Quantifying Soft Tissue Shape and Symmetry: Patients with Cleft Lip/Palate and Facial Paralysis

Background: The objective of this study was to demonstrate simple three-dimensional analyses of facial soft tissue shape and asymmetry. Methods: There were 2 study samples: one retrospective comprised patients with repaired cleft lip and palate (CL/P) and control subjects; and the other prospective comprised patients with unilateral facial paralysis (FP) and control subjects. The data collected were digitized three-dimensional facial landmarks. Scores for shape and asymmetry of subjects' faces and for different facial regions were generated using Procrustes methods. Pivotal bootstrap methods and analysis of variance were used to test for significant differences in the scores between the patients and controls, and plots of the scores were generated to compare differences among the subjects. Results: (1) Shape scores: The CL/P patients demonstrated significant overall and regional facial differences (P ≤ 0.01). The patients were further from the control mean, especially those with unilateral CL/P. Patients with FP demonstrated significant differences (P ≤ 0.05) for the lower face only. (2) Asymmetry scores: CL/P and FP patients demonstrated significant overall and regional facial differences (CL/P, P ≤ 0.0001; FP, P ≤ 0.01). CL/P and FP patients were more asymmetric and were further from the control mean, and patients with unilateral CL/P were more asymmetric than the bilateral CL/P patients. Conclusion: Clinicians can use the analyses to isolate differences and/or changes in the face due to shape or asymmetry, or a combination of both; based on the score plots, the extent of the shape and asymmetry differences can be compared among subjects and the extent of changes due to surgery measured. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Published online 20 March 2018. Received for publication August 30, 2017; accepted January 22, 2018. Presented at the International/American/Canadian Association for Dental Research (IADR/AADR/CADR), March 22–25, 2017, San Francisco, CA. This study was funded by National Institute of Dental and Craniofacial Research Grants # DE025295, DE019742, and DE024503. Disclosure: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by Tufts University School of Dental Medicine. Supplemental digital content is available for this article. Clickable URL citations appear in the text. Carroll Ann Trotman, BDS, MA, MS, Department of Orthodontics, Tufts University of Dental Medicine, 1 Kneeland Street, Boston, MA 02111, E-mail: carroll_ann.trotman@tufts.edu Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Assessment of Functional Rhinoplasty with Spreader Grafting Using Acoustic Rhinomanometry and Validated Outcome Measurements

Background: Rhinoplasty is 1 of the most common aesthetic and reconstructive plastic surgical procedures performed within the United States. Yet, data on functional reconstructive open and closed rhinoplasty procedures with or without spreader graft placement are not definitive as only a few studies have examined both validated measurable objective and subjective outcomes of spreader grafting during rhinoplasty. The aim of this study was to utilize previously validated measures to assess objective, functional outcomes in patients who underwent open and closed rhinoplasty with spreader grafting. Methods: We performed a retrospective review of consecutive rhinoplasty patients. Patients with internal nasal valve insufficiency who underwent an open and closed approach rhinoplasty between 2007 and 2016 were studied. The Cottle test and Nasal Obstruction Symptom Evaluation survey was used to assess nasal obstruction. Patient-reported symptoms were recorded. Acoustic rhinometry was performed pre- and postoperatively. Average minimal cross-sectional area of the nose was measured. Results: One hundred seventy-eight patients were reviewed over a period of 8 years. Thirty-eight patients were included in this study. Of those, 30 patients underwent closed rhinoplasty and 8 open rhinoplasty. Mean age was 36.9 ± 18.4 years. The average cross-sectional area in closed and open rhinoplasty patients increased significantly (P = 0.019). There was a functional improvement in all presented cases using the Nasal Obstruction Symptom Evaluation scale evaluation. Conclusions: Closed rhinoplasty with spreader grafting may play a significant role in the treatment of nasal valve collapse. A closed approach rhinoplasty including spreader grafting is a viable option in select cases with objective and validated functional improvement. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Published online 19 March 2018. Received for publication May 31, 2017; accepted November 7,2017. Disclaimer: The Beth Israel Deaconess Medical Center patients' medical records are the source of information used in this study. Data extrapolated, statistical analysis performed, and conclusions reached are the result of the work done by authors of this study. Disclosure: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by the authors. Samuel J. Lin, MD, MBA, Division of Plastic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis St., Suite 5A, Boston, MA 02215, E-mail: sjlin@bidmc.harvard.edu Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Surface Areas of Textured Breast Implants: Implications for the Biofilm Theory of Capsule Formation

Background: Increased surface area of mammary implants is suggested as a causative agent for the development of biofilms, which may lead to capsular contraction. The aim of this study was to quantify the surface areas of round implants of different textures and examine how these data can be interpreted with regard to clinical observation. Methods: Surface areas of textured round breast implants were calculated from previously reported confocal scanning microscopic assessment, and dimensions sourced from 3 breast implant manufacturers (McGhan, Mentor, and Silimed). Statistical comparisons were made between manufacturers for different implant volumes, profiles, and texturing. Results: There was a difference in surface area between manufacturers for all implant profiles and between manufacturers for equivalent volume implants (F (3, 253) = 2,828.87; P

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Bilateral Sciatic Neuropathy following Gluteal Augmentation With Autologous Fat Grafting

Summary: As gluteal augmentation continues to gain in popularity among patients seeking aesthetic enhancements, a thorough knowledge of the postoperative complications associated with this procedure is crucial. This case report concerns a 31-year-old woman who suffered bilateral foot drop secondary to sciatic neuropathy and as a result was wheelchair-bound for several months, following gluteal autologous fat grafting in the Dominical Republic. One year later, the patient had persistent left foot drop and sensory deficits. This is a devastating but seldom reported complication that all plastic surgeons need to be aware of when performing this operation. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Published online 19 March 2018. Received for publication October 25, 2017; accepted January 12, 2018. Disclosure: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by the authors. Vasileios Vasilakis, MD, Long Island Plastic Surgical Group, 999 Franklin Avenue, Garden City, NY 11530 Email: vvasilakis@lipsg.com Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Partial Versus Total Trapeziectomy Thumb Arthroplasty: An Expertise-based Feasibility Study

Background: There are numerous surgical techniques for the treatment of first carpometacarpal joint osteoarthritis, however, controversy exists as to whether outcomes differ between techniques. This feasibility study aimed to determine if a large-scale, health-related quality of life and functional outcomes study comparing 2 surgical techniques, complete trapeziectomy with ligament reconstruction and tendon interposition (T + LRTI) versus partial trapeziectomy and tendon interposition (PT + TI) arthroplasty, is possible. Methods: Patients with advanced stage arthritis (Eaton stages II–IV) of the thumb were invited to undergo either T + LRTI or PT + TI at 1 of the 2 hand surgery practices. Feasibility outcomes included: (1) Process: recruitment rate; (2) Resources: eligibility rate, eligibility criteria, retention, and compliance rates (completion of health-related quality of life questionnaires, Disabilities of the Arm, Shoulder, and Hand, EuroQol-5D-3L, and SF-36, and functional measurements, grip, key pinch, and tip pinch strength, at 1-week preoperatively and 1, 3, 6, and 12 months postoperatively); (3) Management: determining the practices' commitment to the study; and (4) Scientific: calculation of the variances and treatment effect sizes (ES) of differences between procedures. Data from baseline measurements and 6-month follow-up were used for analysis. Results: Sixty patients were screened, of which 34 (57%) were eligible for surgery. Twenty-one (81%) of the 26 ineligible patients were excluded due to previous or additional planned surgical procedures on the same hand, particularly carpal tunnel release (n = 17). Twenty patients consented; 12 in the T + LRTI and 8 in the PT + TI group. The highest completion rate for the 3 questionnaires and the functional measurements, for both groups was at 6-month time point. Compliance rates for questionnaire completion at 6-months were calculated at 50% and 75% for the T + LRTI and PT + TI group, respectively. Functional measurement completion rate was 50% and 63% for T + LRTI and PT + TI groups, respectively. Treatment ES were group dependent, with Disabilities of the Arm, Shoulder, and Hand, EuroQol-5D-3L usual activities and anxiety/depression showing a large ES in the PT + TI group; the T + LRTI group showed large ES in EQ-5D state of health today. Conclusions: Authors conclude that a large-scale study is feasible and dependent on: (1) increasing sample size to account for the high attrition rate; (2) liberalizing inclusion criteria to include patients with carpal tunnel syndrome; (3) allotting more time at follow-up visits to ensure completion of all measurements; and (4) increasing staff involvement (ie, develop rapport with patients and maintain stability with research assistants). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Published online 19 March 2018. Received for publication October 23, 2017; accepted January 19, 2018. Supported by The Educational Foundation of the Canadian Society of Plastic Surgeons, Granted May 22, 2011. Disclosure: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by funding from the CSPS Educational Fund. Supplemental digital content is available for this article. Clickable URL citations appear in the text. Hamilton Integrated Research Ethics Board (HiREB) Registration Number: 11–3530. Achilleas Thoma, MD, MSc, Department of Surgery, Division of Plastic Surgery, Department of HEI, 206 James Street South, Suite 101, Hamilton, ON, L8P 3A9, E-mail: athoma@mcmaster.ca Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Genetic Requirement of talin1 for Proliferation of Cranial Neural Crest Cells during Palate Development

