Variation in Reported Learning Outcomes and Measurement Instruments in Hip Arthroscopy Simulation Training: A Systematic Review.

PURPOSE: To systematically review the current literature on the effectiveness of hip arthroscopy simulation training and to determine the consistency of reporting and validation of simulation used in hip arthroscopy. METHODS: Three databases (PubMed, EMBase, and CINAHL) were screened using PRISMA guidelines in January 2022 for published literature on virtual simulation in hip arthroscopy. Studies reporting on the use of hip arthroscopy simulation training in orthopedic surgical trainees were included and assessed for quality and risk of bias using MINORS criteria. The number of participants, participant education level, experience, simulator type, validation type, method of assessment, and simulation outcomes were extracted from included studies. RESULTS: Of the 286 articles screened, 11 met inclusion criteria for review evaluating 323 orthopedic trainees with a mean of 29.36 participants per study published between 2012 and 2021, most commonly in the United Kingdom (55%). The four most reported surgical skills evaluated were visualization and probing tasks (82%), mean time to perform the task (73%), number of cartilage and soft tissue collisions (73%), and number of hand movements (73%). The most described measurement instruments included a simulation built-in scoring system (55%), Arthroscopic Surgical Skill Evaluation Tool (ASSET) Global Rating Scale (GRS) (27%), and motion analysis system (18%). Construct validity was the most reported overall type of validity (82%), followed by face validity (36%), transfer validity (18%) and content validity (18%). Construct validity was also the most reported validity for the simulator and measurement instrument (55% and 89%, respectively). CONCLUSIONS: There is significant variation in reported learning outcomes and measurement instruments for evaluating the effectiveness of hip arthroscopic-based education. This study highlights that simulation training may be an effective tool for evaluation of hip arthroscopy skills. LEVEL OF EVIDENCE: Level III, systematic review of level I to III studies.

Biological augmentation of meniscal repair: a systematic review.

PURPOSE: Orthopedic literature remains divided on the utility of biologic augmentation to optimize outcomes after isolated meniscal repair. The aim of this systematic review is to analyze the clinical outcomes and re-operation rates of biologically augmented meniscal repairs. METHODS: PubMed, CINAHL, Cochrane, and EMBASE databases were queried in October 2020 for published literature on isolated meniscal repair with biological augmentation. Studies were assessed for quality and risk of bias by two appraisal tools. Patient demographics, meniscal tear characteristics, surgical procedure, augmentation type, post-operative rehabilitation, patient reported outcome measures, and length of follow-up were recorded, reviewed, and analyzed by two independent reviewers. RESULTS: Of 3794 articles, 18 met inclusion criteria and yielded 537 patients who underwent biologic augmentation of meniscal repair. The biologically augmented repair rates were 5.8-27.0% with PRP augmentation, 0.0-28.5% with fibrin clot augmentation, 0.0-12.9% with marrow stimulation, and 0.0% with stem cell augmentation. One of seven studies showed lower revision rates with augmented meniscal repair compared to standard repair techniques, whereas five of seven found no benefit. Three of ten studies found significant functional improvement of biologically augmented repair versus standard repair techniques and six of ten studies found no difference. There was significant heterogeneity in methods for biologic preparation, delivery, and post-operative rehabilitation protocols. CONCLUSION: Patients reported significant improvements in functional outcomes scores after repair with biological augmentation, though the benefit over standard repair controls is questionable. Revision rates after biologically augmented meniscal repair also appear similar to standard repair techniques. Clinicians should bear this in mind when considering biologic augmentation in the setting of meniscal repair. LEVEL OF EVIDENCE: IV.

Rehabilitation variability after rotator cuff repair.

