Editorial.

No abstract available

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Management of Type I and Type II laryngeal clefts: controversies and evidence.

Purpose of review: To summarize the pediatric Type I and Type II laryngeal cleft literature, paying special attention to recent trends, including evolution of surgical techniques, standardization of outcome assessments, and utilization of management algorithms. Recent findings: There are a variety of options to choose from whenever considering Type I and Type II cleft repair, including endoscopic repair, transoral robotic surgery, and injection laryngoplasty. Conservative management including feeding therapy and treatment of comorbid medical conditions is recommended prior to repair. Validated outcome measures have arisen for swallow study interpretation and timing, as well as caregiver quality-of-life assessment. In addition, a series of medical algorithms have been proposed, which provide specific recommendations for diagnosis, treatment, and follow-up. Summary: For clefts that fail conservative management, endoscopic repair has become the gold standard. In addition, injection laryngoplasty appears to provide both a diagnostic and therapeutic option in the management of these patients. Transoral robotic-assisted endoscopic repair appears well tolerated and feasible, although broader implementation of this technology remains limited. The development and refinement of best practice algorithms can help standardize management and improve decision-making. Furthermore, incorporating validated outcome measures, recorded and followed over time, will improve both patient care and research efforts moving forward. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Change in Eyelid Position Following Muller's Muscle Conjunctival Resection With a Standard Versus Variable Resection Length.

Purpose: This study compares the use of a standard 7 mm resection length to a variable 4:1 ratio of resection length to desired elevation nomogram when performing Muller's muscle conjunctival resection surgery. Methods: In this cross-sectional case control study, 2 groups were defined. The first underwent Muller's muscle conjunctival resection surgery with a standard 7 mm resection length and the second underwent the same surgery with a variable resection length determined by a 4:1 ratio of resection length to desired elevation nomogram. Groups were matched for age (within 5 years) and sex. Pre- and postoperative photographs were measured digitally. Change in upper marginal reflex distance 1 (MRD1) and final MRD1 were the primary outcome measures. The study was powered to detect a 1 mm difference in MRD1 to a beta error of 0.95. Results: No significant preoperative differences between the groups were noted. No significant difference in final MRD1 (0.1 mm; p = 0.74) or change in MRD1 (0.2 mm; p = 0.52) was noted. Mean resection length to elevation ratios were 3.9:1 for standard group and 4.3:1 for the variable group (p = 0.54). Conclusion: The authors were not able to detect a significant difference in final MRD1 or change in MRD1 for patients undergoing Muller's muscle conjunctival resection surgery with standard or variable resection lengths. These results tend to argue against a purely mechanical mechanism for Muller's muscle conjunctival resection surgery. (C) 2017 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

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Effect of Time to Operative Intervention on Motility Outcomes Following Orbital Floor Fracture Repair in Children.

Purpose: To evaluate the relationship between time to surgical intervention and extraocular motility outcomes in children following repair of an orbital floor fracture with inferior rectus entrapment. Methods: After institution review board's approval, a retrospective, consecutive case series of 28 children with unilateral orbital floor fractures entrapping the inferior rectus muscle was conducted. Clinical examinations and CT images were performed on all children. The main outcomes measures were postoperative motility measurements. Results: Eleven patients underwent surgery within 24 hours of reported injury, while 17 patients underwent surgery after 24 hours. There was no statistically significant difference in average age at the time of surgery (p = 0.47) or average preoperative motility scores (p = 1.0) between the 2 groups. Patients who underwent surgery within 24 hours of reported injury had an improved likelihood of recovery (log hazard ratio = 0.469; 95% confidence interval, -0.42 to 1.36). Conclusions: Our exploratory study suggests that surgical reduction of inferior rectus entrapment in pediatric orbital floor fractures within 24 hours from the time of injury shows an improved, but nonstatistically significant, likelihood of recovery in motility deficits with earlier surgical intervention. (C) 2017 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

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Diffuse Staining for Activated NOTCH1 Correlates With NOTCH1 Mutation Status and is Associated With Worse Outcome in Adenoid Cystic Carcinoma.

NOTCH1 is frequently mutated in adenoid cystic carcinoma (ACC). To test the idea that immunohistochemical (IHC) staining can identify ACCs with NOTCH1 mutations, we performed IHC for activated NOTCH1 (NICD1) in 197 cases diagnosed as ACC from 173 patients. NICD1 staining was positive in 194 cases (98%) in 2 major patterns: subset positivity, which correlated with tubular/cribriform histology; and diffuse positivity, which correlated with a solid histology. To determine the relationship between NICD1 staining and NOTCH1 mutational status, targeted exome sequencing data were obtained on 14 diffusely NICD1-positive ACC specimens from 11 patients and 15 subset NICD1-positive ACC specimens from 15 patients. This revealed NOTCH1 gain-of-function mutations in 11 of 14 diffusely NICD1-positive ACC specimens, whereas all subset-positive tumors had wild-type NOTCH1 alleles. Notably, tumors with diffuse NICD1 positivity were associated with significantly worse outcomes (P=0.003). To determine whether NOTCH1 activation is unique among tumors included in the differential diagnosis with ACC, we performed NICD1 IHC on a cohort of diverse salivary gland and head and neck tumors. High fractions of each of these tumor types were positive for NICD1 in a subset of cells, particularly in basaloid squamous cell carcinomas; however, sequencing of basaloid squamous cell carcinomas failed to identify NOTCH1 mutations. These findings indicate that diffuse NICD1 positivity in ACC correlates with solid growth pattern, the presence of NOTCH1 gain-of-function mutations, and unfavorable outcome, and suggest that staining for NICD1 can be helpful in distinguishing ACC with solid growth patterns from other salivary gland and head and neck tumors. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Diagnostic Utility of SATB2 in Metastatic Krukenberg Tumors of the Ovary: An Immunohistochemical Study of 70 Cases With Comparison to CDX2, CK7, CK20, Chromogranin, and Synaptophysin.

SATB2 is a sensitive marker for colorectal adenocarcinomas. No study has investigated its diagnostic utility in metastatic Krukenberg tumors (MKTs) of the ovary. Here we performed immunohistochemical staining SATB2 in 70 MKTs of various origins (stomach 27, colorectum 13, appendix 20 including 19 metastatic adenocarcinomas ex goblet cell carcinoids [AdexGCC] and 1 conventional poorly differentiated carcinoma with signet ring cells, breast 5, bladder 3, lung 2) to assess its diagnostic utility. We also compared SATB2 with CDX2, CK7, CK20, chromogranin, and synaptophysin in MKTs of gastric origin (MKTs-stomach), those of colorectal origin (MKTs-colorectum) and those due to appendiceal AdexGCCs (MKT-AdexGCCs) for their sensitivity and specificity to distinguish these tumors. SATB2 staining was seen in 1/27 (4%) MKTs-stomach (40% cells), 7/13 (54%) MKTs-colorectum (mean: 17% cells, median: 7%, range: 2% to 60%), and 19/19 (100%) of MKT-AdexGCCs (mean: 97% cells, median: 100%, range: 80% to 100%) (P0.05) or synaptophysin (59%, 63%, 84%, respectively; P>0.05) but they had significant difference in CK7 staining (93%, 8%, 42%, respectively; P

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Radiologically Undetected Hepatocellular Carcinoma in Patients Undergoing Liver Transplantation: An Immunohistochemical Correlation With LI-RADS Score.

Orthotopic liver transplantation is the best option for patients with carefully selected unresectable disease because of underlying liver dysfunction. The 5-year survival rate after orthotopic liver transplantation for early detected hepatocellular carcinoma (HCC) is high, and a similar or even higher rate is reported in those with radiologically undetected HCC. This study evaluated and compared the histologic features of pretransplant radiologically undetected (14 patients, 25 tumors) versus detected (36 patients, 45 tumors) HCCs. Tumor size, tumor differentiation, number of unpaired arteries, mitotic count per 10 high-power fields, CD34 immunostain to assess microvessel density, and Ki67 immunostain were compared with the Liver Imaging Reporting and Data System score, which was retrospectively assigned to each tumor in both groups. The Liver Imaging Reporting and Data System score was significantly higher in the HCC detected group (P=2 cm, whereas 51% of the detected HCCs were >=2 cm in size. Higher rate of moderate to poor tumor differentiation was noted in the detected HCCs compared with the undetected group (89% vs. 60%; P=0.004). No statistically significant difference in the number and distribution of unpaired arteries, or mitotic count was observed in 2 groups (although fewer unpaired arteries were identified in the undetected group). The detected HCCs had a higher rate of 2+ CD34 staining compared with the undetected HCCs (68% vs. 27%; P=0.002), whereas the opposite was observed for 1+ CD34 staining (59% undetected HCCs vs. 17% detected HCCs; P=0.002). Ki67 proliferative index was not statistically different between the 2 groups (120.8/1000 cells detected HCCs vs. 81.8/1000 cells undetected HCCs; P=0.36). The factors associated with failing to detect HCCs pretransplant by radiologic studies include small tumor size (

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Optimizing Nipple Position following Nipple-Sparing Mastectomy.

