Conceptual Principles in Pediatric Craniomaxillofacial Reconstruction.

Pediatric craniomaxillofacial reconstruction must be approached through the lens of growth and durability. A systematic approach of matching defects to donor tissue drives the selection of autologous reconstructive technique. The menu of available methods for reconstruction can be organized in a manner similar to adults, with special considerations for growth and development. Reconstructive surgeons have the opprtunity to promote and maintain young patients' sense of identity during psychosocial development.

Pediatric Cranial Vault Pathology.

A wide variety of diagnoses can be approached with a common framework for diagnosis, extirpation, and reconstruction of pediatric cranial vault pathologies. Durability of reconstruction is critical for the range of pediatric patients from infancy to adolescence. Rigid reconstruction, preferably with autologous tissue when possible, promotes brain protection and satisfactory aesthetic outcome. Careful planning can allow for immediate definitive reconstruction of defects without need for further surgical intervention.

Multidisciplinary Optimal Outcomes Reporting and Team Clinic Retention in Isolated Nonsyndromic Cleft Palate.

OBJECTIVE: Optimal Outcomes Reporting was recently introduced to categorize outcomes after cleft palate repair. We seek to propose an expanded version of Optimal Outcomes Reporting and to determine if correlation exists between the expanded outcomes and persistence with team care follow-up through age 9. DESIGN: Retrospective cohort study. SETTING: Cleft team at large pediatric hospital. PATIENTS: Patients with isolated nonsyndromic cleft palate (n = 83) born from 2001-2012. MAIN OUTCOME MEASURES: Patients who continued to present at age 5 or greater were assessed for optimal outcomes. Optimal outcomes were: surgery - no fistula or velopharyngeal insufficiency; otolaryngology - no obstructive sleep apnea or signs of chronic middle ear disease; audiology - no hearing loss; speech-language pathology - no assessed need for speech therapy. RESULTS: Of the 83 patients identified, 41 were assessed for optimal outcomes. Optimal outcome in any discipline was not associated with follow-up through age 9 (0.112 ≤ p ≤ 0.999). For all disciplines, the group with suboptimal outcomes had a higher proportion of patients from geographic areas in the most disadvantaged quartile of social vulnerability index, with the strongest association in the group with suboptimal speech outcome (OR 6.75, 95% CI 0.841-81.1). CONCLUSIONS: Optimal outcomes and retention in team clinic were not statistically significantly associated, but clinically relevant associations were found between patients in the most disadvantaged quartile of social vulnerability and their outcomes. A patient-centered approach, including caregiver education about long-term care for patients with cleft palate, would allow for enhanced resource utilization to improve retention for patients of concern.

Improving the Care of Our Patients: Twenty-Three Years of the James Barrett Brown Resident Research Day.

BACKGROUND: James Barrett Brown was one of the founders of Plastic and Reconstructive Surgery as a specialty in the United States. Susan Mackinnon started the James Barrett Brown Resident Research Day in 1997 in his honor to serve as an annual opportunity for trainees to present their research to the Division and a visiting contemporary leader in plastic surgery. We sought to determine the proportion of Resident Research Day projects that have progressed to publication. METHODS: Available internal records from 1998 to 2019 were used to identify presenters and projects. Academic productivity of presenters was estimated with the h-index from the Scopus database. RESULTS: One hundred forty-five students, residents, and fellows presented 276 projects at Resident Research Day from 1998 to 2019. These presentations were associated with 144 unique peer-reviewed publications, representing 52% of the presented projects. They were published an average of 1.8 years after presentation, and the presenter was the first or last author on 67% of them. The current average h-index of trainees who published at least 1 project (8.3) is significantly higher than the h-index of those who did not (5.0, P < 0.001). CONCLUSIONS: The James Barrett Brown Resident Research Day not only honors the legacy of Brown but also enhances scholarly activity of trainees. The opportunity to present and publish research teaches project planning, implementation, and data analysis, followed by manuscript preparation and the publication process. This important skill set can provide the foundation for the academic careers of future leaders in plastic surgery.

A Case of Nonsyndromic Craniosynostosis in an Infant Child of Jehovah's Witness Parents: Is Surgical Correction Appropriate?

An infant with nonsyndromic craniosynostosis is brought to clinic by his Jehovah's Witness parents to discuss treatment. Five potential courses of action are discussed in the context of biomedical ethics principles. The potential conflict between parents' autonomy to make decisions for their child and the surgeon's ethical duty of beneficence to the patient is explored.

Identifying Common Peroneal Neuropathy before Foot Drop.