Background: Craniofacial malformations are among the most common congenital anomalies. Cranial neural crest cells (CNCCs) form craniofacial structures involving multiple cellular processes, perturbations of which contribute to craniofacial malformations. Adhesion of cells to the extracellular matrix mediates bidirectional interactions of the cells with their extracellular environment that plays an important role in craniofacial morphogenesis. Talin (tln) is crucial in cell-matrix adhesion between cells, but its role in craniofacial morphogenesis is poorly understood. Methods: Talin gene expression was determined by whole mount in situ hybridization. Craniofacial cartilage and muscles were analyzed by Alcian blue in Tg(mylz2:mCherry) and by transmission electron microscopy. Pulse-chase photoconversion, 5-ethynyl-2'-deoxyuridine proliferation, migration, and apoptosis assays were performed for functional analysis. Results: Expression of tln1 was observed in the craniofacial cartilage structures, including the palate. The Meckel's cartilage was hypoplastic, the palate was shortened, and the craniofacial muscles were malformed in tln1 mutants. Pulse-chase and EdU assays during palate morphogenesis revealed defects in CNCC proliferation in mutants. No defects were observed in CNCC migration and apoptosis. Conclusions: The work shows that tln1 is critical for craniofacial morphogenesis in zebrafish. Loss of tln1 leads to a shortened palate and Meckel's cartilage along with disorganized skeletal muscles. Investigations into the cellular processes show that tln1 is required for CNCC proliferation during palate morphogenesis. The work will lead to a better understanding of the involvement of cytoskeletal proteins in craniofacial morphogenesis. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Published online 19 March 2018. Received for publication October 31, 2017; accepted November 16, 2017. Presented at the 57th Annual Meeting of New England Society of Plastic and Reconstructive Surgeons, June 11, 2016, Bretton Woods, N.H.; 39th Annual Meeting of Society of Craniofacial Genetics and Developmental Biology, August 4, 2016, Boston, Mass.; 62nd Annual Meeting of Plastic Surgeon Research Council, May 5, 2017, Durham, N.C. Disclosure: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by the authors. Supplemental digital content is available for this article. Clickable URL citations appear in the text. Drs. Ishii and Mukherjee contributed equally to this work. Eric C. Liao, MD, PhD, Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114., E-mail: cliao@partners.org Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Lateral Branch of the Thoracodorsal Nerve (LaT Branch) Transfer for Biceps Reinnervation

Summary: In cases of significant upper extremity trauma, the thoracodorsal nerve is a reliable secondary option for the restoration of elbow flexion. In all previous descriptions, however, the entire nerve is transferred. We describe a case utilizing the lateral thoracodorsal nerve (LaT) branch for biceps reinnervation with an associated cadaver study. Transfer of the LaT branch to the biceps branch was performed on a patient who had sustained a traumatic brachial plexus injury that left him without elbow flexion. Also, 4 cadavers (8 upper extremities) were dissected to identify the bifurcation of the thoracodorsal nerve and confirm the feasibility of transferring the LaT branch to the biceps motor branch. Axon counts of the thoracodorsal proper, LaT branch, musculocutaneous proper, and the biceps branch were also obtained. A bifurcation of the thoracodorsal nerve was present in all cadaver specimens, with an average distance of 7.5 cm (range, 6.2–9.8 cm) from the insertion of the latissimus dorsi muscle. Axon counts revealed a donor-to-recipient ratio of 0.85:1. Follow-up of our patient at 1 year showed improvement of elbow flexion manual muscle testing grade from 0 to 4/5. Furthermore, electromyography at 1 year confirmed biceps reinnervation and showed normal readings of the latissimus compared with preoperative electromyography. Transfer of the LaT branch is a viable and minimally morbid option for biceps reinnervation after traumatic branchial plexus injury. Further follow-up of our patient and larger prospective studies are needed to understand the true potential of this nerve transfer. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Published online 19 March 2018. Received for publication November 22, 2017; accepted January 12, 2018. Disclosure: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by the authors. Supplemental digital content is available for this article. Clickable URL citations appear in the text. Presented at Plastic Surgery: The Meeting 2016, Los Angeles, Calif. Alexander M. Spiess, MD, Department of Plastic Surgery, University of Pittsburgh Medical Center, 3550 Terrace Street, Scaife Hall, Suite 6B, Pittsburgh, PA 15261, E-mail: spiessam@upmc.edu Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Management of High-energy Avulsive Ballistic Facial Injury: A Review of the Literature and Algorithmic Approach

Background: High-energy avulsive ballistic facial injuries pose one of the most significant reconstructive challenges. We conducted a systematic review of the literature to evaluate management trends and outcomes for the treatment of devastating ballistic facial trauma. Furthermore, we describe the senior author's early and definitive staged reconstructive approach to these challenging patients. Methods: A Medline search was conducted to include studies that described timing of treatment, interventions, complications, and/or aesthetic outcomes. Results: Initial query revealed 41 articles, of which 17 articles met inclusion criteria. A single comparative study revealed that early versus delayed management resulted in a decreased incidence of soft-tissue contracture, required fewer total procedures, and resulted in shorter hospitalizations (level 3 evidence). Seven of the 9 studies (78%) that advocated delayed reconstruction were from the Middle East, whereas 5 of the 6 studies (83%) advocating immediate or early definitive reconstruction were from the United States. No study compared debridement timing directly in a head-to-head fashion, nor described flap selection based on defect characteristics. Conclusions: Existing literature suggests that early and aggressive intervention improves outcomes following avulsive ballistic injuries. Further comparative studies are needed; however, although evidence is limited, the senior author presents a 3-stage reconstructive algorithm advocating early and definitive reconstruction with aesthetic free tissue transfer in an attempt to optimize reconstructive outcomes of these complex injuries. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Published online 19 March 2018. Received for publication December 21, 2017; accepted January 12, 2018. Presented at the International Society of Craniofacial Surgery, October 28, 2017, Cancun, Mexico. Disclosure: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by the authors. Eduardo D. Rodriguez, MD, DDS, Wyss Department of Plastic Surgery, New York University Langone Medical Center, 305 East 33rd Street, New York, NY 10016, E-mail: eduardo.rodriguez@nyumc.org Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Comparing the Outcome of Different Biologically Derived Acellular Dermal Matrices in Implant-based Immediate Breast Reconstruction: A Meta-analysis of the Literatures

Background: Acellular dermal matrices (ADMs) have been used extensively in implant-based breast reconstruction. It was reported that due to the different sources and processing methods, the outcomes of ADMs in implant-based breast reconstructions are expected to differ. We designed this study to statistically analyze and discuss the outcome of 3 commonly used ADMs, Alloderm, Strattice, and Surgimend in implant-based breast reconstruction. Methods: Comprehensive review of the literatures searched on electronic databases was done to identify studies published between 2006 and 2017 comparing the outcome of ADMs. Pooled random effect estimates for each complication and 95% confidence interval (CI) were calculated. One-way analysis of variance and Bonferroni test were used to compare statistical significance between and within groups, respectively. Multiple linear regression was done to include confounding factors and R statistic program for forest plot. Results: Twenty-one studies met the inclusion with a total of 1,659, 999, and 912 breasts reconstructions in Alloderm, Strattice, and Surgimend, respectively. Seven complications extracted including major and minor infection, seroma, implant loss, hematoma, capsular contracture, and localized erythema. Pooled total complication rates were 23.82% (95% CI, 21.18–26.47%) in Strattice, 17.98% (95% CI, 15.49–20.47%) in Surgimend, 16.21% (95% CI, 14.44–17.99%) in Alloderm. Seroma rate was the highest in Strattice group (8.61%; 95% CI, 6.87–10.35%). There was no statistical significance between and within groups. Conclusion: Although Strattice exhibited a higher overall pooled complication rate compared with Alloderm and Surgimend, the incidence of individual complication varies between studies. A cost analysis of different ADMs may aid in choosing the type of ADMs to be used. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Published online 19 March 2018. Received for publication December 27, 2017; accepted January 19, 2018. Disclosure: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by the authors. Yew L. Loo, MBChB (UK), Flat 908, Kent Building, 47 Hope Street, London City Island, London, United Kingdom, E14 0QL, E-mail: yewloong@doctors.org.uk Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Ketorolac May Increase Hematoma Risk in Reduction Mammaplasty: A Case-control Study

Background: Ketorolac is a potent nonsteroidal anti-inflammatory drug that has valuable analgesic properties but also a hypothetical risk of increased bleeding due to inhibition of platelet activation. The clinical significance of this risk, however, is unclear when it is used after reduction mammaplasty. Our study objective was to therefore examine the association between ketorolac exposure and hematoma occurrence after breast reduction surgery. We hypothesized that there was no association between ketorolac exposure and hematoma occurrence in breast reduction surgery. Methods: A case-control design was used. Data from charts of all reduction mammaplasties that developed hematomas requiring surgical evacuation (cases) at our university-based hospitals were retrieved and matched to data from charts of reduction mammaplasty patients who did not indicate this complication (controls). Matching occurred in a 1:1 ratio based on 4 criteria: age, body mass index, institution, and preexisting hypertension. Charts were reviewed for retrospective information on exposure to ketorolac. Odds ratio (OR) was calculated with an OR > 1 favoring an association. Results: From 2002 to 2016, 40 cases of hematoma met inclusion criteria and were matched with 40 controls (N = 80). Cases had a significantly lower body mass index than controls; however, the other baseline patient demographics were similar between the 2 groups. There was an association between hematoma formation and exposure to ketorolac (OR, 2.4; 95% confidence interval, 0.8–7.4; P = 0.114) and a trend for greater risk of hematoma formation, although this was not statistically significant. Conclusions: Based on this level 3 evidence, there appears to be an association between perioperative ketorolac exposure and hematoma after breast reduction surgery, but it was not statistically significant. Although this study was adequately powered, the OR of 2.4 was associated with a wide confidence interval. A larger sample size may increase the precision of the results and may also make the association definitive. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Published online 19 March 2018. Received for publication December 28, 2017; accepted January 12, 2018. Presented at the Canadian Society of Plastic Surgery meeting, June 2017, Winnipeg, MB. Disclosure: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by the authors. Ethics approval to proceed with this study was granted by the Hamilton Integrated Research Ethics Board (#1094-C). This study has been registered with ClinicalTrials.gov (NCT03280043). Achilleas Thoma, MD, MSc, FRCSC, 206 James Street South, Suite 101, Hamilton, Ontario, Canada, L8P 3A9, E-mail: athoma@mcmaster.ca. Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Three-dimensional Printed Surgical Simulator for Kirschner Wire Placement in Hand Fractures