Background: The best treatment for nipple malposition following nipple-sparing mastectomy is prevention. This article reviews basic elements for success in nipple-sparing mastectomy and offers an option to patients with grade 2-3 breast ptosis who strongly desire to preserve the nipple. Methods: Retrospective review identified patients undergoing nipple-sparing mastectomy and immediate reconstruction. Results: Patient selection centered on realistic goals for postoperative breast size, nipple position, and when not to save the nipple. The choice of device considered projection and nipple centralization as equal components and led to wider, lower profile devices selectively for the first stage of reconstruction. In severe grade 2-3 nipple ptosis, an inferior vertical incision or wedge excision was used to enhance nipple position postoperatively. Eighteen consecutive patients underwent 32 implant-based breast reconstructions following nipple-sparing mastectomy with the vertical incision. The average age was 45 years old, and the average body mass index was 26.7. Direct-to-implant reconstruction was performed in 25%, whereas 75% had tissue expander-implant reconstruction. Overall complications included infection (3%) and nipple necrosis (3%) leading to explant in 1 reconstruction. Conclusions: The final nipple position following nipple-sparing mastectomy can be optimized with preoperative planning. The vertical incision, combined with proper patient selection and choice of device, may increase eligibility for nipple- sparing procedures in patients with grade 2-3 ptosis who desire nipple preservation. 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. Copyright (C) 2017 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Validation of the Unilateral Cleft Lip Severity Index for Surgeons and Laypersons.

Background: Severity of the primary unilateral cleft lip/nose deformity (UCL/N) is postulated to play a key role in postoperative complications, aesthetic result, and need for secondary surgery. There is no validated and widely accepted classification scheme of initial cleft severity. The purpose of this study was to validate the Unilateral Cleft Lip Cleft Severity Index as a reliable tool for evaluating presurgical UCL/N deformity by both surgeons and laypersons. Methods: Twenty-five participants (10 surgeons and 15 laypeople) evaluated 25 sets of randomly selected presurgical standardized photographs of UCL/N patients. Each participant rated patients on a scale of 1-4 using the Cleft Severity Index. Interrater reliability for surgeons, laypersons, and all participants was determined using an intraclass correlation coefficient. Histograms and regression analysis were performed to compare average ratings between groups. Results: Interrater reliability for all groups was classified as 'very good' determined by intraclass correlation coefficients of 0.837 (laymen), 0.885 (surgeons), and 0.848 (all participants). These results indicate that there was a high degree of interrater across all 3 groups and that both surgeons and laypersons can reliability rate cleft severity using the Cleft Severity Index. Conclusions: This study validates the use of the Cleft Severity Index by both surgeons and laypersons as a reliable tool for evaluating the degree of presurgical severity of patients with UCL/N. The Unilateral Cleft Lip Cleft Severity Index can thus serve as a reproducible and reliable grading system for primary UCL/N deformity and to categorize patients for future outcomes studies. 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. Copyright (C) 2017 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Validation of a Unilateral Cleft Lip Surgical Outcomes Evaluation Scale for Surgeons and Laypersons.

Background: A standardized evaluation tool is needed for the assessment of surgical outcomes in cleft lip surgery. Current scales for evaluating unilateral cleft lip/nose (UCL/N) aesthetic outcomes are limited in their reliability, ease of use, and application. The Unilateral Cleft Lip Surgical Outcomes Evaluation (UCL SOE) scale measures symmetry of 4 components and sums these for a total score. The purpose of this study was to validate the SOE as a reliable tool for use by both surgeons and laypersons. Methods: Twenty participants (9 surgeons and 12 laypeople) used the SOE to evaluate 25 sets of randomly selected presurgical and postsurgical standardized photographs of UCL/N patients. Interrater reliability for surgeon and laypeople was determined using an intraclass correlation coefficient (ICC). Results: Individual surgeons and laypeople both reached an ICC in the 'fair to good' range (ICC = 0.42 and 0.59, respectively). Averaging 2 evaluators in the surgeon group improved the ICC to 0.58 and in the laypeople group to 0.74, respectively. Averaging 3 evaluators increased the ICC for surgeons to the 'good' range (ICC = 0.71) and the ICC for laypeople to the 'very good' range (ICC = 0.82). Conclusions: Surgeon and layperson raters can reliably use the SOE to assess the aesthetics results after surgical repair of UCL/N, and improved reliability and reproducibility is achieved by averaging the scores of multiple reviewers. 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. Copyright (C) 2017 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Managing Asthma in Low-Income, Underrepresented Minority, and Other Disadvantaged Pediatric Populations: Closing the Gap

Abstract

Purpose of Review

In this article, we review current understanding of the epidemiology and etiology of disparities in asthma. We also highlight current and emerging literature on solutions to tackle disparities while underscoring gaps and pressing future directions.

Recent Findings

Tailored, multicomponent approaches including the home, school, and clinician-based interventions show great promise.

Summary

Managing asthma in disadvantaged populations can be challenging as they tend to have disproportionately worse outcomes due to a multitude of factors. However, multifaceted, innovative interventions that are sustainable and scalable are key to improving outcomes.

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Acid–base safety during the course of a very low-calorie-ketogenic diet

Abstract

Background and Aims

Very low-calorie ketogenic (VLCK) diets have been consistently shown to be an effective obesity treatment, but the current evidence for its acid-base safety is limited. The aim of the current work was to evaluate the acid-base status of obese patients during the course of a VLCK diet.

Method

Twenty obese participants undertook a VLCK diet for 4 months. Anthropometric and biochemical parameters, and venous blood gases were obtained on four subsequent visits: visit C-1 (baseline); visit C-2, (1-2 months); maximum ketosis; visit C-3 (2-3 months), ketosis declining; and visit C-4 at 4 months, no ketosis. Results were compared with 51 patients that had an episode of diabetic ketoacidosis as well as with a group that underwent a similar VLCK diet in real life conditions of treatment.

Results

Visit C1 blood pH (7.37 ± 0.03); plasma bicarbonate (24.7 ± 2.5 mmol/l); plasma glucose (96.0 ± 11.7 mg/l) as well as anion gap or osmolarity were not statistically modified at four months after a total weight reduction of 20.7 kg in average and were within the normal range throughout the study. Even at the point of maximum ketosis all variables measured were always far from the cut-off points established to diabetic ketoacidosis.

Conclusion

During the course of a VLCK diet there were no clinically or statistically significant changes in glucose, blood pH, anion gap and plasma bicarbonate. Hence the VLCK diet can be considered as a safe nutritional intervention for the treatment of obesity in terms of acid-base equilibrium.

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Acid–base safety during the course of a very low-calorie-ketogenic diet

Abstract

Background and Aims

Very low-calorie ketogenic (VLCK) diets have been consistently shown to be an effective obesity treatment, but the current evidence for its acid-base safety is limited. The aim of the current work was to evaluate the acid-base status of obese patients during the course of a VLCK diet.

Method

Twenty obese participants undertook a VLCK diet for 4 months. Anthropometric and biochemical parameters, and venous blood gases were obtained on four subsequent visits: visit C-1 (baseline); visit C-2, (1-2 months); maximum ketosis; visit C-3 (2-3 months), ketosis declining; and visit C-4 at 4 months, no ketosis. Results were compared with 51 patients that had an episode of diabetic ketoacidosis as well as with a group that underwent a similar VLCK diet in real life conditions of treatment.

Results

Visit C1 blood pH (7.37 ± 0.03); plasma bicarbonate (24.7 ± 2.5 mmol/l); plasma glucose (96.0 ± 11.7 mg/l) as well as anion gap or osmolarity were not statistically modified at four months after a total weight reduction of 20.7 kg in average and were within the normal range throughout the study. Even at the point of maximum ketosis all variables measured were always far from the cut-off points established to diabetic ketoacidosis.

Conclusion

During the course of a VLCK diet there were no clinically or statistically significant changes in glucose, blood pH, anion gap and plasma bicarbonate. Hence the VLCK diet can be considered as a safe nutritional intervention for the treatment of obesity in terms of acid-base equilibrium.

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Editorial.

No abstract available

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Management of Type I and Type II laryngeal clefts: controversies and evidence.

Purpose of review: To summarize the pediatric Type I and Type II laryngeal cleft literature, paying special attention to recent trends, including evolution of surgical techniques, standardization of outcome assessments, and utilization of management algorithms. Recent findings: There are a variety of options to choose from whenever considering Type I and Type II cleft repair, including endoscopic repair, transoral robotic surgery, and injection laryngoplasty. Conservative management including feeding therapy and treatment of comorbid medical conditions is recommended prior to repair. Validated outcome measures have arisen for swallow study interpretation and timing, as well as caregiver quality-of-life assessment. In addition, a series of medical algorithms have been proposed, which provide specific recommendations for diagnosis, treatment, and follow-up. Summary: For clefts that fail conservative management, endoscopic repair has become the gold standard. In addition, injection laryngoplasty appears to provide both a diagnostic and therapeutic option in the management of these patients. Transoral robotic-assisted endoscopic repair appears well tolerated and feasible, although broader implementation of this technology remains limited. The development and refinement of best practice algorithms can help standardize management and improve decision-making. Furthermore, incorporating validated outcome measures, recorded and followed over time, will improve both patient care and research efforts moving forward. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Is Dexmedetomidine a Miracle Drug for Sedation in Patients With Neuroacanthocytosis With Involuntary Movements?.

