Inhibition of Erb-B2 Receptor Tyrosine Kinase 3 and Associated Regulatory Pathways Potently Impairs Malignant Peripheral Nerve Sheath Tumor Proliferation and Survival.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, currently untreatable Schwann cell-derived neoplasms with hyperactive mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. To identify potential therapeutic targets, previous studies used genome-scale shRNA screens that implicated the neuregulin-1 receptor erb-B2 receptor tyrosine kinase 3 (erbB3) in MPNST proliferation and/or survival. The current study shows that erbB3 is commonly expressed in MPNSTs and MPNST cell lines and that erbB3 knockdown inhibits MPNST proliferation and survival. Kinomic and microarray analyses of Schwann and MPNST cells implicate Src- and erbB3-mediated calmodulin-regulated signaling as key pathways. Consistent with this, inhibition of upstream (canertinib, sapitinib, saracatinib, and calmodulin) and parallel (AZD1208) signaling pathways involving mitogen-activated protein kinase and mammalian target of rapamycin reduced MPNST proliferation and survival. ErbB inhibitors (canertinib and sapitinib) or erbB3 knockdown in combination with Src (saracatinib), calmodulin [trifluoperazine (TFP)], or proviral integration site of Moloney murine leukemia kinase (AZD1208) inhibition even more effectively reduces proliferation and survival. Drug inhibition enhances an unstudied calmodulin-dependent protein kinase IIα phosphorylation site in an Src-dependent manner. The Src family kinase inhibitor saracatinib reduces both basal and TFP-induced erbB3 and calmodulin-dependent protein kinase IIα phosphorylation. Src inhibition (saracatinib), like erbB3 knockdown, prevents these phosphorylation events; and when combined with TFP, it even more effectively reduces proliferation and survival compared with monotherapy. These findings implicate erbB3, calmodulin, proviral integration site of Moloney murine leukemia kinases, and Src family members as important therapeutic targets in MPNSTs and demonstrate that combinatorial therapies targeting critical MPNST signaling pathways are more effective.

Fibroblast GSK-3α Promotes Fibrosis via RAF-MEK-ERK Pathway in the Injured Heart.

BACKGROUND: Heart failure is the leading cause of mortality, morbidity, and health care expenditures worldwide. Numerous studies have implicated GSK-3 (glycogen synthase kinase-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms seem to play overlapping, unique and even opposing functions in the heart. Previously, we have shown that of the 2 isoforms of GSK-3, cardiac fibroblast GSK-3ß acts as a negative regulator of myocardial fibrosis in the ischemic heart. However, the role of cardiac fibroblast-GSK-3α in the pathogenesis of cardiac diseases is completely unknown. METHODS: To define the role of cardiac fibroblast-GSK-3α in myocardial fibrosis and heart failure, GSK-3α was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or Postn-promoter-driven Cre recombinase. Control and GSK-3α KO mice were subjected to cardiac injury and heart parameters were evaluated. The fibroblast kinome mapping was carried out to delineate molecular mechanism followed by in vivo and in vitro analysis. RESULTS: Fibroblast-specific GSK-3α deletion restricted fibrotic remodeling and preserved function of the injured heart. We observed reductions in cell migration, collagen gel contraction, α-SMA protein levels, and expression of ECM genes in TGFß1-treated KO fibroblasts, indicating that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion did not affect SMAD3 activation, suggesting the profibrotic role of GSK-3α is SMAD3 independent. The molecular studies confirmed decreased ERK signaling in GSK-3α-KO CFs. Conversely, adenovirus-mediated expression of a constitutively active form of GSK-3α (Ad-GSK-3αS21A) in fibroblasts increased ERK activation and expression of fibrogenic proteins. Importantly, this effect was abolished by ERK inhibition. CONCLUSIONS: GSK-3α-mediated MEK-ERK activation is a critical profibrotic signaling circuit in the injured heart, which operates independently of the canonical TGF-ß1-SMAD3 pathway. Therefore, strategies to inhibit the GSK-3α-MEK-ERK signaling circuit could prevent adverse fibrosis in diseased hearts.

Tunable assembly of host-guest colloidal crystals.