Summary: Closed reduction and percutaneous pinning (CRPP) of hand fractures can be a deceptively challenging procedure that requires significant hands-on time to teach and learn. We created a realistic three-dimensional simulator that can be used for teaching junior residents the CRPP. Computer-aided design and computer-aided manufacturing (CAD/CAM) software was used to create a three-dimensional hand model incorporating several common hand fractures: Bennett's fracture, transverse fifth metacarpal neck, and transverse second proximal phalanx. Three-dimensional printing was used to create molds in which the bones and soft tissue were poured. A polyurethane foam was utilized for the bones with iron incorporated to render them radiopaque, whereas silicone of varying viscosities was used for the soft tissues. Five plastic surgery residents and 5 consultants evaluated the model. Individuals then completed an anonymous 12-question survey evaluating the model based on realism, educational utility, and overall usefulness. Survey responses obtained from both residents and consultants were strongly in favor of the simulator. Average realism was graded as 4.48/5 by residents and 4.68/5 by consultants. Average educational utility was graded as 5/5 by residents and 4.95/5 by consultants. Average overall usefulness was graded as 5/5 by both groups. We created an anatomically accurate and realistic simulator for CRPP of hand fractures that was low cost and easily reproducible. Initial feedback was encouraging in regard to realism, educational utility, and overall usefulness. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Published online 19 March 2018. Received for publication January 3, 2018; accepted January 19, 2018. Disclosure: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by the authors. Supplemental digital content is available for this article. Clickable URL citations appear in the text. This manuscript has not been previously published nor is it under consideration elsewhere. Presented at the 71st Annual Meeting of the Canadian Society of Plastic Surgeons, June 21, 2017, Winnipeg, MB, Canada; Plastic Surgery The Meeting, October 9, 2017, Orlando, FL; and The American Association for Hand Surgery Annual Meeting, January 10–13, 2018, Phoenix, AZ. Christian Petropolis, MD, FRCSC, Section of Plastic Surgery, Department of Surgery, University of Manitoba, GC-401 General Hospital, 820 Sherbrook Street, Winnipeg, MB, Canada, E-mail: cpetropolis@me.com Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Influences of different lower cervical bone graft heights on the size of the intervertebral foramen: multiple planar dynamic measurements with laser scanning

Abstract

The aim of this study is to evaluate the influences of different bone graft heights on the size of the intervertebral foramen, which will help determine the optimal graft height in clinical practice. Six fresh adult cadavers were used, with the C5-C6 vertebral column segment defined as the functional spinal unit (FSU). After discectomy, the C5/6 intervertebral height was set as the baseline height (normal disc height). We initially used spiral computed tomography (CT) to scan and measure the middle area of the intervertebral foramen when at the baseline height. Data regarding the spatial relationship of C5-C6 were subsequently collected with a laser scanner. Grafting with four different sized grafts, namely, grafts of 100, 130, 160, and 190% of the baseline height, was implanted. Moreover, we scanned to display the FSU in the four different states using Geomagic8.0 studio software. Multiple planar dynamic measurements (MPDM) were adopted to measure the intervertebral foramen volume, middle area, and areas of internal and external opening. MPDM with a laser scanner precisely measured the middle area of the intervertebral foramen as spiral CT, and it is easy to simulate the different grafts implanted. With the increase of the bone graft height, the size of the intervertebral foramen began to decrease after it increased to a certain point, when grafts of 160% of the baseline height implanted. MPDM of the intervertebral foramens with laser scanning three-dimensional (3D) reconstitution are relatively objective and accurate. The recommended optimal graft height of cervical spondylosis is 160% of the mean height of adjacent normal intervertebral spaces.

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Effect of photobiomodulation on connective tissue remodeling and regeneration of skeletal muscle in elderly rats

Abstract

The purpose of this study was to evaluate the effects of low-level laser therapy (LLLT) on morphological aspects, IL-6 and IL-1β expressions, as well as the distribution and organization of collagen in the tibialis anterior (TA) muscle of elderly rats submitted to cryoinjury. Histological photomicrographs were taken of TA muscles stained with HE and picrosirius red. Immunohistochemistry was used for the evaluation of IL-6 and IL-1β. Male Wistar rats, aged 20 months, were distributed into three groups: (1) control animals not injured or treated with LLLT (n = 5), (2) cryoinjury without LLLT treatment (n = 15), and (3) cryoinjury treated with infrared LLLT (n = 15). LLLT was applied to the TA 2 h after of the injury induction and consisted of daily applications until the sacrifice (1, 3, and 7 days). The following parameters were used: λ = 780 nm, power density 1 W/cm², output power 40 mW, 10 s per point, 8 points, and 3.2 J of total energy. In the histomorphological analysis, the treated group exhibited a significant decrease in inflammatory infiltrate (p < 0.001) as well as an increase immature fibers and new blood vessels at 7 days compared to the untreated group (p < 0.05). Furthermore, treatment induced a better collagen distribution and organization at 7 days in comparison to the untreated group (p < 0.05). In conclusion, LLLT demonstrated a modulatory effect on the muscle repair process in elderly animals with regard to the collagen remodeling and morphological aspects of muscle tissue.

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Photobiomodulation effect on children’s scars

Abstract

The management of burn scars has become one of the major clinical challenges in the developing countries which involve enormous treatment cost; this needs new methods for better cost benefit relationship. The objective of the study is to analyze the effectiveness of low-level laser therapy on post-burn scar tissue in children. A randomized controlled study included 15 children, ranging from 2 to 10 years of age, presenting with burn scars. They received diode laser and topical treatment. Each scar was divided into two halves. One half was treated with laser therapy and topical treatment (study area), and the other half was treated with topical treatment only (control area). The children were evaluated before and after 3 months of the study by Vancouver Scar Scale (VSS), ultrasonography (U/S), and laser Doppler perfusion imaging. Significant improvement was reported in the studied area compared to the control area for patients with P values (P = 0.005) and (P = 0.0001) for VSS and U/S scores, respectively. No difference was detected for blood perfusion to the scar between both areas (P = 0.18). In addition, no adverse effect was reported. Photobiomodulation is an efficient and safe therapeutic modality for post-burn hypertrophic scars in children and should be considered a part of combination therapy for better results.

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Nerve detection during surgery: optical spectroscopy for peripheral nerve localization

Abstract

Precise nerve localization is of major importance in both surgery and regional anesthesia. Optically based techniques can identify tissue through differences in optical properties, like absorption and scattering. The aim of this study was to evaluate the potential of optical spectroscopy (diffuse reflectance spectroscopy) for clinical nerve identification in vivo. Eighteen patients (8 male, 10 female, age 53 ± 13 years) undergoing inguinal lymph node resection or resection or a soft tissue tumor in the groin were included to measure the femoral or sciatic nerve and the surrounding tissues. In vivo optical measurements were performed using Diffuse Reflectance Spectroscopy (400–1600 nm) on nerve, near nerve adipose tissue, muscle, and subcutaneous fat using a needle-shaped probe. Model-based analyses were used to derive verified quantitative parameters as concentrations of optical absorbers and several parameters describing scattering. A total of 628 optical spectra were recorded. Measured spectra reveal noticeable tissue specific characteristics. Optical absorption of water, fat, and oxy- and deoxyhemoglobin was manifested in the measured spectra. The parameters water and fat content showed significant differences (P < 0.005) between nerve and all surrounding tissues. Classification using k-Nearest Neighbor based on the derived parameters revealed a sensitivity of 85% and a specificity of 79%, for identifying nerve from surrounding tissues. Diffuse Reflectance Spectroscopy identifies peripheral nerve bundles. The differences found between tissue groups are assignable to the tissue composition and structure.

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Comparison of the effect of root surface modification with citric acid, EDTA, and aPDT on adhesion and proliferation of human gingival fibroblasts and osteoblasts: an in vitro study

Abstract

Root demineralization is used in Periodontics as an adjuvant for mechanical treatment. The aim of this study was to evaluate the effects of root surface modification with mechanic, chemical, and photodynamic treatments on adhesion and proliferation of human gingival fibroblasts and osteoblasts. Root fragments were treated by scaling and root planing (C—control group), EDTA (pH 7), citric acid plus tetracycline (CA—pH 1), and antimicrobial photodynamic therapy (aPDT) with toluidine blue O and red laser (pH 4). Cells were seeded (104 cells/well, 6th passage) on root fragments of each experimental group and cultured for 24, 48, and 72 h. Cells were counted in scanning electron microscopy images by a calibrated examiner. For fibroblasts, the highest number of cells were present at 72-h period (p < 0.05). EDTA group showed a very low number of cells in relation to CA group (p < 0.05). CA and aPDT group presented higher number of cells in all periods, but without differences between other treatment groups (p > 0.05). For osteoblasts, there was a significant increase in cell numbers for aPDT group at 72 h (p < 0.05). In conclusion, aPDT treatment provided a positive stimulus to osteoblast growth, while for fibroblasts, aPDT and CA had a tendency for higher cell growth.

