients with locally advanced larynx cancer who fail induction chemotherapy and undergo TL.

9. select article Improving efficiency in epistaxis transfers in a large health system: Analyzing emergency department treatment variability as pretext for a clinical care pathway

   Research articleAbstract only

   Improving efficiency in epistaxis transfers in a large health system: Analyzing emergency department treatment variability as pretext for a clinical care pathway

   Clare Richardson, Anish Abrol, Chelsea S. Hamill, Nicole Maronian, ... Brian D'Anza

   In Press, Corrected Proof, Available online 16 April 2019

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   Abstract

   Introduction

   Epistaxis is a common condition with an estimated $100 million in health care costs annually. A significant portion of this stems from Emergency Department (ED) management and hospital transfers. Currently there is no data in the literature clearly depicting the differences in treatment of epistaxis between Emergency Medicine (EM) physicians and Otolaryngologists. Clinical care pathways (CCP) are a way to standardize care and increase efficiency. Our goal was to evaluate the variability in epistaxis management between EM and Otolaryngology physicians in order to determine the potential impact of a system wide clinical care pathway.

   Materials and methods

   A retrospective case study was conducted of all patients transferred between emergency departments for epistaxis over an 18-month period. Exclusion criteria comprised patients under 18 years old, recent sinonasal surgery, bleeding disorders, and recent facial trauma.

   Results

   73 patients met inclusion criteria. EM physicians used nasal cautery in 8%, absorbable packing in 1% and non-absorbable packing in 92% (with 33% being bilateral). In comparison, Otolaryngologists used nasal cautery in 37%, absorbable packing in 34%, and non-absorbable packing in 23%. Eighty percent of patients treated by an Otolaryngology physician required less invasive intervention than previously performed by EM physicians prior to transfer.

   Conclusions

   Epistaxis management varied significantly between Emergency Medicine and Otolaryngology physicians. Numerous patients were treated immediately with non-absorbable packing. On post-transfer Otolaryngology evaluation, many of these patients required less invasive interventions. This study highlights the variability of epistaxis treatment within our hospital system and warrants the need for a standardized care pathway.

10. select article Predicting transient hypocalcemia in patients with unplanned parathyroidectomy after thyroidectomy

    Research articleAbstract only

    Predicting transient hypocalcemia in patients with unplanned parathyroidectomy after thyroidectomy

    Ramez Philips, Phillip Nulty, Nolan Seim, Yubo Tan, ... Garth Essig

    In Press, Corrected Proof, Available online 16 April 2019

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    Abstract

    Objective

    To assess the utility of rapid parathyroid hormone (PTH) values in predicting transient post-operative hypocalcemia in patients with unplanned parathyroidectomy during total or completion thyroidectomy.

    Methods

    All patients who underwent total or completion thyroidectomy between January 2010 and January 2015 were reviewed. Incidences of post-operative hypocalcemia were compared in patients with and without unplanned parathyroidectomy. Unplanned parathyroidectomy was defined as intra-operative incidental or intentional parathyroidectomy. Logistic regression assessed for predictors of hypocalcemia and optimum amount of calcium supplementation.

    Results

    Thirty-eight (13.6%) patients had evidence of incidental parathyroidectomy and 39/280 (13.9%) patients had parathyroid autotransplantation intra-operatively. Central neck dissection and malignancy were identified as risk factors for unplanned parathyroidectomy (p = 0.001, p = 0.060). Patients with unplanned parathyroidectomy were more likely to have hypocalcemia (p = 0.002) and hypoparathyroidism (p < 0.0005). PTH value was the only significant predictor of hypocalcemia in these patients. In patients with a post-operative PTH of ≤15, initial calcium supplementation ≥ 1000 mg decreased the risk of hypocalcemia (p < 0.05).

    Conclusion

    Post-operative PTH value predicts hypocalcemia in patients undergoing total and completion thyroidectomy with unplanned parathyroidectomy. In patients with a post-operative PTH < 15, initial calcium supplementation with ≥1000 mg of elemental calcium is recommended.

11. select article Clinical practice patterns in laryngeal cancer and introduction of CT lung screening

    Research articleAbstract only

    Clinical practice patterns in laryngeal cancer and introduction of CT lung screening

    Krzysztof Piersiala, Lee M. Akst, Alexander T. Hillel, Simon R. Best

    In Press, Corrected Proof, Available online 12 April 2019

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    Abstract

    Objectives

    After the publication of large clinical trials, in January 2014 The U.S. Preventive Services Task Force (USPSTF) recommended annual lung cancer screening with low-dose CT in a well-defined group of high-risk smokers. A significant proportion of patients with laryngeal cancer (LC) meet the introduced criteria, and we hypothesized that clinical practice would change as a result of these evidence-based guidelines.

    Methods

    Retrospective chart review of patients diagnosed with LC and treated at Johns Hopkins Hospital who met USPSTF criteria for annual chest screening and were followed for at least 3 consecutive years in the years surrounding the introduction of screening guidelines (January 2010 to December 2017) was performed to identify those who had recommended screening CT chest.

    Results

    A total of 151 patients met the inclusion criteria of the study and were followed for a total of 746 patient-years. 184/332 (55%) patient-years in the pre-guidelines period and 246/414 (59%) in the post-guidelines period included at least one recommended chest imaging (CT or PET-CT; p = 0.27). 248/332 (75%) patient-years in the pre-guidelines period and 314/414 (76%) in the post-guidelines period included any radiological chest imaging (X-ray, CT or PET-CT; p = 0.72). Screening scans were ordered by OHNS (45%), Medical Oncology (31%), Radiation Oncology (8%), and primary care (14%) with 70% of patients missing at least one year of indicated screening.

    Conclusions

    The implementation of new lung cancer screening guidelines did not change clinical practice in the management of patients with LC and many patients do not receive recommended screening. Further study concerning potential barriers to effective evidence-based screening and coordination of care is warranted.

12. select article Wideband Tympanmetry Results of Bone Cement Ossiculoplasty

    Research articleAbstract only

    Wideband Tympanmetry Results of Bone Cement Ossiculoplasty

    O. Yigit, S. Tokgoz-Yilmaz, E. Tahir, M.D. Bajin, ... L. Sennaroglu

    In Press, Corrected Proof, Available online 12 April 2019

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    Abstract

    Objective

    We aim to investigate hearing sensitivity and wideband tympanometry results in bone cement ossiculoplasty cases in present study.

    Study design

    A prospective study.

    Setting

    Ossiculoplasty patients were grouped according to the anatomical location of bone cement application by surgery note. Ossiculoplasty and tympanoplasty patients were retrospectively invited to the clinic and evaluated. 30 bone cement ossiculoplasty cases as well as 30 Type I tympanoplasty cases (intact ossicular chain) and 30 healthy controls were included in the study and Wideband Tympanometry was performed. Tympanometric peak pressure, equivalent middle ear volume, static admittance, tympanogram width, resonance frequency, average wideband tympanometry and absorbance measurements were analyzed.

    Results

    A statistically significant improvement was observed in the hearing levels of all ossiculoplasty and type I tympanoplasty patients (p < 0.05). Bone cement ossiculoplasty groups demonstrated the remarkable differences than the type I tympanoplasty and control group in Wideband Tympanometry test parameters. In some parameters, malleus-stapes and manubriostapedioplasty groups demonstrated similarities to Type I tympanoplasty and control groups.

    Conclusion

    Bone cement is an effective application for ossiculoplasty. Wideband tympanometry is a promising method for the evaluation of the middle ear dynamics.

13. select article Intracapsular hemorrhage rates in non-fixated nylon sheet orbital implants for orbital fracture management

    Research articleAbstract only

    Intracapsular hemorrhage rates in non-fixated nylon sheet orbital implants for orbital fracture management

    Mark A. Prendes, Brett Gudgel, Enoch B. Kassa, Amelia M. Todd, ... H.B. Harold Lee

    In Press, Corrected Proof, Available online 9 April 2019

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    Abstract

    Purpose

    To examine the incidence of intracapsular hemorrhage in orbital fracture repair with non-fixated nylon sheet implants.

    Methods

    A retrospective chart review of 227 patients presenting from January 2013 to December 2016 for orbital fracture repair with nylon sheet implants.

    Results

    Of the 331 orbital fractures repaired over 4 years, a total of 227 met inclusion criteria. The average implant thickness was 0.38 mm and no implants were fixated. Four total implants (1.8%) were removed due to complications; one each secondary to exploration for ongoing postoperative diplopia, immediate post-operative orbital hemorrhage, a cystic mass anterior to the implant, and pain. There were no cases of intracapsular hemorrhage nor infection for any of the 227 patients over 4 years.

    Conclusions

    To the authors knowledge, this represents the largest case series to date to assess the rate of intracapsular hemorrhage in non-fixated nylon sheet orbital implants. In the 227 cases reviewed over a 4-year period, there were no cases of intracapsular hemorrhage. This suggests a much lower complication rate than previously reported.

    Précis

    A case series of 227 patients who underwent orbital fracture repair with non-fixated nylon sheet implants.