Entropy compartmentalization provides new self-assembly routes to colloidal host-guest (HG) structures. Leveraging host particle shape to drive the assembly of HG structures has only recently been proposed and demonstrated. However, the extent to which the guest particles can dictate the structure of the porous network of host particles has not been explored. In this work, by modifying only the guest shape, we show athermal, binary mixtures of star-shaped host particles and convex polygon-shaped guest particles assemble as many as five distinct crystal structures, including rotator and discrete rotator guest crystals, two homoporous host crystals, and one heteroporous host crystal. Edge-to-edge alignment of neighboring stars results in the formation of three distinct pore motifs, whose preferential formation is controlled by the size and shape of the guest particles. Finally, we confirm, via free volume calculations, that assembly is driven by entropy compartmentalization, where the hosts and guests contribute differently to the free energy of the system; free volume calculations also explain differences in assembly based on guest shape. These results provide guest design rules for assembling colloidal HG structures, especially on surfaces and interfaces.

Diagnostic KASP markers differentiate Vanilla planifolia, V. odorata, V. pompona, and their hybrids using leaf or cured pod tissues.

BACKGROUND: Vanilla is a globally important spice crop used in a variety of food, cosmetic, and pharmaceutical products. V. planifolia is the primary commercial species with V. x tahitensis also permissible for food use. Other aromatic species, including V. pompona, are used for food throughout Central and South America. Supply chain complexity hinders the vanilla bean industry and can lead to false claims of genetic and geographical origins to obtain higher prices. Beans of some species can be differentiated by experienced buyers, but hybrids and morphological differences caused by environmental variability or disease would best be resolved by diagnostic tests. METHODS AND RESULTS: Kompetitive Allele Specific Polymerase Chain Reaction is a widely used molecular marker that can genotype single nucleotide polymorphisms efficiently and inexpensively. Assays were designed to differentiate V. planifolia, V. x tahitensis, and V. pompona using publicly available vanilla genomics data. Ten KASP assays on chromosomes 1 through 7, the ITS region, and plastid-encoded rbcL gene successfully differentiated V. planifolia, V. odorata, and V. x tahitensis. Additional KASP assays on chromosomes 1 through 4, the ITS region, and rbcL gene successfully differentiated V. planifolia and V. pompona. Further, a method for extracting KASP-quality DNA from cured vanilla bean seeds was developed and successfully differentiated V. planifolia, V. odorata, V. x tahitensis, V. pompona, and their hybrids. CONCLUSION: The methods and results from this study can be used to identify interspecific hybrids, ensure the authenticity of cured vanilla beans, and reduce abuse within the vanilla supply chain.

Combinatorial regulation of endothelial gene expression by ets and forkhead transcription factors.

Vascular development begins when mesodermal cells differentiate into endothelial cells, which then form primitive vessels. It has been hypothesized that endothelial-specific gene expression may be regulated combinatorially, but the transcriptional mechanisms governing specificity in vascular gene expression remain incompletely understood. Here, we identify a 44 bp transcriptional enhancer that is sufficient to direct expression specifically and exclusively to the developing vascular endothelium. This enhancer is regulated by a composite cis-acting element, the FOX:ETS motif, which is bound and synergistically activated by Forkhead and Ets transcription factors. We demonstrate that coexpression of the Forkhead protein FoxC2 and the Ets protein Etv2 induces ectopic expression of vascular genes in Xenopus embryos, and that combinatorial knockdown of the orthologous genes in zebrafish embryos disrupts vascular development. Finally, we show that FOX:ETS motifs are present in many known endothelial-specific enhancers and that this motif is an efficient predictor of endothelial enhancers in the human genome.

Inconsistency and Ambiguity Within the International Classification of Disease 10 Procedure Coding System for Hip Fractures.

