Detection of Hybrid Fusion Transcripts, Aberrant Transcript Expression, and Specific Single Nucleotide Variants in Acute Leukemia and Myeloid Disorders with Recurrent Gene Rearrangements.

INTRODUCTION: A variety of gene rearrangements and molecular alterations are key drivers in the pathobiology of acute leukemia and myeloid disorders; current classification systems increasingly incorporate these findings in diagnostic algorithms. Therefore, clinical laboratories require versatile tools, which can detect an increasing number and variety of molecular and cytogenetic alterations of clinical significance. METHODS: We validated an RNA-based next-generation sequencing (NGS) assay that enables the detection of: (i) numerous hybrid fusion transcripts (including rare/novel gene partners), (ii) aberrantly expressed EVI1 (MECOM) and IKZF1 (Del exons 4-7) transcripts, and (iii) hotspot variants in KIT, ABL1, NPM1 (relevant in the context of gene rearrangement status). RESULTS: For hybrid fusion transcripts, the assay showed 98-100% concordance for known positive and negative samples, with an analytical sensitivity (i.e., limit of detection) of approximately 0.8% cells. Samples with underlying EVI1 (MECOM) translocations demonstrated increased EVI1 (MECOM) expression. Aberrant IKZF1 (Del exons 4-7) transcripts detectable with the assay were also present on orthogonal reverse transcription PCR. Specific hotspot mutations in KIT, ABL1, and NPM1 detected with the assay showed 100% concordance with orthogonal testing. Lastly, several illustrative samples are included to highlight the assay's clinically relevant contributions to patient workup. CONCLUSION: Through its ability to simultaneously detect various gene rearrangements, aberrantly expressed transcripts, and hotspot mutations, this RNA-based NGS assay is a valuable tool for clinical laboratories to supplement other molecular and cytogenetic methods used in the diagnostic workup and in clinical research for patients with acute leukemia and myeloid disorders.

Novel Strategies for Evaluating and Improving Plastic Surgery Applicant Selection.

SUMMARY: Residency applicant evaluation and selection is a critical part of developing and maintaining a high-quality plastic surgery residency program. Currently, many programs rely on objective measures such as the United States Medical Licensing Exam scores, number of research publications, grade point average, Alpha Omega Alpha Honor Medical Society status, or a combination of these objective metrics. However, there is a growing body of literature suggesting that the current means of residency applicant evaluation and selection may not be the best predictive factors of future resident success. The aim of this study was to identify nontraditional means of evaluating plastic surgery residency candidates and discuss how these means have been implemented at the authors' institution. After reviewing industry hiring practices, the authors propose that standardized interviewing and personality testing can help evaluate some of the previously intangible parts of an applicant that may play a role in teamwork, commitment, and dedication to patient care.

MRI Features of Free Liquid Silicone in the Transgender Female Breast.

OBJECTIVE: To define MRI features of free liquid silicone injection (FLSI) of the breast in transgender women considering surgical management. METHODS: This study was IRB-approved. MRI images from transgender women with FLSI imaged between 2009 and 2019 were reviewed. Presence and location of fibrotic masses (FMs) in the breast(s) and pectoralis muscle and patterns of granulomas were correlated with clinicopathologic findings. Background enhancement was quantified. Comparisons were performed using two-tailed Fisher exact and Student's t test. RESULTS: Of 21 transgender women with FLSI (mean age 46.8 years), 13/21 (61.9%) had a dominant FM measuring over 4 cm; these were limited to breast and pectoralis in 6/21 (28.6%), breast in 9/21 (42.9%), and pectoralis only in 2/21 (9.5%). Four of 21 patients (19.0%) had no FMs, and 4/21 (19.0%) had masses under 4 cm. Mean size of the dominant FM was 7.4 cm (range 4-12 cm). FMs were enhancing in 5/13 (38.5%) and contained T2 high signal granulomas in 8/13 (61.5%). While 18/21 (85.8%) of cases showed mild to moderate overall background enhancement, the majority 7/13 (61.5%) of dominant FM were non-enhancing. About half of cases (11/21, 52.4%) had diffuse foci, and half (10/21, 47.6%) had diffuse foci and masses throughout the breast and pectoralis muscle. These foci and masses displayed T2 high signal in 13/21 (61.9%). There were no occult carcinomas observed. CONCLUSION: MRI performed on symptomatic FLSI patients considering surgical treatment is helpful in assessing the extent of silicone infiltration and fibrotic reaction of the breast and pectoralis muscle.