    1. Research articleAbstract only

       Aberrant expressed long non-coding RNAs in laryngeal squamous-cell carcinoma

       Hu Li, Fu-Ling Wang, Wei Li, Yong-Hua Fei, ... Mei Zhang

       In Press, Accepted Manuscript, Available online 9 May 2019

       Purchase PDF

       Abstract

       Purpose

       Laryngeal squamous-cell carcinoma (LSCC) is the second most common malignant tumor of head and neck squamous cell carcinoma. The study was aimed to identify key long non-coding RNAs (lncRNAs) biomarkers for LSCC.

       Methods

       Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between LSCC and adjacent tissues were obtained based on The Cancer Genome Atlas. DElncRNA-DEmRNAs co-expression and DElncRNA-nearby-target DEmRNA interaction networks were constructed. Receiver operating characteristic and survival analysis were performed. A published dataset were as used to validate the result of bioinformatics analysis.

       Results

       We obtained 1103 DEmRNAs and 306 DElncRNAs between LSCC and adjacent tissues. A total of 338 DElncRNA-DEmRNA co-expression pairs and 229 DElncRNA-nearby-target DEmRNA pairs were obtained. Ten DElncRNAs and six DEmRNAs has great diagnostic value for LSCC. HOXB9 has potential prognostic value for LSCC. The results of GSE84957 validation were generally consistent with our results.

       Conclusion

       Our study provided clues for understanding the mechanism and developing potential biomarkers for LSCC.

    2. select article Impact of payer status on survival in parotid malignancy

       Research articleAbstract only

       Impact of payer status on survival in parotid malignancy

       Vanessa Stubbs, Karthik Rajasekaran, Jinbo Chen, Steven Cannady, ... Jason Newman

       In Press, Accepted Manuscript, Available online 9 May 2019

       Purchase PDF

       Abstract

       Objective

       In the setting of current national healthcare reform, it becomes especially relevant to understand the current state of healthcare disparities with regards to insurance status. To determine the impact of payer status on survival in parotid malignancy, we utilized the National Cancer Database (NCDB).

       Study design

       Retrospective database review.

       Setting

       National Cancer Database (2004–2012).

       Subjects and methods

       The NCDB was queried for cases of primary malignancy of the parotid gland between 2004 and 2012. The impact of payer status on overall survival was evaluated, as well as the relationship of insurance status with patient and tumor variables.

       Results

       15,815 cases met inclusion criteria. A majority had private insurance (47.8%), followed by Medicare (40.9%), Medicaid (5.0%), uninsured (3.2%) and other government sources (1.3%). Medicare patients had the lowest 5 and 10-year survival rates (50.7% (95% CI [49.3–52.1]) and 27.8% (95% CI [25.0–30.9]), respectively). On multivariable analysis, uninsured, Medicare, and Medicaid patients had worse overall survival than the privately insured (HR 1.42, 95% CI [1.17–1.74]; HR 1.29, 95% CI [1.17–1.42]; HR 1.36, 95% CI [1.13–1.62], respectively). Uninsured and Medicaid patients were more likely than the privately insured to present with advanced stage disease, nodal metastasis and longer times to treatment following diagnosis.

       Conclusion

       In parotid malignancy, uninsured, Medicaid, and Medicare patients have worse survival outcomes compared to those with private insurance. Uninsured and Medicaid patients also present with more advanced stage disease and have increased wait times before definitive treatment is initiated.

    3. select article Clinicopathological features of papillary thyroid microcarcinoma with a diameter less than or equal to 5 mm

       Research articleAbstract only

       Clinicopathological features of papillary thyroid microcarcinoma with a diameter less than or equal to 5 mm

       Lei Yan, Jayjay Blanco, Vijaya Reddy, Samer Al-Khudari, ... Paolo Gattuso

       In Press, Accepted Manuscript, Available online 8 May 2019

       Purchase PDF

       Abstract

       Purpose

       This retrospective study was conducted to assess the epidemiological, clinical and histologic characteristics of incidentally identified and presurgically diagnosed papillary thyroid microcarcinomas less than or equal to 5 mm in size (small PTMC).

       Materials and methods

       Cases from October 2003 to February 2018 were retrieved from pathology databases, and their clinicopathological features were reviewed.

       Results

       There were a total of 182 cases of small PTMCs, 141 women and 41 men. The mean age at diagnosis was 53.5. Most of the small PTMCs were not detected on clinical examination and workup and were diagnosed incidentally during pathologic examination. 21.4% of small PTMCs showed multifocality, with 21 cases of unilateral multifocal lesions and 18 cases with bilateral multifocal tumors. Small PTMCs were most often follicular variant (51.9%) followed by classic type (47.5%). The average size of follicular variants appeared to be larger than that of the classic type PTMCs (2.84 ± 1.43 mm vs 2.26 ± 1.51 mm, P = 0.01). A total of 66 cases (36.3%) had regional lymph node sampling or selective neck dissection and 15 of these cases identified lymph node metastasis (22.7%). 46.7% of patients with node positive microcarcinomas were male compared with 16% male in group with negative lymph nodes (P = 0.03).

       Conclusions

       Small PTMCs (≤5 mm) are often multifocal and bilateral and histology is commonly both the classical and follicular variant of PTC. While often diagnosed incidentally small PTMC can lead to regional lymph node involvement in a significant portion of cases and evaluation of the regional lymph nodes should be considered in the clinical management of these patients.

    4. select article An unusual case of sudden sensorineural hearing loss after cycling class

       Case reportAbstract only

       An unusual case of sudden sensorineural hearing loss after cycling class

       Vivian F. Kaul, Sarah Kidwai, Adam Lupicki, Maura Cosetti

       In Press, Corrected Proof, Available online 25 April 2019

       Purchase PDF

       Abstract

       In this case report, our patient developed sudden sensorineural hearing loss (SSNHL) after loud noise exposure during a popular cardiovascular group exercise cycling class. To increase awareness among all healthcare professionals of the effects of these modern-day group fitness classes on hearing loss, we describe this case and review the current literature on SSNHL and its management. A 35-year old man developed SSNHL in the setting of loud noise exposure during a high intensity aerobic exercise class. After a short course of oral steroids with no improvement, intratympanic steroids were administered weekly for three weeks. The patient showed minimal improvement; thus, hyperbaric oxygen therapy was conducted. Serial audiograms continued to show severe to profound mixed hearing loss in the right ear. In conclusion, individuals who participate in loud, high-intensity aerobic group-exercise classes should be careful of the potential for noise-induced hearing loss. Aerobic exercise may make these individuals more susceptible to noise-induced hearing loss. Early intervention is critical for any chance of recovery.

    5. select article Practice patterns and knowledge among California pediatricians regarding human papillomavirus and its relation to head and neck cancer

       Research articleAbstract only

       Practice patterns and knowledge among California pediatricians regarding human papillomavirus and its relation to head and neck cancer

       Michael H. Berger, Yarah M. Haidar, Benjamin Bitner, Monica Trent, Tjoson Tjoa

       In Press, Corrected Proof, Available online 25 April 2019

       Purchase PDF

       Abstract

       Objective

       To identify practice patterns regarding human papillomavirus (HPV) vaccination efforts and vaccination rates in context of head and neck cancer prevention, identify barriers to vaccination, and identify gaps in knowledge regarding the link between HPV and head and neck cancer in the pediatrician population.

       Study design/Methods

       A 27-question cross-sectional survey was distributed to members of the four California chapters of the American Academy of Pediatrics.

       Results

       Of the completed responses, 89.4% identified as "always" recommending the HPV vaccine to patients, but only 19.5% of pediatricians estimated that >75% of their eligible patients had completed the HPV vaccination series. 71.5% of respondents felt that further education about HPV's link to head and neck cancer them more comfortable discussing vaccination. Physicians who were in practice longer were less likely to respond that additional education about HPV and its link to head and neck cancer would make them more comfortable discussing vaccination with patients (p = 0.043). Physicians who were in practice longer were more likely to correctly respond that HPV type 16 is the most common strain linked to head and neck cancer (p = 0.021).

       Conclusion

       There is need to improve both the knowledge base and comfort level of pediatricians in counseling their patients during vaccine recommendations. Otolaryngologists have a critical role in providing education to physicians, trainees, and the general public in the effort to combat the epidemic of HPV-associated head and neck cancer.

    6. select article The molecular differences between human papillomavirus-positive and -negative oropharyngeal squamous cell carcinoma: A bioinformatics study

       Research articleAbstract only

       The molecular differences between human papillomavirus-positive and -negative oropharyngeal squamous cell carcinoma: A bioinformatics study

       Jiaming Wang, Xiaoxi Xi, Wei Shang, Aneesha Acharya, ... Xianda Hu

       In Press, Corrected Proof, Available online 23 April 2019

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       Abstract

       Objective

       To investigate the genetic and epigenetic differences between human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) and HPV-negative OPSCC.

       Methods

       Microarray data of HPV-positive and -negative OPSCC were retrieved from NCBI GEO datasets. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DE-miRNAs) were identified by performing differential expression analysis. A functional enrichment analysis was performed to explore the biological processes and signaling pathways that DEGs and DE-miRNAs were involved in, respectively. A protein-protein interaction (PPI) network of DEGs was constructed to identify hub genes. miRNA-target network and miRNA-miRNA functional synergistic network were each constructed in order to identify risk-marker miRNAs. An miRNA-target-pathway network was constructed in order to explore the function of identified risk-marker miRNAs.