BACKGROUND: The International Statistical Classification of Diseases (ICD), 10th Revision Procedure Coding System (PCS) was created to increase the granularity of procedural coding. These codes are entered by hospital coders from information derived from the medical record. Concern exists that this increase in complexity could lead to inaccurate data. METHODS: Medical records and ICD-10-PCS codes were reviewed for operatively treated geriatric hip fractures from January 2016 through February 2019 at a tertiary referral medical center. Definitions for each of the 7-unit figures from the 2022 American Medical Association's ICD-10-PCS official codebook were compared to the medical, operative, and implant records. RESULTS: There were 56% (135 of 241) of PCS codes that had ambiguous, partially incorrect, or frankly incorrect figures within the code. One or more inaccurate figures were noted in 72% (72 of 100) of fractures treated with arthroplasty compared to 44.7% (63 of 141) treated with fixation (P < .01). There was at least 1 frankly incorrect figure contained in 9.5% (23 of 241) of codes. Approach was coded ambiguously for 24.8% (29 of 117) of pertrochanteric fractures. Device/implant codes were partially incorrect in 34.9% (84 of 241) of all hip fracture PCS codes. Hemi and total hip arthroplasties were partially incorrect in 78.4% (58 of 74) and 30.8% (8/26) of device/implant codes, respectively. Significantly more femoral neck (69.4%, 86 of 124) than pertrochanteric fractures (41.9%, 49 of 117) had 1 or more incorrect or partially correct figures (P < .01). CONCLUSION: Despite the increased granularity of ICD-10-PCS codes, the application of this system is inconsistent and often incorrect when applied to hip fracture treatments. The definitions in the PCS system are difficult to be utilized by coders and do not reflect the operation performed.

Extensor Mechanism Disruption Remains a Challenging Problem.

BACKGROUND: Extensor mechanism disruption (EMD) following total knee arthroplasty (TKA) is a devastating problem commonly treated with allograft or synthetic reconstruction. Understanding of reconstruction success rates and patient recorded outcomes is lacking. METHODS: Patients who have an EMD after TKA undergoing mesh or whole-extensor allograft reconstruction between 2011 and 2019, with minimum 2-year follow-up were reviewed at two tertiary care centers. Functional failure was defined as extensor lag >30 degrees, amputation, or fusion, as well as revision extensor mechanism reconstruction (EMR). Survivorship was assessed using Kaplan-Meier curves, and factors for success were determined with logistic regressions. RESULTS: Of fifty-six EMRs (49 patients), 50.0% (28/56) were functionally successful at 3.2 years of mean follow-up (range, 0.2 to 7.4). In situ survivorship of the reconstructions at 36 months was 75.0% (42 of 58). There were 50.0% (14 of 28) of functionally failed EMRs that retained their reconstruction at last follow-up. Mean extensor lag among successes and failures was 5.4 and 71.0° (P = .01), respectively. Mean Knee Injury and Osteoarthritis Outcome Score, Joint Replacement scores were 67.1 and 48.8 among successes and failures (P = .01). There were 64.0% (16 of 25) of successes and 1 of 19 failures that obtained a Knee Injury and Osteoarthritis Outcome Score, Joint Replacement score above the minimum patient-acceptable symptom state for TKA. Survivorship and success rates were similar between reconstruction methods (P = .86; P = .76). All-cause mortality was 8.2% (4 of 49), each with EMR failure prior to death. All-cause reoperation rate was 42.9% (24 of 56), with a 14.3% (8 of 56) rate of revision EMR and 10.7% (6 of 56) rate of above-knee-amputation or modular fusion. CONCLUSIONS: This multicenter investigation of mesh or allograft EMR demonstrated modest functional success at 3.2 years. Complication and reoperation rates were high, regardless of EMR technique. Therefore, EMD after TKA remains problematic.

Evaluation of Factors Affecting Return to Work Following Carpal Tunnel Release: A Statewide Cohort Study of Workers' Compensation Subjects.

PURPOSE: Most randomized trials comparing open carpal tunnel release (OCTR) to endoscopic carpal tunnel release (ECTR) are not specific to a working population and focus mainly on how surgical technique has an impact on outcomes. This study's primary goal was to evaluate factors affecting days out of work (DOOW) following carpal tunnel release (CTR) in a working population and to evaluate for differences in medical costs, indemnity payments, disability ratings, and opioid use between OCTR and ECTR with the intent of determining whether one or the other surgical method was a determining factor. METHODS: Using the Ohio Bureau of Workers' Compensation claims database, individuals were identified who underwent unilateral isolated CTR between 1993 and 2018. We excluded those who were on total disability, who underwent additional surgery within 6 months of their index CTR, including contralateral or revision CTR, and those not working during the same month as their index CTR. Outcomes were evaluated at 6 months after surgery. Multivariable linear regression was performed to evaluate covariates associated with DOOW. RESULTS: Of the 4596 included participants, 569 (12.4%) and 4027 (87.6%) underwent ECTR and OCTR, respectively. Mean DOOW were 58.4 for participants undergoing OCTR and 56.6 for those undergoing ECTR. Carpal tunnel release technique was not predictive of DOOW. Net medical costs were 20.7% higher for those undergoing ECTR. Multivariable linear regression demonstrated the following significant predictors of higher DOOW: preoperative opioid use, legal representation, labor-intensive occupation, increasing lag time from injury to filing of a worker's compensation claim, and female sex. Being married, higher income community, and working in the public sector were associated with fewer DOOW. CONCLUSIONS: In a large statewide worker's compensation population, demographic, occupational, psychosocial, and litigatory factors have a significant impact on DOOW following CTR, whereas differences in surgical technique between ECTR and OCTR did not. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.

