Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.

While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7-expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. TRAF7-mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7-driven meningiomas and developmental heart defects.

A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus.

Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016-23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients.

Scaffold association factor B (SAFB) is required for expression of prenyltransferases and RAS membrane association.

Inhibiting membrane association of RAS has long been considered a rational approach to anticancer therapy, which led to the development of farnesyltransferase inhibitors (FTIs). However, FTIs proved ineffective against KRAS-driven tumors. To reveal alternative therapeutic strategies, we carried out a genome-wide CRISPR-Cas9 screen designed to identify genes required for KRAS4B membrane association. We identified five enzymes in the prenylation pathway and SAFB, a nuclear protein with both DNA and RNA binding domains. Silencing SAFB led to marked mislocalization of all RAS isoforms as well as RAP1A but not RAB7A, a pattern that phenocopied silencing FNTA, the prenyltransferase α subunit shared by farnesyltransferase and geranylgeranyltransferase type I. We found that SAFB promoted RAS membrane association by controlling FNTA expression. SAFB knockdown decreased GTP loading of RAS, abrogated alternative prenylation, and sensitized RAS-mutant cells to growth inhibition by FTI. Our work establishes the prenylation pathway as paramount in KRAS membrane association, reveals a regulator of prenyltransferase expression, and suggests that reduction in FNTA expression may enhance the efficacy of FTIs.

Superficial temporal artery perforator flaps for reconstruction of intraoral defects.

BACKGROUND: Intraoral defects after tumor resection are often reconstructed with free tissue transfer. However, in patients who are not good candidates for free tissue transfer, regional flaps based on the superficial temporal artery can be utilized. The authors present our technique to reconstruct intraoral defects with the superficial temporal artery perforator (STAP) flap and early outcomes. METHODS: Five patients underwent STAP flaps for defects including the hard palate, buccal sulcus, floor of mouth, and retromolar trigone between 2017 and 2019. The mean defect size was 5.6 × 3.4 cm2 (3 × 3 cm2 - 7 × 4 cm2 ). The mean age was 74 (57-88) and all patients had recurrent cancer. External Doppler, indocyanine green laser angiography, and FLIR thermal imaging were used intra-operatively to identify the best perforators and plan for flap design. RESULTS: The mean flap size was 7.6 × 3.5 cm2 (6 × 3 cm2 - 10 × 5 cm2 ). Four flaps were based off of the posterior branch of the STA, while the fifth was based off of the anterior branch. Two donor sites were closed primarily, and three required skin grafts. One patient experienced partial flap necrosis. There were no complete flap losses and no donor site complications. Average follow up was 14.6 months (9-20 months). All patients maintained preoperative level of speech, mastication, and oral continence. CONCLUSIONS: The STAP flap can be based on the anterior or posterior branch of the superficial temporal artery and is a useful regional flap for intraoral defects after tumor resection.

Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-ß-dependent mechanisms.

Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-ß receptor expression and signaling, and blocking TGF-ß receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-ß signaling with BET bromodomain inhibition may offer new therapeutic benefits.

Use of FLIR ONE Smartphone Thermography in Burn Wound Assessment.

OBJECTIVE: Forward-looking infrared (FLIR) thermography technology uses a handheld camera that measures skin infrared emissivity, captures photographs, and can be analyzed through specialized software. Forward-looking infrared images can be used to analyze and correlate burn wound temperature with burn depth, burn progression, and the number of days needed for healing. FLIR ONE is a miniature, smartphone-compatible thermal imaging camera that has been used to assess inflammation in diabetic foot ulcers, as well as locating perforators in flap surgery. However, FLIR ONE's reliability in burn wound assessment has not been evaluated. This case series investigates the accuracy of FLIR ONE in comparison with the widely used indocyanine green (ICG) angiography in assessing burn wounds. METHODS: Five acute third-degree burn wounds were assessed using ICG angiography and FLIR ONE imaging (infrared thermography) to determine burn extent before surgical intervention. Patients were taken to the operating room within 48 hours of presentation; FLIR ONE images were captured approximately 35 to 45 cm above the wound surface. Margins of unsalvageable tissue as determined by ICG and FLIR ONE were marked and compared. RESULTS: The area of unsalvageable tissue as determined by FLIR ONE closely corresponded to the area determined by ICG. FLIR ONE overestimated unsalvageable tissue margins by approximately 1 to 2 cm. The area estimated by ICG consistently overlapped with more than 90% of the area estimated by FLIR ONE. CONCLUSIONS: There is a strong correlation between FLIR ONE and ICG when assessing salvageable tissue in third-degree burn wounds. FLIR ONE maximizes the convenience and cost-effectiveness of infrared thermography technology but may overestimate unsalvageable tissue area. FLIR ONE is promising as an adjunct to current imaging modalities such as ICG but requires further study for comparison.