       Results

       Microarray data from 3 datasets (GSE39366, GSE40774, and GSE55550) was included and analyzed. The PPI network identified 3 hub genes (VCAM1, UBD, and RPA2). MiR-107 and miR-142-3p were found to play the most significant role in both the DE-miRNA-target network as well as in the miRNA-miRNA functional synergistic network. MiR-107 was involved in HPV-induced tumorigenesis by targeting many genes (CAV1, CDK6, MYB, and SERPINB5) and regulating the p53 signaling pathway, the PI3K-Akt signaling pathway, and the autophagy pathway. In addition, miR-142-3p was implicated in HPV-induced tumorigenesis by targeting the PPFIA1 gene and regulating transcriptional dysregulation and other cancerous pathways.

       Conclusion

       Three genes (VCAM1, UBD, and RPA2), two miRNAs (miR-107 and miR-142-3p), and four pathways (p53, PI3K-Akt, autophagy, and transcription dysregulation in cancer) were identified to play critical roles in distinguishing HPV-positive OPSCC from HPV-negative OPSCC.

    7. select article Vitamin D deficiency and its relationship to cancer stage in patients who underwent thyroidectomy for papillary thyroid carcinoma.

       Research articleAbstract only

       Vitamin D deficiency and its relationship to cancer stage in patients who underwent thyroidectomy for papillary thyroid carcinoma.

       Anita Sulibhavi, Matthew L. Rohlfing, Scharukh M. Jalisi, David B. McAneny, ... J. Pieter Noordzij

       In Press, Corrected Proof, Available online 22 April 2019

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       Abstract

       Purpose

       As imaging technology improves and more thyroid nodules and malignancies are identified, it is important to recognize factors associated with malignancy and poor prognosis. Vitamin D has proven useful as a prognostic tool for other cancers and may be similarly useful in thyroid cancer. This study explores the relationship of Vitamin D to papillary thyroid carcinoma stage while accounting for socioeconomic covariates.

       Materials and methods

       The medical records of all patients who underwent thyroidectomy at one institution between 2000 and 2015 were reviewed. Subjects with non-papillary thyroid cancer pathology, prior malignancy, and without Vitamin D levels were excluded. The remaining 334 patient records were examined for cancer stage, Vitamin D levels, Vitamin D deficiency listed in history, and demographic and comorbid factors.

       Results

       Vitamin D laboratory values showed no significant relationship to cancer stage (p = 0.871), but patients with Vitamin D deficiency documented in the medical record were more likely to have advanced disease (28.6% versus 14.7%; p = 0.028). The patients with documented Vitamin D deficiency also had lower 25-hydroxyvitamin D nadirs (21.5 ng/mL versus 26.5 ng/mL, p = 0.008) and were more likely to be on Vitamin D supplementation (92.6% versus 41.8%, p < 0.001).

       Conclusions

       The results suggest that Vitamin D deficiency may have value as a negative prognostic indicator in papillary thyroid cancer and that pre-operative laboratory evaluation may be less useful. This is important because Vitamin D deficiency is modifiable. While different racial subgroups had different rates of Vitamin D deficiency, neither race nor socioeconomic status showed correlation with cancer stage.

    8. select article Failed larynx preservation and survival in patients with advanced larynx cancer

       Research articleAbstract only

       Failed larynx preservation and survival in patients with advanced larynx cancer

       Cheryl C. Nocon, Jessica Yesensky, Gaurav S. Ajmani, Mihir K. Bhayani

       In Press, Corrected Proof, Available online 22 April 2019

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       Abstract

       Purpose

       To evaluate the survival benefit of total laryngectomy (TL) after induction chemotherapy in locally advanced laryngeal cancer patients.

       Materials and methods

       This is a retrospective study utilizing the National Cancer Database, which captures >80% of newly diagnosed head and neck squamous cell carcinoma cases in the United States. We included patients diagnosed with advanced stage laryngeal squamous cell carcinoma between 2004 and 2013 (n = 5649) who received either TL (n = 4113; 72.8%) or induction chemotherapy followed by either radiation therapy (n = 1431) or TL (n = 105). Kaplan-Meier curves and Cox proportional hazards regression were used to evaluate overall survival. A Cox regression model was computed to examine how the prognostic impact of treatment differed by clinical stage.

       Results

       In multivariable analysis, when compared to patients receiving TL alone, those receiving induction chemotherapy followed by TL experienced no significant difference in survival (HR 0.85, 95% CI 0.63–1.13), while those receiving induction chemotherapy followed by radiation experienced poorer survival (HR 1.15, 95% CI 1.06–1.26). Induction chemotherapy followed by TL was associated with improved survival compared to induction chemotherapy and radiation (P = .042). Among patients with T4a tumors, TL (P < .001) and induction chemotherapy followed by TL (P = .002) were both associated with improved survival compared to induction chemotherapy and radiation. There were no survival differences between TL and induction chemotherapy followed by TL (HR 0.76, 95% CI 0.52–1.10).

       Conclusions

       Larynx preservation may be attempted without compromising survival in patients with locally advanced larynx cancer who fail induction chemotherapy and undergo TL.

    9. select article Improving efficiency in epistaxis transfers in a large health system: Analyzing emergency department treatment variability as pretext for a clinical care pathway

       Research articleAbstract only

       Improving efficiency in epistaxis transfers in a large health system: Analyzing emergency department treatment variability as pretext for a clinical care pathway

       Clare Richardson, Anish Abrol, Chelsea S. Hamill, Nicole Maronian, ... Brian D'Anza

       In Press, Corrected Proof, Available online 16 April 2019

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       Abstract

       Introduction

       Epistaxis is a common condition with an estimated $100 million in health care costs annually. A significant portion of this stems from Emergency Department (ED) management and hospital transfers. Currently there is no data in the literature clearly depicting the differences in treatment of epistaxis between Emergency Medicine (EM) physicians and Otolaryngologists. Clinical care pathways (CCP) are a way to standardize care and increase efficiency. Our goal was to evaluate the variability in epistaxis management between EM and Otolaryngology physicians in order to determine the potential impact of a system wide clinical care pathway.

       Materials and methods

       A retrospective case study was conducted of all patients transferred between emergency departments for epistaxis over an 18-month period. Exclusion criteria comprised patients under 18 years old, recent sinonasal surgery, bleeding disorders, and recent facial trauma.

       Results

       73 patients met inclusion criteria. EM physicians used nasal cautery in 8%, absorbable packing in 1% and non-absorbable packing in 92% (with 33% being bilateral). In comparison, Otolaryngologists used nasal cautery in 37%, absorbable packing in 34%, and non-absorbable packing in 23%. Eighty percent of patients treated by an Otolaryngology physician required less invasive intervention than previously performed by EM physicians prior to transfer.

       Conclusions

       Epistaxis management varied significantly between Emergency Medicine and Otolaryngology physicians. Numerous patients were treated immediately with non-absorbable packing. On post-transfer Otolaryngology evaluation, many of these patients required less invasive interventions. This study highlights the variability of epistaxis treatment within our hospital system and warrants the need for a standardized care pathway.

    10. select article Predicting transient hypocalcemia in patients with unplanned parathyroidectomy after thyroidectomy

        Research articleAbstract only

        Predicting transient hypocalcemia in patients with unplanned parathyroidectomy after thyroidectomy

        Ramez Philips, Phillip Nulty, Nolan Seim, Yubo Tan, ... Garth Essig

        In Press, Corrected Proof, Available online 16 April 2019

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        Abstract

        Objective

        To assess the utility of rapid parathyroid hormone (PTH) values in predicting transient post-operative hypocalcemia in patients with unplanned parathyroidectomy during total or completion thyroidectomy.

        Methods

        All patients who underwent total or completion thyroidectomy between January 2010 and January 2015 were reviewed. Incidences of post-operative hypocalcemia were compared in patients with and without unplanned parathyroidectomy. Unplanned parathyroidectomy was defined as intra-operative incidental or intentional parathyroidectomy. Logistic regression assessed for predictors of hypocalcemia and optimum amount of calcium supplementation.

        Results

        Thirty-eight (13.6%) patients had evidence of incidental parathyroidectomy and 39/280 (13.9%) patients had parathyroid autotransplantation intra-operatively. Central neck dissection and malignancy were identified as risk factors for unplanned parathyroidectomy (p = 0.001, p = 0.060). Patients with unplanned parathyroidectomy were more likely to have hypocalcemia (p = 0.002) and hypoparathyroidism (p < 0.0005). PTH value was the only significant predictor of hypocalcemia in these patients. In patients with a post-operative PTH of ≤15, initial calcium supplementation ≥ 1000 mg decreased the risk of hypocalcemia (p < 0.05).

        Conclusion

        Post-operative PTH value predicts hypocalcemia in patients undergoing total and completion thyroidectomy with unplanned parathyroidectomy. In patients with a post-operative PTH < 15, initial calcium supplementation with ≥1000 mg of elemental calcium is recommended.