A Multidisciplinary Transitional Pain Management Program Is Associated With Reduced Opioid Dependence After Primary Total Joint Arthroplasty.

BACKGROUND: Overprescription of opioids after total joint arthroplasty (TJA) increases risks of opioid dependence, overdose, and death. The authors hypothesized that a multidisciplinary, perioperative pain management program (the Transitional Pain Service or TPS) for TJA would lead to fewer patients becoming opioid dependent. METHODS: A TPS was implemented at a Veterans Affairs Medical Center focused on nonopioid pain management, cessation support, and prospective data tracking. A historical control, interventional study design was used to assess opioid use at 90 days post-discharge. Secondary analysis of the implementation group included post-operative outcome scores, time to opioid cessation, and median opioid tablets consumed at 90 days. RESULTS: Fewer patients in the TPS group demonstrated persistent opioid use at 90 days post-discharge (0.7% vs 9.9%; P = .004). Independent predictors of total opioid tablet prescriptions included TPS (ß = -19.41; 95% confidence interval [CI] -35.37 to -3.47), number of tablets prescribed at discharge (ß = 1.08; 95% CI 0.86-1.31), and TKA surgery (ß = 16.84; 95% CI 4.58-29.10). Under the TPS, median tablets consumed was 20.5 for THA and 36.5 for TKA; median time to cessation was shorter in THA (7 days; 95% CI 2-10) when compared to TKA (13 days; 95% CI 11-16). CONCLUSION: In opioid-naïve veterans undergoing TJA, the TPS was associated with a 93% reduction in opioid dependence and a 60% reduction in opioid tablet prescriptions at 90 days post-discharge. Under the TPS, median 90-day opioid consumption was 20.5 and 36.5 tablets for THA and TKA, respectively. Widespread adoption of similar programs may greatly reduce opioid use and dependence in orthopedic patients nationally. LEVEL OF EVIDENCE: III.

Shape-driven entropic self-assembly of an open, reconfigurable, binary host-guest colloidal crystal.

Entropically driven self-assembly of hard anisotropic particles, where particle shape gives rise to emergent valencies, provides a useful perspective for the design of nanoparticle and colloidal systems. Hard particles self-assemble into a rich variety of crystal structures, ranging in complexity from simple close-packed structures to structures with 432 particles in the unit cell. Entropic crystallization of open structures, however, is missing from this landscape. Here, we report the self-assembly of a two-dimensional binary mixture of hard particles into an open host-guest structure, where nonconvex, triangular host particles form a honeycomb lattice that encapsulates smaller guest particles. Notably, this open structure forms in the absence of enthalpic interactions by effectively splitting the structure into low- and high-entropy sublattices. This is the first such structure to be reported in a two-dimensional athermal system. We discuss the observed compartmentalization of entropy in this system, and show that the effect of the size of the guest particle on the stability of the structure gives rise to a reentrant phase behavior. This reentrance suggests the possibility for a reconfigurable colloidal material, and we provide a proof-of-concept by showing the assembly behavior while changing the size of the guest particles in situ. Our findings provide a strategy for designing open colloidal crystals, as well as binary systems that exhibit co-crystallization, which have been elusive thus far.

The Role of Antiseptic Irrigation Solutions and Topical Antibiotics in Total Joint Arthroplasty.

Prosthetic joint infections (PJI) are devastating complications. Antiseptic irrigation fluids have shown promising in vitro results in eradicating planktonic bacteria and decreasing biofilm burden. Topical antibiotics, specifically vancomycin, represents another potentially cost-effective way to prevent acute postoperative PJI. We provide a review of the current literature and recommendations on these measures. Overall, a current lack of high-powered, prospective studies exists to definitively support the use of any specific antiseptic solution or topical antibiotic in primary or revision total joint arthroplasty. Some studies support the use of dilute povidone-iodine lavage when combined with vancomycin powder. Data also exists to support the cost effectiveness of povidone-iodine, with the necessary risk reduction to justify its cost. Contradictory evidence exists demonstrating no differences in PJI rates with these measures and possibly higher rates of aseptic wound complications associated with vancomycin power. Further study is warranted. (Journal of Surgical Orthopaedic Advances 30(4):226-230, 2021).