BACKGROUND: Common peroneal neuropathy shares the same pathophysiology as carpal tunnel syndrome. However, management is often delayed because of the traditional misconception of recognizing foot drop as the defining symptom for diagnosis. The authors believe recognizing common peroneal neuropathy before foot drop can relieve pain and help improve quality of life. METHODS: One hundred eighty-five patients who underwent surgical common peroneal neuropathy decompression between 2011 and 2017 were included. The mean follow-up time was 249 ± 28 days. Patients were classified into two stages of severity based on clinical presentation: pre-foot drop and overt foot drop. Demographics, presenting symptoms, clinical signs, electrodiagnostic studies and response to surgery were compared between these two groups. Multivariate regression analysis was used to identify variables that predicted outcome following surgery. RESULTS: Overt foot drop patients presented with significantly lower preoperative motor function (percentage of patients with Medical Research Council grade ≤ 1: overt foot drop, 90 percent; pre-foot drop, 0 percent; p < 0.001). Pre-foot drop patients presented with a significantly higher preoperative pain visual analogue scale score (pre-foot drop, 6.2 ± 0.2; overt foot drop, 4.6 ± 0.3; p < 0.001) and normal electrodiagnostic studies (pre-foot drop, 31.4 percent; overt foot drop, 0.1 percent). Postoperatively, both groups of patients showed significant improvement in quality-of-life score (pre-foot drop, 2.6 ± 0.3; overt foot drop, 2.7 ± 0.3). Patients with obesity or a traumatic cause for common peroneal neuropathy were less likely to have improvements in quality of life after surgical decompression. CONCLUSION: Increased recognition of common peroneal neuropathy can aid early management, relieve pain, and improve quality of life. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Tissue Expander Complications Do Not Preclude a Second Successful Implant-Based Breast Reconstruction.

BACKGROUND: Implant-based breast reconstruction is the most common method of breast reconstruction in the United States, but the outcomes of subsequent implant-based reconstruction after a tissue expander complication are rarely studied. The purpose of this study was to determine the long-term incidence of implant loss in patents with a previous tissue expander complication. METHODS: This is a retrospective review of the long-term outcomes of all patients with tissue expander complications at a large academic medical center from 2003 to 2013. Patients with subsequent tissue expander or implant complications were compared to those with no further complications to assess risk factors for additional complications or reconstructive failure. RESULTS: One hundred sixty-two women were included in this study. The mean follow-up period was 8.3 ± 3.1 years. Forty-eight women (30 percent) went on to undergo a second tissue expander or implant placement. They did not differ from women who went on to autologous reconstruction or no further reconstruction. Of these, 34 women (71 percent) had no further complications and 38 women (79 percent) had a successful implant-based reconstruction at final follow-up. There were no patient or surgical factors significantly associated with a second complication or implant loss. CONCLUSIONS: Following tissue expander complications, it is reasonable to offer women a second attempt at tissue expansion and implant placement. This study demonstrates that long-term success rates are high, and there are no definitive patient or surgical factors that preclude a second attempt at implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Systemic Preoperative Antibiotics with Mandible Fractures: Are They Indicated at the Time of Injury?

Mandible fractures are the most common result of facial trauma. The proximity of oral flora to the site of both the injury and resulting surgical instrumentation makes managing infection a unique challenge. The benefit of antibiotic prophylaxis at the time of surgical treatment of mandible fractures is well established. However, the routine use of antibiotics between the time of injury and surgery is of unclear benefit. We aim to define the role of antibiotics in the preoperative period: from the time of injury to surgical intervention. Demographic and clinical data were collected retrospectively on all patients who were treated for mandible fracture by the Division of Plastic and Reconstructive Surgery at our institution between 2003 and 2013. The use of both preoperative (between injury and surgery) and perioperative (at the time of surgery) systemic antibiotics was recorded along with the incidence of postoperative infections and other complications. Complete data were available for 269 patients. Of the 216 patients who received preoperative antibiotics, 22 (10%) developed an infection postoperatively. Of the 53 patients who did not receive preoperative antibiotics, 2 (4%) developed infection ( p = 0.184). Likewise, preoperative antibiotics were not significantly associated with hardware complication rates. In our retrospective review, the use of antibiotics between injury and surgical repair had no impact on postoperative infection rates. These data suggest that preoperative antibiotic use may actually be associated with an increased incidence of postoperative infection. Our results do not support the routine use of antibiotics between injury and surgical repair in patients with mandible fractures.

Overuse of Chest CT in Patients With Stage I and II Breast Cancer: An Opportunity to Increase Guidelines Compliance at an NCCN Member Institution.