BACKGROUND: There has been increasing recognition of the importance for standardized postoperative rehabilitation protocols. Despite published guidelines in 2016 by the American Society of Shoulder and Elbow Therapists (ASSET), optimal postoperative rehabilitation after rotator cuff repair (RCR) remains an area of active academic debate. The goals of this study were (1) to assess the variability of RCR rehabilitation protocols published online, (2) to study the congruence between online RCR rehabilitation protocols and the ASSET consensus statement, and (3) to identify differences in online RCR rehabilitation protocols from before and after 2016. METHODS: A web-based search was conducted for publicly available RCR rehabilitation protocols from websites of all Accreditation Council for Graduate Medical Education (ACGME) academic orthopedic institutions. A supplemental 10-page Google search was also performed with the search terms "rotator cuff repair rehabilitation protocol." Collected protocols were grouped by tear size (small/medium or large/massive) and examined for information relating to the following categories: protocol demographics, adjunctive therapy use, immobilization/range of motion, and strengthening. Findings were compared to the ASSET statement's recommendations. Protocols published before and after ASSET's 2016 publication were compared for differences. RESULTS: A total of 66 online RCR rehabilitation protocols were collected. Only 16 of 187 (8.5%) ACGME institutions provided online RCR rehabilitation protocols. The collected protocols recommend more aggressive rehabilitation in comparison to ASSET, specifically regarding immobilization time, passive range of motion initiation, active assisted range of motion initiation, and strengthening initiation (P < .001). Protocols published after 2016 trended toward more conservative recommendations in comparison to protocols published before 2016. Regardless of this trend, the majority of these recommendations were still largely more aggressive than ASSET's recommendations. CONCLUSION: Despite an attempt by ASSET to provide standardization, this study highlights the marked variations that still exist regarding RCR rehabilitation. Additionally, online RCR rehabilitation protocols tend to make more aggressive recommendations than the ASSET consensus statement. Further research is needed to address these variations and to either validate, alter, or reject the ASSET recommendations.

Paget-Schroetter syndrome in athletes: a comprehensive and systematic review.

BACKGROUND: Paget-Schroetter syndrome (PSS) is a rare condition of axillosubclavian vein thrombosis often seen in athletes with a history of repetitive external rotation and abduction of the shoulder. The purpose of this review was to analyze the literature and characterize PSS in the athletic population, including risk of PSS by sport. We also provide a comprehensive review of PSS to inform clinicians on the pathophysiology, detection, and management of the condition. METHODS: Four databases were reviewed to identify cases of PSS occurring in athletes. Data on patient demographics, reported sport, diagnosis, treatment, management, return to sport, and complications were extracted and analyzed by 2 independent reviewers. RESULTS: Of the 123 cases of PSS identified, baseball and weight lifting had the highest incidence (26.8% and 19%, respectively), followed by swimming, football, and basketball. The average return to sport was 4.7 months, and 26.7% of subjects reported complications, most commonly pulmonary embolism. CONCLUSION: In athletes presenting with upper extremity pain and swelling with a history of playing baseball or weight lifting, PSS should be higher on a clinicians differential diagnosis list. Swimmers, football, and basketball players are less likely to present with PSS but are still more likely than other types of athletes to develop the condition. Clinician awareness of PSS in athletes is critical to avoid delays in treatment and misdiagnosis, and to allow for a timely return to sport with minimal complications.

Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively.

PurposeOsteogenesis imperfecta (OI) is a heritable skeletal dysplasia. Dominant pathogenic variants in COL1A1 and COL1A2 explain the majority of OI cases. At least 15 additional genes have been identified, but those still do not account for all OI phenotypes that present. We sought the genetic cause of mild and lethal OI phenotypes in an unsolved family.MethodsWe performed exome sequencing on seven members of the family, both affected and unaffected.ResultsWe identified a variant in cyclic AMP responsive element binding protein 3-like 1 (CREB3L1) in a consanguineous family. The variant caused a prenatal/perinatal lethal OI in homozygotes, similar to that seen in OI type II as a result of mutations in type I collagen genes, and a mild phenotype (fractures, blue sclerae) in multiple heterozygous family members. CREB3L1 encodes old astrocyte specifically induced substance (OASIS), an endoplasmic reticulum stress transducer. The variant disrupts a DNA-binding site and prevents OASIS from acting on its transcriptional targets including SEC24D, which encodes a component of the coat protein II complex.ConclusionThis report confirms that CREB3L1 is an OI-related gene and suggests the pathogenic mechanism of CREB3L1-associated OI involves the altered regulation of proteins involved in cellular secretion.

Precision needle-punch tumor enrichment from paraffin blocks improves the detection of clinically actionable genomic alterations and biomarkers.