The Impact of Smoking in Workers' Compensation Patients Receiving Spinal Cord Stimulation.

The objective of this study was to determine the impact of smoking on clinical outcomes in workers' compensation (WC) patients receiving spinal cord stimulation (SCS). One hundred and ninety-six patients from the Ohio Bureau of Workers' Compensation were identified who received SCS with implantation occurring between 2007-2012. Patients were divided into smokers (n = 120) and nonsmokers (n = 76). Population characteristics before and after implantation were analyzed between the two groups. A multivariate logistic regression was run to determine predictors of return to work (RTW) status. Our regression determined smoking (p = 0.006; odds ratio [OR] = 0.260) and body mass index (p = 0.036; OR = 0.905) to be negative predictors of RTW status. After implantation, smokers were less likely to RTW after 6 months and had higher pain scores after 6 and 12 months. Both smokers and nonsmokers had significance reductions in opioid use after SCS implantation. (Journal of Surgical Orthopaedic Advances 30(3):185-189, 2021).

Systemic inflammatory dynamics during chemoradiotherapy predict response, relapse, metastasis, and survival in esophageal carcinoma.

BACKGROUND AND OBJECTIVES: Lymphopenia associated with chemoradiotherapy predicts prognosis in esophageal carcinoma. The purpose of our study was to evaluate alterations in hematologic measures of inflammation during chemoradiation. METHODS: We performed an observational study evaluating adults treated with chemoradiation in the neoadjuvant or definitive setting for stage II-III esophageal carcinoma. Multivariable logistic regression evaluated predictors of pathologic response. Survival was analyzed by time-varying multivariable Cox proportional hazards regressions. RESULTS: A total of 94 patients were included with median follow-up of 1.6 years. Elevated neutrophil:lymphocyte ratio (NLR) was predictive of incomplete pathologic response to neoadjuvant chemoradiation (OR, 1.07; P = .0030) as well as shorter distant metastasis-free survival (HR, 1.01; P = .0369) and reduced overall survival (HR, 1.01; P = .0448). An NLR > 5.55 in week two of chemoradiation predicted shorter overall survival (P = .0070). Upon adjusted analysis, NLR was independently associated with reduced probability of complete pathologic response (OR, 0.80; P = .0291), as well as poor histologic response to neoadjuvant chemoradiation (OR, 1.05; P = .0303), shorter disease-free survival (HR, 1.02; P = .0077), and reduced overall survival (HR, 1.02; P = .0070). CONCLUSIONS: Dynamic time-dependent changes in NLR during chemoradiation predict response, relapse, metastasis, and survival in esophageal carcinoma. Prospective validation is warranted.

A mean-field approach to simulating anisotropic particles.

We introduce a mean-field theoretical framework for generalizing isotropic pair potentials to anisotropic shapes. This method is suitable for generating pair potentials that can be used in both Monte Carlo and molecular dynamics simulations. We demonstrate the application of this theory by deriving a Lennard-Jones (LJ)-like potential for arbitrary geometries along with a Weeks-Chandler-Anderson-like repulsive variant, showing that the resulting potentials behave very similarly to standard LJ potentials while also providing a nearly conformal mapping of the underlying shape. We then describe an implementation of this potential in the simulation engine HOOMD-blue and discuss the challenges that must be overcome to achieve a sufficiently robust and performant implementation. The resulting potential can be applied to smooth geometries like ellipsoids and to convex polytopes. We contextualize these applications with reference to the existing methods for simulating such particles. The pair potential is validated using standard criteria, and its performance is compared to existing methods for comparable simulations. Finally, we show the results of self-assembly simulations, demonstrating that this method can be used to study the assembly of anisotropic particles into crystal structures.

Displaced Femoral Neck Fractures in Workers' Compensation Patients Aged 45-65 Years: Is It Best to Fix the Fracture or Replace the Joint?