    11. select article Clinical practice patterns in laryngeal cancer and introduction of CT lung screening

        Research articleAbstract only

        Clinical practice patterns in laryngeal cancer and introduction of CT lung screening

        Krzysztof Piersiala, Lee M. Akst, Alexander T. Hillel, Simon R. Best

        In Press, Corrected Proof, Available online 12 April 2019

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        Abstract

        Objectives

        After the publication of large clinical trials, in January 2014 The U.S. Preventive Services Task Force (USPSTF) recommended annual lung cancer screening with low-dose CT in a well-defined group of high-risk smokers. A significant proportion of patients with laryngeal cancer (LC) meet the introduced criteria, and we hypothesized that clinical practice would change as a result of these evidence-based guidelines.

        Methods

        Retrospective chart review of patients diagnosed with LC and treated at Johns Hopkins Hospital who met USPSTF criteria for annual chest screening and were followed for at least 3 consecutive years in the years surrounding the introduction of screening guidelines (January 2010 to December 2017) was performed to identify those who had recommended screening CT chest.

        Results

        A total of 151 patients met the inclusion criteria of the study and were followed for a total of 746 patient-years. 184/332 (55%) patient-years in the pre-guidelines period and 246/414 (59%) in the post-guidelines period included at least one recommended chest imaging (CT or PET-CT; p = 0.27). 248/332 (75%) patient-years in the pre-guidelines period and 314/414 (76%) in the post-guidelines period included any radiological chest imaging (X-ray, CT or PET-CT; p = 0.72). Screening scans were ordered by OHNS (45%), Medical Oncology (31%), Radiation Oncology (8%), and primary care (14%) with 70% of patients missing at least one year of indicated screening.

        Conclusions

        The implementation of new lung cancer screening guidelines did not change clinical practice in the management of patients with LC and many patients do not receive recommended screening. Further study concerning potential barriers to effective evidence-based screening and coordination of care is warranted.

    12. select article Wideband Tympanmetry Results of Bone Cement Ossiculoplasty

        Research articleAbstract only

        Wideband Tympanmetry Results of Bone Cement Ossiculoplasty

        O. Yigit, S. Tokgoz-Yilmaz, E. Tahir, M.D. Bajin, ... L. Sennaroglu

        In Press, Corrected Proof, Available online 12 April 2019

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        Abstract

        Objective

        We aim to investigate hearing sensitivity and wideband tympanometry results in bone cement ossiculoplasty cases in present study.

        Study design

        A prospective study.

        Setting

        Ossiculoplasty patients were grouped according to the anatomical location of bone cement application by surgery note. Ossiculoplasty and tympanoplasty patients were retrospectively invited to the clinic and evaluated. 30 bone cement ossiculoplasty cases as well as 30 Type I tympanoplasty cases (intact ossicular chain) and 30 healthy controls were included in the study and Wideband Tympanometry was performed. Tympanometric peak pressure, equivalent middle ear volume, static admittance, tympanogram width, resonance frequency, average wideband tympanometry and absorbance measurements were analyzed.

        Results

        A statistically significant improvement was observed in the hearing levels of all ossiculoplasty and type I tympanoplasty patients (p < 0.05). Bone cement ossiculoplasty groups demonstrated the remarkable differences than the type I tympanoplasty and control group in Wideband Tympanometry test parameters. In some parameters, malleus-stapes and manubriostapedioplasty groups demonstrated similarities to Type I tympanoplasty and control groups.

        Conclusion

        Bone cement is an effective application for ossiculoplasty. Wideband tympanometry is a promising method for the evaluation of the middle ear dynamics.

    13. select article Intracapsular hemorrhage rates in non-fixated nylon sheet orbital implants for orbital fracture management

        Research articleAbstract only

        Intracapsular hemorrhage rates in non-fixated nylon sheet orbital implants for orbital fracture management

        Mark A. Prendes, Brett Gudgel, Enoch B. Kassa, Amelia M. Todd, ... H.B. Harold Lee

        In Press, Corrected Proof, Available online 9 April 2019

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        Abstract

        Purpose

        To examine the incidence of intracapsular hemorrhage in orbital fracture repair with non-fixated nylon sheet implants.

        Methods

        A retrospective chart review of 227 patients presenting from January 2013 to December 2016 for orbital fracture repair with nylon sheet implants.

        Results

        Of the 331 orbital fractures repaired over 4 years, a total of 227 met inclusion criteria. The average implant thickness was 0.38 mm and no implants were fixated. Four total implants (1.8%) were removed due to complications; one each secondary to exploration for ongoing postoperative diplopia, immediate post-operative orbital hemorrhage, a cystic mass anterior to the implant, and pain. There were no cases of intracapsular hemorrhage nor infection for any of the 227 patients over 4 years.

        Conclusions

        To the authors knowledge, this represents the largest case series to date to assess the rate of intracapsular hemorrhage in non-fixated nylon sheet orbital implants. In the 227 cases reviewed over a 4-year period, there were no cases of intracapsular hemorrhage. This suggests a much lower complication rate than previously reported.

        Précis

        A case series of 227 patients who underwent orbital fracture repair with non-fixated nylon sheet implants.

Autoimmunity

Chaperones of the class I peptide-loading complex facilitate the constitutive presentation of endogenous antigens on HLA-DP84GGPM87 Publication date: Available online 8 May 2019 Source: Journal of Autoimmunity Author(s): Mark Anczurowski, Kenji Sugata, Yukiko Matsunaga, Yuki Yamashita, Chung-Hsi Wang, Tingxi Guo, Kenji Murata, Hiroshi Saijo, Yuki Kagoya, Kayoko Saso, Marcus O. Butler, Naoto Hirano Abstract Recent work has delineated key differences in the antigen processing and presentation mechanisms underlying HLA-DP alleles encoding glycine at position 84 of the DPβ chain (DP84GGPM87). These DPs are unable to associate with the class II-associated Ii peptide (CLIP) region of the invariant chain (Ii) chaperone early in the endocytic pathway, leading to continuous presentation of endogenous antigens. However, little is known about the chaperone support involved in the loading of these endogenous antigens onto DP molecules. Here, we demonstrate the proteasome and TAP dependency of this pathway and reveal the ability of HLA class I to compete with DP84GGPM87 for the presentation of endogenous antigens, suggesting that shared subcellular machinery may exist between the two classes of HLA. We identify physical interactions of prototypical class I-associated chaperones with numerous DP alleles, including TAP2, tapasin, ERp57, calnexin, and calreticulin, using a conventional immunoprecipitation and immunoblot approach and confirm the existence of these interactions in vivothrough the use of the BioID2 proximal biotinylation system in human cells. Based on immunological assays, we then demonstrate the ability of each of these chaperones to facilitate the presentation of endogenously derived, but not exogenously derived, antigens on DP molecules. Considering previous genetic and clinical studies linking DP84GGPM87 to disease frequency and severity in autoimmune disease, viral infections, and cancer, we suggest that the above chaperones may form the molecular basis of these observable clinical differences through facilitating the presentation of endogenously derived antigens to CD4+ T cells.

The role of protein SUMOylation in rheumatoid arthritis Publication date: Available online 8 May 2019 Source: Journal of Autoimmunity Author(s): Sajad Dehnavi, Mahvash Sadeghi, Thomas P. Johnston, George Barreto, Mojtaba Shohan, Amirhossein Sahebkar Abstract Small ubiquitin-like modifier (SUMO) proteins, as a subgroup of post-translational modifiers, act to change the function of proteins. Through their interactions with different targets, immune pathways, and the responses they elicit, can be affected by these SUMO conjugations. Thus, both a change to protein function and involvement in immune pathways has the potential to promote an efficient immune response to either a pathogenic challenge, or the development of an imbalance that could lead to an autoimmune-based disease. Also, a variety of changes such as mutations and polymorphisms can interfere with common functions of these modifications and move an effective immune response in the direction of an autoimmune disease. The present review discusses the general characteristics of SUMO proteins and focuses on their involvement in rheumatoid arthritis as an autoimmune disease.

Chronic inflammatory demyelinating polyneuropathy as an autoimmune disease Publication date: Available online 6 May 2019 Source: Journal of Autoimmunity Author(s): Yhojan Rodríguez, Nikhil Vatti, Carolina Ramírez-Santana, Christopher Chang, Oscar Mancera-Páez, M. Eric Gershwin, Juan-Manuel Anaya Abstract Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease characterized by neurological symptoms and signs of progressive weakness, paresthesias, and sensory dysfunction. Other symptoms include reduced or absent tendon reflexes, cranial nerve involvement, autonomic symptoms, ataxia, and neuropathic pain. Unlike other autoimmune diseases, CIDP generally affects older individuals and has a male predominance. The onset is generally insidious and can take up to 8 weeks with a relapsing-recovery pattern. Like all autoimmune diseases, the etiology is multifactorial, with both genetic and environmental factors contributing to it. Case reports of CIDP have found associations with multiple pathogenic organisms including Hepatitis B and C viruses, Bartonella henselae, Mycoplasma pneumoniae, Human immunodeficiency virus, Cytomegalovirus and Epstein-Barr virus. Possible antigenic self-targets include myelin protein 0, myelin protein 2, peripheral myelin protein 22, Connexin 32, and myelin basic protein. Antibodies targeting the Ranvier node proteins such as contactin-1, contactin-associated protein 1, and neurofascin 155 have been described. CIDP is treated with rehabilitation and pharmacological modalities. Pharmacological treatments target autoimmune dysfunction and include corticosteroids, intravenous immunoglobulin, subcutaneous immunoglobulin, plasma exchange, immunosuppressive and immunomodulatory agents such as methotrexate, cyclophosphamide, rituximab, and mycophenolate mofetil. Although there are few observational studies and randomized clinical trials with limited evidence supporting the use of immunosuppressive drugs, they are widely used in clinical practice. A comprehensive review of CIDP is presented herein in light of the autoimmune tautology.