Background: While many molecular assays can detect mutations at low tumor purity and variant allele frequencies, complex biomarkers such as tumor mutational burden (TMB), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH) require higher tumor purity for accurate measurement. Scalable, quality-controlled, tissue-conserving methods to increase tumor nuclei percentage (TN%) from tumor specimens are needed for complex biomarkers and hence necessary to maximize patient matching to approved therapies or clinical trial enrollment. We evaluated the clinical utility and performance of precision needle-punch enrichment (NPE) compared with traditional razor blade macroenrichment of tumor specimens on molecular testing success. Methods: Pathologist-directed NPE was performed manually on formalin-fixed, paraffin embedded (FFPE) blocks. Quality control of target capture region and quantity of residual tumor in each tissue block was determined via a post-enrichment histologic slide recut. Resultant tumor purity and biomarker status were determined by the computational analysis pipeline component of the FDA-approved next-generation sequencing (NGS) assay, FoundationOne®CDx. Following NPE implementation for real-world clinical samples, assay performance and biomarker (MSI, TMB, gLOH) detection were analyzed. Results: In real-world clinical samples, enrichment rate via NPE was increased to ~50% over a 2.5-year period, exceeding the prior use of razor blade macro-enrichment (<30% of cases) prior to NPE implementation due to proven efficacy in generating high quality molecular results from marginal samples and the ease of use for both pathologist and histotechnologists. NPE was associated with lower test failures, higher computational tumor purity, and higher rates of successful TMB, MSI and gLOH determination when stratified by pre-enriched (incipient) tumor nuclei percentage. In addition, challenging cases in which tumor content was initially insufficient for testing were salvaged for analysis of biomarker status, gene amplification/deletion, and confident mutant or wild-type gene status determination. Conclusions: Pathologist-directed precision enrichment from tissue blocks (aka NPE) increases tumor purity, and consequently, yields a greater number of successful tests and complex biomarker determinations. Moreover, this process is rapid, safe, inexpensive, scalable, and conserves patient surgical pathology material. NPE may constitute best practice with respect to enriching tumor cells from low-purity specimens for biomarker detection in molecular laboratories.

Potential pathogenic germline variant reporting from tumor comprehensive genomic profiling complements classic approaches to germline testing.

Existing guidance regarding clinically informed germline testing for patients with cancer is effective for evaluation of classic hereditary cancer syndromes and established gene/cancer type associations. However, current screening methods may miss patients with rare, reduced penetrance, or otherwise occult hereditary risk. Secondary finding of suspected germline variants that may confer inherited cancer risk via tumor comprehensive genomic profiling (CGP) has the potential to help address these limitations. However, reporting practices for secondary finding of germline variants are inconsistent, necessitating solutions for transparent and coherent communication of these potentially important findings. A workflow for improved confidence detection and clear reporting of potential pathogenic germline variants (PPGV) in select cancer susceptibility genes (CSG) was applied to a research dataset from real-world clinical tumor CGP of > 125,000 patients with advanced cancer. The presence and patterns of PPGVs identified across tumor types was assessed with a focus on scenarios in which traditional clinical germline evaluation may have been insufficient to capture genetic risk. PPGVs were identified in 9.7% of tumor CGP cases using tissue- and liquid-based assays across a broad range of cancer types, including in a number of "off-tumor" contexts. Overall, PPGVs were identified in a similar proportion of cancers with National Comprehensive Cancer Network (NCCN) recommendations for germline testing regardless of family history (11%) as in all other cancer types (9%). These findings suggest that tumor CGP can serve as a tool that is complementary to traditional germline genetic evaluation in helping to ascertain inherited susceptibility in patients with advanced cancer.