Impact of increasing age on functioning free muscle transplantation for facial palsy reconstruction.

BACKGROUND: Management of facial paralysis in older patients is controversial. The purpose of this study is to evaluate the impact of increasing age on functioning free muscle transplantation (FFMT). PATIENTS AND METHODS: Twenty-nine facial paralysis patients over 50 years old received FFMT. A separate group of patients aged 41-50 years old were included as control. Outcome assessments included use of the SMILE evaluation system for excursion, a cortical adaptation scoring system for brain plasticity, and a subjective satisfaction assessment score. Meta-analysis of literature over the past 50 years was also performed to examine the impact of older age. RESULTS: The mean change in excursion movement was 13.39 ± 5.49 mm. Weakest excursion was found in the oldest age group (11.74 ± 4.84 mm, p = .097), in concordance with the meta-analysis. There was significant difference between the three different neurotizers (p = .036). Excursion and satisfaction score were significantly worse in the older cohort with the cross face-nerve graft FFMT. CONCLUSIONS: FFMT is a viable option in the elderly patient group but performs weaker in excursion. The choice of neurotizer is dependent on the patient's goals and the suitable age at which the benefits outweigh the risks.

MORAb-202, an Antibody-Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity.

Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody-drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload.

Thoracic Outlet Syndrome: Past and Present-88 Surgeries in 30 Years at Chang Gung.

BACKGROUND: Thoracic outlet syndrome (TOS) is a highly controversial clinical entity. There is much debate on its terminology, existence, diagnosis, and treatment. The purpose of this study was to describe our opinions about these controversial topics of TOS and the treatment of TOS over the past 30 years. METHODS: From 1985 to 2014, a total of 80 patients underwent decompressive surgery for TOS. Eight patients requested a second surgery on the contralateral limb. They all had at least 1-year follow-up. Preoperative evaluation included provocative tests, plain X-ray, magnetic resonance angiography/computed tomography angiography, and electromyography. Surgical intervention for each patient involved a supraclavicular approach and near-total resection of the anterior scalene muscle and the first rib and of any cervical rib if it was present. Rib resection was performed with the use of Kerrison bone punch forceps. The operative time was typically 2 hours. RESULTS: Major postoperative complications were rare. Nearly all patients (98%) experienced significant symptom relief, with improvement in soreness and tightness of the shoulder, neck, and arm immediately on the first postoperative day or within a few weeks thereafter. There were no cases with symptoms recurring. CONCLUSIONS: It is evident that decompressive surgery through a supraclavicular approach for TOS not only is an effective and safe procedure but also provides a diagnosis of the cause of TOS. For a patient who meets the criteria for surgical indication, decompressive surgery usually results in resolution of symptoms and no recurrence.

The effect of systemic injury score on the decision making of mangled lower extremities.

PURPOSE: Mangled lower extremity with Mangled extremity severity score (MESS) more than 7 are considered unsalvageable. We are looking for a factor helps us predicting the salvage potential in the patient with MESS score between 7 and 9. MATERIALS AND METHODS: We reviewed the patients with lower extremities open fracture type IIIB or IIIC and received salvaged procedure or amputation in CGMH between 2002/01 and 2010/09. The patients are subgroup according to their MESS score. ISS score, Gustilo open fracture classification were compared between patient with successful salvage and patient with delay amputation. Logistic regression and stepwise modeling were used to determine the effect of each covariate. RESULTS: 242 patients were enrolled in the study. 33 patients had primary amputation, 160 patients had successfully salvaged limbs and 49 patients received delay amputation. Among patients with MESS score less than 7, 116 patients had successful salvage limbs and 7 patients received delay amputation. Among patient with MESS between 7 and 9, 44 patients discharged with salvaged limbs and 39 patients were failed to salvage their limbs. Successful salvaged patients in this group had significant lower ISS score in compare to delay amputated patients. Patients with ISS score more than 18 in this group has higher delay amputated rate (P value=0.01). CONCLUSION: Systemic injury severity score can help us tell potentially salvaged patient from potentially amputated patient. In patients with MESS score between 7 and 9 concurrently have ISS score less then 17 are potentially salvageable. Level of Evidence & Study Type: Level 3 Retrospective cohort study/prognostic study.