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Dental anxiety in patients attending a student dental clinic

Abstract

Background

This study investigated the expectations and experiences of a sample of new patients visiting an Australian regional university Student Dental Clinic with regard to anxiety provoking and alleviating stimuli in the clinical environment. Differences in anxiety levels were examined by age, gender and the type of procedure undergone.

Methods

The number of dental patients who participated in the study was 102 (56 males, 43 females). The study used a pre-treatment/post-treatment design to assess the effect of the dental procedure on anxiety levels of patients. The Modified Dental Anxiety Scale (MDAS) was used to measure anxiety levels in patients at pre-treatment. Questions were also asked about factors which may increase (length of the appointment, invasiveness of procedure) or decrease (perceived student interpersonal skills and clinical ability) dental fear.

Results

Females reported higher total MDAS scores (M = 11.93) compared to males (M = 9.94). Younger patients (M = 12.15) had higher dental anxiety than older patients (M = 9.34). There was a reduction in dental anxiety from pre-treatment (M = 1.92) to post-treatment (M = 1.23) on the single item anxiety measure though most of the treatment being undergone by patients was for less complex procedures.

Conclusions

Patients' anticipatory experience of anxiety was higher than the anxiety experience after having undergone treatment at the student dental clinic. Student interpersonal skills and clinical ability as perceived by the patient can lessen dental anxiety in patients. Clinical Supervisor-student ratios need to be more equivalent in order to reduce the time length of appointments which currently are associated with increased patient anxiety levels in student dental clinics.

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Treatment-related features improve machine learning prediction of prognosis in soft tissue sarcoma patients

Abstract

Background and purpose

Current prognostic models for soft tissue sarcoma (STS) patients are solely based on staging information. Treatment-related data have not been included to date. Including such information, however, could help to improve these models.

Materials and methods

A single-center retrospective cohort of 136 STS patients treated with radiotherapy (RT) was analyzed for patients' characteristics, staging information, and treatment-related data. Therapeutic imaging studies and pathology reports of neoadjuvantly treated patients were analyzed for signs of response. Random forest machine learning-based models were used to predict patients' death and disease progression at 2 years. Pre-treatment and treatment models were compared.

Results

The prognostic models achieved high performances. Using treatment features improved the overall performance for all three classification types: prediction of death, and of local and systemic progression (area under the receiver operatoring characteristic curve (AUC) of 0.87, 0.88, and 0.84, respectively). Overall, RT-related features, such as the planning target volume and total dose, had preeminent importance for prognostic performance. Therapy response features were selected for prediction of disease progression.

Conclusions

A machine learning-based prognostic model combining known prognostic factors with treatment- and response-related information showed high accuracy for individualized risk assessment. This model could be used for adjustments of follow-up procedures.

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STK24 expression is modulated by DNA copy number/methylation in lung adenocarcinoma and predicts poor survival

Future Oncology, Ahead of Print.


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Contents

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Continuing Medical Education Exam: April 2018

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Self-expandable metal stents in malignant biliary obstruction: Back to the roots with uncovered stents as the “new” standard?

Biliary obstruction can arise from different types of malignant disease, including pancreatic cancer, intrinsic cholangiocarcinoma, gallbladder cancer, and metastatic disease. The most common cause of malignant distal biliary obstruction is pancreatic cancer; jaundice will develop in 70% to 90% of patients during the course of their disease. Pancreatic cancer is usually advanced at presentation, and curative intended resection is possible in less than 15% of patients.1 In the United States the incidence of pancreatic cancer is calculated at 12.5 per 100,000 women and men per year according to the SEERS database (National Cancer Institute, Surveillance, Epidemiology, and End Result Program, 2010-2014).

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Information for readers

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Response:

We thank Drs Baldaque-Silva and Omae1 for their comments on the recent articles2,3 published on the use of endoscopic submucosal dissection (ESD) for the treatment of early Barrett's neoplasia, and we commend them for the excellent results4 reported, which further strengthen the evidence base for this technique.

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How do we assess what lies beneath in eosinophilic esophagitis?

The working definition for eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated disorder characterized histologically by esophageal inflammation with intraepithelial eosinophils and clinically by symptoms of esophageal dysfunction.1 Although this definition has proved valuable for the standardization of the diagnosis and research criteria, it is becoming clear that it only scratches the surface. To say it another way, the findings from analysis of a mucosal biopsy sample reveal only the tip of an iceberg of inflammation and fibrosis that lie beneath in the esophageal wall.

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Endoscopic submucosal dissection for nonpolypoid colorectal dysplasia in patients with inflammatory bowel disease: in medias res

The implementation of the Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease (IBD) Patients: International Consensus Recommendations (SCENIC) is under way.1 The recommendations are being incorporated into practice.2 The chromoendoscopy and targeted biopsy technique continues to be disseminated in gastroenterology meetings. Training sessions2 and methods to perform chromoendosopy and targeted biopsy have been conducted and described, respectively.

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Endoscopic submucosal dissection learning curve and role in the treatment of Barrett's neoplasia

We read with interest the articles by Yang et al1 and by Subramaniam et al2 on the role of endoscopic submucosal dissection (ESD) for the treatment of neoplastic Barrett's esophagus (NBE). Conventional multimodal endoscopic treatment has some limitations, such as recurrence of neoplasia and intestinal metaplasia in 4% and 8% of cases, respectively, and adverse events in 19% of patients.3

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Colorectal polyp snaring: the smaller, the colder, the bigger!

No doubt, one day we'll enjoy a tremendous minimization of the risk of postcolonoscopy colorectal cancer (CRC) resulting from our desperate effort to improve the quality of colonoscopy. We must admit, however, that the most immediately tangible effect is not so much represented by the desired increase in the diagnosis of clinically relevant (ie, advanced) lesions but rather by an unexpected upsurge in the detection of small colorectal polyps. When we couple an excellent level of cleansing with a meticulous exploration of the mucosa, the most likely outcome for a screening colonoscopy is indeed represented by our warmly anticipated improvement in the adenoma detection rate brought about by the detection of at least 1 diminutive or small polyp.

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Retraction notice to “Long-term outcomes of per-oral endoscopic myotomy in patients with achalasia with a minimum follow-up of 2 years: an international multicenter study”

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://ift.tt/2GNuKz7 article has been retracted due to overlapping/duplicate material.Data from some patients from this study have previously been published in other journals without cross-referencing. Twenty patients overlap with a paper by Kumbhari et al.1 Thirty-five patients overlap with the study by Ngamruengphong et al.2

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Unde venis? Geographic profiling for the prevention of gastric cancer

In the middle of the 14th century, when the Black Death was decimating the population in Asia and Europe, the Venetian Republic established a system of isolation for travelers arriving to the port of Ragusa (now Dubrovnik), then the gateway for Asian trade to Europe. Before these travelers were allowed to proceed to their destination, they had to spend a period of 40 days (hence quarantine, from the Italian word for 40, quaranta) in a nearby island. The insightful Venetian legislators preceded the concept of incubation, reasoning that those in whom any plague did not develop within 40 days were healthy and could move on.

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The ASGE’S vision for developing clinical practice guidelines: the path forward

Clinical practice guidelines have played a pivotal role in shaping healthcare delivery. Based on the National Academy of Medicine (previously known as the Institute of Medicine) report, Clinical Practice Guidelines We Can Trust,1 practice guidelines are defined as statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and as assessment of the benefits and harms of alternative care options. Over the last few decades significant advances have been made in the field of guideline development that highlight the importance of methodologic rigor, greater transparency, and actionable recommendations.

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Fine-needle biopsy sampling under EUS guidance: Is one needle tip really better than the other?

We read with interest the article by Abdelfatah et al1 regarding the use of 2 new types of core biopsy devices in the sampling of solid lesions under EUS guidance. We commend the authors on their effort to study the sampling capabilities of 2 novel needles, each with a unique tip design. We and others have recently demonstrated a superior tissue yield over conventional FNA using either 1 of the 2 devices2-6; hence the concern over the substantially lower diagnostic yield rates reported by Abdelfatah et al.

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Editors

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In upcoming issues...

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ASGE update

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Focus on...

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LIMD2 Is Overexpressed in BRAF V600E-Positive Papillary Thyroid Carcinomas and Matched Lymph Node Metastases

Abstract

We previously described that LIM domain containing 2 (LIMD2) overexpression was closely correlated with metastatic process in papillary thyroid carcinoma (PTC). We here evaluated the expression of LIMD2 in a series of non-metastatic and metastatic PTC and their matched lymph node metastases via immunohistochemistry. LIMD2 was expressed in 74 (81%) of primary PTC and 35 (95%) of lymph node metastases. Sub-analysis performed in 37 matched samples demonstrated that in four cases, LIMD2 is expressed in lymph node metastases, while it is not expressed in primary tumors. Moreover, in eight cases, the staining intensity of LIMD2 was stronger in the patient-matched lymph node metastases than in the primary tumors. Next, the expression of LIMD2 was correlated with clinical pathological parameters and BRAF V600E and RET/PTC mutational status. The expression of LIMD2 in primary tumors was correlated with the presence of BRAF V600E mutation (P = 0.0338). Western blot analysis in thyroid cell lines demonstrated that LIMD2 is expressed in two PTC cell lines, while it is not expressed in normal thyroid and follicular thyroid carcinoma cell lines. Importantly, its expression was higher in a PTC cell line that harbors BRAF V600E mutation than in a PTC cell line that harbors RET/PTC1. The available genomic profiling data generated by The Cancer Genome Atlas Research Network confirmed that LIMD2 expression is higher in BRAF-like PTC samples. Our data suggest that LIMD2 may play an important role in the metastatic process of PTC, predominantly in BRAF V600E-positive tumors.