Peripheral Pruning: A Safe Approach to Thinning Extra-Large Anterolateral Thigh Flaps.

BACKGROUND: Thinning of anterolateral thigh (ALT) flaps has been described to achieve optimal contouring. Previous studies caution against thinning large flaps owing to the risk of vascular compromise leading to partial or total flap necrosis. This study aims to demonstrate a reliably safe method for thinning extra-large (>240 cm) flaps. METHODS: A retrospective review of 53 consecutive ALT flaps performed at a single institution was completed. Of these flaps, 18 (34%) were thinned primarily by sharp excision of sub-Scarpa's fat along the periphery of the flap using loupe magnification. A central cuff of fat is left to surround and protect the perforator. RESULTS: There were 53 total flaps in our series. Eighteen of the flaps were thinned by peripheral pruning. Eleven (61%) of the flaps reconstructed defects of the lower extremity, whereas 4 (22%) reconstructed upper extremity defects and 3 (17%) reconstructed scalp defects (Table 1). The mean size of the thinned flap group was 35% larger than the nonthinned group (n = 18, 261 cm ± 109 cm vs n = 35, 192 cm ± 146 cm). Ten thinned flaps (55%) were extra large, with flap areas over 240 cm. The average amount of excised fat weighed 41 g ± 18 g. The average body mass index in the thinned flap group was 28.8 kg/m, which is classified as overweight. The average body mass index in the nonthinned flap group was 24.6 kg/m, which is classified as normal weight (Table 2). There were no cases of partial flap necrosis in the thinned flap group. A single case of total flap loss occurred in the thinned flap group secondary to hematoma formation during administration of therapeutic heparin for a mechanical heart valve. There were no other complications in the thinned flap group. CONCLUSIONS: This is the first study to demonstrate a reliable technique for primary thinning of extra-large ALT flaps in the Western population. No complications related to thinning were observed. Peripheral pruning of sub-Scarpa's fat is a safe and reliable method of thinning extra-large ALT flaps without increasing the risk of flap necrosis.

Pediatric Facial Fractures: An Assessment of Airway Management.

Pediatric facial fractures present unique and challenging management considerations, especially with regards to airway management. Anatomical differences in children increase both airway resistance and the difficulty of intubation. A surgical airway may be required if intubation is unable to be performed. The purpose of this study was to examine a single center's experience with pediatric facial fractures to determine the frequency of advanced airway use, as well as the risk factors that may predispose a patient to requiring an advanced airway. A retrospective review of all facial fractures at a level 1 trauma center was performed from 2000 to 2012. Patients age 18 years and younger were included. Patient demographics were collected, as well as location of fractures, concomitant injuries, services consulted, and surgical management strategies. Information was collected regarding the need for an advanced airway, including intubation and the need for a surgical airway. A total of 285 patients met inclusion criteria. Of these, 57 patients (20%) required emergency intubation and 5 (1.8%) required a surgical airway. Intubation was significantly related to fractures of the midface, frontal sinuses, spine, skull, and pelvis, as well as depressed Glasgow coma scores and traumatic brain injury. The need for a surgical airway is extremely uncommon (1.8%), and tracheostomy was only needed in the setting of penetrating head trauma. Both emergent intubation and tracheostomy are associated with complications, but these complications must be weighed against the potentially life-saving measure of securing an airway.

Microscopic versus open approach to craniosynostosis: a long-term outcomes comparison.

The purpose of this retrospective study was to evaluate the long-term outcomes of using the microscopic minimally invasive approach for the treatment of nonsyndromic craniosynostosis. During the last 10 years, 180 consecutive patients with nonsyndromic craniosynostosis were treated: 67 patients were treated with microscopic minimally invasive approach, and 113 were treated with the open approach. In the microscopic group, there was 1 intraoperative complication (1.5%). There were 10 postoperative complications (14.9%), of which 9 required major reoperations and 1 required a minor procedure. The major complications occurred in 7 unicoronal patients (58.3%) and 2 metopic patients (25.0%). In the open-approach group, there were 8 complications (7.1%), 2 patients required major reoperations and 6 required minor procedures. Chi-squared test showed that there was no statistically significant difference in the overall complication rate between the microscopic and open approaches. However, in the unicoronal patients, the complication rate was significantly higher in the microscopic group (P < 0.001). In conclusion, the microscopic approach is our treatment of choice in nonsyndromic patients with sagittal and lambdoidal craniosynostosis. We no longer use the microscopic approach in patients with unicoronal or metopic craniosynostosis because of the high complication rate.

CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow.

Intellectual and developmental disabilities result from abnormal nervous system development. Over a 1,000 genes have been associated with intellectual and developmental disabilities, driving continued efforts toward dissecting variant functionality to enhance our understanding of the disease mechanism. This report identified two novel variants in CC2D1A in a cohort of four patients from two unrelated families. We used multiple model systems for functional analysis, including Xenopus, Drosophila, and patient-derived fibroblasts. Our experiments revealed that cc2d1a is expressed explicitly in a spectrum of ciliated tissues, including the left-right organizer, epidermis, pronephric duct, nephrostomes, and ventricular zone of the brain. In line with this expression pattern, loss of cc2d1a led to cardiac heterotaxy, cystic kidneys, and abnormal CSF circulation via defective ciliogenesis. Interestingly, when we analyzed brain development, mutant tadpoles showed abnormal CSF circulation only in the midbrain region, suggesting abnormal local CSF flow. Furthermore, our analysis of the patient-derived fibroblasts confirmed defective ciliogenesis, further supporting our observations. In summary, we revealed novel insight into the role of CC2D1A by establishing its new critical role in ciliogenesis and CSF circulation.

Role of Ribeye PXDLS/T-binding cleft in normal synaptic ribbon function.

Non-spiking sensory hair cells of the auditory and vestibular systems encode a dynamic range of graded signals with high fidelity by vesicle exocytosis at ribbon synapses. Ribeye, the most abundant protein in the synaptic ribbon, is composed of a unique A domain specific for ribbons and a B-domain nearly identical to the transcriptional corepressor CtBP2. CTBP2 and the B-domain of Ribeye contain a surface cleft that binds to proteins harboring a PXDLS/T peptide motif. Little is known about the importance of this binding site in synaptic function. Piccolo has a well-conserved PVDLT motif and we find that overexpressed Ribeye exhibits striking co-localization with Piccolo in INS-cells, while two separate mutants containing mutations in PXDLS/T-binding region, fail to co-localize with Piccolo. Similarly, co-transfected Ribeye and a piccolo fragment containing the PVDLT region co-localize in HEK cells. Expression of wild-type Ribeye-YFP in zebrafish neuromast hair cells returns electron densities to ribbon structures and mostly rescued normal synaptic transmission and morphological phenotypes in a mutant zebrafish lacking most Ribeye. By contrast, Ribeye-YFP harboring a mutation in the PXDLS/T-binding cleft resulted in ectopic electron dense aggregates that did not collect vesicles and the persistence of ribbons lacking electron densities. Furthermore, overexpression failed to return capacitance responses to normal levels. These results point toward a role for the PXDLS/T-binding cleft in the recruitment of Ribeye to ribbons and in normal synaptic function.

A novel SMARCC1 -mutant BAFopathy implicates epigenetic dysregulation of neural progenitors in hydrocephalus.