No abstract available

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Susceptibility to Dengue Virus and Genetic Polymorphisms of Tumor Necrosis Factor Alpha: A Comment

Viral Immunology , Vol. 0, No. 0.


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Chikungunya Virus-Induced Arthritis: Role of Host and Viral Factors in the Pathogenesis

Viral Immunology , Vol. 0, No. 0.


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Distribution Patterns of the Vulnerable Vessels Around Cervical Nerve Roots: A Computed Tomography-Based Study.

Objective: The aim of the study was to evaluate the prevalence of vulnerable vessels around the target of cervical transforaminal epidural steroid injection at the C3-C7 cervical nerve root levels in a clinical setting. Design: Retrospective, cross-sectional study was conducted. Participants: Patients complaining of neck or arm pain with no previous surgical history and who had undergone both precontrast and contrast-enhanced neck computed tomography were included retrospectively. Results: In 26 (21.0%) of 124 patients, none of the vulnerable vessels around the target of cervical transforaminal epidural steroid injection around both sides of the C3-C7 nerve roots were observed. Of 248 cervical root levels, the C3 level had 103 vessels (41.5%), the C4 level had 110 vessels (44.4%), the C5 level had 98 vessels (39.5%), the C6 level had 59 vessels (23.8%), and the C7 level had 34 vessels (13.7%) close to each target nerve root. In addition, variations of the vertebral artery at the C4-C7 level were observed in 11 (8.9%) of 124 patients. Conclusions: To prevent unexpected critical complications involving injury to vulnerable vessels during cervical transforaminal epidural steroid injection, it is recommended to routinely evaluate the vulnerable vessels around the cervical nerve root with computed tomography or Doppler ultrasound before cervical transforaminal epidural steroid injection, especially for the upper cervical nerve root level. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Effect of Full-Length Carbon Fiber Insoles on Lower Limb Kinetics in Patients With Midfoot Osteoarthritis: A Pilot Study.

Objectives: We investigated the effects of full-length carbon fiber (FCF) insoles on gait, muscle activity, kinetics, and pain in patients with midfoot osteoarthritis (OA). Design: We enrolled 13 patients with unilateral midfoot OA (mild: Visual Analog Scale [VAS] range, 1-3; moderate, VAS range, 4-7) and healthy controls. All participants were asked to walk under two conditions: with and without FCF insole. The outcome measures were ground reaction force, quantitative gait parameters, electromyography activities and pain severity (VAS). Results: In the patients with moderate midfoot OA, significantly longer gait cycle and higher muscle activity of lower limb during loading-response phase were observed while walking without FCF insoles. In the mild midfoot OA group, there was no significant difference in VAS score (without, 2.0 +/- 1.0 vs. with, 2.0 +/- 0.5) with FCF insole use. However, significantly reduced VAS score (without, 5.5 +/- 1.4 vs. with, 2.0 +/- 0.5) and muscle activity of the tibialis anterior and increased muscle activity of gastrocnemius were observed in the moderate midfoot OA group by using an FCF insole (P

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Validation of the American Joint Commission on Cancer (8th edition) changes for patients with stage III gastric cancer: survival analysis of a large series from a Specialized Eastern Center

Abstract

The 8th edition of the TNM was released in 2016 and included major revisions, especially for stage III. We aimed to compare the prognostic value of the 7th and 8th editions of the AJCC TNM classification for stage III gastric cancer. Clinical data from 1557 patients operated on for stage III gastric cancer according to the 7th edition between 2007 and 2014 were analyzed and compared using the 7th and 8th TNM classifications. A proposed staging system was established, and the three systems were compared in terms of prognostic performance. The stage shifted for 669 (42.96%) patients. It shifted from IIIA to IIIB (one patient, 0.06%), IIIB to IIIA (230 patients, 14.8%), IIIB to IIIC (94 patients, 6.0%), and IIIC to IIIB (344 patients, 22.1%). However, the new AJCC subgroupings did not prove distinctive for survival levels between T3N3aM0 (stage IIIB) and T3N3bM0 (stage IIIC) or between T4aN3aM0 (stage IIIB) and T4aN3bM0 (stage IIIC) when <30 lymph nodes (LNs) were resected. The performance of the 8th edition (c-index, 0.614; 95% confidence interval [CI], 0.596–0.633) revealed no relevant improvement compared to the 7th edition (c-index, 0.624; 95% CI, 0.605–0.643). The proposed staging system generated the best prognostic stratification. The 8th TNM edition may not provide better accuracy in predicting the prognosis of stage III gastric cancer. The proposed staging system, comprised of a combination of the number of LNs harvested and the 7th and 8th AJCC classifications, may improve predictive capacities for stage III gastric cancer.

The aim of this study was to compare the prognostic value of the 7th and 8th editions of the AJCC TNM classification for stage III gastric cancer. Furthermore, a proposed staging system was established, and the three systems were compared in terms of prognostic performance.

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Comparative Study of the Photocatalytic Degradation of the Herbicide 2,4-D Using WO 3 /TiO 2 and Fe 2 O 3 /TiO 2 as Catalysts

Abstract

In this study, a comparison of the photocatalytic activity efficiency of the catalysts WO₃/TiO₂, Fe₂O₃/TiO₂, and TiO₂ in the degradation of the herbicide 2,4-D and its main by-product (2,4-dichlorophenol, 2,4-DCP), under natural sunlight, visible, and UV light, was carried out. The catalysts were synthesized by the sol-gel method. All the catalysts showed anatase crystalline phase, and they exhibited similar values of band gap, specific surface area, and crystallite size; however, different photocatalytic activity was observed under the different light sources. Complete degradation of 2,4-D and near to 89% of mineralization using WO₃/TiO₂ and Fe₂O₃/TiO₂ was achieved after 150 min under solar light, while using TiO₂ sol-gel, lower degradation rate was obtained. By using artificial light (UV and visible lamp), the degradation and mineralization rates were lower than those obtained under natural sunlight. The produced 2,4-DCP intermediate was completely degraded after 240 min under sunlight only with the modified catalysts.

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Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.

Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.

Results: The FGFR inhibitor–resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.

Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment. Clin Cancer Res; 23(18); 5527–36. ©2017 AACR.

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AACR Cancer Progress Report 2017: Harnessing Research Discoveries to Save Lives

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Detection of Driver and Resistance Mutations in Leptomeningeal Metastases of NSCLC by Next-Generation Sequencing of Cerebrospinal Fluid Circulating Tumor Cells

Purpose: Leptomeningeal metastases are more common in non–small cell lung cancer (NSCLC) with EGFR mutations. The diagnosis is difficult by traditional imaging only, and leads to poor understanding of resistance mechanisms of leptomeningeal metastases.

Experimental Design: We compared the CellSearch Assay, the Thinprep cytologic test (TCT), and brain magnetic resonance imaging (MRI) in 21 NSCLC patients with suspected leptomeningeal metastases. Next-generation sequencing that included 416 cancer-associated genes was also performed on cerebrospinal fluid circulating tumor cells (CSFCTC) of 19 patients.

Results: Twenty-one patients were diagnosed with leptomeningeal metastases, and CSFCTCs were captured by CellSearch in 20 patients (median, 969 CSFCTCs/7.5 mL; range, 27–14,888). CellSearch had a sensitivity of 95.2% for leptomeningeal metastases diagnosis, which was higher than that of TCT (12/21, 57.1%), MRI (10/21, 47.6%), and MRI plus TCT (19/21, 90.5%), respectively. CTCs were found only in 5 of 14 patients (median, 2 CTCs/7.5 mL; range, 2–4), which was a much lower ratio than CSFCTCs. Genetic profiles of CSFCTCs were highly concordant with molecular mutations identified in the primary tumor (17/19, 89.5%). The resistance gene EGFR T790M was detected in 7 of 9 patients with extracranial lesions, but was detected in only 1 of 14 CSFCTC samples. Other potential resistant mutations, such as MET amplification and ERBB2 mutation, were also identified in CSFCTCs.

Conclusions: CSFCTCs captured by CellSearch may be a more sensitive and effective way to diagnose leptomeningeal metastases, and may serve as a liquid biopsy medium for gene profiles in NSCLC patients with leptomeningeal metastases. Clin Cancer Res; 23(18); 5480–8. ©2017 AACR.

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Anti-CD137 and PD-1/PD-L1 Antibodies En Route toward Clinical Synergy

T-cell costimulation and coinhibition can be respectively exploited by blocking and agonist mAbs. Both strategies can be synergistically combined in mouse models. Early clinical results from combinations of anti–PD-1 mAbs in conjunction with agonist anti-CD137 (4-1BB) mAbs show excellent safety and promising efficacy. Clin Cancer Res; 23(18); 5326–8. ©2017 AACR.