Myelin oligodendrocyte glycoprotein revisited—sensitive detection of MOG-specific T-cells in multiple sclerosis Publication date: Available online 1 May 2019 Source: Journal of Autoimmunity Author(s): Mattias Bronge, Sabrina Ruhrmann, Claudia Carvalho-Queiroz, Ola B. Nilsson, Andreas Kaiser, Erik Holmgren, Caterina Macrini, Stephan Winklmeier, Edgar Meinl, Lou Brundin, Mohsen Khademi, Tomas Olsson, Guro Gafvelin, Hans Grönlund Abstract Autoreactive CD4+ T-cells are believed to be a main driver of multiple sclerosis (MS). Myelin oligodendrocyte glycoprotein (MOG) is considered an autoantigen, yet doubted in recent years. The reason is in part due to low frequency and titers of MOG autoantibodies and the challenge to detect MOG-specific T-cells. In this study we aimed to analyze T-cell reactivity and frequency utilizing a novel method for detection of antigen-specific T-cells with bead-bound MOG as stimulant. Peripheral blood mononuclear cells (PBMCs) from natalizumab treated persons with MS (n = 52) and healthy controls (HCs) (n = 24) were analyzed by IFNγ/IL-22/IL-17A FluoroSpot. A higher number of IFNγ (P = 0.001), IL-22 (P = 0.003), IL-17A (P < 0.0001) as well as double and triple cytokine producing MOG-specific T-cells were detected in persons with MS compared to HCs. Of the patients, 46.2–59.6% displayed MOG-reactivity. Depletion of CD4+ T-cells or monocytes or blocking HLA-DR completely eliminated the MOG specific response. Anti-MOG antibodies did not correlate with T-cell MOG-responses. In conclusion, we present a sensitive method to detect circulating autoreactive CD4+ T-cells producing IFNγ, IL-22 or IL-17A using MOG as a model antigen. Further, we demonstrate that MOG-specific T-cells are present in approximately half of persons with MS. Graphical abstract

Primary immunodeficiency and autoimmunity: A comprehensive review Publication date: May 2019 Source: Journal of Autoimmunity, Volume 99 Author(s): Laura Amaya-Uribe, Manuel Rojas, Gholamreza Azizi, Juan-Manuel Anaya, M. Eric Gershwin Abstract The primary immunodeficiency diseases (PIDs) include many genetic disorders that affect different components of the innate and adaptive responses. The number of distinct genetic PIDs has increased exponentially with improved methods of detection and advanced laboratory methodology. Patients with PIDs have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies and autoimmune diseases (ADs), the latter being the first manifestation of PIDs in several cases. There are two types of PIDS. Monogenic immunodeficiencies due to mutations in genes involved in immunological tolerance that increase the predisposition to develop autoimmunity including polyautoimmunity, and polygenic immunodeficiencies characterized by a heterogeneous clinical presentation that can be explained by a complex pathophysiology and which may have a multifactorial etiology. The high prevalence of ADs in PIDs demonstrates the intricate relationships between the mechanisms of these two conditions. Defects in central and peripheral tolerance, including mutations in AIRE and T regulatory cells respectively, are thought to be crucial in the development of ADs in these patients. In fact, pathology that leads to PID often also impacts the Treg/Th17 balance that may ease the appearance of a proinflammatory environment, increasing the odds for the development of autoimmunity. Furthermore, the influence of chronic and recurrent infections through molecular mimicry, bystander activation and super antigens activation are supposed to be pivotal for the development of autoimmunity. These multiple mechanisms are associated with diverse clinical subphenotypes that hinders an accurate diagnosis in clinical settings, and in some cases, may delay the selection of suitable pharmacological therapies. Herein, a comprehensively appraisal of the common mechanisms among these conditions, together with clinical pearls for treatment and diagnosis is presented.

Ischemic stroke in giant-cell arteritis: French retrospective study Publication date: May 2019 Source: Journal of Autoimmunity, Volume 99 Author(s): Aaron Pariente, Alexis Guédon, Sonia Alamowitch, Sara Thietart, Fabrice Carrat, Stephen Delorme, Jean Capron, Carlotta Cacciatore, Michael Soussan, Azeddine Dellal, Olivier Fain, Arsene Mekinian Abstract Acute cerebrovascular ischemic events are a rare and severe complication of giant cell arteritis (GCA). We aimed to determine the prevalence of GCA-related stroke, the overall survival and the relapse-free survival in patients with GCA. A multicentric retrospective analysis was performed on 129 patients with GCA diagnosed between September 2010 and October 2018 in two University Hospitals. Among 129 GCA patients, 18 (16%) presented an acute ischemic cerebrovascular event. Patients with stroke were older (83 [67–96] years versus 76 [58–96]; p = 0.014) and more frequently males (61% versus 30%; p = 0.014) than those without stroke. The frequency of anterior ischemic optic neuropathy was higher in patients with stroke (n = 6, 33%) than patients without stroke (n = 12, 11%)(p = 0.02). Overall survival was significantly decreased in GCA patients with stroke (4.4 months), comparatively to patients without stroke (221.7 months; log rank test = 0.006). The 3-years relapse-free survival was decreased in patients with stroke (8.42 versus78.0 months; log rank = 0.0001), as well as the time with sustained remission (78 versus 139 months; log rank test = 0.0004). This study shows the prevalence and risk factors of ischemic stroke in GCA.

Autophagy promotes aortic adventitial fibrosis via the IL-6/Jak1 signaling pathway in Takayasu's arteritis Publication date: May 2019 Source: Journal of Autoimmunity, Volume 99 Author(s): Rongyi Chen, Ying Sun, Xiaomeng Cui, Zongfei Ji, Xiufang Kong, Sifan Wu, Qingrong Huang, Xiaoming Dai, Si Zhang, Lili Ma, Lindi Jiang Abstract Background Autophagy is a ubiquitous and evolutionarily conserved self-rescue process. Studies have shown that autophagy is involved in the pathogenesis of multiple diseases; however, whether autophagy is associated with the pathogenesis of Takayasu's arteritis (TA), a large vessel idiopathic inflammatory disease characterized by vascular fibrosis, remains unclear. Moreover, although IL-6 is believed to be a direct target for TA treatment, anti-IL-6 treatment could not block TA-associated fibrosis in some cases, which impairs the aortic function of patients and can result in death. Thus, identify the mechanisms associated with TA is extremely important. Based on the relationship between autophagy and IL-6, we investigated the role of autophagy in the vascular fibrosis of TA induced by IL-6. Methods Autophagy proteins (LC3 and Atg3), IL-6, and markers of fibrosis (collagen 1 and α-SMA) were detected in tissues with TA lesions via immunochemistry, immunofluorescence, and Western blot, respectively. Different stages of autophagy were analyzed by the specific inhibitors, 3-methyladenosine (early stage), hydroxychloroquine sulfate (late stage), and bafilomycin A1 (late stage). Autophagosomes were detected using electron microscopy and a viral-vector transfection assay. The fibrosis profiles induced by IL-6-dependent autophagy was assessed with an ELISA. Results The expression of autophagy, IL-6, and fibrosis markers were elevated and correlated with each other in the adventitia tissues of TA patients. Furthermore, exogenous IL-6/IL-6Rα could significantly increase autophagy and fibrosis in vitro. An autophagy inhibitor was found to significantly block both autophagy and fibrosis induced by IL-6. Finally, IL-6 was found to significantly promote autophagy-induced fibrosis through the activation of the Jak1 pathway. Conclusions IL-6-induced autophagy plays an important role in vascular fibrosis of TA. Targeting autophagy pathways might represent a novel therapeutic option for the treatment of TA.