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Imaging of Cerebrovascular Function in Chronic Traumatic Brain Injury

Journal of Neurotrauma, Ahead of Print.


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Delayed Administration of BQ788, an ETB Antagonist, after Experimental Traumatic Brain Injury Promotes Recovery of Blood–Brain Barrier Function and Reduction of Cerebral Edema in Mice

Journal of Neurotrauma, Ahead of Print.


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Update on Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. Incidence of MCC continues to rise, and risk factors include advanced age, pale skin, chronic sun exposure, and immune suppression. Diagnosing MCC utilizes a combination of morphology and immunohistochemistry. Merkel cell polyomavirus (MCPyV) is present in approximately 70–80% of MCCs and represents a key pathogenic driver in those MCCs. In contrast, MCPyV-negative MCCs arise through progressive accumulation of ultraviolet-light induced somatic mutations. Staging of MCC proceeds according to the American Joint Commission on Cancer (AJCC) 8th Edition, which utilizes features of the primary tumor together with regional lymph node(s) (clinically and/or pathologically detected) and/or distant metastases. Many potentially useful biomarkers have been studied to refine risk stratification in MCC. In recent years, the host immune infiltrate has been leveraged as immune checkpoint blockade has emerged as an efficacious mode of treatment for patients with advanced MCC.

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Human Papillomavirus-Related Neuroendocrine Carcinomas of the Head and Neck

Abstract

Human papillomavirus (HPV)-related head and neck carcinoma (HNC) represents an important subgroup of head and neck cancer that is characterized by a consistent microscopic appearance and a favorable prognosis. A growing experience with HPV testing, however, has uncovered variants that deviate from the prototypic HPV-HNC with respect to morphology. While these HPV-HNCs may deviate morphologically from the prototype, they do not appear to stray far from the favorable clinical outcome assigned to HPV-positive status. In effect, HPV positivity trumps traditional prognostic features predicated on morphology such as tumor grade and histologic subtype when it comes to predicting clinical behavior. For the diagnostic pathologist, the pedestrian task of tumor grading and subtyping would seem to be of little prognostic or therapeutic relevance when it comes to HPV-HNC. Recognition and documentation of neuroendocrine differentiation is a most notable exception. Forms of HPV-HNC have now been reported that morphologically resemble small cell carcinoma (SCC) and large cell neuroendocrine carcinoma (LCNEC) of other sites, and that immunohistochemically exhibit neuroendocrine differentiation. Despite the presence of HPV, these SCCs and LCNECs share the same aggressive clinical behavior of their counterparts in the lung and other sites where the high grade neuroendocrine phenotype is associated with early distant spread and poor overall survival. Consequently, the high grade neuroendocrine phenotype should be regarded as an aggressive form of HPV-HNC where tumor morphology displaces HPV positivity as the most important prognostic feature.

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Transverse Cervical Artery Pseudoaneurysm: An Unusual Delayed Complication of Radical Neck Dissection

Abstract

Pseudoaneurysm formation in the transverse cervical artery, post radical neck dissection, leading to massive hemorrhage, is a rare but life threatening occurrence. We report a patient with pseudoaneurysm of transverse cervical artery, post salvage radical neck dissection, presenting with recurrent and significant hemorrhage after 3 weeks of surgery. A pseudoaneurysm involving transverse cervical artery was revealed by digital subtraction angiography and treated by endovascular coil embolization.

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The Role of Preoperative Computed Tomography of Temporal Bone in Atticotomy as a New Tool for Determining the Approach

Abstract

The temporal bone is a complex anatomical structure and so preoperatively computed tomography (CT) of the temporal bone is important for choice of the surgical procedure. In this study, evaluation of the surgical difficulty to conduct transmastoid atticotomy with the coronary cut of CT temporal bone. Additional, attic pathology intraoperative is evaluated. The current research is a retrospective study of 79 patients with chronic suppurative otitis media (safe type) with the preoperative opacity of the attic in CT temporal bone. The researcher correlates difficulty to do transmastoid attictomy with the distance in mm between the roof of external audiatory canal (EAC) and tegmen with ruler directly in the coronary cut of CT temporal bone at the the level of internal auditory canal (IAC). The researcher also compares attic pathology intraoperative with preoperative CT attic opacity. In group of surgically difficulty average distance between the superior wall of EAC and tegmen on preoperative CT at the level of IAC is 2–5 mm while distance in easily surgical approach is from 6 to 10 mm. 68.4%(54/79) of cases had pathology in attic in the form of granulation tissue in 50 cases and glue in 4 cases. Preoperative CT temporal bone is very important to detect atticotomy approach either transmastoid or transcanal, through measuring the distance in mm between the roof of EAC and tegmen with ruler directly in the coronal cut of CT temporal bone at the level of internal auditory canal. The opacity of the attic in Preoperative CT does not mean that there is a pathology in the attic.

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Eradicating Cancer Stem Cells: Concepts, Issues, and Challenges

Opinion statement:

The cells of malignant cancers result in the evolution of cells with stem-like characteristics, commonly known as cancer stem cells (CSCs). Progress of anticancer therapies is severely hampered because of disease relapse mostly in a more aggressive form due to CSCs. These CSCs are more or less like embryonic or tissue stem cells, known for their capacity of self-renewal, exactly recapitulate of the original tumor. Deregulation of key stem cell pathways like Wnt, Hedgehog (Hh), and Notch is attributed towards the rise of CSCs. Recent breakthroughs offer better insights into CSC signaling. Scientists have developed several combinatorial therapies like targeting one/multiple of these CSC pathways. The article summarized various markers used to identify CSCs and discuss major signaling pathways in them. The futuristic probabilities to use CSC therapeutics in clinical development have been discussed. Our views have been highlighted on the future directions for targeting advances in the clinical development.

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Human c-SRC kinase (CSK) overexpression makes T cells dummy

Abstract

Adoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide–MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on correct pMHC recognition on the outside and a restricted clustering on the inside of the cell. Since the majority of the adverse events are due to TCR recognition of the wrong target, we tested if blocking the signalling would affect the binding. By over-expressing the c-SRC kinase (CSK), a negative regulator of LCK, in redirected T cells, we showed that peripheral blood T cells inhibited anti-CD3/anti-CD28-induced phosphorylation of ERK, whereas TCR proximal signalling was not affected. Similarly, overexpression of CSK together with a therapeutic TCR prevented pMHC-induced ERK phosphorylation. Downstream effector functions were also almost completely blocked, including pMHC-induced IL-2 release, degranulation and, most importantly, target cell killing. The lack of effector functions contrasted with the unaffected TCR expression, pMHC recognition, and membrane exchange activity (trogocytosis). Therefore, co-expression of CSK with a therapeutic TCR did not compromise target recognition and binding, but rendered T cells incapable of executing their effector functions. Consequently, we named these redirected T cells "dummy T cells" and propose to use them for safety validation of new TCRs prior to therapy.

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Abscopal effects of radiotherapy and combined mRNA-based immunotherapy in a syngeneic, OVA-expressing thymoma mouse model

Abstract

Background

Tumor metastasis and immune evasion present major challenges of cancer treatment. Radiotherapy can overcome immunosuppressive tumor microenvironments. Anecdotal reports suggest abscopal anti-tumor immune responses. This study assesses abscopal effects of radiotherapy in combination with mRNA-based cancer vaccination (RNActive^®).

Methods

C57BL/6 mice were injected with ovalbumin-expressing thymoma cells into the right hind leg (primary tumor) and left flank (secondary tumor) with a delay of 4 days. Primary tumors were irradiated with 3 × 2 Gy, while secondary tumors were shielded. RNA and combined treatment groups received mRNA-based RNActive^® vaccination.

Results

Radiotherapy and combined radioimmunotherapy significantly delayed primary tumor growth with a tumor control in 15 and 53% of mice, respectively. In small secondary tumors, radioimmunotherapy significantly slowed growth rate compared to vaccination (p = 0.002) and control groups (p = 0.01). Cytokine microarray analysis of secondary tumors showed changes in the cytokine microenvironment, even in the non-irradiated contralateral tumors after combination treatment.

Conclusion

Combined irradiation and immunotherapy is able to induce abscopal responses, even with low, normofractionated radiation doses. Thus, the combination of mRNA-based vaccination with irradiation might be an effective regimen to induce systemic anti-tumor immunity.

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The role of interleukin-2, all- trans retinoic acid, and natural killer cells: surveillance mechanisms in anti-GD2 antibody therapy in neuroblastoma

Abstract

Although anti-disialoganglioside (GD2) antibodies are successfully used for neuroblastoma therapy, a third of patients with neuroblastoma experience treatment failure or serious toxicity. Various strategies have been employed in the clinic to improve antibody-dependent cell-mediated cytotoxicity (ADCC), such as the addition of interleukin (IL)-2 to enhance natural killer (NK) cell function, adoptive transfer of allogeneic NK cells to exploit immune surveillance, and retinoid-induced differentiation therapy. Nevertheless, these mechanisms are not fully understood. We developed a quantitative assay to test ADCC induced by the anti-GD2 antibody Hu14.18K322A in nine neuroblastoma cell lines and dissociated cells from orthotopic patient-derived xenografts (O-PDXs) in culture. IL-2 improved ADCC against neuroblastoma cells, and differentiation with all-trans retinoic acid stabilized GD2 expression on tumor cells and enhanced ADCC as well. Degranulation was highest in licensed NK cells that expressed CD158b (P < 0.001) and harbored a killer-cell immunoglobulin-like receptor (KIR) mismatch against the tumor-specific human leukocyte antigen (HLA; P = 0.016). In conclusion, IL-2 is an important component of immunotherapy because it can improve the cytolytic function of NK cells against neuroblastoma cells and could lower the antibody dose required for efficacy, thereby reducing toxicity. The effect of IL-2 may vary among individuals and a biomarker would be useful to predict ADCC following IL-2 activation. Sub-populations of NK cells may have different levels of activity dependent on their licensing status, KIR expression, and HLA–KIR interaction. Better understanding of HLA–KIR interactions and the molecular changes following retinoid-induced differentiation is necessary to delineate their role in ADCC.