Importance: Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery. A few familial forms of congenital hydrocephalus (CH) have been identified, but the cause of most sporadic cases of CH remains elusive. Recent studies have implicated SMARCC1 , a component of the B RG1- a ssociated factor (BAF) chromatin remodeling complex, as a candidate CH gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, CH-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo . Objectives: The aims of this study are to (i) assess the extent to which rare, damaging de novo mutations (DNMs) in SMARCC1 are associated with cerebral ventriculomegaly; (ii) describe the clinical and radiographic phenotypes of SMARCC1 -mutated patients; and (iii) assess the pathogenicity and mechanisms of CH-associated SMARCC1 mutations in vivo . Design setting and participants: A genetic association study was conducted using whole-exome sequencing from a cohort consisting of 2,697 ventriculomegalic trios, including patients with neurosurgically-treated CH, totaling 8,091 exomes collected over 5 years (2016-2021). Data were analyzed in 2023. A comparison control cohort consisted of 1,798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents sourced from the Simons simplex consortium. Main outcomes and measures: Gene variants were identified and filtered using stringent, validated criteria. Enrichment tests assessed gene-level variant burden. In silico biophysical modeling estimated the likelihood and extent of the variant impact on protein structure. The effect of a CH-associated SMARCC1 mutation on the human fetal brain transcriptome was assessed by analyzing RNA-sequencing data. Smarcc1 knockdowns and a patient-specific Smarcc1 variant were tested in Xenopus and studied using optical coherence tomography imaging, in situ hybridization, and immunofluorescence microscopy. Results: SMARCC1 surpassed genome-wide significance thresholds in DNM enrichment tests. Six rare protein-altering DNMs, including four loss-of-function mutations and one recurrent canonical splice site mutation (c.1571+1G>A) were detected in unrelated patients. DNMs localized to the highly conserved DNA-interacting SWIRM, Myb-DNA binding, Glu-rich, and Chromo domains of SMARCC1 . Patients exhibited developmental delay (DD), aqueductal stenosis, and other structural brain and heart defects. G0 and G1 Smarcc1 Xenopus mutants exhibited aqueductal stenosis and cardiac defects and were rescued by human wild-type SMARCC1 but not a patient-specific SMARCC1 mutant. Hydrocephalic SMARCC1 -mutant human fetal brain and Smarcc1 -mutant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2 . Conclusions: SMARCC1 is a bona fide CH risk gene. DNMs in SMARCC1 cause a novel human BAFopathy we term " S MARCC1- a ssociated D evelopmental D ysgenesis S yndrome (SaDDS)", characterized by cerebral ventriculomegaly, aqueductal stenosis, DD, and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodeling complex for human brain morphogenesis and provide evidence for a "neural stem cell" paradigm of human CH pathogenesis. These results highlight the utility of trio-based WES for identifying risk genes for congenital structural brain disorders and suggest WES may be a valuable adjunct in the clinical management of CH patients. KEY POINTS: Question: What is the role of SMARCC1 , a core component of the B RG1- a ssociated factor (BAF) chromatin remodeling complex, in brain morphogenesis and congenital hydrocephalus (CH)? Findings: SMARCC1 harbored an exome-wide significant burden of rare, protein-damaging de novo mutations (DNMs) (p = 5.83 × 10 -9 ) in the largest ascertained cohort to date of patients with cerebral ventriculomegaly, including treated CH (2,697 parent-proband trios). SMARCC1 contained four loss-of-function DNMs and two identical canonical splice site DNMs in a total of six unrelated patients. Patients exhibited developmental delay, aqueductal stenosis, and other structural brain and cardiac defects. Xenopus Smarcc1 mutants recapitulated core human phenotypes and were rescued by the expression of human wild-type but not patient-mutant SMARCC1 . Hydrocephalic SMARCC1 -mutant human brain and Smarcc1 -mutant Xenopus brain exhibited similar alterationsin the expression of key transcription factors that regulate neural progenitor cell proliferation. Meaning: SMARCC1 is essential for human brain morphogenesis and is a bona fide CH risk gene. SMARCC1 mutations cause a novel human BAFopathy we term " S MARCC1- a ssociated D evelopmental D ysgenesis S yndrome (SaDDS)". These data implicate epigenetic dysregulation of fetal neural progenitors in the pathogenesis of hydrocephalus, with diagnostic and prognostic implications for patients and caregivers.

Updates on Excisional Procedures for Lymphedema.

Significance: Excisional procedures for lymphedema have been used for over a century, and many surgeons have abandoned the old techniques as improvements in nonsurgical management and microsurgery have limited their clinical utility. Nonetheless, excisional procedures remain relevant as an important tool in the comprehensive surgical management of lymphedema. Recent Advances: Modifications to the Charles procedure and other direct excisional procedures have improved the complication profile and patient outcomes. Moreover, the use of liposuction techniques for minimally invasive tissue excision has expanded the scope of excisional surgery to benefit patients with less severe lymphedema. Recent operations combining excisional and physiologic procedures may prove to have superior results to stand-alone procedures. Critical Issues: No standard protocol exists for the comprehensive surgical management of lymphedema. Proper patient selection for any procedure requires robust outpatient assessment, cooperation with physiotherapy treatment teams, careful patient stratification, and a clear understanding of the procedure's goal. Future Directions: Larger, prospective trials will be needed to elucidate the ideal timing and combinations of techniques to optimize outcomes for patients with late-stage lymphedema.

Saved by the SPY: Ulnar Artery Reconstruction With LCFA Graft for Hypothenar Hammer Syndrome.

Introduction: Hypothenar Hammer syndrome refers to thrombosis/aneurysm of ulnar artery at Guyon's canal in wrist, with resultant arterial insufficiency in the ulnar artery distribution.1 Patients typically describe unilateral symptoms in the fourth and/or fifth fingers of the hand. Symptoms can range from asymptomatic to pain, pallor, paresthesia, weakness, cold intolerance, and eventually ulceration, necrosis, and gangrene of the distal digits.1 Treatment options range from conservative, lifestyle management, to medication, and ultimately to surgical intervention. In this case report, we outline the second successful lateral circumflex femoral artery (LCFA) graft reconstruction of the ulnar artery in the setting of Hypothenar Hammer Syndrome conducted by the senior author. However, during this procedure, the use of intraoperative intravenous (IV) injection of indocyanine green (ICG) dye (hereafter ICG) imaging helped identify an additional area of stenosis previously unseen on pre-operative MRA, therefore enabling us to perform a more adequate resection and repair. To our knowledge, the use of intraoperative ICG for Hypothenar Hammer Syndrome and/or ulnar artery reconstruction has not been documented in the literature.