Tumor Mutational Burden in Real-World Patients With Pancreatic Cancer: Genomic Alterations and Predictive Value for Immune Checkpoint Inhibitor Effectiveness.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is largely considered a nonimmunogenic malignancy; however, approximately 1%, of patients may have tumors with deficient mismatch repair, high microsatellite instability, or high tumor mutational burden (TMB ≥10 mutations/Mb), which may be predictive of response to immune checkpoint inhibitor (ICI) therapy. We sought to analyze outcomes of patients with high-TMB and pathogenic genomic alterations observed in this population. METHODS: This study included patients with PDAC who underwent comprehensive genomic profiling (CGP) at Foundation Medicine (Cambridge, MA). Clinical data were obtained from a US-wide real-world clinicogenomic pancreatic database. We report genomic alterations in those with high and low TMB, and compare outcomes on the basis of receipt of single-agent ICI or therapy regimens not containing ICI. RESULTS: We evaluated 21,932 patients with PDAC who had tissue CGP data available, including 21,639 (98.7%) with low-TMB and 293 (1.3%) with high-TMB. Among patients with high-TMB, a greater number of alterations were observed in BRCA2, BRAF, PALB2, and genes of the mismatch repair pathway, whereas fewer alterations were observed in KRAS. Among patients who received an ICI (n = 51), those with high-TMB had more favorable median overall survival when compared with the low-TMB subset (25.7 v 5.2 months; hazard ratio, 0.32; 95% CI, 0.11 to 0.91; P = .034). CONCLUSION: Longer survival was observed in patients with high-TMB receiving ICI compared with those with low-TMB. This supports the role of high-TMB as a predictive biomarker for efficacy of ICI therapy in PDAC. Additionally, we report higher rates of BRAF and BRCA2 mutations and lower rates of KRAS mutation among patients with PDAC and high-TMB, which to our knowledge, is a novel finding.

Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer.

PURPOSE: Approximately 8% to 10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents. EXPERIMENTAL DESIGN: We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multigene sequencing panel and identified 73 patients (9.2%) with KRAS wild-type (WT) pancreatic cancer. RESULTS: Overall, 43.8% (32/73) of KRAS WT cases had evidence of an alternative driver of the MAPK pathway, including BRAF mutations and in-frame deletions and receptor tyrosine kinase fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative KRAS WT cases (12/41) demonstrated activating alterations in other oncogenic drivers, such as GNAS, MYC, PIK3CA, and CTNNB1. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid models carrying BRAF in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a KRAS WT tumor with a ROS1 fusion. Clinically, patients with KRAS WT tumors were significantly younger in age of onset (median age: 62.6 vs. 65.7 years; P = 0.037). SMAD4 mutations were associated with a particularly poor prognosis in KRAS WT cases. CONCLUSIONS: This study defines the genomic underpinnings of KRAS WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials. See related commentary by Kato et al., p. 4527.

Programmatic Precision Oncology Decision Support for Patients With Gastrointestinal Cancer.

PURPOSE: With the growing number of available targeted therapeutics and molecular biomarkers, the optimal care of patients with cancer now depends on a comprehensive understanding of the rapidly evolving landscape of precision oncology, which can be challenging for oncologists to navigate alone. METHODS: We developed and implemented a precision oncology decision support system, GI TARGET, (Gastrointestinal Treatment Assistance Regarding Genomic Evaluation of Tumors) within the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute. With a multidisciplinary team, we systematically reviewed tumor molecular profiling for GI tumors and provided molecularly informed clinical recommendations, which included identifying appropriate clinical trials aided by the computational matching platform MatchMiner, suggesting targeted therapy options on or off the US Food and Drug Administration-approved label, and consideration of additional or orthogonal molecular testing. RESULTS: We reviewed genomic data and provided clinical recommendations for 506 patients with GI cancer who underwent tumor molecular profiling between January and June 2019 and determined follow-up using the electronic health record. Summary reports were provided to 19 medical oncologists for patients with colorectal (n = 198, 39%), pancreatic (n = 124, 24%), esophagogastric (n = 67, 13%), biliary (n = 40, 8%), and other GI cancers. We recommended ≥ 1 precision medicine clinical trial for 80% (406 of 506) of patients, leading to 24 enrollments. We recommended on-label and off-label targeted therapies for 6% (28 of 506) and 25% (125 of 506) of patients, respectively. Recommendations for additional or orthogonal testing were made for 42% (211 of 506) of patients. CONCLUSION: The integration of precision medicine in routine cancer care through a dedicated multidisciplinary molecular tumor board is scalable and sustainable, and implementation of precision oncology recommendations has clinical utility for patients with cancer.

CTC1 Mutations in a patient with dyskeratosis congenita.