Histologically proven AMA positive primary biliary cholangitis but normal serum alkaline phosphatase: Is alkaline phosphatase truly a surrogate marker? Publication date: May 2019 Source: Journal of Autoimmunity, Volume 99 Author(s): Chunyan Sun, Xiao Xiao, Li Yan, Li Sheng, Qixia Wang, Pan Jiang, Min Lian, Yanmei Li, Yiran Wei, Jun Zhang, Yong Chen, Bo Li, You Li, Binyuan Huang, Yikang Li, Yanshen Peng, Xiaoyu Chen, Jingyuan Fang, Dekai Qiu, Jing Hua Abstract Background and aims The most highly directed and specific autoantibody in human immunopathology is the serologic hallmark of primary biliary cholangitis (PBC), antimitochondrial antibodies (AMAs). However the clinical significance of finding a positive AMA, with normal alkaline phosphatase (ALP) remains enigmatic. Methods We took advantage of 169 consecutive outpatients who were identified as having a positive AMA, but normal ALP levels between January 2012 and January 2018. A liver biopsy was performed on 67/169 of these AMA positive normal ALP patients. Results In all 169 patients we reconfirmed the AMA and also performed anti-gp210 and anti-sp100, liver stiffness (LSM) assessed by vibration-controlled transient elastography (VCTE), an abdominal computed tomography (CT) scan, and either a magnetic resonance imaging (MRI) or ultrasound. The liver biopsies were reviewed by two unbiased observers. 87.6% of the 169 patients were females with a mean age of 46; the median AMA titer 1:320; an elevated serum IgM was found in 53.3%. Importantly, in patients with a liver biopsy, 55（82.1%）out of 67 had varying degrees of cholangitis activity, diagnostic of PBC. Conclusion In patients who were AMA-positive but had normal ALP levels, more than 80% were associated with histological classic PBC. These data emphasize the importance of a positive AMA, even with a normal ALP and also question the role of ALP as a sole surrogate marker of cholangitis.

PAM3 supports the generation of M2-like macrophages from lupus patient monocytes and improves disease outcome in murine lupus Publication date: May 2019 Source: Journal of Autoimmunity, Volume 99 Author(s): Begum Horuluoglu, Defne Bayik, Neslihan Kayraklioglu, Emilie Goguet, Mariana J. Kaplan, Dennis M. Klinman Abstract Systematic Lupus Erythematosus (SLE) is an autoimmune syndrome of unclear etiology. While T and B cell abnormalities contribute to disease pathogenesis, recent work suggests that inflammatory M1-like macrophages also play a role. Previous work showed that the TLR2/1 agonist PAM3CSK4 (PAM3) could stimulate normal human monocytes to preferentially differentiate into immunosuppressive M2-like rather than inflammatory M1-like macrophages. This raised the possibility of PAM3 being used to normalize the M1:M2 ratio in SLE. Consistent with that possibility, monocytes from lupus patients differentiated into M2-like macrophages when treated with PAM3 in vitro. Furthermore, lupus-prone NZB x NZW F1 mice responded similarly to weekly PAM3 treatment. Normalization of the M2 macrophage frequency was associated with delayed disease progression, decreased autoantibody and inflammatory cytokine synthesis, reduced proteinuria and prolonged survival in NZB x NZW F1 mice. The ability of PAM3 to bias monocyte differentiation in favor of immunosuppressive macrophages may represent a novel approach to the therapy of SLE.

Elevated autoimmunity in residents living near abandoned uranium mine sites on the Navajo Nation Publication date: May 2019 Source: Journal of Autoimmunity, Volume 99 Author(s): Esther Erdei, Chris Shuey, Bernadette Pacheco, Miranda Cajero, Johnnye Lewis, Robert L. Rubin Abstract Specific autoantibodies were assessed among residents of the Navajo Nation in New Mexico chronically exposed to metal mixtures from uranium mine wastes and in drinking water supplies. Age and the extent of exposure to legacy waste from 100 abandoned uranium mine and mill sites were associated with antibodies to denatured DNA, previously known to be an early indicator of medication-induced autoimmunity. Surprisingly, autoantibodies to native DNA and/or chromatin were also linked to environmental exposure, specifically uranium consumption through drinking water for both men and women, while urinary arsenic was negatively associated with these autoantibodies in women. These findings suggest that contaminants derived from uranium mine waste enhanced development of autoantibodies in some individuals, while arsenic may be globally immunosuppressive with gender-specific effects. Specific autoantibodies may be a sensitive indicator of immune perturbation by environmental toxicants, an adverse effect not considered in current drinking water standards or regulatory risk assessment evaluations.

EJNMMI Radiopharmacy and Chemistry

Endorsement of International Consensus Radiochemistry Nomenclature Guidelines

Open letter to journal editors on: International Consensus Radiochemistry Nomenclature Guidelines

Molecular imaging of multiple sclerosis: from the clinical demand to novel radiotracers Brain PET imaging with different tracers is mainly clinically used in the field of neurodegenerative diseases and brain tumors. In recent years, the potential usefulness of PET has also gained attention in the...

Automated synthesis of [11C]L-glutamine on Synthra HCN plus synthesis module L-Glutamine (L-Gln) is the most abundant amino acid present in the human body and is involved in numerous metabolic pathways. Glutaminolysis is the metabolic process deployed by many aggressive cancers such as...

Radiosynthesis and in vivo evaluation of 11C-labeled BMS-193885 and its desmethyl analog as PET tracers for neuropeptide Y1 receptors Neuropeptide Y (NPY) has been implicated in a wide variety of physiological processes, including feeding, learning, memory, emotion, cardiovascular homeostasis, hormone secretion, and circadian rhythms. NPY Yl...

Pediatric Surgery Case Reports

Melanotic neuroectodermal tumor of infancy Publication date: July 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 46 Author(s): Hao Tran Kiem, Kim Hoa Nguyen Thi, Phu Tran Xuan, Loi Nguyen Hong, Son Nguyen Huu, Duy Phan Canh, Carlos Rodriguez Galindo, McKay McKinnon Abstract Introduction Melanotic neuroectodermal tumor of infancy (MNTI) is a rare, rapidly growing pigmented neoplasm of neural crest origin generally arising in infants during the first year of life. Case We report a 15-month old male who presented with a 2-month history of a rapidly growing mass in the anterior. A biopsy showed melanotic neuroectodermal tumor, and complete resection with negative margins was subsequently achieved. The patient is in remission at 11 months from surgery. Conclusion Due to its rapid growth potential and locally destructive behaviour, early diagnosis is extremely important to limit local expansion. The treatment of choice for melanotic neuroectodermal tumor of infancy (MNTI) is surgical excision.

Robot-assisted Heller myotomy for achalasia Publication date: June 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 45 Author(s): Giulia Fusi, Francesco Molinaro, Francesco Ferrara, Edoardo Bindi, Chiara Pellegrino, Chiara Calani, Mario Messina, Rossella Angotti Abstract Achalasia is a rare neuromuscular esophageal disorder in children. There are many surgical options to treatment including botulinum toxin (Botox) injections, oral pharmacologic therapies with nitrates and calcium channel blockers, pneumatic dilation (PD), and surgical myotomy (open surgery, endoscopy, laparoscopy and recently robotic approach). In pediatric age, usually, Heller's myotomy is the main choice. Laparoscopic approach is known and standardized. Few robotic have been published. We decided to report our first case to share our experience with scientific community.

Unexpected finding of an intra-peritoneal toothpick during laparoscopic appendectomy Publication date: June 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 45 Author(s): Mohamad El Mahmoud, Mohammad Al Onazi, Saad H. Aldosari, Sarah A. Hadi, Reema Alsadhan

Bilateral chest wall mesenchymal hamartomas treated with sclerotherapy and cryoablation Publication date: June 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 45 Author(s): Kristen A. Calabro, John McGrath, Elizabeth Bowdish Abstract Mesenchymal hamartoma of the chest wall is a rare disorder, traditionally treated with mutilating radical excision. We report a case of an infant with bilateral mesenchymal hamartomas (MH) complicated with aneurysmal bone cyst (ABC) features. We subsequently describe a novel technique combining sclerotherapy and cryoablation to achieve non-operative tumor burden reduction in an effort to minimize disfigurement making the MH amenable to less morbid resection. A 3.5-month-old male presented with bilateral, complex, mixed cystic and solid, chest wall masses consistent with a chest wall mesenchymal hamartoma. Under ultrasound and fluoroscopic guidance, the aneurysmal bone cyst components were aspirated and contrast studies performed to exclude venous drainage. Doxycycline sclerotherapy was performed using dwelling volumes approximately 50–60% of the estimated cyst cavity size. Repeat sclerotherapy was performed on days 85, 147, 229 and 267, with interval imaging guiding timing and location of therapy. The ABC components responded well to sclerotherapy with significant size decrease of the cystic components. Overall lesion size decreased significantly, with new bone formation noted in response to treatment. The first treatment of computer tomographic (CT)-guided cryoablation was then performed on day 329 to attempt further reduce the size of the solid components. Multiple cryoablation probes were advanced into the mass under CT fluoroscopy. Deep components were treated initially with a series of freeze/thaw cycles. Cryoprobes were then retracted to treat the more superficial portions of the lesion. CT guided cryoablation was repeated on day 601.

Urethral mucosa prolapse in a post-partum patient Publication date: June 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 45 Author(s): Godwin Turyasingura Abstract A 23 year old Ugandan, Black, Mukiga, mother of two presented to us one year after delivery with severe lower abdominal pain, failure to pass urine, slight vaginal bleeding and a mass protruding from her vagina. Vaginal examination revealed she had a prolapsed urethral mucosa which was undergoing ischemic necrosis. Her condition was successfully treated by surgical excision of the prolapsed mucosa. The patient had no urinary, genital or other symptoms at 6 weeks, 6 months and at one and half years follow up.