Proximal versus Distal Nerve Transfer for Biceps Reinnervation-A Comparative Study in a Rat's Brachial Plexus Injury Model.

BACKGROUND: The exact role of proximal and distal nerve transfers in reconstruction strategies of brachial plexus injury remains controversial. We compared proximal with distal nerve reconstruction strategies in a rat model of brachial plexus injury. METHODS: In rats, the C6 spinal nerve with a nerve graft (proximal nerve transfer model, n = 30, group A) and 50% of ulnar nerve (distal nerve transfer model, n = 30, group B) were used as the donor nerves. The targets were the musculocutaneous nerve and the biceps muscle. Outcomes were recorded at 4, 8, 12, and 16 weeks postoperatively. Outcome parameters included grooming test, biceps muscle weight, compound muscle action potentials, tetanic contraction force, and axonal morphology of the donor and target nerves. RESULTS: The axonal morphology of the 2 donor nerves revealed no significant difference. Time interval analysis in the proximal nerve transfer group showed peak axon counts at 12 weeks and a trend of improvement in all functional and physiologic parameters across all time points with statistically significant differences for grooming test, biceps compound action potentials, tetanic muscle contraction force, and muscle weight at 16 weeks. In contrast, in the distal nerve transfer group, the only statistically significant difference was observed between the 4 and 8 week time points, followed by a plateau from 8 to 16 weeks. CONCLUSIONS: Outcomes of proximal nerve transfers are ultimately superior to distal nerve transfers in our experimental model. Possible explanations for the superior results include a reduced need for cortical adaptation and higher proportions of motor units in the proximal nerve transfers.

A case of astroblastoma: Radiological and histopathological characteristics and a review of current treatment options.

BACKGROUND: Astroblastoma is a rare neuroepithelial tumor that often originates in the cerebral hemisphere of children and young adults. Diagnosis of this obscure neoplasm can be difficult because these tumors are so infrequently encountered and share common radiological and neuropathological features of other glial neoplasms. As such, it should be included in the differential diagnosis of astrocytoma and ependymoma if the clinical and radiographic features suggest it. Standardized treatment of astroblastomas remains under dispute because of the lack of knowledge regarding the tumor and a paucity of studies in the literature. CASE DESCRIPTION: We present a case of a low-grade astroblastoma diagnosed in a 30-year-old female with seizures, headache, and vision changes. She underwent gross total resection and, without evidence of high-grade features, adjuvant therapy was not planned postoperatively. Post-operative surveillance suggested early recurrence, warranting referral to radiation therapy. Patient ended up expiring despite adjuvant therapy secondary to extensive recurrence and tumor metastasis. CONCLUSIONS: Astroblastoma must be considered in the differential of supratentorial tumors in children and young adults. Treatment of such, as suggested by most recent literature, includes gross total resection and adjuvant radiotherapy for lesions exhibiting high-grade features.

An evolutionary perspective on the history of flap reconstruction in the upper extremity.

Examining the evolution of flap reconstruction of the upper extremity is similar to studying the evolution of biological species. This analogy provides a perspective to appreciate the contributing factors that led to the development of the current arsenal of techniques. It shows the trajectory for the future and provides a glimpse of the factors that that will be influential in the future.

Reconstruction of unicoronal plagiocephaly with a hypercorrection surgical technique.