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Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells

Abstract

Ovarian cancer (OC) is the leading cause of gynecological cancer-related death in North America. Most ovarian cancer patients (OCPs) experience disease recurrence after first-line surgery and chemotherapy; thus, there is a need for novel second-line treatments to improve the prognosis of OC. Although peripheral blood-derived NK cells are known for their ability to spontaneously lyse tumour cells without prior sensitization, ascites-derived NK cells (ascites-NK cells) isolated from OCPs exhibit inhibitory phenotypes, impaired cytotoxicity and may play a pro-tumourigenic role in cancer progression. Therefore, it is of interest to improve the cytotoxic effector function of impaired OCP ascites-NK cells at the tumour environment. We investigated the efficacy of using an artificial APC-based ex vivo expansion technique to generate cytotoxic, expanded NK cells from previously impaired OCP ascites-NK cells, for use in an autologous model of NK cell immunotherapy. We are the first to obtain a log-scale expansion of OCP ascites-NK cells that upregulate the surface expression of activating receptors NKG2D, NKp30, NKp44, produce robust amounts of anti-tumour cytokines in the presence of OC cells and mediate direct tumour cytotoxicity against ascites-derived, primary OC cells obtained from autologous patients. Our findings demonstrate that it is possible to generate cytotoxic OCP ascites-NK cells from previously impaired OCP ascites-NK cells, which presents a promising immunotherapeutic target for the second-line treatment of OC. Future work should focus on evaluating the in vivo efficacy of autologous NK cell immunotherapy through the intraperitoneal delivery of NK cell expansion factors to a preclinical xenograft mouse model of human OC.

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Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1+ TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy

Abstract

Rectal cancer, which comprises 30% of all colorectal cancer cases, is one of the most common forms of cancer in the world. Patients with locally advanced rectal cancer (LARC) are often treated with neoadjuvant chemoradiotherapy (neoCRT) followed by surgery. However, after neoCRT treatment, approximately one-third of the patients progress to local recurrence or distant metastasis. In these studies, we found that patients with tumors that exhibited cytosolic HMGB1(Cyto-HMGB1) translocation and/or the presence of PD-1+ tumor-infiltrating lymphocytes (TILs) before treatment had a better clinical outcome. The better outcome is likely due to the release of HMGB1, which triggers the maturation of dendritic cells (DCs) via TLR4 activation, and the subsequent recruitment of PD-1+ tumor-infiltrating lymphocytes to the tumor site, where they participate in immune-scavenging. In conclusion, our results provide evidence that cyto-HMGB1 and/or PD-1+TIL are not only predictive biomarkers before treatment, but they can also potentially designate patients for personalized oncological management including immunotherapy.

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A novel biologic platform elicits profound T cell costimulatory activity and antitumor immunity in mice

Abstract

Combination immunotherapies utilizing complementary modalities that target distinct tumor attributes or immunosuppressive mechanisms, or engage different arms of the antitumor immune response, can elicit greater therapeutic efficacy than the component monotherapies. Increasing the number of agents included in a therapeutic cocktail can further increase efficacy, however, this approach poses numerous challenges for clinical translation. Here, a novel platform to simplify combination immunotherapy by covalently linking immunotherapeutic agonists to the costimulatory receptors CD134 and CD137 into a single heterodimeric drug, "OrthomAb", is shown. This reagent not only retains costimulatory T cell activity, but also elicits unique T cell functions that are not programmed by either individual agonist, and preferentially expands effector T cells over Tregs. Finally, in an aggressive melanoma model OrthomAb elicits better therapeutic efficacy compared to the unlinked agonists. This demonstration that two drugs can be combined into one provides a framework for distilling complex combination drug cocktails into simpler delivery platforms.

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Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach

Abstract

Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing. A suitable good manufacturing practice (GMP) environment is a key prerequisite and platform for the development, validation, and manufacture of such cell-based therapies, but may also represent a bottleneck for clinical translation. The German Cancer Consortium (DKTK) and the Paul-Ehrlich-Institut (PEI) have initiated joint efforts of researchers and regulators to facilitate and advance early phase, academia-driven clinical trials. Starting with a workshop held in 2016, stakeholders from academia and regulatory authorities in Germany have entered into continuing discussions on a diversity of scientific, manufacturing, and regulatory aspects, as well as the benefits and risks of clinical application of CAR/TCR-based cell therapies. This review summarizes the current state of discussions of this cooperative approach providing a basis for further policy-making and suitable modification of processes.

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Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model

Abstract

Vaccination with DNA that encodes cancer antigens is a simple and convenient way to raise immunity against cancer and has already shown promise in the clinical setting. Conventional plasmid DNA is commonly used which together with the encoded antigen also includes bacterial immunostimulatory CpG motifs to target the DNA sensor Toll-like receptor 9. Recently DNA vaccines using doggybone DNA (dbDNA™), have been developed without the use of bacteria. The cell-free process relies on the use of Phi29 DNA polymerase to amplify the template followed by protelomerase TelN to complete individual closed linear DNA. The resulting DNA contains the required antigenic sequence, a promoter and a poly A tail but lacks bacterial sequences such as an antibiotic resistance gene, prompting the question of immunogenicity. Here we compared the ability of doggybone DNA vaccine with plasmid DNA vaccine to induce adaptive immunity using clinically relevant oncotargets E6 and E7 from HPV. We demonstrate that despite the inability to trigger TLR9, doggybone DNA was able to induce similar levels of cellular and humoral immunity as plasmid DNA, with suppression of established TC-1 tumours.

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An IL-15 superagonist/IL-15Rα fusion complex protects and rescues NK cell-cytotoxic function from TGF-β1-mediated immunosuppression

Abstract

Natural killer (NK) cells are innate cytotoxic lymphocytes that play a fundamental role in the immunosurveillance of cancers. NK cells of cancer patients exhibit impaired function mediated by immunosuppressive factors released from the tumor microenvironment (TME), such as transforming growth factor (TGF)-β1. An interleukin (IL)-15 superagonist/IL-15 receptor α fusion complex (IL-15SA/IL-15RA; ALT-803) activates the IL-15 receptor on CD8 T cells and NK cells, and has shown significant anti-tumor activity in several in vivo studies. This in vitro study investigated the efficacy of IL-15SA/IL-15RA on TGF-β1-induced suppression of NK cell-cytotoxic function. IL-15SA/IL-15RA inhibited TGF-β1 from decreasing NK cell lysis of four of four tumor cell lines (H460, LNCap, MCF7, MDA-MB-231). IL-15SA/IL-15RA rescued healthy donor and cancer patient NK cell-cytotoxicity, which had previously been suppressed by culture with TGF-β1. TGF-β1 downregulated expression of NK cell-activating markers and cytotoxic granules, such as CD226, NKG2D, NKp30, granzyme B, and perforin. Smad2/3 signaling was responsible for this TGF-β1-induced downregulation of NK cell-activating markers and cytotoxic granules. IL-15SA/IL-15RA blocked Smad2/3-induced transcription, resulting in the rescue of NK cell-cytotoxic function from TGF-β1-induced suppression. These findings suggest that in addition to increasing NK cell function via promoting the IL-15 signaling pathway, IL-15SA/IL-15RA can function as an inhibitor of TGF-β1 signaling, providing a potential remedy for NK cell dysfunction in the immunosuppressive tumor microenvironment.

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Epstein–Barr virus strain heterogeneity impairs human T-cell immunity

Abstract

The Epstein–Barr virus (EBV) establishes lifelong infections in > 90% of the human population. Although contained as asymptomatic infection by the immune system in most individuals, EBV is associated with the pathogenesis of approximately 1.5% of all cancers in humans. Some of these EBV-associated tumors have been successfully treated by the infusion of virus-specific T-cell lines. Recent sequence analyses of a large number of viral isolates suggested that distinct EBV strains have evolved in different parts of the world. Here, we assessed the impact of such sequence variations on EBV-specific T-cell immunity. With the exceptions of EBNA2 and the EBNA3 family of proteins, an overall low protein sequence disparity of about 1% was noted between Asian viral isolates, including the newly characterized M81 strain, and the prototypic EBV type 1 and type 2 strains. However, when T-cell epitopes including their flanking regions were compared, a substantial proportion was found to be polymorphic in different EBV strains. Importantly, CD4+ and CD8+ T-cell clones specific for viral epitopes from one strain often showed diminished recognition of the corresponding epitopes in other strains. In addition, T-cell recognition of a conserved epitope was affected by amino acid exchanges within the epitope flanking region. Moreover, the CD8+ T-cell response against polymorphic epitopes varied between donors and often ignored antigen variants. These results demonstrate that viral strain heterogeneity may impair antiviral T-cell immunity and suggest that immunotherapeutic approaches against EBV should preferably target broad sets of conserved epitopes including their flanking regions.