Pediatric pulmonary mucormycosis in a diabetic patient treated with extended pleurectomy and Clagett procedure Publication date: June 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 45 Author(s): Rebecca C. Gologorsky, Sora Ely, Kara A. Rothenberg, Carol Glaser, Jeffrey B. Velotta Abstract Mucor is a ubiquitous fungus that is non-pathogenic in healthy people. In immunocompromised hosts, nonfunctional or absent neutrophils and macrophages result in fungal invasion and infection [1]. Invasive mucor (mucormycosis) most commonly involves the sinuses, brain, or lungs. Pulmonary mucormycosis typically presents in patients with a history of organ transplantation or hematologic malignancy [2], and is rare in patients with diabetes alone. The epidemiology and management of pediatric pulmonary mucormycosis is poorly described. We report an unusual occurrence of this disease, complicated by segmental pulmonary artery thrombus in a 15-year-old with poorly controlled diabetes. His severe, medication-resistant infection was ultimately treated successfully with antifungal medication combined with aggressive surgical debridement. The pulmonary artery segmental thrombus resolved after treatment of the underlying infection without anticoagulation.

Segmental dilatation of colon detected on prenatal ultrasound Publication date: June 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 45 Author(s): Naoko Uga, Tatsuya Suzuki, Kouhei Sakurai, Tetsuya Tsukamoto, Tomonori Tsuchiya, Yasuhiro Kondo, Atsuki Naoe, Shunsuke Watanabe, Toshihiro Yasui, Fujio Hara Abstract Segmental dilatation of the colon is a rare condition in which there is an abrupt segment of dilated colon between regions of normal colon, without obstruction. The condition causes bilious vomiting and abdominal distention in the neonate, and causes constipation or anemia in infants and adults. We herein report a case of segmental dilatation of the descending colon detected on prenatal sonography. The patient was born at 39 weeks' gestation, weighing 3720 g. At 10 months, he developed constipation and enterocolitis. At 1 year of age, the patient underwent laparoscopic-assisted resection of dilated colon with end-to-end anastomosis. Resection of the dilated segment alone was not sufficient, according to frozen biopsy. Therefore, we resected an additional 3 cm both proximally and distally, where teniae coli were grossly evident. Histological examination of the dilated segment showed muscular layer hypertrophy with hyperplasia and widening of Auerbach's plexus. The patient's 7-month follow-up was unremarkable. With improved quality of prenatal sonography, more patients will be diagnosed with segmental dilatation of the intestine. This is the first report in the English literature of segmental dilatation of the colon detected on prenatal ultrasound.

Intrabronchial valves for persistent pulmonary air leaks in children Publication date: June 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 45 Author(s): Faisal G. Qureshi, Ahmed Abdelrahman, Mirza Zain Baig, Stephen Megison, Muhanned Abu-Hijleh Abstract Background Surgery to address parenchymal lung disease in children is rare. One of the complications of the surgery is a persistent air leak (PAL). Intrabronchial valves (IBV), which received FDA approval for treating PAL in recent years, limit or exclude the inflow of air towards the pleura and allow air and secretions to flow towards central airways. The valves have been effective in adults with PAL but little has been published on their use in children. Methods Retrospective chart review was performed after IRB approval on patients treated with IBV after surgical excision of lung parenchyma. A literature review was then performed. Results 2 pediatric patients are presented. Patient 1, a 10 year old girl underwent excision of a lung mass that developed persistent air leak. Traditional conservative methods did not seal the air leak for 23 days but an IBV sealed the leak in 24 h. Patient 2, a 6 year old boy underwent a pneumonectomy with post-operative bronhical leak. The bronchus was repaired but a leak persisted for 36 days. An IBV sealed the leak immediately. Conclusion Intrabronchial valves can be used for the management of persistent pulmonary air leaks. We propose a tentative algorithm for using the devices in children with PAL.

Urachal cyst and enteric duplication in a pediatric patient Publication date: June 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 45 Author(s): Allen K. Chen, Michael J. Allshouse Abstract Here we present an unusual case of a 3-year-old male with multiple congenital developmental abnormalities discovered during laparotomy: an urachal cyst and enteric duplication. This combination of anomalies has not been described before.

Sleeve lobectomy for an arteriovenous malformation in the bronchus intermedius in a child Publication date: June 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 45 Author(s): Aditya Sengupta, Othman Aljohani, Howaida El-Said, Aparna Rao, Matthew Brigger, Raghav Murthy Abstract Arteriovenous malformations within the tracheobronchial tree in pediatric patients uncommonly present as hemoptysis, and can usually be treated with percutaneous transcatheter embolization. When this fails, parenchymal-sparing operations are needed. While these have been popularized for the management of bronchial neoplasms in children and adults, such bronchoplastic techniques are not commonly performed in children with tracheobronchial vascular malformations and acute hemoptysis. Here, we present a patient with recurrent hemoptysis who was found to have an arteriovenous malformation in the bronchus intermedius, and had failed numerous attempts at coil embolization. Via a right thoracotomy approach, we successfully performed a right middle lobectomy and sleeve resection of the bronchus intermedius. The post-operative recovery was uneventful, and there were no further episodes of hemoptysis. Thus, by applying the principles of bronchoplastic resection, such parenchymal-preserving surgery can be successfully used to manage symptomatic bronchial arteriovenous malformations with hemoptysis.

Development Genes and Evolution

Analysis of the wnt1 regulatory chromosomal landscape Abstract One of the earliest patterning events in the vertebrate neural plate is the specification of mes/r1, the territory comprising the prospective mesencephalon and the first hindbrain rhombomere. Within mes/r1, an interface of gene expression defines the midbrain–hindbrain boundary (MHB), a lineage restriction that separates the mesencephalon and rhombencephalon. wnt1 is critical to mes/r1 development and functions within the MHB as a component of the MHB gene regulatory network (GRN). Despite its importance to these critical and early steps of vertebrate neurogenesis, little is known about the factors responsible for wnt1 transcriptional regulation. In the zebrafish, wnt1 and its neighboring paralog, wnt10b, are expressed in largely overlapping patterns, suggesting co-regulation. To understand wnt1 and wnt10b transcriptional control, we used a comparative genomics approach to identify relevant enhancers. We show that the wnt1-wnt10b locus contains multiple cis-regulatory elements that likely interact to generate the wnt1 and wnt10b expression patterns. Two of 11 conserved enhancers tested show activity restricted to the midbrain and MHB, an activity that is conserved in the distantly related spotted gar orthologous elements. Three non-conserved elements also play a likely role in wnt1regulation. The identified enhancers display dynamic modes of chromatin accessibility, suggesting controlled deployment during embryogenesis. Our results suggest that the control of wnt1 and wnt10b expression is under complex regulation involving the interaction of multiple enhancers.

GSK3β controls the timing and pattern of the fifth spiral cleavage at the 2–4 cell stage in Lymnaea stagnalis Abstract Establishment of the body plan of multicellular organisms by the primary body axis determination and cell-fate specification is a key issue in biology. We have examined the mRNA localization of three Wnt pathway components gsk3β, β-catenin, and disheveled and investigated the effects of four selective inhibitors of these proteins on the early developmental stages of the spiral cleavage embryo of the fresh water snail Lymnaea (L.) stagnalis. mRNAs for gsk3β and β-catenin were distributed uniformly throughout the embryo during development whereas disheveled mRNA showed specific localization with intra- and inter-blastomere differences in concentration along the A-V axis during spiral cleavages. Remarkably, through inhibitor studies, we identified a short sensitive period from the 2- to 4-cell stage in which GSK3β inhibition by the highly specific 1-azakenpaullone (AZ) and by LiCl induced a subsequent dramatic developmental delay and alteration of the cleavage patterns of blastomeres at the fifth cleavage (16- to 24-cell stage) resulting in exogastrulation and other abnormalities in later stages. Inhibition of β-Catenin or Disheveled had no effect. Our inhibitor experiments establish a novel role for GSK3β in the developmental timing and orientated cell division of the snail embryo. Further work will be needed to identify the downstream targets of the kinase.

From genes to environment in shaping of an embryo: understanding embryonic-extraembryonic interactions at the BSDB autumn meeting in Oxford Abstract The British Society for Developmental Biology Autumn Meeting, held in Oxford in September 2018, was the third in a series of international workshops which have been focussed on development at the extraembryonic-embryonic interface. This workshop, entitled "Embryonic-Extraembryonic Interactions: from Genetics to Environment" built on the two previous workshops held in 2011 (Leuven, Belgium) and 2015 (Göttingen, Germany). This workshop brought together researchers utilising a diverse range of organisms (including both vertebrate and invertebrate species) and a range of experimental approaches to answer core questions in developmental biology. This meeting report highlights some of the major themes emerging from the workshop including an evolutionary perspective as well as recent advances that have been made through the adoption of emerging techniques and technologies.