BACKGROUND: Optimal surgical management of displaced femoral neck fractures (dFNFs) in subjects 45-65 years old is unclear. We evaluated days out of work (dOOW), medical and indemnity costs, and secondary outcomes at 2 years between internal fixation (IF), hemiarthroplasty (HA), and total hip arthroplasty (THA) among workers' compensation (WC) subjects with isolated dFNFs aged 45-65. METHODS: We retrospectively identified 105 Ohio Bureau of WC subjects with isolated subcapital dFNFs aged 45-65 with 2 years of follow-up. In total, 37 (35.2%) underwent IF, 23 (21.9%) THA, and 45 (42.9%) HA from 1993 to 2017. Linear regression was used to determine if surgery type was predictive of dOOW postoperatively and to evaluate inflation-adjusted net medical and indemnity costs at 2 years. RESULTS: IF subjects were younger (52.9) than THA (58.5, P < .001) and HA (58.4, P < .001) subjects. Mean dOOW for THA subjects at 6 months, 1 year, and 2 years was 90.8, 114.6, and 136.6. This was significantly lower than IF (136.3, 182.0, 236.6) and HA (114.6, 153.3, 247.6) subjects at all time points. Medical costs were similar. Mean indemnity costs were 3.0 and 2.4 times higher among IF (P < .001) and HA (P = .007) groups compared to THA, respectively. Rates of postoperative permanent disability awards were 13.0%, 43.2%, and 35.6% for the THA, IF, and HA groups (P = .050). IF and HA subjects had a 24.3% and 11.1% revision rate. Overall, 77.8% and 100% of the IF and HA revisions were conversions to THA. CONCLUSION: WC subjects aged 45-65 with dFNFs treated with THA had fewer dOOW, lower indemnity costs, and less disability at 2 years. Longer follow-up will help determine the durability and long-term outcomes of these surgeries.

Differential escape mechanisms in cetuximab-resistant head and neck cancer cells.

Acquired cetuximab resistance is a challenge for oncologists treating advanced head and neck carcinoma (HNC). While intrinsic cetuximab resistance mechanism in colorectal cancer is known, resistance in HNC is unclear. We established two different cetuximab resistant HNC cell lines by culturing epidermal growth factor (EGFR) expressing UM-SCC-1 and UM-SCC-6 cell lines in the presence of 5 µg/ml cetuximab. We then explored potential mechanisms of resistance. We found that the 2 cell lines developed resistance by different mechanisms. Specifically, we found that UM-SCC-1 resistant cells (UM-SCC-1R) showed enhanced EGF-induced downstream signals while UM-SCC-6 resistant cells (UM-SCC-6R) demonstrated EGF-independent signaling. Global kinase activity (kinomic) profiling revealed unique signaling differences in the two resistant cell lines. However, both of the resistant lines demonstrated increased phospho-serine 727 and total STAT3 expression compared to the parental lines. STAT3 knockdown promoted increased cytotoxicity both in the presence and absence of cetuximab in the resistant lines suggesting that STAT3 may be a common target in cetuximab resistance.

DICER1 mutations are frequent in müllerian adenosarcomas and are independent of rhabdomyosarcomatous differentiation.

Müllerian adenosarcomas are biphasic epithelial-mesenchymal tumors with benign epithelial and malignant mesenchymal components. The sarcoma component may be low or high grade; the latter is often seen in the presence of stromal overgrowth, which correlates with worse clinical outcome. Heterologous differentiation may also occur, usually in association with stromal overgrowth. DICER1 mutations have been reported primarily in a small subset of adenosarcomas with rhabdomyosarcomatous elements, but whether these are specific to the rhabdomyosarcomatous phenotype is unclear. In this study, we examined the clinical, pathologic, and genomic features of 19 müllerian adenosarcomas enriched for tumors with rhabdomyosarcomatous differentiation, as well as eight uterine carcinosarcomas with a rhabdomyosarcoma component. Somatic hotspot mutations in the RNase IIIb domain of DICER1 were identified in 8/19 (42%) adenosarcomas, of which four showed rhabdomyosarcomatous differentiation. DICER1 mutations were detected in 4/6 (67%) cases with a rhabdomyosarcoma component and in 4/11 (36%) cases without rhabdomyosarcoma. At least two DICER1 mutations were identified in 7/8 (88%) tumors, of which four had a truncating mutation. The hotspot DICER1 mutation in the remaining tumor was hemizygous and associated with loss of heterozygosity. Other less frequent recurrent somatic pathogenic alterations included Ras or PI3K/PTEN pathway aberrations (5/19 each, 26%), CDK4/MDM2 amplifications (3/19, 16%), and mutations in TP53 (3/19) and ARID1A (3/19). Two tumors demonstrated homozygous BAP1 deletion. One tumor harbored an ESR1-NCOA3 fusion gene. Carcinosarcomas with rhabdomyosarcomatous differentiation showed frequent mutations in TP53 (7/8, 88%) and the PI3K/PTEN pathway (6/8, 75%) but lacked DICER1 mutations. The findings highlight the importance of DICER1 mutations in müllerian adenosarcoma tumorigenesis and show that these alterations are not exclusive to heterologous rhabdomyosarcomatous differentiation.