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome caused by mutations in seven genes involved in telomere biology, with approximately 50% of cases remaining genetically uncharacterized. We report a patient with classic DC carrying a compound heterozygous mutation in the CTC1 (conserved telomere maintenance component 1) gene, which has recently implicated in the pleiotropic syndrome Coats plus. This report confirms a molecular link between DC and Coats plus and expands the genotype-phenotype complexity observed in telomere-related genetic disorders.

Terrible triad of the elbow and associated variants: a systematic review.

Background: The terrible triad of the elbow (TTE) is a complex injury consisting of simultaneous elbow dislocation or subluxation, radial head fracture, and coronoid fracture. During the initial assessment of a TTE, the typical severity of presenting pain, swelling, and limited range of motion may limit the ability to perform a thorough physical examination and thus divert a clinician's attention away from additional injuries to the ipsilateral upper extremity. Therefore, the purpose of this study was to review the literature for reported cases of concomitant ipsilateral upper extremity injuries associated with a TTE and discuss various strategies to increase clinician awareness to avoid underdiagnosis and missed diagnoses. Methods: A systematic review of five databases in four languages (English, Spanish, French, and Portuguese), from inception to May 2021, was conducted. Articles describing a TTE with a concomitant osseous, chondral, ligamentous, or musculotendinous injury occurring on the ipsilateral upper extremity were included. The patients were divided into two groups, those presenting with a classic TTE and concomitant ipsilateral upper extremity injury (group 1) and those in whom a TTE variant was described (group 2). A TTE variant was defined as a combination of osseous and/or chondral injuries to the elbow other than the classic description of TTE, in which at least two of the three classical elements of a TTE (elbow dislocation, coronoid fracture, and radial head fracture) were present in addition to other unique elbow osteoarticular injury. Results: Nineteen articles met inclusion criteria and were further analyzed. A total of 27 patients were analyzed, 23 from group 1 and 4 from group 2. Overall, 33 concomitant injuries were documented in group 1, the most common being an olecranon fracture (27.3%), followed by Essex-Lopresti injury, triceps tendon avulsion, and carpal fracture-dislocation with 4 (12.1%) cases each. Group 2 had four patients, all of whom presented with a unique variant of the classically described TTE. Conclusion: Despite a characteristic radiographic appearance of the classic TTE, additional injuries of the ipsilateral extremity or variants of the classic TTE may be easily missed, especially in cases resulting from high-energy mechanisms of injury. By analyzing the available data on associated injuries and variants that may occur with a TTE, we hope to increase awareness so that clinicians may recognize these less common but more complex injury patterns.

Systematic review of prevalence, risk factors, and management of instability following reverse shoulder arthroplasty.

Background: Since its approval for use, reverse shoulder arthroplasty (RSA) has become the primary treatment for cuff tear arthropathy, with indications expanding more recently to include revision fracture, osteoarthritis with significant glenoid bone loss, tumor, and chronic instability. Instability is a well-described postoperative complication, occurring in 1to 31% of relatively small cohorts and case series. Given the relative infrequency of instability, there remains a need for a comprehensive review of instability with a focus on risk factors and management. Our goal of this systematic review is to describe the prevalence, risk factors, and management strategies for instability following RSA. Methods: A systematic review of the PubMed, EMBASE, MEDLINE, Scopus, and Cochrane Library databases was performed according to PRISMA guidelines. Inclusion criteria included primary RSA cohorts ≥ 100 patients, revision RSA cohorts of any size, and minimum 1-year follow-up. The primary outcome of interest was postoperative instability. MINORS criteria were used to assess study bias. Descriptive statistical analysis was performed with data reported as ranges. Results: Seventeen studies that included 7885 cases of RSA were reviewed. The mean follow-up ranged from 12 to 84 months. Mean age ranged from 64 to 77 years old, and males represented 19 to 39% of cohorts. There were 204 (2.5%) dislocations in 7885 cases, accounting for a rate of instability from 0.4 to 49% across all studies. By intervention, instability rates ranged from 1 to 5% (primary RSA cases), 1 to 49% (revision RSA cases only), and 0.4 to 10% (mixed cohorts). Subscapularis insufficiency and proximal humerus fractures, and fracture sequelae (malunion and nonunion) were identified as risk factors for instability. Closed reduction and casting and revision RSA were reported as successful treatment strategies with acceptable rates of stable prostheses (28-100% and 55-100%, respectively, across studies). Hemiarthroplasty or resection arthroplasty due to recurrent instability was not uncommon after 2 or more episodes of instability. Conclusion: Instability following RSA occurs infrequently (1-5%) following primary RSA and more commonly following revision RSA (1-49%). RSA for acute proximal humerus fracture and fracture sequelae carries a higher risk of instability. Subscapularis repair appears to be a protective factor. While instability may be successfully treated with closed management or revision RSA, recurrent instability may ultimately require hemiarthroplasty or resection arthroplasty.