See related article by Tolcher et al., p. 5349

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ATF3 Repression of BCL-XL Determines Apoptotic Sensitivity to HDAC Inhibitors across Tumor Types

Purpose: Histone deacetylase inhibitors (HDACi) are epigenome-targeting small molecules approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma. They have also demonstrated clinical activity in acute myelogenous leukemia, non–small cell lung cancer, and estrogen receptor–positive breast cancer, and trials are underway assessing their activity in combination regimens including immunotherapy. However, there is currently no clear strategy to reliably predict HDACi sensitivity. In colon cancer cells, apoptotic sensitivity to HDACi is associated with transcriptional induction of multiple immediate-early (IE) genes. Here, we examined whether this transcriptional response predicts HDACi sensitivity across tumor type and investigated the mechanism by which it triggers apoptosis.

Experimental Design: Fifty cancer cell lines from diverse tumor types were screened to establish the correlation between apoptotic sensitivity, induction of IE genes, and components of the intrinsic apoptotic pathway.

Results: We show that sensitivity to HDACi across tumor types is predicted by induction of the IE genes FOS, JUN, and ATF3, but that only ATF3 is required for HDACi-induced apoptosis. We further demonstrate that the proapoptotic function of ATF3 is mediated through direct transcriptional repression of the prosurvival factor BCL-X_L (BCL2L1). These findings provided the rationale for dual inhibition of HDAC and BCL-X_L, which we show strongly cooperate to overcome inherent resistance to HDACi across diverse tumor cell types.

Conclusions: These findings explain the heterogeneous responses of tumor cells to HDACi-induced apoptosis and suggest a framework for predicting response and expanding their therapeutic use in multiple cancer types. Clin Cancer Res; 23(18); 5573–84. ©2017 AACR.

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Precision Medicine in Pediatric Oncology: Translating Genomic Discoveries into Optimized Therapies

Survival of children with cancers has dramatically improved over the past several decades. This success has been achieved through improvement of combined modalities in treatment approaches, intensification of cytotoxic chemotherapy for those with high-risk disease, and refinement of risk stratification incorporating novel biologic markers in addition to traditional clinical and histologic features. Advances in cancer genomics have shed important mechanistic insights on disease biology and have identified "driver" genomic alterations, aberrant activation of signaling pathways, and epigenetic modifiers that can be targeted by novel agents. Thus, the recently described genomic and epigenetic landscapes of many childhood cancers have expanded the paradigm of precision medicine in the hopes of improving outcomes while minimizing toxicities. In this review, we will discuss the biologic rationale for molecularly targeted therapies in genomically defined subsets of pediatric leukemias, solid tumors, and brain tumors. Clin Cancer Res; 23(18); 5329–38. ©2017 AACR.

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Mechanism of Action and Clinical Impact of Ribociclib--Letter

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Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma

Purpose: Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve and pretreated BRAF-mutant melanoma.

Experimental Design: The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50–700 mg) or twice-daily (75–150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic BRAF-mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib.

Results: Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of BRAF V600E–mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300 mg once daily was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar–plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months [95% confidence interval (CI), 7.4–not reached (NR)]. In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9–3.7).

Conclusions: Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma. Clin Cancer Res; 23(18); 5339–48. ©2017 AACR.

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In Situ Vaccination after Accelerated Hypofractionated Radiation and Surgery in a Mesothelioma Mouse Model

Purpose: How best to sequence and integrate immunotherapy into standard of care is currently unknown. Clinical protocols with accelerated nonablative hypofractionated radiation followed by surgery could provide an opportunity to implement immune checkpoint blockade.

Experimental Design: We therefore assessed the impact of nonablative hypofractionated radiation on the immune system in combination with surgery in a mouse mesothelioma model. Blunt surgery (R1 resection) was used to analyze the short-term effect, and radical surgery (R0 resection) was used to analyze the long-term effect of this radiation protocol before surgery.

Results: Nonablative hypofractionated radiation led to a specific immune activation against the tumor associated with significant upregulation of CD8⁺ T cells, limiting the negative effect of an incomplete resection. The same radiation protocol performed 7 days before radical surgery led to a long-term antitumor immune protection that was primarily driven by CD4⁺ T cells. Radical surgery alone or with a short course of nonablative radiation completed 24 hours before radical surgery did not provide this vaccination effect. Combining this radiation protocol with CTLA-4 blockade provided better results than radiation alone. The effect of PD-1 or PD-L1 blockade with this radiation protocol was less effective than the combination with CTLA-4 blockade.

Conclusions: A specific activation of the immune system against the tumor contributes to the benefit of accelerated, hypofractionated radiation before surgery. Nonablative hypofractionated radiation combined with surgery provides an opportunity to introduce immune checkpoint blockades in the clinical setting. Clin Cancer Res; 23(18); 5502–13. ©2017 AACR.

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Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors

Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1–blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors.

Experimental Design: Utomilumab (0.45–5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method.

Results: Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations. Six patients (26.1%) had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8⁺ T cells was observed in responders versus nonresponders.

Conclusions: The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors. Clin Cancer Res; 23(18); 5349–57. ©2017 AACR.

See related commentary by Pérez-Ruiz et al., p. 5326

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Mouse PDX Trial Suggests Synergy of Concurrent Inhibition of RAF and EGFR in Colorectal Cancer with BRAF or KRAS Mutations

Purpose: To evaluate the antitumor efficacy of cetuximab in combination with LSN3074753, an analog of LY3009120 and pan-RAF inhibitor in 79 colorectal cancer patient-derived xenograft (PDX) models.

Experimental Design: Seventy-nine well-characterized colorectal cancer PDX models were employed to conduct a single mouse per treatment group (n = 1) trial.

Results: Consistent with clinical results, cetuximab was efficacious in wild-type KRAS and BRAF PDX models, with an overall response rate of 6.3% and disease control rate (DCR) of 20.3%. LSN3074753 was active in a small subset of PDX models that harbored KRAS or BRAF mutations. However, the combination treatment displayed the enhanced antitumor activity with DCR of 35.4%. Statistical analysis revealed that BRAF and KRAS mutations were the best predictors of the combinatorial activity and were significantly associated with synergistic effect with a P value of 0.01 compared with cetuximab alone. In 12 models with BRAF mutations, the combination therapy resulted in a DCR of 41.7%, whereas either monotherapy had a DCR of 8.3%. Among 44 KRAS mutation models, cetuximab or LSN3074753 monotherapy resulted in a DCR of 13.6% or 11.4%, respectively, and the combination therapy increased DCR to 34.1%. Molecular analysis suggests that EGFR activation is a potential feedback and resistant mechanism of pan-RAF inhibition.

Conclusions: MAPK and EGFR pathway activations are two major molecular hallmarks of colorectal cancer. This mouse PDX trial recapitulated clinical results of cetuximab. Concurrent EGFR and RAF inhibition demonstrated synergistic antitumor activity for colorectal cancer PDX models with a KRAS or BRAF mutation. Clin Cancer Res; 23(18); 5547–60. ©2017 AACR.

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Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer

Purpose: Chemokine receptor 1 (CXCR1) is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSCs). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSCs in human breast cancer xenografts. This phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in patients with metastatic breast cancer (MBC) (trial registration ID: NCT02001974).

Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a 3-day run-in with reparixin oral tablets three times a day, followed by paclitaxel 80 mg/m²/week (days 1, 8, and 15 for 28-day cycle) + reparixin tablets three times a day for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy.

Results: There were neither G4–5 adverse events nor serious adverse events related to study therapy and no interactions between reparixin and paclitaxel to influence their respective pharmacokinetic profiles. A 30% response rate was recorded, with durable responses >12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSCs.

Conclusions: Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally three times a day, was selected for further study in a randomized phase II trial (NCT02370238). Clin Cancer Res; 23(18); 5358–65. ©2017 AACR.

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Overexpression of RCC2 Enhances Cell Motility and Promotes Tumor Metastasis in Lung Adenocarcinoma by Inducing Epithelial-Mesenchymal Transition

Purpose: Investigate the role of regulator of chromosome condensation 2 (RCC2) on lung adenocarcinoma (LUAD) metastasis.

Experimental Design: Clinical specimens were used to assess the impact of RCC2 on LUAD metastasis. Mouse models, cytobiology, and molecular biology assays were performed to elucidate the function and underlying mechanisms of RCC2 in LUAD.