Background: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend that patients with clinical stage I/II breast cancer undergo advanced imaging for staging only when symptomatic. Regardless, many asymptomatic patients undergo chest CT. The goal of this study was to assess the use and results of chest CT in these patients at an NCCN Member Institution. Methods: Patients with breast cancer diagnosed between 1998 and 2012 were identified in a prospectively maintained database. All patients with clinical stage I/II disease who did not receive neoadjuvant chemotherapy were included. Data collected included demographics, tumor size, node status, chest CT within 6 months of diagnosis, imaging findings, need for additional workup, and identification of metastatic disease. Appropriate statistical tests were used for analysis. Results: From 1998 to 2012, 3,321 patients were diagnosed with early-stage breast cancer. Of these, 2,062 (62.1%) had clinical stage I breast cancer at diagnosis and 1,259 (37.9%) had stage II; 227 patients (11%) with stage I and 456 (36.2%) with stage II breast cancer received staging chest CT. Of patients undergoing CT, 184 (26.9%) were found to have pulmonary nodules, which measured ≤5 mm for 128 patients (69.6%), 5 to 10 mm for 46 patients (25.0%), 11 to 20 mm for 6 patients (3.2%), and ≥20 mm for 4 patients (2.2%). Patients undergoing chest CT for staging subsequently underwent a mean of 2.34 (range, 0-16) additional CTs in follow-up. Of all patients undergoing chest CT for staging, only 9 (1.3%) were ultimately diagnosed with pulmonary metastases at an average of 25 months (range, 0-97) after initial staging chest CT. Conclusions: A significant percentage of patients with stage I/II breast cancer underwent unnecessary chest CT as part of their initial workup. Nearly one-third of these patients were found to have pulmonary nodules, but only 1.3% were ever diagnosed with pulmonary metastases. Adherence to NCCN Guidelines will reduce the excessive use of CT chest imaging.

Staging studies have limited utility for newly diagnosed stage I-II breast cancer.

BACKGROUND: For stage I-II breast cancer, routine radiologic staging in the absence of symptoms suggesting distant metastasis is not recommended. This study aims to determine the yield of these studies at a National Comprehensive Cancer Network member institution. METHODS: Patients presenting with clinical stage I-II breast cancer between 1998 and 2012 were identified in a prospective database. Charts were reviewed to document staging studies (computed tomography, bone scan, and positron emission tomography) performed within 6 mo of diagnosis. Results and additional diagnostic procedures were recorded. Appropriate statistical tests were used for the analysis. RESULTS: A total of 3291 patients were included (2044 stage I and 1247 stage II). Eight hundred eighty-two patients (27%) received computed tomography, bone scan, or positron emission tomography within 6 mo of diagnosis. Three hundred twelve patients were stage I (15% of the stage I cohort) and 570 patients were stage II (46% of the stage II cohort). Patients receiving staging studies were more often younger and had estrogen receptor/progesterone receptor-negative or HER2/neu-positive tumors. Of the 882 patients, 194 (22%) required additional imaging and/or biopsies to further evaluate abnormalities. Only 11 of those (5%) were confirmed to have metastasis (1.2% of the imaged patients, 0.3% of the total cohort). Of these, 1 was stage I at presentation and 10 were stage II. CONCLUSIONS: Identification of distant metastasis among stage I-II patients was rare. Even among patients judged appropriate for staging, only 1.2% were diagnosed with metastatic disease. These findings suggest that even at a National Comprehensive Cancer Network member institution staging studies are overused and lead to additional testing in over 20% of patients.

Structural basis for VEGF-C binding to neuropilin-2 and sequestration by a soluble splice form.

Vascular endothelial growth factor C (VEGF-C) is a potent lymphangiogenic cytokine that signals via the coordinated action of two cell surface receptors, Neuropilin-2 (Nrp2) and VEGFR-3. Diseases associated with both loss and gain of VEGF-C function, lymphedema and cancer, respectively, motivate studies of VEGF-C/Nrp2 binding and inhibition. Here, we demonstrate that VEGF-C binding to Nrp2 is regulated by C-terminal proteolytic maturation. The structure of the VEGF-C C terminus in complex with the ligand binding domains of Nrp2 demonstrates that a cryptic Nrp2 binding motif is released upon proteolysis, allowing specific engagement with the b1 domain of Nrp2. Based on the identified structural requirements for Nrp2 binding to VEGF-C, we hypothesized that the endogenous secreted splice form of Nrp2, s9Nrp2, may function as a selective inhibitor of VEGF-C. We find that s9Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and cellular signaling. These data provide critical insight into VEGF-C/Nrp2 binding and inhibition.

Effect of C-terminal sequence on competitive semaphorin binding to neuropilin-1.