MatchMiner: an open-source platform for cancer precision medicine.

Widespread, comprehensive sequencing of patient tumors has facilitated the usage of precision medicine (PM) drugs to target specific genomic alterations. Therapeutic clinical trials are necessary to test new PM drugs to advance precision medicine, however, the abundance of patient sequencing data coupled with complex clinical trial eligibility has made it challenging to match patients to PM trials. To facilitate enrollment onto PM trials, we developed MatchMiner, an open-source platform to computationally match genomically profiled cancer patients to PM trials. Here, we describe MatchMiner's capabilities, outline its deployment at Dana-Farber Cancer Institute (DFCI), and characterize its impact on PM trial enrollment. MatchMiner's primary goals are to facilitate PM trial options for all patients and accelerate trial enrollment onto PM trials. MatchMiner can help clinicians find trial options for an individual patient or provide trial teams with candidate patients matching their trial's eligibility criteria. From March 2016 through March 2021, we curated 354 PM trials containing a broad range of genomic and clinical eligibility criteria and MatchMiner facilitated 166 trial consents (MatchMiner consents, MMC) for 159 patients. To quantify MatchMiner's impact on trial consent, we measured time from genomic sequencing report date to trial consent date for the 166 MMC compared to trial consents not facilitated by MatchMiner (non-MMC). We found MMC consented to trials 55 days (22%) earlier than non-MMC. MatchMiner has enabled our clinicians to match patients to PM trials and accelerated the trial enrollment process.

Porphyrins are not present in feline ocular tissues or corneal sequestra.

OBJECTIVE: To determine if feline lacrimal glands, glands of the third eyelid, corneas, and corneal sequestra contain porphyrins, which could be responsible for the brown/amber discoloration of corneal sequestra and tears in affected cats. PROCEDURES: Samples of grossly normal cornea, lacrimal gland, gland of the third eyelid, and sequestra obtained via keratectomy were collected. Porphyrin concentrations of the homogenate were determined by spectrofluorometry with protoporphyrin IX and coproporphyrin III dihydrochloride used as standards. A hamster harderian gland was used as a positive control. RESULTS: Normal tissues were harvested from one eye each of 14 nonclient owned, adult, mixed-breed, short-hair cats euthanized for reasons not associated with this study. Eighteen sequestra were acquired from cats undergoing unilateral lamellar keratectomies. Breeds of the affected cats included eight Himalayan, five domestic shorthair, and one each of four other breeds. Only the positive control and standards contained levels of porphyrins above background. All feline samples examined were histologically normal with no evidence of porphyrins. CONCLUSIONS: Porphyrins are absent in normal feline lacrimal glands, corneas, and corneal sequestra. Porphyrins do not appear to be the cause of the brown/amber color of feline corneal sequestra.

Biallelic variants in MESD, which encodes a WNT-signaling-related protein, in four new families with recessively inherited osteogenesis imperfecta.