Results: RCC2 expression was frequently increased in LUADs (88/122, 72.13%). It was confirmed by analysis of a larger cohort of TCGA RNA-seq data containing 488 LUADs and 58 normal lung tissues (P < 0.001). Importantly, increased level of RCC2 was significantly associated with T status of tumor (P = 0.002), lymph node metastasis (P = 0.004), and advanced clinical stage (P = 0.001). Patients with LUAD with higher expression of RCC2 had shorter overall survival. Cox regression analysis demonstrated that RCC2 was an independent poorer prognostic factor for patients with LUAD. Moreover, forced expression of RCC2 promoted intrapulmonary metastasis in vivo and significantly enhanced LUAD cell migration, invasion, and proliferation in vitro. Further study found that RCC2 induced epithelial–mesenchymal transition (EMT) and also stimulated the expression of MMP-2 and MMP-9. In addition, RCC2 was able to activate JNK, while inhibition of JNK suppressed the effect of RCC2 on LUAD cell migration, invasion, EMT, and the expression of MMP-2 and MMP-9.

Conclusions: RCC2 plays a pivotal role in LUAD metastasis by inducing EMT via activation of MAPK–JNK signaling. Clin Cancer Res; 23(18); 5598–610. ©2017 AACR.

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A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers

Purpose: Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in approximately 20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with antitumor activity in FGFR1-amplified SQCLC cell lines and patient-derived xenografts.

Experimental Design: On the basis of these data, we performed a phase I study of AZD4547 in patients with previously treated stage IV FGFR1-amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses.

Results: Fifteen FGFR1-amplified patients were treated. The most common related adverse events (AE) were gastrointestinal and dermatologic. Grade ≥3–related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). Two of 15 patients (13.3%) were progression-free at 12 weeks, and the median overall survival was 4.9 months. Molecular tests, including next-generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry, showed poor correlation between gene amplification and expression, potential genomic modifiers of efficacy, and heterogeneity in 8p11 amplicon.

Conclusions: AZD4547 was tolerable at a dosage of 80 mg oral twice a day, with modest antitumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational covariates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease. Clin Cancer Res; 23(18); 5366–73. ©2017 AACR.

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Treatment of Pancreatic Cancer Patient-Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin

Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo antitumor efficacy of metabolic inhibitors, as single agents, in a panel of patient-derived PDAC xenograft models (PDX) and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors.

Experimental Design: Mice with established PDAC tumors from 6 to 13 individual PDXs were randomized and treated, once daily for 4 weeks, with either sterile PBS (vehicle) or the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), and mitochondrial complex I inhibitor phenformin/metformin.

Results: Among the agents tested, phenformin showed significant tumor growth inhibition (>30% compared with vehicle) in 5 of 12 individual PDXs. Metformin, at a fivefold higher dose, displayed significant tumor growth inhibition in 3 of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Gene set enrichment analysis conducted using the baseline gene expression profile of pancreatic tumors identified a gene expression signature that inversely correlated with phenformin sensitivity, which is in agreement with the phenformin gene expression signature of NIH Library of Integrated Network-based Cellular Signatures (LINCS). The PDXs that were more sensitive to phenformin showed a baseline reduction in amino acids and elevation in oxidized glutathione. There was no correlation between phenformin response and genetic alterations in KRAS, TP53, SMAD4, or PTEN.

Conclusions: Phenformin treatment showed relatively higher antitumor efficacy against established PDAC tumors, compared with the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished PDAC tumor progression and prolonged tumor doubling time. Overall, our results serve as a foundation for further evaluation of phenformin as a therapeutic agent in pancreatic cancer. Clin Cancer Res; 23(18); 5639–47. ©2017 AACR.

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Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis

Purpose: We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma.

Experimental Design: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, C_t, for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, ¹²³I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between C_t and progression-free survival (PFS).

Results: NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their C_t values were correlated (Spearman r = 0.67, P < 0.0001), although bone marrow C_t was 7.9 ± 0.5 C_t stronger than blood C_t. When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity (P < 0.0001 and P = 0.007). Bone marrow and blood C_t values correlated with PFS (P < 0.001; P = 0.001) even when bone marrow was morphologically negative (P = 0.001; P = 0.014). Multivariate analysis showed that bone marrow and blood C_t values were associated with PFS independently of clinical disease and MYCN gene status (P < 0.001; P = 0.055).

Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. Clin Cancer Res; 23(18); 5374–83. ©2017 AACR.

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Highlights of This Issue

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Mast cells derived from human induced pluripotent stem cells are useful for allergen tests

Publication date: Available online 14 September 2017
Source:Allergology International
Author(s): Akira Igarashi, Yasuhiro Ebihara, Tomoaki Kumagai, Hiroyuki Hirai, Kinya Nagata, Kohichiro Tsuji
BackgroundSeveral methods have been developed to detect allergen-specific IgE in sera. The passive IgE sensitization assay using human IgE receptor-expressing rat cell line RBL-2H3 is a powerful tool to detect biologically active allergen-specific IgE in serum samples. However, one disadvantage is that RBL-2H3 cells are vulnerable to high concentrations of human sera. Only a few human cultured cell lines are easily applicable to the passive IgE sensitization assay. However, the use of human induced pluripotent stem cells (iPSCs) to generate human mast cells (MCs) has not yet been reported.MethodsThe nuclear factor-kappa B (NF-κB)-responsive luciferase reporter gene was stably introduced into a human iPSC line 201B7, and the transfectants were induced to differentiate into MCs (iPSC-MCs). The iPSC-MCs were sensitized overnight with sera from subjects who were allergic to cedar pollen, ragweed pollen, mites, or house dust, and then stimulated with an extract of corresponding allergens. Activation of iPSC-MCs was evaluated by β-hexosaminidase release, histamine release, or luciferase intensity.ResultsiPSCs-MCs stably expressed high-affinity IgE receptor and functionally responded to various allergens when sensitized with human sera from relevant allergic subjects. This passive IgE sensitization system, which we termed the induced mast cell activation test (iMAT), worked well even with undiluted human sera.ConclusionsiMAT may serve as a novel determining system for IgE/allergens in the clinical and research settings.



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GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome

High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. Eliminating GUCY2C signaling exacerbated RIGS, amplifying radiation-induced mortality, weight loss, mucosal bleeding, debilitation, and intestinal dysfunction. Durable expression of GUCY2C, guanylin, and uroguanylin mRNA and protein by intestinal epithelial cells was preserved following lethal irradiation inducing RIGS. Oral delivery of the heat-stable enterotoxin (ST), an exogenous GUCY2C ligand, opposed RIGS, a process requiring p53 activation mediated by dissociation from MDM2. In turn, p53 activation prevented cell death by selectively limiting mitotic catastrophe, but not apoptosis. These studies reveal a role for the GUCY2C paracrine hormone axis as a novel compensatory mechanism opposing RIGS, and they highlight the potential of oral GUCY2C agonists (Linzess; Trulance) to prevent and treat RIGS in cancer therapy and nuclear disasters. Cancer Res; 77(18); 5095–106. ©2017 AACR.

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SOX5/6/21 Prevent Oncogene-Driven Transformation of Brain Stem Cells

Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult. Cancer Res; 77(18); 4985–97. ©2017 AACR.

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Methods of Academic Course Planning for Cancer Biology PhD Students to Enhance Knowledge of Clinical Oncology

Little is known about how clinical oncology concepts are taught to PhD students or the most effective methods of doing so. In this study, electronic surveys were sent to faculty and students at PhD training programs, assessing their institution's methods of clinical oncology education and their perspective on optimal approaches to clinical oncology education. Only 40.0% of students reported any clinical oncology component to their institution's training, and only 26.5% had a clinician on their graduate advisory committee. Forty-three percent of students believed that they had a good understanding for translating basic science research into clinical practice, and 77.2% of all participants believed dual degree MD/PhD students were superior to PhD students in this regard. Lectures on clinical oncology research topics were the most valuable type of experience for all participants and were also the most common type of experience utilized. Working with a clinician to develop a clinical trial with correlative endpoints was also highly valued, but was only utilized by approximately 10% of programs. Faculty rated the value of nearly all types of clinical oncology exposure significantly lower than did students. Inclusion of the approaches identified in this study is likely to enhance PhD training in oncology-related disciplines. Cancer Res; 77(18); 4741–4. ©2017 AACR.

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Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers

Early detection of metastasis can be aided by circulating tumor cells (CTC), which also show potential to predict early relapse. Because of the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood samples analyzed from 36 patients, PV had significantly higher number of CTCs compared with preoperative Pe (P < 0.0001) and intraoperative Pe (P < 0.001) blood. CTC clusters with large number of CTCs were observed in 50% of patients, with PV often revealing larger clusters. Long-term surveillance indicated that presence of clusters in preoperative Pe blood predicted a trend toward poor prognosis. Gene expression analysis by RT-qPCR revealed enrichment of p53 signaling and extracellular matrix involvement in PV and Pe samples. Ki67 expression was detected in 62.5% of PV samples and 59.2% of Pe samples, with the majority (72.7%) of patients positive for Ki67 expression in PV having single CTCs as opposed to clusters. Gene ontology analysis revealed enrichment of cell migration and immune-related pathways in CTC clusters, suggesting survival advantage of clusters in circulation. Clusters display characteristics of therapeutic resistance, indicating the aggressive nature of these cells. Thus, CTCs isolated from early stages of lung cancer are predictive of poor prognosis and can be interrogated to determine biomarkers predictive of recurrence. Cancer Res; 77(18); 5194–206. ©2017 AACR.