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Combined sublethal irradiation and agonist anti-CD40 enhance donor T cell accumulation and control of autochthonous murine pancreatic tumors

Abstract

Tumor-reactive T lymphocytes can promote the regression of established tumors. However, their efficacy is often limited by immunosuppressive mechanisms that block T cell accumulation or function. ACT provides the opportunity to ameliorate immune suppression prior to transfer of tumor-reactive T cells to improve the therapeutic benefit. We evaluated the combination of lymphodepleting whole body irradiation (WBI) and agonist anti-CD40 (αCD40) antibody on control of established autochthonous murine neuroendocrine pancreatic tumors following the transfer of naïve tumor-specific CD8 T cells. Sublethal WBI had little impact on disease outcome but did promote T cell persistence in the lymphoid organs. Host conditioning with αCD40, an approach known to enhance APC function and T cell expansion, transiently increased donor T cell accumulation in the lymphoid organs and pancreas, but failed to control tumor progression. In contrast, combined WBI and αCD40 prolonged T cell proliferation and dramatically enhanced accumulation of donor T cells in both the lymphoid organs and pancreas. This dual conditioning approach also promoted high levels of inflammation in the pancreas and tumor, induced histological regression of established tumors, and extended the lifespan of treated mice. Prolonged survival was entirely dependent upon adoptive transfer, but only partially dependent upon IFNγ production by donor T cells. Our results identify the novel combination of two clinically relevant host conditioning approaches that synergize to overcome immune suppression and drive strong tumor-specific T cell accumulation within well-established tumors.

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Engaging Anaphase Catastrophe Mechanisms to Eradicate Aneuploid Cancers

Cancer cells often have supernumerary centrosomes that promote genomic instability, a pathognomonic feature of cancer. During mitosis, cancer cells with supernumerary centrosomes undergo bipolar cell division by clustering centrosomes into two poles. When supernumerary centrosome clustering is antagonized, cancer cells are forced to undergo multipolar division leading to death of daughter cells. This proapoptotic pathway, called anaphase catastrophe, preferentially eliminates aneuploid cancer cells and malignant tumors in engineered mouse models. Anaphase catastrophe occurs through the loss or inhibition of the centrosomal protein CP110, a direct cyclin-dependent kinase 1 (CDK1) and CDK2 target. Intriguingly, CP110 is repressed by the KRAS oncoprotein. This sensitizes KRAS-driven lung cancers (an unmet medical need) to respond to CDK2 inhibitors. Anaphase catastrophe-inducing agents like CDK1 and CDK2 antagonists are lethal to cancer cells with supernumerary centrosomes, but can relatively spare normal cells with two centrosomes. This mechanism is proposed to provide a therapeutic window in the cancer clinic following treatment with a CDK1 or CDK2 inhibitor. Taken together, anaphase catastrophe is a clinically tractable mechanism that promotes death of neoplastic tumors with aneuploidy, a hallmark of cancer. Mol Cancer Ther; 17(4); 1–8. ©2018 AACR.

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Ongoing brain rhythms shape I-wave properties in a computational model

Publication date: Available online 20 March 2018
Source:Brain Stimulation
Author(s): Natalie Schaworonkow, Jochen Triesch
BackgroundResponses to transcranial magnetic stimulation (TMS) are notoriously variable. Previous studies have observed a dependence of TMS-induced responses on ongoing brain activity, for instance sensorimotor rhythms. This suggests an opportunity for the development of more effective stimulation protocols through closed-loop TMS-EEG. However, it is not yet clear how features of ongoing activity affect the responses of cortical circuits to TMS.Objective/HypothesisHere we investigate the dependence of TMS-responses on power and phase of ongoing oscillatory activity in a computational model of TMS-induced I-waves.MethodsThe model comprises populations of cortical layer 2/3 (L2/3) neurons and a population of cortical layer 5 (L5) neurons and generates I-waves in response to TMS. Oscillatory input to the L2/3 neurons induces rhythmic fluctuations in activity of L5 neurons. TMS pulses are simulated at different phases and amplitudes of the ongoing rhythm.ResultsThe model shows a robust dependence of I-wave properties on phase and power of ongoing rhythms, with the strongest response occurring for TMS at maximal L5 depolarization. The amount of phase-modulation depends on stimulation intensity, with stronger modulation for lower intensity.ConclusionThe model predicts that responses to TMS are highly variable for low stimulation intensities if ongoing brain rhythms are not taken into account. Closed-loop TMS-EEG holds promise for obtaining more reliable TMS effects.



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Topographic and microscopic anatomical description of the emissary sinus of foramen ovale in adult humans

Publication date: Available online 20 March 2018
Source:Clinical Neurology and Neurosurgery
Author(s): Luciano César Pereira Campos Leonel, Severino Denício Gonçalves de Sousa, Edson Aparecido Liberti
ObjectiveAlthough the Emissary Sinus of Foramen Ovale (ESFO) was first described by Trolard in 1868, its definition remains confused and neglected in the medical literature. This structure represents a vein, two veins, a venous plexus, or a dural sinus? Does it really exist? To understand this topic, this work aimed to describe the anatomy, topography, and microscopic features of the ESFO, precisely characterizing its structure, routes and anatomical correlations.Patients and MethodsESFO from the skull's base of adults were dissected into fifty anatomical blocks and evaluated using Hematoxylin and Eosin, Picro-sirius red and Weigert staining, and by Scanning Electron Microscopy (SEM).ResultsESFO was always present between cavernous sinus and pterygoid plexus on both antimeres, its inferior route passing through the foramen ovale and/or sphenoidal emissary foramen (foramen of Vesalius), anterior to the mandibular branch of trigeminal nerve. Its microscopic arrangement resembled what was found on transverse sinus, that is composed by layers of collagen fibers oriented on transversal and longitudinal planes. It wasn't possible to identify the media and adventitial tunica, features seen in veins, and the elastic layer was very thin near its lumen. SEM analysis showed that, like the transverse sinus, the ESFO was composed by parallel cells that presented a rhombus shape containing central rounded nuclei.ConclusionIn summary, the venous channel passing through the foramen ovale and/or sphenoidal emissary foramen (foramen of Vesalius) is a dural venous sinus constituted by dura mater layers and should be considered during surgical approaches near the foramen ovale in the middle cranial fossa.



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Morphometric analysis of posterior fossa and craniovertebral junction in subtypes of Chiari Malformation

Publication date: Available online 20 March 2018
Source:Clinical Neurology and Neurosurgery
Author(s): Recep Basaran, Mustafa Efendioglu, Mehmet Senol, Selcuk Ozdogan, Nejat Isik
ObjectivesChiari malformations (CMs) are a group of disorders defined by anatomic anomalies of the cerebellum, brainstem, and craniovertebral junction (CVJ). In this study, we aimed to investigate morphometry of posterior fossa and CVJ in subtypes of CM and in control group, and to bring up a matter a correlation with demographic data and subtypes of CM.Patients and MethodsThe study group included patients managed for CM between 2012 and 2016 and control group. Radiological evaluation was studied by special programs and formulas. Intracranial volumes and morphometric datas of posterior fossa and CVJ were recorded retrospectively.ResultsOf the 141 patients, 91 had CM and 50 were control group participants. Mean age was 34.75. Patients were classified as CM-0 (n:10), CM-1 (n:45), CM-1.5 (n:21), CM-2 (n:15). There were statistically significance between Chiari subtypes by syringomyelia (SM) presence (p˂0.01), SM localization (p˂0.01), posterior fossa volume (PFV) (p˂0.01), length of clivus (LoC) and length of subocciput (LoSO) (p˂0.01 for both), angle between clivus and subocciput (C-SO angle) (p˂0.01), and clivo-dental angle (C-D angle) (p˂0.01).ConclusionOn morphometric comparison of CM subtypes we concluded that etiological differences lead to morphological differences. CM-2 has remarkable differences from both other subtypes and the control group.



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First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study, Published online: 21 March 2018; doi:10.1038/s41416-018-0057-2

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study

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An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes, Published online: 21 March 2018; doi:10.1038/s41416-018-0030-0

An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes

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NF1 mutations in conjunctival melanoma

NF1 mutations in conjunctival melanoma

<i>NF1</i> mutations in conjunctival melanoma, Published online: 21 March 2018; doi:10.1038/s41416-018-0046-5

NF1 mutations in conjunctival melanoma

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Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer, Published online: 21 March 2018; doi:10.1038/s41416-018-0053-6

Nationwide comprehensive human papillomavirus (HPV) genotyping of invasive cervical cancer

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Correction to: Health-Related Information-Seeking Behaviors and Preferences Among Mexican Patients with Cancer

Abstract

The original version of this article unfortunately contained a mistake. The name of "Viridiana Perez-Montessoro" is now corrected in the author group of this article. The original article has been corrected.

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Improved risk stratification by circulating tumor cell counts in pancreatic cancer

Purpose: Pancreatic cancer is one of the most devastating diseases with a 5-year survival rate of 3-5%. Here we investigated if circulating tumor cells (CTCs) may predict metastatic spread and survival in pancreatic cancer patients. Experimental Design: In a prospective study we enrolled 69 pancreatic cancer patients. In peripheral blood CTCs were identified by MACS enrichment (anti-cytokeratin/anti-EpCam) and subsequent automated analysis after combined anti-cytokeratin/anti-CD45/DAPI staining. CTC results were correlated to established clinicopathologic risk factors, detection of disseminated tumor cells (DTCs) in bone marrow and clinical outcome (follow up time: 48 months). Results: Median patient survival was 11 months (0-48 months). Thirty-eight patients were male and 31 female, and the majority received gemcitabine (58/69). CTCs were present in 23/69 patients (33.3%) ranging from 1-19 cells (17 with >1CTC). While clinicopathologic parameters and DTC status did not correlate with CTC incidence, progression-free survival (PFS) and overall survival (OS) were significantly reduced in CTC-positive patients in univariate (p=0.009, PFS; p=0.030, OS, both logrank) and multivariate analysis (HR: 4.543; CI: 1.549-13.329; p=0.006, PFS; HR: 2.093; CI: 1.081-4.050; p=0.028, OS, both Cox regression). Also within patients receiving chemotherapy, PFS was significantly reduced in CTC-positive patients in univariate (p=0.013) and multivariate (HR: 4.203; CI: 1.416-12.471; p=0.010) analysis. Conclusions:  CTCs affect the outcome of patients with pancreatic cancer independent from other risk factors, including patients receiving (adjuvant) cytotoxic therapy. CTC stratification may allow a better upfront identification of patients with a longer life span who might profit from new adjuvant therapies.