OBJECT Successful surgical repair of unicoronal plagiocephaly remains a challenge for craniofacial surgeons. Many of the surgical techniques directed at correcting the stigmata associated with this craniofacial deformity (for example, ipsilateral supraorbital rim elevation [vertical dystopia], ipsilateral temporal constriction, C-shaped deformity of the face, and so on) are not long lasting and often result in deficient correction and the need for secondary revision surgery. The authors posit that the cause of this relapse was intrinsic deficiencies of the current surgical techniques. The aim of this study was to determine if correction of unilateral coronal plagiocephaly with a novel hypercorrection surgical technique could prevent the relapse of the characteristics associated with unicoronal plagiocephaly. METHODS The authors performed a retrospective analysis of 40 consecutive patients who underwent surgical repair of unicoronal plagiocephaly at their institution between 1999 and 2009. In all cases, the senior author (S.R.B.) used a hypercorrection technique for surgical reconstruction. Hypercorrection consisted of significant overcorrection of the affected ipsilateral frontal and anterior temporal areas in the sagittal and coronal planes. Demographic, perioperative, and follow-up data were collected for comparison. The postsurgical appearance of the forehead was documented clinically and photographically and then evaluated and scored by 2 independent graders using the expanded Whitaker scoring system. A relapse was defined as a recurrence of preoperative features that required secondary surgical correction. RESULTS The mean age of the patients at the time of the operation was 13 months (range 8-28 months). The mean follow-up duration was 57 months (range 3 months to 9.8 years). The postsurgical hypercorrection appearance persisted on average 6-8 months but gradually dissipated and normalized. No patients exhibited a relapse of unicoronal plagiocephalic characteristics that required surgical correction. In all cases the aesthetic results were excellent. Only 3 patients required reoperation for the management of persistent calvarial bone defects (2 cases) and removal of a symptomatic granuloma (1 case). CONCLUSIONS Our study demonstrates that patients who undergo unicoronal plagiocephaly repair with a hypercorrection surgical technique avoid long-term relapse. Our results suggest that the surgical technique used in the correction of unilateral coronal synostosis is strongly associated with the prevention of postsurgical relapse and that the use of this novel method decreases the need for surgical revision.

A systematic review of interethnic variability in facial dimensions.

BACKGROUND: The earliest recorded facial proportional analysis is in the Greek neoclassical canons (c. 450 b.c.). In contemporary times, there has not yet been a study that describes the relative differences in facial proportions among the world's different ethnic groups. The specific aim of this project was to perform a systematic review of data from the existing literature to evaluate the degree of variability in the facial dimensions among various ethnic groups. METHODS: A PubMed database review identified primary articles containing measurements of facial proportions from various ethnic groups. These facial measurements included the heights and widths of the upper, middle, and lower face, which are the features originally described by the neoclassical canons. Coefficients of variation were calculated to derive a unit-free comparison of the degree of variability among different ethnic groups in each of the neoclassically measured facial dimensions. RESULTS: The authors' literature search identified 239 potential articles. After screening for the inclusion and exclusion criteria, seven relevant articles were selected. These articles contained data on 11 linear facial measurements from 2359 male and female individuals from 27 different ethnic groups; features that demonstrated the largest differences among the different ethnic populations were forehead height, interocular distance, and nasal width. CONCLUSIONS: The greatest interethnic variability in facial proportions exists in the height of the forehead. More pronounced differences among the ethnic groups are also present in the measurements of the eyes, nose, and mouth. There is no significant difference between sexes in the neoclassical facial proportions.

HPV16 E7 oncogene expression in normal human epithelial cells causes molecular changes indicative of an epithelial to mesenchymal transition.

Cancer-associated epithelial to mesenchymal transition (EMT) is crucial for invasion and metastasis. Molecular hallmarks of EMT include down-regulation of the epithelial adhesion protein E-cadherin and de-novo expression of N-cadherin and the mesenchymal intermediate filament proteins vimentin and fibronectin. Expression of HPV16 E7 in normal human epithelial cells caused increased levels of vimentin and fibronectin, whereas the epithelial adhesion protein E-cadherin was expressed at decreased levels. Similar expression patterns of vimentin, fibronectin and E-cadherin were also detected in cells expressing HPV16 E6 and E7 or the entire HPV16 early transcriptional unit. HPV16 E6 and E7 were each able to induce N-cadherin expression. Interestingly, these changes in expression levels of EMT-associated proteins are not similarly reflected at the level of mRNA expression, suggesting that HPV16 oncoproteins also modulate EMT through non-transcriptional mechanisms. Hence, HPV16 oncoproteins may contribute to malignant progression through EMT induction.