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Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation

In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. Cancer Res; 77(18); 4745–54. ©2017 AACR.

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HDAC1 Upregulation by NANOG Promotes Multidrug Resistance and a Stem-like Phenotype in Immune Edited Tumor Cells

Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here, we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell-cycle inhibitors CDKN2D and CDKN1B induced stem-like features. Silencing of TRIM17 and NOXA induced immune and drug resistance in tumor cells by increasing antiapoptotic MCL1. Importantly, HDAC inhibition synergized with Ag-specific adoptive T-cell therapy to control immune refractory cancers. Our results reveal that NANOG influences the epigenetic state of tumor cells via HDAC1, and they encourage a rational application of epigenetic modulators and immunotherapy in treatment of NANOG+ refractory cancer types. Cancer Res; 77(18); 5039–53. ©2017 AACR.

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Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755–62. ©2017 AACR.

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Cancer-Associated Fibroblasts Share Characteristics and Protumorigenic Activity with Mesenchymal Stromal Cells

Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship with MSCs is not clear. Here, we have isolated from primary human neuroblastoma tumors a population of αFAP- and FSP-1–expressing CAFs that share phenotypic and functional characteristics with bone marrow–derived MSCs (BM-MSC). Analysis of human neuroblastoma tumors also confirmed the presence of αFAP- and FSP-1–positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSCs) enhanced in vitro neuroblastoma cell proliferation, survival, and resistance to chemotherapy and stimulated neuroblastoma tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The protumorigenic activity of MSCs in vitro and in xenografted mice was dependent on the coactivation of JAK2/STAT3 and MEK/ERK1/2 in neuroblastoma cells. In a mouse model of orthotopically implanted neuroblastoma cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type of protumorigenic CAF in the tumor microenvironment of neuroblastoma and to STAT3 and ERK1/2 as mediators of their activity. Cancer Res; 77(18); 5142–57. ©2017 AACR.

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The Damaging Effect of Passenger Mutations on Cancer Progression

Genomic instability and high mutation rates cause cancer to acquire numerous mutations and chromosomal alterations during its somatic evolution; most are termed passengers because they do not confer cancer phenotypes. Evolutionary simulations and cancer genomic studies suggest that mildly deleterious passengers accumulate and can collectively slow cancer progression. Clinical data also suggest an association between passenger load and response to therapeutics, yet no causal link between the effects of passengers and cancer progression has been established. To assess this, we introduced increasing passenger loads into human cell lines and immunocompromised mouse models. We found that passengers dramatically reduced proliferative fitness (∼3% per Mb), slowed tumor growth, and reduced metastatic progression. We developed new genomic measures of damaging passenger load that can accurately predict the fitness costs of passengers in cell lines and in human breast cancers. We conclude that genomic instability and an elevated load of DNA alterations in cancer is a double-edged sword: it accelerates the accumulation of adaptive drivers, but incurs a harmful passenger load that can outweigh driver benefit. The effects of passenger alterations on cancer fitness were unrelated to enhanced immunity, as our tests were performed either in cell culture or in immunocompromised animals. Our findings refute traditional paradigms of passengers as neutral events, suggesting that passenger load reduces the fitness of cancer cells and slows or prevents progression of both primary and metastatic disease. The antitumor effects of chemotherapies can in part be due to the induction of genomic instability and increased passenger load. Cancer Res; 77(18); 4763–72. ©2017 AACR.

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Highlights from Recent Cancer Literature

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Huwe1 Sustains Normal Ovarian Epithelial Cell Transformation and Tumor Growth through the Histone H1.3-H19 Cascade

Ubiquitination-directed protein degradation is important in many cancers for tumor initiation and maintenance, and E3 ligases containing HECT domains are emerging as new therapeutic targets. In contrast to many other E3 ligases, the role of HUWE1 in ovarian cancer where HUWE1 is dysregulated has been unclear. Here we report that genetic deletion of Huwe1 in the mouse inhibits transformation of ovary surface epithelium cells without significantly affecting cell survival and apoptosis, and that Huwe1 deletion after tumors have been initiated inhibits tumor growth. In Huwe1-deficient cells, expression of histone H1.3 increased, inhibiting the expression of noncoding RNA H19. H19 silencing phenocopied the effects of Huwe1 deficiency, whereas H1.3 silencing partially rescued the expression of H19 and the Huwe1-null phenotype. Inducible silencing of HUWE1 in human ovarian cancer cells produced a similar phenotype. Mechanistically, HUWE1 bound and ubiquitinated H1.3, which was consequently marked for destruction by proteasomes. Our results establish that HUWE1 plays an essential role in promoting ovarian cancer. Cancer Res; 77(18); 4773–84. ©2017 AACR.

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Posttranscriptional Regulation of PARG mRNA by HuR Facilitates DNA Repair and Resistance to PARP Inhibitors

The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9–mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3′ untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP-1 protein binds and posttranslationally modifies HuR in PARPi-treated PDAC cells. In a mouse xenograft model of human PDAC, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared with PARPi therapy alone. Our results highlight the HuR–PARG axis as an opportunity to enhance PARPi-based therapies. Cancer Res; 77(18); 5011–25. ©2017 AACR.

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Hsp72 and Nek6 Cooperate to Cluster Amplified Centrosomes in Cancer Cells

Cancer cells frequently possess extra amplified centrosomes clustered into two poles whose pseudo-bipolar spindles exhibit reduced fidelity of chromosome segregation and promote genetic instability. Inhibition of centrosome clustering triggers multipolar spindle formation and mitotic catastrophe, offering an attractive therapeutic approach to selectively kill cells with amplified centrosomes. However, mechanisms of centrosome clustering remain poorly understood. Here, we identify a new pathway that acts through NIMA-related kinase 6 (Nek6) and Hsp72 to promote centrosome clustering. Nek6, as well as its upstream activators polo-like kinase 1 and Aurora-A, targeted Hsp72 to the poles of cells with amplified centrosomes. Unlike some centrosome declustering agents, blocking Hsp72 or Nek6 function did not induce formation of acentrosomal poles, meaning that multipolar spindles were observable only in cells with amplified centrosomes. Inhibition of Hsp72 in acute lymphoblastic leukemia cells resulted in increased multipolar spindle frequency that correlated with centrosome amplification, while loss of Hsp72 or Nek6 function in noncancer-derived cells disturbs neither spindle formation nor mitotic progression. Hence, the Nek6–Hsp72 module represents a novel actionable pathway for selective targeting of cancer cells with amplified centrosomes. Cancer Res; 77(18); 4785–96. ©2017 AACR.

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Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma

Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1–induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models. Our results offer preclinical proof of concept for use of a Chk1 inhibitor to safely enhance the efficacy of gemcitabine, particularly in aggressive KRAS-driven LKB1-deficient lung adenocarcinomas. Cancer Res; 77(18); 5068–76. ©2017 AACR.

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Nrf2 Mutagenic Activation Drives Hepatocarcinogenesis

Nrf2, a master regulator of oxidative stress, is considered a prominent target for prevention of hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide. Here we report that Nrf2-deficient mice resisted diethylnitrosamine (DEN)-induced hepatocarcinogenesis without affecting P450-mediated metabolic activation of DEN. Nrf2 expression, nuclear translocation, and transcriptional activity were enhanced in liver tumors. Overactivated Nrf2 was required for hepatoma growth in DEN-induced HCC. Following DEN treatment, Nrf2 genetic disruption reduced expression of pentose phosphate pathway-related enzymes, the depletion of which has been associated with an amelioration of HCC incidence. Conversely, enhanced Nrf2 activity was attributable to alterations in the ability to bind its endogenous inhibitor Keap1. Our findings provide a mechanistic rationale for Nrf2 blockade to prevent and possibly treat liver cancer. Cancer Res; 77(18); 4797–808. ©2017 AACR.

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CTLA4 Promotes Tyk2-STAT3-Dependent B-cell Oncogenicity

CTL–associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4–Tyk2–STAT3 signal pathway was also active in tumor-associated nonmalignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4-induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B-cell lymphoma proliferation and survival. Cancer Res; 77(18); 5118–28. ©2017 AACR.

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Spi-B-Mediated Silencing of Claudin-2 Promotes Early Dissemination of Lung Cancer Cells from Primary Tumors

Dissociation from epithelial sheets and invasion through the surrounding stroma are critical early events during epithelial cancer metastasis. Here we find that a lymphocyte lineage–restricted transcription factor, Spi-B, is frequently expressed in human lung cancer tissues. The Spi-B–expressing cancer cells coexpressed vimentin but repressed E-cadherin and exhibited invasive behavior. Increased Spi-B expression was associated with tumor grade, lymphatic metastasis, and short overall survival. Mechanistically, Spi-B disrupted intercellular junctions and enhanced invasiveness by reconfiguring the chromatin structure of the tight junction gene claudin-2 (CLDN2) and repressing its transcription. These data suggest that Spi-B participates in mesenchymal invasion, linking epithelial cancer metastasis with a lymphatic transcriptional program. Cancer Res; 77(18); 4809–22. ©2017 AACR.