The bone disorder osteogenesis imperfecta (OI) is genetically heterogeneous. Most affected individuals have an autosomal dominant disorder caused by heterozygous variants in either of the type I collagen genes (COL1A1 or COL1A2). To date, two reports have linked Mesoderm Development LRP Chaperone (MESD) to autosomal recessive OI type XX. Four different biallelic pathogenic variants in MESD were shown to cause a progressively deforming phenotype, associated with recurrent fractures and oligodontia in five individuals in five families. Recently, compound heterozygosity for a frameshift predicted to lead to a premature termination codon in exon 2 of the 3-exon gene and a second frameshift in the terminal exon in MESD were detected in three stillbirths in one family with severe OI consistent with the neonatal lethal phenotype. We have identified four additional individuals from four independent families with biallelic variants in MESD: the earlier reported c.632dupA (p.Lys212Glufs∗19) and c.676C>T (p.Arg226∗)-which are associated with a severe form of OI-and one new pathogenic variant, c.603-606delTAAA (p.Asn201Lysfs∗15), which causes a neonatal lethal form of OI. MESD acts in the WNT signaling pathway, where it is thought to play a role in the folding of the WNT co-receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/LRP6) and in chaperoning their transit to the cell surface. Our report broadens the phenotypic and genetic spectrum of MESD-related OI, provides additional insight into the pathogenic pathways, and underscores the necessity of MESD for normal WNT signaling in bone formation.

Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions.

PURPOSE: Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion-associated colorectal cancer. EXPERIMENTAL DESIGN: We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results. RESULTS: We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in BRAF and RAS wild-type tumors and were enriched in right-sided and mismatch repair-deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to MLH1 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled BRAF V600E-mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an ALK-CAD fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an ALK L1196Q gatekeeper mutation. The second patient, whose tumor contained an ROS1-GOPC fusion, continues to benefit from entrectinib after 9 months of therapy. CONCLUSIONS: RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in RAS and BRAF wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.

FGFR2 Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma.

We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. SIGNIFICANCE: FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro, and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic.This article is highlighted in the In This Issue feature, p. 2355.

A structural equation model looking at student's participatory behavior and their success in Calculus I.

BACKGROUND: Government projections in the USA indicate that the country will need a million more science, technology, engineering, and mathematics (STEM) graduates above and beyond those already projected by the year 2022. Of crucial importance to the STEM pipeline is success in Calculus I, without which continuation in a STEM major is not possible. The STEM community at large, and mathematics instructors specifically, need to understand factors that influence and promote success in order to mitigate the alarming attrition trend. Previous work in this area has defined success singularly in terms of grades or persistence; however, these definitions are somewhat limiting and neglect the possible mediating effects of affective constructs like confidence, mindset, and enjoyment on the aforementioned markers of success. Using structural equation modeling, this paper explored the effect of participation on grades in freshman college calculus and investigated whether these effects were mediated by affective variables. RESULTS: Results indicated that participation had no significant direct effect on any of the success components in the final model-a finding that was not only counterintuitive but actually contradicted previous research done on this data. Participation was however highly correlated with two other exogenous variables indicating it would be inappropriate to dismiss it as being unrelated to success. Furthermore, the results suggested a cluster of affective success components and an achievement component with confidence being the intermediary between the two. CONCLUSIONS: This paper extends upon previous work with this data set in which the effect of participatory behaviors on success was investigated wherein success was measured singularly with expected course grade and affective components of success were not considered. The limited explanatory power of the model, coupled with the seemingly contradictory results, indicates that participatory behaviors alone might be insufficient to capture the complexity of the success response variable.

Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangioma.

Infantile hemangioma (IH) is the most common vascular tumor of infancy, and it uniquely regresses in response to oral propranolol. MicroRNAs (miRNAs) have emerged as key regulators of vascular development and are dysregulated in many disease processes, but the role of miRNAs in IH growth has not been investigated. We report expression of C19MC, a primate-specific megacluster of miRNAs expressed in placenta with rare expression in postnatal tissues, in glucose transporter 1-expressing (GLUT-1-expressing) IH endothelial cells and in the plasma of children with IH. Tissue or circulating C19MC miRNAs were not detectable in patients having 9 other types of vascular anomalies or unaffected children, identifying C19MC miRNAs as the first circulating biomarkers of IH. Levels of circulating C19MC miRNAs correlated with IH tumor size and propranolol treatment response, and IH tissue from children treated with propranolol or from children with partially involuted tumors contained lower levels of C19MC miRNAs than untreated, proliferative tumors, implicating C19MC miRNAs as potential drivers of IH pathogenesis. Detection of C19MC miRNAs in the circulation of infants with IH may provide a specific and noninvasive means of IH diagnosis and identification of candidates for propranolol therapy as well as a means to monitor treatment response.