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Adjuvant treatment for POLE proofreading domain-mutant cancers: sensitivity to radiotherapy, chemotherapy, and nucleoside analogs

Purpose: Pathogenic POLE proofreading domain mutations are found in many malignancies where they are associated with ultramutation and favorable prognosis. The extent to which this prognosis depends on their sensitivity to adjuvant treatment is unknown, as is the optimal therapy for advanced-staged or recurrent POLE-mutant cancers. Experimental design: We examined the recurrence-free survival of women with POLE-mutant and POLE-wild-type endometrial cancers (ECs) in the observation arm of the randomized PORTEC-1 EC trial (N=245 patients with stage I EC for analysis). Sensitivity to radiotherapy and selected chemotherapeutics was compared between Pole-mutant mouse embryonic stem (mES) cells, generated using CRISPR-Cas9 (Pole mutations D275A/E275A, and cancer-associated P286R, S297F, V411L) and isogenic wild-type cell lines. Results: In the observation arm of the PORTEC-1 trial (N=245), women with POLE-mutant ECs (N=16) had an improved recurrence-free survival (10yr RFS 100% vs 80.1% for POLE-wild-type; HR=0.143, 95% CI=0.001-0.996, P=0.049). Pole mutations did not increase sensitivity to radiotherapy nor to chemotherapeutics in mES cells. In contrast, Pole-mutant cells displayed significantly increased sensitivity to cytarabine and fludarabine (IC50 Pole P286R-mutant vs wild-type: 0.05 vs 0.17 μM for cytarabine, 4.62 vs 11.1 μM for fludarabine; P <0.001 for both comparisons). Conclusions: The favorable prognosis of POLE-mutant cancers cannot be explained by increased sensitivity to currently used adjuvant treatments. These results support studies exploring minimization of adjuvant therapy for early-stage POLE-mutant cancers, including endometrial and colorectal cancers. Conversely, POLE mutations result in hypersensitivity to nucleoside analogs, suggesting the use of these compounds as a potentially effective targeted treatment for advanced-stage POLE-mutant cancers.

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Phase I Study of MEDI3617, a Selective Angiopoietin-2 Inhibitor Alone and Combined With Carboplatin/Paclitaxel, Paclitaxel, or Bevacizumab for Advanced Solid Tumors

Purpose: This first-in-human study aimed to determine the maximum tolerated dose (MTD) and safety of MEDI3617, a selective anti-angiopoietin-2 (Ang2) monoclonal antibody, alone and combined with bevacizumab or cytotoxic chemotherapy. Experimental Design: This phase I/Ib, multicenter, open-label, dose escalation and dose expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy (5-1500 mg every 3 weeks [Q3W]) or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W. Dose expansions included a monotherapy cohort in platinum-resistant ovarian cancer and a bevacizumab combination cohort in bevacizumab-refractory malignant glioma. Safety/tolerability, pharmacokinetics, pharmacodynamics, and clinical activity were assessed. Results: We enrolled 116 patients. No formal MTD was identified (monotherapy or combination therapy). MEDI3617 demonstrated linear pharmacokinetics and maximal accumulation of peripheral Ang2 binding at doses above 300 mg Q3W. MEDI3617 monotherapy safety profile was acceptable, except in advanced ovarian cancer (prolonged grade 3 edema-associated adverse events [AEs] occurred). Otherwise, MEDI3617 combined with chemotherapy or bevacizumab was well tolerated. The AE profiles of MEDI3617 and bevacizumab were largely non-overlapping. Overall response rates in ovarian cancer and glioma monotherapy dose expansion arms were 6% and 0%, respectively. Conclusions: Recommended MEDI3617 monotherapy dosage is 1500 mg Q3W or 1000 mg Q2W, except in ovarian cancer. Although peripheral edema has occurred with other Ang2 inhibitors, the severity and duration seen here in ovarian cancer potentially identifies a new, clinically significant safety signal for this class of agents. Based on limited clinical activity, MEDI3617 development was discontinued.

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Anaplastic lymphoma kinase mutation (ALK F1174C) in small cell carcinoma of the prostate and molecular response to alectinib

Purpose: Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise de novo or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase (ALK) gene are involved in neuroblastoma, lung cancer, and other malignancies but its role in SCCP has not been documented. We describe a patient with refractory de novo SCCP with ALK F1174C activating mutation who obtained clinical benefit from treatment with ALK inhibitor. Experimental Design: Next-generation sequencing (NGS) was used to analyze primary and circulating tumor DNA (ctDNA). Prostate cancer databases were queried for alterations in ALK gene, mRNA and its impact in clinical outcomes. In vitro prostate cell line/organoid models were generated by lentiviral-mediated expression of ALK and ALK F1174C and assessed for response to ALK inhibitors crizotinib and alectinib. Results: NGS analysis of the primary tumor and ctDNA of a 39-year old patient with refractory SSCP identified ALK F1174C mutation. Treatment with second-generation ALK inhibitor alectinib resulted in radiographic stable disease for over 6 months, symptomatic improvement, and significant molecular response as reflected by declining ctDNA allele fraction. Analysis of prostate cancer datasets showed that ALK amplification was associated with poor outcome. In prostate cancer cells and organoids, ALK F1174C expression enhanced growth and induced expression of the neuroendocrine marker neuron specific enolase. Alectinib was more effective than crizotinib in inhibiting ALK F1174C-expressing cell growth. Conclusions: These findings implicate ALK activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting ALK molecular alterations in some patients with SCCP.

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Letter from the Editor: Abdominal Imaging

This issue focuses on a variety of topics in abdominal imaging. The first articles were dedicated to emergent conditions and the subsequent ones review a wide range of benign and malignant lesions in various compartments of the abdomen and pelvis. The common thread highlighted throughout the volume is the essential role the radiologist plays in establishing the correct diagnosis.

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Nucleus basalis of Meynert degeneration precedes and predicts cognitive impairment in Parkinson’s disease

Abstract

Currently, no reliable predictors of cognitive impairment in Parkinson's disease exist. We hypothesized that microstructural changes at grey matter T₁-weighted MRI and diffusion tensor imaging in the cholinergic system nuclei and associated limbic pathways underlie cognitive impairment in Parkinson's disease. We performed a cross-sectional comparison between patients with Parkinson's disease with and without cognitive impairment. We also performed a longitudinal 36-month follow-up study of cognitively intact Parkinson's disease patients, comparing patients who remained cognitively intact to those who developed cognitive impairment. Patients with Parkinson's disease with cognitive impairment showed lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert, compared to patients with Parkinson's disease without cognitive impairment. These results were confirmed both with region of interest and voxel-based analyses, and after partial volume correction. Lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert was predictive for developing cognitive impairment in cognitively intact patients with Parkinson's disease, independent of other clinical and non-clinical markers of the disease. Structural and microstructural alterations in entorhinal cortex, amygdala, hippocampus, insula, and thalamus were not predictive for developing cognitive impairment in Parkinson's disease. Our findings provide evidence that degeneration of the nucleus basalis of Meynert precedes and predicts the onset of cognitive impairment, and might be used in a clinical setting as a reliable biomarker to stratify patients at higher risk of cognitive decline.

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Characterization of EEG signals revealing covert cognition in the injured brain

Abstract

Patients with severe brain injury are difficult to assess and frequently subject to misdiagnosis. 'Cognitive motor dissociation' is a term used to describe a subset of such patients with preserved cognition as detected with neuroimaging methods but not evident in behavioural assessments. Unlike the locked-in state, cognitive motor dissociation after severe brain injury is prominently marked by concomitant injuries across the cerebrum in addition to limited or no motoric function. In the present study, we sought to characterize the EEG signals used as indicators of cognition in patients with disorders of consciousness and examine their reliability for potential future use to re-establish communication. We compared EEG-based assessments to the results of using similar methods with functional MRI. Using power spectral density analysis to detect EEG evidence of task performance (Two Group Test, P ≤ 0.05, with false discovery rate correction), we found evidence of the capacity to follow commands in 21 of 28 patients with severe brain injury and all 15 healthy individuals studied. We found substantial variability in the temporal and spatial characteristics of significant EEG signals among the patients in contrast to only modest variation in these domains across healthy controls; the majority of healthy controls showed suppression of either 8–12 Hz 'alpha' or 13–40 Hz 'beta' power during task performance, or both. Nine of the 21 patients with EEG evidence of command-following also demonstrated functional MRI evidence of command-following. Nine of the patients with command-following capacity demonstrated by EEG showed no behavioural evidence of a communication channel as detected by a standardized behavioural assessment, the Coma Recovery Scale – Revised. We further examined the potential contributions of fluctuations in arousal that appeared to co-vary with some patients' ability to reliably generate EEG signals in response to command. Five of nine patients with statistically indeterminate responses to one task tested showed a positive response after accounting for variations in overall background state (as visualized in the qualitative shape of the power spectrum) and grouping of trial runs with similar background state characteristics. Our findings reveal signal variations of EEG responses in patients with severe brain injuries and provide insight into the underlying physiology of cognitive motor dissociation. These results can help guide future efforts aimed at re-establishment of communication in such patients who will need customization for brain–computer interfaces.

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