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Adipose Progenitor Cell Secretion of GM-CSF and MMP9 Promotes a Stromal and Immunological Microenvironment That Supports Breast Cancer Progression

A cell population with progenitor-like phenotype (CD45-CD34+) resident in human white adipose tissue (WAT) is known to promote the progression of local and metastatic breast cancer and angiogenesis. However, the molecular mechanisms of the interaction have not been elucidated. In this study, we identified two proteins that were significantly upregulated in WAT-derived progenitors after coculture with breast cancer: granulocyte macrophage colony-stimulating factor (GM-CSF) and matrix metallopeptidase 9 (MMP9). These proteins were released by WAT progenitors in xenograft and transgenic breast cancer models. GM-CSF was identified as an upstream modulator. Breast cancer–derived GM-CSF induced GM-CSF and MMP9 release from WAT progenitors, and GM-CSF knockdown in breast cancer cells neutralized the protumorigenic activity of WAT progenitors in preclinical models. GM-CSF neutralization in diet-induced obese mice significantly reduced immunosuppression, intratumor vascularization, and local and metastatic breast cancer progression. Similarly, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth. Combined GM-CSF neutralization and MMP9 inhibition synergistically reduced angiogenesis and tumor progression. High-dose metformin inhibited GM-CSF and MMP9 release from WAT progenitors in in vitro and xenograft models. In obese syngeneic mice, metformin treatment mimicked the effects observed with GM-CSF neutralization and MMP9 inhibition, suggesting these proteins as new targets for metformin. These findings support the hypothesis that GM-CSF and MMP9 promote the protumorigenic effect of WAT progenitors on local and metastatic breast cancer. Cancer Res; 77(18); 5169–82. ©2017 AACR.

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CIB2 Negatively Regulates Oncogenic Signaling in Ovarian Cancer via Sphingosine Kinase 1

Sphingosine kinase 1 (SK1) is a key regulator of the cellular balance between proapoptotic and prosurvival sphingolipids. Oncogenic signaling by SK1 relies on its localization to the plasma membrane, which is mediated by the calcium and integrin binding protein CIB1 via its Ca2+-myristoyl switch function. Here we show that another member of the CIB family, CIB2, plays a surprisingly opposite role to CIB1 in the regulation of SK1 signaling. CIB2 bound SK1 on the same site as CIB1, yet it lacks the Ca2+-myristoyl switch function. As a result, CIB2 blocked translocation of SK1 to the plasma membrane and inhibited its subsequent signaling, which included sensitization to TNFα-induced apoptosis and inhibition of Ras-induced neoplastic transformation. CIB2 was significantly downregulated in ovarian cancer and low CIB2 expression was associated with poor prognosis in ovarian cancer patients. Notably, reintroduction of CIB2 in ovarian cancer cells blocked plasma membrane localization of endogenous SK1, reduced in vitro neoplastic growth and tumor growth in mice, and suppressed cell motility and invasiveness both in vitro and in vivo. Consistent with the in vitro synergistic effects between the SK1-specific inhibitor SK1-I and standard chemotherapeutics, expression of CIB2 also sensitized ovarian cancer cells to carboplatin. Together, these findings identify CIB2 as a novel endogenous suppressor of SK1 signaling and potential prognostic marker and demonstrate the therapeutic potential of SK1 in this gynecologic malignancy. Cancer Res; 77(18); 4823–34. ©2017 AACR.

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The Minimal Clinically Important Difference for the Rasch Neuropsychiatric Inventory Irritability and Aggression Scale for Traumatic Brain Injury

Publication date: Available online 14 September 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): James F. Malec, Flora M. Hammond
ObjectiveTo determine the Minimal Clinically Important Difference (MCID) for a Rasch measure derived from the Irritability/Lability and Agitation/Aggression subscales of the Neuropsychiatric Inventory (NPI-TBI-IA).DesignDistribution-based statistical methods were applied to retrospective data to determine candidates for the MCID. These candidates were evaluated by anchoring the NPI-TBI-IA to Global Impression of Change (GIC) ratings by participants, significant others, and a supervising physician.Main Outcome MeasureNPI-TBI-IA.SettingPostacute rehabilitation outpatient clinic.Participants274 cases with observer ratings; 232 cases with self-ratings by participants with moderate-severe TBI at least 6 months post-injury.ResultsFor observer ratings on the NPI-TBI-IA, anchored comparisons found an improvement of ½ SD was associated with at least minimal general improvement on GIC by a significant majority (69-80%); ½ SD improvement on participant NPI-TBI-IA self-ratings was also associated with at least minimal improvement on the GIC by a substantial majority (77-83%). The percent indicating significant global improvement did not increase markedly on most ratings at higher levels of improvement on the NPI-TBI-IA.ConclusionsA ½ SD improvement on the NPI-TBI-IA indicates the MCID for both observer and participant ratings on this measure.



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Benefits of the Restorative Exercise and Strength Training for Operational Resilience and Excellence Yoga Program for Chronic Lower Back Pain in Service Members: A Pilot Randomized Control Trial

Publication date: Available online 14 September 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Krista Beth Highland, Audrey Schoomaker, Winifred Rojas, Josh Suen, Ambareen Ahmed, Zhiwei Zhang, Sarah Fink Carlin, Christian Calilung, Michael Kent, Chester Buckenmaier
ObjectiveTo examine the feasibility and preliminary effectiveness of an individualized yoga program.DesignPilot randomized control trial.SettingMilitary medical center.ParticipantsPatients (N=68) with chronic LBP.InterventionsRestorative Exercise and Strength Training for Operational Resilience and Excellence (RESTORE) program (9-12 individual yoga sessions) or treatment-as-usual (control) for 8-week period.Main Outcome MeasuresThe primary outcome was past 24-hour pain scores (Defense and Veterans Pain Rating Scale). Secondary outcomes included disability (Roland-Morris Disability Questionnaire), physical functioning, and symptom burden (Patient Reported Outcomes Measurement Information System-29 subscales). Assessment occurred at baseline, Week 4, Week 8, 3-month follow-up, and 6-month follow-up. Exploratory outcomes included the proportion of participants in each group reporting clinically meaningful changes at 3-month and 6-month follow-ups.ResultsGeneralized linear mixed models with sequential Bonferroni-corrected pairwise significance tests and chi-square analyses examined longitudinal outcomes. Secondary outcome significance tests were Bonferroni-adjusted for multiple outcome tests. The RESTORE group reported improved pain, compared to the control group. Secondary outcomes did not retain significance after Bonferroni-adjustments for multiple outcomes. Though, a greater proportion RESTORE participants reported clinically-meaningfully changes in all outcome at 3-month follow-up and symptom burden at 6-month follow-up.ConclusionRESTORE may be a viable non-pharmacologic approach to LBP with minimal side effects and research efforts are needed to compare effectiveness of RESTORE delivery formats (e.g., group versus individual) or to other treatment modalities.



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Rasch Analysis, Dimensionality, and Scoring of the Neuropsychiatric Inventory (NPI) Irritability and Aggression Subscales in Individuals with Traumatic Brain Injury

Publication date: Available online 14 September 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): James F. Malec, Timothy E. Stump, Patrick O. Monahan, Jacob Kean, Dawn Neumann, Flora M. Hammond
ObjectiveTo develop, for versions completed by individuals with traumatic brain injury (TBI) and an observer, a more precise metric for the Neuropsychiatric Inventory (NPI) Irritability and Aggression scales using all behavioral item ratings for use with individuals with TBI and address the dimensionality of the represented behavioral domains.DesignRasch and confirmatory factor analyses of retrospective baseline NPI data from three treatment studies.SettingPostacute rehabilitation clinic.Participants287 cases with observer ratings; 238 cases with self-ratings by participants with complicated mild, moderate or severe TBI at least 6 months post-injury.Main Outcome MeasureFrequency and severity ratings from NPI Irritability/Lability and Agitation/Aggression subscales.ResultsConfirmatory factor analyses of both observer and participant ratings showed good fit for either a one-factor or two-factor solution. Consistent with this, the Rasch model also fit the data well with aggression items indicating the more severe end of the construct and irritability items populating the milder end.ConclusionsIrritability and aggression appear to represent different levels of severity of a single construct. The derived Rasch metric offers a measure of this construct based on responses to all specific items that is appropriate for parametric statistical analysis and may be useful in research and clinical assessments of individuals with TBI.