Ultrahigh Frequency Ultrasound Imaging of the Hand: A New Diagnostic Tool for Hand Surgery.

BACKGROUND: Ultrasonography is a cost-effective, noninvasive, and expedient imaging modality with numerous clinical applications. Conventional ultrasound uses transducers with frequencies that range from 5 to 12 MHz. However, ultrahigh frequency ultrasound (UHFUS) is capable of producing frequencies up to 70 MHz, which can achieve tissue resolution up to 30 µm. The purpose of our study is to present the capabilities of a novel technology and to describe its possible clinical applications for hand surgery. METHODS: The Vevo 2100 (VisualSonics, Toronto, Canada) system was used to perform all ultrasound exams. Four unique linear array transducers were employed. All studies were performed by the authors, who have no formal training in ultrasound techniques, on 5 healthy resident volunteers and 1 clinical patient under institutional review board approval. RESULTS: A series of 10 static images per participant and dynamic, real-time videos were obtained at various locations within the hand and wrist. UHFUS is capable of quickly and reliably imaging larger structures such as foreign bodies, soft tissue masses, and the flexor tendons, and diagnosing an array of pathologies within these structures. In addition, UHFUS can identify much finer structures such as the intimal layer of the arteries in the hand and individual fascicles within the digital nerves to provide data about vessel quality and vascular and neural pathologies. CONCLUSIONS: UHFUS is a novel technology that shows multiple advantages over conventional ultrasound for imaging the fine superficial structures of the hand and wrist, and can be deployed by the surgeon at the point of care.

Bowler's Thumb: Case Report and Review of the Literature.

OBJECTIVE: Traumatic neuropathy of the ulnar digital nerve of the thumb occurs in patients who undergo chronic frictional irritation of the nerve. The condition is aptly termed bowler's thumb, as it commonly afflicts patients who bowl and keep their thumb in the ball for an extended period of time. It is a pathology that rarely appears in the literature and for which standard treatment is unclear. METHODS: A 68-year-old man with a history of avid bowling presented with a chief complaint of left thumb numbness and tingling for several months. Physical examination demonstrated a small tender mass along the ulnar surface of the left thumb with a positive Tinel's sign and diminished 2-point discrimination distal to the mass. The patient's symptoms did not improve with conservative measures. Here, we describe his surgical treatment and review the current literature. RESULTS: Our patient underwent neurolysis of the ulnar digital nerve of the thumb, with placement of a porcine extracellular matrix nerve wrap. The patient reported improvement of symptoms within 2 weeks and was able to return to his previous level of activity. In the literature, treatment has included from conservative measures such as pressure relief and splinting to surgical intervention including neurolysis, transposition, or neurectomy with nerve grafting. CONCLUSIONS: We present neurolysis for treating bowler's thumb as a viable option that may relieve symptoms rapidly while obviating need for adductor transection. Porcine extracellular matrix nerve wrap can be placed in an attempt to prevent recurrence of neuroma, but long-term follow-up is necessary.

Nanospheres delivering the EGFR TKI AG1478 promote optic nerve regeneration: the role of size for intraocular drug delivery.

Promoting nerve regeneration involves not only modulating the postinjury microenvironment but also ensuring survival of injured neurons. Sustained delivery of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been shown to promote the survival and regeneration of neurons, but systemic administration is associated with significant side effects. We fabricated poly(lactic-co-glycolic acid) (PLGA) microspheres and nanospheres containing the EGFR TKI 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) for intravitreal administration in a rat optic nerve crush injury model. Upon administration, less backflow from the injection site was observed when injecting nanospheres compared to microspheres. Two weeks after intravitreal delivery, we were able to detect microspheres and nanospheres in the vitreous using coumarin-6 fluorescence, but fewer microspheres were observed compared to the nanospheres. At four weeks only nanospheres could be detected. AG1478 microspheres and nanospheres promoted optic nerve regeneration at two weeks, and at four weeks evidence of regeneration was found only in the nanosphere-injected animals. This observation could be attributed to the ease of administration of the nanospheres versus the microspheres, which in turn led to an increased amount of spheres delivered to the vitreous in the nanosphere group compared to the microsphere group. These data provide evidence for use of PLGA nanospheres to deliver AG1478 intravitreally in a single administration to promote nerve regeneration.