Symmetries in hard polygon systems determine plastic colloidal crystal mesophases in two dimensions.

Orientational ordering is a necessary step in the crystallization of molecules and anisotropic colloids. Plastic crystals, which are possible mesophases between the fluid and fully ordered crystal, are translationally ordered but exhibit no long range orientational order. Here, we study the two-dimensional phase behavior of hard regular polygons with edge number n = 3-12. This family of particles provides a model system to isolate the effect of shape and symmetry on the existence of plastic crystal phases. We show that the symmetry group of the particle, G, and the symmetry group of the local environment in the crystal, H, together determine plastic colloidal crystal phase behavior in two dimensions. If G contains completely the symmetry elements of H, then a plastic crystal phase is absent. If G and H share some but not all nontrivial symmetry elements, then a plastic crystal phase exists with preferred particle orientations that recover the absent symmetry elements of the crystal; we call this phase the discrete plastic crystal phase. If G and H share no nontrivial symmetry elements, then a plastic crystal phase exists without preferred orientations, which we call an indiscrete plastic crystal.

Outcomes of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy for refractory Cushing's disease.

PURPOSE: Hypofractionated stereotactic radiotherapy (HSRT) for refractory Cushing's disease may offer a condensed treatment schedule for patients with large tumors abutting the optic chiasm unsuitable for stereotactic radiosurgery (SRS). To-date only four patients have been treated by HSRT in the published literature. We investigated the feasibility, toxicity, and efficacy of HSRT compared to SRS. METHODS: After approval, we retrospectively evaluated patients treated at our institution for refractory Cushing's disease with SRS or HSRT. Study outcomes included biochemical control, time to biochemical control, local control, and late complications. Binary logistic regression and Cox proportional hazards regression evaluated predictors of outcomes. RESULTS: Patients treated with SRS (n = 9) and HSRT (n = 9) were enrolled with median follow-up of 3.4 years. Clinicopathologic details were balanced between the cohorts. Local control was 100% in both cohorts. Time to biochemical control was 6.6. and 9.5 months in the SRS and HSRT cohorts, respectively (p = 0.6258). Two patients in each cohort required salvage bilateral adrenalectomy. Late complications including secondary malignancy, radionecrosis, cranial nerve neuropathy, and optic pathway injury were minimal for either cohort. CONCLUSIONS: HSRT is an appropriate treatment approach for refractory Cushing's disease, particularly for patients with large tumors abutting the optic apparatus. Prospective studies are needed to validate these findings and identify factors suggesting optimal fractionation approaches.

Multilevel Lumbar Fusion Is a Risk Factor for Lower Return to Work Rates Among Workers' Compensation Subjects With Degenerative Disc Disease.

Discogenic fusion is associated with variable outcomes, especially if multiple levels are fused. This study sought to determine the impact of fused levels on return to work (RTW) status in a workers' compensation (WC) setting. Nine hundred thirty-seven subjects were selected for study. The primary outcome was the ability to RTW within 2 years following fusion and to sustain this level for greater than 6 months. Many secondary outcomes were collected. A multivariate logistic regression model was used to determine the impact of multilevel fusion on RTW status. Of the multilevel fusion group, 21.7% met the RTW criteria versus 28.1% of the single-level fusion group (p < .028). Multilevel fusion was a negative predictor of RTW status (p < .041; OR 0.71). Additional negative predictors included prolonged time out of work, male gender, chronic opioid analgesia, and legal representation. Multilevel fusion led to poor clinical outcomes while overall RTW rates were low, which suggests a limited role of discogenic fusion within the WC setting. (Journal of Surgical Orthopaedic Advances 27(3):209-218, 2018).