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Evaluation of delivery costs for external beam radiation therapy and brachytherapy for locally advanced cervical cancer using time-driven activity-based costing

Publication date: Available online 14 September 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Kristine Bauer-Nilsen, Colin Hill, Daniel M. Trifiletti, Bruce Libby, Donna H. Lash, Melody Lain, Deborah Christodoulou, Constance Hodge, Timothy N. Showalter
PurposeThis study aims to evaluate the delivery costs, using time-driven activity-based costing (TDABC), and reimbursement for definitive radiation therapy for locally advanced cervical cancer.Methods and MaterialsProcess maps were created to represent each step of the radiation treatment process and included personnel, equipment, and consumable supplies used to deliver care. Personnel were interviewed to estimate time involved to deliver care. Salary data, equipment purchasing information and facilities costs were also obtained. We defined the capacity cost rate (CCR) for each resource, and then calculated the total cost of patient care based upon CCR and time for each resource. Costs were compared to 2016 Medicare reimbursement and relative value units (RVUs).ResultsThe total cost of radiation therapy for cervical cancer was $12,861.68, with personnel costs comprising 49.8%. Brachytherapy cost $8,610.68 (66.9% of total) and consumed 423 minutes of attending radiation oncologist time (80.0% of total). EBRT cost $4,055.01 in costs (31.5% of total). Personnel costs were higher for brachytherapy than for the sum of simulation and EBRT delivery ($4,798.73 vs. $1,404.72). A full radiation therapy course provides radiation oncologists 149.77 RVUs with IMRT or 135.90 RVUs with 3DCRT, with total reimbursement of $23,321.71 and $16,071.90 respectively. Attending time per RVU is approximately 4-fold higher for brachytherapy (5.68 minutes) than 3DCRT (1.63 minutes) or IMRT (1.32 minutes).ConclusionTDABC was used to calculate the total cost of definitive radiation therapy for cervical cancer, revealing that brachytherapy delivery and personnel resources comprised the majority of costs. However, current reimbursement policy does not reflect the increased attending physician effort and delivery costs of brachytherapy. We hypothesize that the significant discrepancy between treatment costs and physician effort versus reimbursement may be a potential driver of reported national trends towards poor compliance with brachytherapy and suggest re-evaluation of payment policies to incentivize quality care.

Teaser

Time-driven activity-based costing methodology was applied to calculate the delivery costs of definitive radiation therapy for locally advanced cervical cancer. Brachytherapy was more costly and consumed more attending radiation oncologist time than external beam radiation therapy. Comparison of the delivery costs and physician time requirements to current reimbursement revealed a financial disincentive against brachytherapy, which should be studied as a potential contributor to the reported national poor compliance rates for cervical cancer brachytherapy.


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Stereotactic Body Radiotherapy as an Alternative to Transarterial Chemoembolization for Hepatocellular Carcinoma

Publication date: Available online 14 September 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Eli Sapir, Yebin Tao, Matthew J. Schipper, Latifa Bazzi, Paula M. Novelli, Paulina Devlin, Dawn Owen, Kyle C. Cuneo, Theodore S. Lawrence, Neehar D. Parikh, Mary Feng
BackgroundThere is little data to guide non-surgical treatment selection for patients with HCC. Therefore, we conducted a large, single institutional comparison of transarterial chemoembolization (TACE) and SBRT outcomes in similar groups of patients.MethodsFrom 2006 to 2014, 209 patients with 1-2 tumors underwent TACE (n=84) to 114 tumors or image-guided SBRT (n=125) to 173 tumors. Propensity score analysis with inverse probability of treatment weighting was used to compare outcomes between treatments while adjusting for imbalances in treatment assignment. Local control (LC), toxicity, and overall survival (OS) were retrospectively analyzed.ResultsTACE and SBRT groups were similar with respect to the number of tumors treated per patient, underlying liver disease and baseline liver function. Patients treated with SBRT were older (65 vs 61 yrs, p=0.01) and had smaller tumors (2.3 vs 2.9 cm, p < 0.001), and less frequently underwent liver transplantation (8% vs. 18%, p = 0.01). 1- and 2-yr LC favored SBRT: 97% and 91% for SBRT and 47% and 23%, for TACE (HR 66.5, p < 0.001). For patients treated with TACE, higher AFP (HR 1.11 per doubling, p =0.008) and segmental portal vein thrombosis (HR 9.9, p < 0.001) were associated with worse LC. Predictors associated with LC after SBRT were not identified. Grade 3+ toxicity occurred after 13% and 8% of TACE and SBRT treatments, respectively (p = 0.05). There was no difference in OS between patients treated with TACE or SBRT.ConclusionSBRT is a safe alternative to TACE for 1-2 tumors, and provides better LC, with no observed difference in OS. Prospective comparative trials of TACE and SBRT are warranted.



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Extreme Chromosome 17 Copy Number Instability is a Prognostic Factor in Patients with Gastroesophageal Adenocarcinoma: A Retrospective Cohort Study

Abstract

Gastric and esophageal cancers frequently show genomic instability and aneuploidy. Chromosomal copy number instability (CIN) is a form of genomic instability that exerts pleiotropic effects on cellular biology and is a source of genetic heterogeneity in a population of cells. CIN results in cell-to-cell variation in chromosome copy number which can be detected and quantified by fluorescence in situ hybridization (FISH). CIN is a biomarker associated with differential response to a number of chemotherapy compounds. We quantified chromosome 17 copy number instability (CIN-17) in 348 gastroesophageal adenocarcinomas by centromeric FISH in cases that were tested for HER2 amplification. We evaluated the association between CIN-17 and clinical outcome after surgical and non-surgical treatment. CIN-17 was detected in 45.4% (158/348) and extreme CIN-17 in 28.4% (99/348). Extreme CIN-17 had no association with outcome in surgically treated patients. However, in patients treated with conventional radiation and/or chemotherapy, extreme CIN-17 was associated with 55% reduction in overall mortality (hazard ratio, 0.448; 95% confidence interval, 0.263-0.763) after adjusting for age and clinical stage at diagnosis. Extreme CIN-17 is detected in over a quarter of gastroesophageal adenocarcinomas and is a favorable prognostic marker in patients treated non-operatively. This article is protected by copyright. All rights reserved.

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Newborn Thyroid Screening: Influence of Pre-Analytic Variables on Dried Blood Spot Thyrotropin Measurement

Thyroid Sep 2017, Vol. 27, No. 9: 1128-1134.


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Disease Severity at Presentation in Patients with Disease-Related Mortality from Differentiated Thyroid Cancer: Implications for the 2015 ATA Guidelines

Thyroid Sep 2017, Vol. 27, No. 9: 1171-1176.


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Future Meetings

Thyroid Sep 2017, Vol. 27, No. 9: 1211-1211.


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Idiopathic Low Ovarian Reserve Is Associated with More Frequent Positive Thyroid Peroxidase Antibodies

Thyroid Sep 2017, Vol. 27, No. 9: 1194-1200.


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Intermittent Dosing of Dabrafenib and Trametinib in Metastatic BRAFV600E Mutated Papillary Thyroid Cancer: Two Case Reports

Thyroid Sep 2017, Vol. 27, No. 9: 1201-1205.


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Clinical Implications of Immunoglobulin G4 to Graves' Ophthalmopathy

Thyroid Sep 2017, Vol. 27, No. 9: 1185-1193.


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Salvage brachytherapy for radiorecurrent prostate cancer: Searching for safety and success

Publication date: Available online 14 September 2017
Source:Brachytherapy
Author(s): Max Peters, Marinus A. Moerland, Jochem R.N. van der Voort van Zyp




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Multiple metastases to bone from squamous cell carcinoma of the oropharynx: unusual findings on positron emission tomography-computed tomography

Publication date: Available online 14 September 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): A. Sayan, Z.-B. Gonen, V. Ilankovan




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Dermoid cyst of the submandibular gland: case report

Publication date: Available online 14 September 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): H. Linnard, L. Newman, A.W. Barrett




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Preoperative screening for sickle cell disease and guidance from the National Institute for Health and Care Excellence (NICE)

Publication date: Available online 14 September 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): A. O'Connor, A. Power, A. Kanatas, J. Russell




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Survival after surgery for oral cancer: a 30-year experience

Publication date: Available online 13 September 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): T.K. Ong, C. Murphy, A.B. Smith, A.N. Kanatas, D.A. Mitchell
Oral squamous cell carcinoma is the most common intraoral malignancy, for which we advocate radical primary resection with adjuvant treatment where indicated. The main aims of this paper are to identify the overall survival of a consecutive series of patients and to relate survival to clinical and pathological factors. Kaplan–Meier curves were produced for site, sex, TNM status, and use of postoperative radiotherapy. The data were analysed using IBM SPSS Statistics for Windows and probabilities of less than 0.05 were accepted as significant. A total of 921 patients were recorded in the database with a diagnosis of oral squamous cell carcinoma out of a total of 1958 with salivary gland conditions or other cancers of the head and neck (43.1%). The earliest date of diagnosis was 1973, and the data were censored at 31 March 2016. The database comprised 340 women (36.9%) and 581 men (63.1%). A total of 339 patients died (34.5%): 117 women (33.7%) and 222 men (65.5%). The mean (range) age at death was 73.4 (31.4–97.5) years for women and 68.7 (33.3–95.5) years for men (t (337)=3.28, p=0.001). Our overall survival was somewhat better than the 56% five-year survival reported for oral cancer in England in 2010, which may be a reflection of the treatment. This work supports the view that aggressive management may improve overall survival.



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