Neuropilins (Nrp) are type I transmembrane proteins that function as receptors for vascular endothelial growth factor (VEGF) and class III Semaphorin (Sema3) ligand families. Sema3s function as potent endogenous angiogenesis inhibitors but require proteolytically processing by furin to compete with VEGF for Nrp binding. This processing liberates a C-terminal arginine (CR) that is necessary for binding to the b1 domain of Nrp, a common feature shared by Nrp ligands. The CR is necessary but not sufficient for potent Nrp inhibition, and the role of upstream residues is unknown. We demonstrate that the second-to-last residue (C-1), immediately upstream of the CR, plays a significant role in controlling competitive ligand binding by orienting the C-terminus for productive Nrp binding. With the use of a peptide library derived from Sema3F, C-1 residues that preferentially adopt an extended bound-like conformation, including proline and ß-branched amino acids, were found to produce the most avid competitors. Consistent with this, analysis of the binding thermodynamics revealed that more favorable entropy is responsible for the observed binding enhancement of C-1 proline. We further tested the effect of the C-1 residue on Sema3F processing by furin and found an inverse relationship between processing and inhibitory potency. Analysis of all Sema3 family members reveals two non-equivalent furin processing sites differentiated by the presence of either a C-1 proline or a C-1 arginine and resulting in up to a 40-fold difference in potency. These data reveal a novel regulatory mechanism of Sema3 activity and define a fundamental mechanism for preferential Nrp binding.

Function of members of the neuropilin family as essential pleiotropic cell surface receptors.

The neuropilin (Nrp) family consists of essential multifunctional vertebrate cell surface receptors. Nrps were initially characterized as receptors for class III Semaphorin (Sema3) family members, functioning in axon guidance. Nrps have also been shown to be critical for vascular endothelial growth factor-dependent angiogenesis. Intriguingly, recent data show that Nrp function in these seemingly divergent pathways is critically determined by ligand-mediated cross-talk, which underlies Nrp function in both physiological and pathological processes. In addition to functioning in these two pathways, Nrps have been shown to specifically function in a number of other fundamental signaling pathways as well. Multiple general mechanisms have been found to directly contribute to the pleiotropic function of Nrp. Here we review critical general features of Nrps that function as essential receptors integrating multiple molecular cues into diverse cellular signaling.

Volume regulation and KCl cotransport in reticulocyte populations of sickle and normal red blood cells.

The potassium chloride co-transporter (KCC) is a member of the electroneutral cation chloride family of cotransporters found in multiple tissues that are involved in transepithelial ion transport and regulation of intracellular ion content and cell volume. We have shown previously that three of the four KCC genes - KCC1, KCC3, and KCC4 - are expressed in red blood cells (RBC) (Exp. Hem. 33:624, 2005). Functionally, the KCC mediates volume reduction of reticulocytes that establishes the higher cellular hemoglobin concentration (CHC) of mature RBC. KCC activity is higher in reticulocytes and diminishes with age. KCC activity in RBC containing sickle hemoglobin (SS RBC) is elevated compared to normal (AA RBC) in part due to reticulocytosis in SS blood. However, we have demonstrated that SS reticulocytes have abnormal regulation of KCC activity leading to increased CHC upon activation of KCC compared to AA reticulocytes (Blood 104:2954, 2004; Blood 109:1734, 2007). These findings implicate KCC as a factor in the dehydration of SS RBC, which leads to elevated Hb S concentration and enhances Hb S polymerization and hemolysis. Because KCC activity correlates with cell age, standard flux measurements on blood samples with different numbers of reticulocytes or young non-reticulocytes are not comparable. The Advia automated cell counter measures cell volume (MCV) and cellular hemoglobin concentration (CHC) in reticulocytes, an age-defined population of cells, and thus circumvents the problem of variable reticulocyte counts among SS and AA blood samples. In this study, reticulocyte CHC measurements on fresh blood demonstrated a clear difference between AA and SS cells, reflecting in vivo dehydration of SS reticulocytes, although there was significant inter-individual variation, and the CHC distributions of the two groups overlapped. After KCC activation in vitro by cell swelling using the nystatin method, the initial changes in reticulocyte MCV and CHC with time were used to estimate flux rates mediated by KCC, assuming that changes were associated with isotonic KCl movements. After 20-30min a final steady state MCV/CHC (set point) was achieved and maintained, reflecting inactivation of the transporter. CHC set points were 26.5-29g/dl in SS reticulocytes compared to 25-26.5g/dl in AA reticulocytes, reflecting abnormal regulation in SS cells. These results were reproducible in the same individual over time. KCC flux derived from CHC ranged from 5 to 10.3mmolK/kgHb/min in SS reticulocytes, compared to 2.9-7.2mmolK/kgHb/min in AA reticulocytes. Such measures of KCC activity in red cell populations controlled for cell age will facilitate further studies correlating KCC activity with phenotypic or genetic variability in sickle cell disease.