Transcriptome profiling reveals male- and female-specific gene expression pattern and novel gene candidates for the control of sex determination and gonad development in Xenopus laevis Abstract Xenopus laevis is an amphibian (frog) species widely used in developmental biology and genetics. To unravel the molecular machinery regulating sex differentiation of Xenopus gonads, we analyzed for the first time the transcriptome of developing amphibian gonads covering sex determination period. We applied microarray at four developmental stages: (i) NF50 (undifferentiated gonad during sex determination), (ii) NF53 (the onset of sexual differentiation of the gonads), (iii) NF56 (sexual differentiation of the gonads), and (iv) NF62 (developmental progression of differentiated gonads). Our analysis showed that during the NF50, the genetic female (ZW) gonads expressed more sex-specific genes than genetic male (ZZ) gonads, which suggests that a robust genetic program is realized during female sex determination in Xenopus. However, a contrasting expression pattern was observed at later stages (NF56 and NF62), when the ZW gonads expressed less sex-specific genes than ZZ gonads, i.e., more genes may be involved in further development of the male gonads (ZZ). We identified sexual dimorphism in the expression of several functional groups of genes, including signaling factors, proteases, protease inhibitors, transcription factors, extracellular matrix components, extracellular matrix enzymes, cell adhesion molecules, and epithelium-specific intermediate filaments. In addition, our analysis detected a sexually dimorphic expression of many uncharacterized genes of unknown function, which should be studied further to reveal their identity and if/how they regulate gonad development, sex determination, and sexual differentiation. Comparison between genes sex-specifically expressed in developing gonads of Xenopus and available transcriptome data from zebrafish, two reptile species, chicken, and mouse revealed significant differences in the genetic control of sex determination and gonad development. This shows that the genetic control of gonad development is evolutionarily malleable.

Divergent Axin and GSK-3 paralogs in the beta-catenin destruction complexes of tapeworms Abstract The Wnt/beta-catenin pathway has many key roles in the development of animals, including a conserved and central role in the specification of the primary (antero-posterior) body axis. The posterior expression of Wnt ligands and the anterior expression of secreted Wnt inhibitors are known to be conserved during the larval metamorphosis of tapeworms. However, their downstream signaling components for Wnt/beta-catenin signaling have not been characterized. In this work, we have studied the core components of the beta-catenin destruction complex of the human pathogen Echinococcus multilocularis, the causative agent of alveolar echinococcosis. We focused on two Axin paralogs that are conserved in tapeworms and other flatworm parasites. Despite their divergent sequences, both Axins could robustly interact with one E. multilocularis beta-catenin paralog and limited its accumulation in a heterologous mammalian expression system. Similarly to what has been described in planarians (free-living flatworms), other beta-catenin paralogs showed limited or no interaction with either Axin and are unlikely to function as effectors in Wnt signaling. Additionally, both Axins interacted with three divergent GSK-3 paralogs that are conserved in free-living and parasitic flatworms. Axin paralogs have highly segregated expression patterns along the antero-posterior axis in the tapeworms E. multilocularis and Hymenolepis microstoma, indicating that different beta-catenin destruction complexes may operate in different regions during their larval metamorphosis.

Experimental duplication of bilaterian body axes in spider embryos: Holm's organizer and self-regulation of embryonic fields Abstract Bilaterally symmetric body plans of vertebrates and arthropods are defined by a single set of two orthogonal axes, the anterior-posterior (or head-tail) and dorsal-ventral axes. In vertebrates, and especially amphibians, complete or partial doubling of the bilaterian body axes can be induced by two different types of embryological manipulations: transplantation of an organizer region or bi-sectioning of an embryo. Such axis doubling relies on the ability of embryonic fields to flexibly respond to the situation and self-regulate toward forming a whole body. This phenomenon has facilitated experimental efforts to investigate the mechanisms of vertebrate body axes formation. However, few studies have addressed the self-regulatory capabilities of embryonic fields associated with body axes formation in non-vertebrate bilaterians. The pioneer spider embryologist Åke Holm reported twinning of spider embryos induced by both types of embryological manipulations in 1952; yet, his experiments have not been replicated by other investigators, and access to spider or non-vertebrate twins has been limited. In this review, we provide a historical background on twinning experiments in spiders, and an overview of current twinning approaches in familiar spider species and related molecular studies. Moreover, we discuss the benefits of the spider model system for a deeper understanding of the ancestral mechanisms of body axes formation in arthropods, as well as in bilaterians.

Independent evolution of complex development in animals and plants: deep homology and lateral gene transfer Abstract The evolution of multicellularity is a premier example of phenotypic convergence: simple multicellularity evolved independently many times, and complex multicellular phenotypes are found in several distant groups. Furthermore, both animal and plant lineages have independently reached extreme levels of morphological, functional, and developmental complexity. This study explores the genetic basis for the parallel evolution of complex multicellularity and development in the animal and green plant (i.e., green algae and land plants) lineages. Specifically, the study (i) identifies the SAND domain—a DNA-binding domain with important roles in the regulation of cell proliferation and differentiation, as unique to animals, green algae, and land plants; and (ii) suggests that the parallel deployment of this ancestral domain in similar regulatory roles could have contributed to the independent evolution of complex development in these distant groups. Given the deep animal-green plant divergence, the limited distribution of the SAND domain is best explained by invoking a lateral gene transfer (LGT) event from a green alga to an early metazoan. The presence of a sequence motif specifically shared by a family of SAND-containing transcription factors involved in the evolution of complex multicellularity in volvocine algae and two types of SAND proteins that emerged early in the evolution of animals is consistent with this scenario. Overall, these findings imply that (i) in addition to be involved in the evolution of similar phenotypes, deep homologous sequences can also contribute to shaping parallel evolutionary trajectories in distant lineages, and (ii) LGT could provide an additional source of latent homologous sequences that can be deployed in analogous roles and affect the evolutionary potentials of distantly related groups.

Early development of the feeding larva of the sea urchin Heliocidaris tuberculata : role of the small micromeres Abstract The two modes of development in sea urchins are direct development, in which the adult develops directly from the gastrula to the adult and does not feed, and indirect development, in which the adult develops indirectly through a feeding larva. In this account of the indirect, feeding larva of Heliocidaris tuberculata, the question raised is whether an evolutionary difference of unequal cell divisions contributes to the development of feeding structures in the indirect larva. In indirect development, the cell divisions at the fourth and fifth cell cycles of the zygote are unequal, with four small micromeres formed at the vegetal pole at the fifth cell division. In direct development, these cell divisions are not unequal. From their position at the head of the archenteron, the small micromeres are strategically located to contribute to the feeding tissues of the larva and the adult of H. tuberculata.

The Notch repressor complex in Drosophila: in vivo analysis of Hairless mutants using overexpression experiments Abstract During development of higher animals, the Notch signalling pathway governs cell type specification by mediating appropriate gene expression responses. In the absence of signalling, Notch target genes are silenced by repressor complexes. In the model organism Drosophila melanogaster, the repressor complex includes the transcription factor Suppressor of Hairless [Su(H)] and Hairless (H) plus general co-repressors. Recent crystal structure analysis of the Drosophila Notch repressor revealed details of the Su(H)-H complex. They were confirmed by mutational analyses of either protein; however, only Su(H) mutants have been further studied in vivo. Here, we analyse three H variants predicted to affect Su(H) binding. To this end, amino acid replacements Phenylalanine 237, Leucines 245 and 247, as well as Tryptophan 258 to Alanine were introduced into the H protein. A cell-based reporter assay indicates substantial loss of Su(H) binding to the respective mutant proteins HFA, HLLAA and HWA. For in vivo analysis, UAS-lines HFA, HLLAA and HWA were generated to allow spatially restricted overexpression. In these assays, all three mutants resembled the HLD control, shown before to lack Su(H) binding, indicating a strong reduction of H activity. For example, the H variants were impaired in wing margin formation, but unexpectedly induced ectopic wing venation. Concurrent overexpression with Su(H), however, suggests that all mutant H protein isoforms are still able to bind Su(H) in vivo. We conclude that a weakening of the cohesion in the H-Su(H) repressor complex is sufficient for disrupting its in vivo functionality.

Silicatein expression in Haliclona indistincta (Phylum Porifera, Order Haplosclerida) at different developmental stages Abstract Silicatein is the main protein responsible for the formation of spicules, tiny structures that constitute the silica skeleton of marine demosponges (Phylum Porifera). A unique innovation in Porifera that evolved from the cathepsin L family of proteins, it has been reported that two amino acids (S and H) are necessary to form the catalytic triad (SHN) to enable silica condensation. However, a diversity of silicatein sequence variants has since been reported with a variable pattern of presence/absence across sponge groups. Variants containing CHN or C/SQN at the active site appear more common in sponges from the Haplosclerida. Here, we report the expression levels of five silicatein variants through different developmental stages in the haplosclerid Haliclona indistincta. All five silicatein variants were expressed at low levels in the free-swimming larvae, which lack spicules and expression significantly increased at the two developmental phases in which spicules were visible. At these two phases, silicateins of CHN and C/SQN types were much more highly expressed than the SHN type indicating a possible ability of active sites with these alternative amino acids to condense silica and a more complex evolutionary story for spicule formation in marine demosponges than previously understood.