Publications by authors named "David Swanson"

298 Publications

Systematic review on effects of bioenergy from edible versus inedible feedstocks on food security.

NPJ Sci Food 2021 May 4;5(1). Epub 2021 May 4.

Department of Biological Systems Engineering, University of Wisconsin-Madison, Madison, WI, USA.

Achieving food security is a critical challenge of the Anthropocene that may conflict with environmental and societal goals such as increased energy access. The "fuel versus food" debate coupled with climate mitigation efforts has given rise to next-generation biofuels. Findings of this systematic review indicate just over half of the studies (56% of 224 publications) reported a negative impact of bioenergy production on food security. However, no relationship was found between bioenergy feedstocks that are edible versus inedible and food security (P value = 0.15). A strong relationship was found between bioenergy and type of food security parameter (P value < 0.001), sociodemographic index of study location (P value = 0.001), spatial scale (P value < 0.001), and temporal scale (P value = 0.017). Programs and policies focused on bioenergy and climate mitigation should monitor multiple food security parameters at various scales over the long term toward achieving diverse sustainability goals.
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http://dx.doi.org/10.1038/s41538-021-00091-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096942PMC
May 2021

Postoperative changes in vertical ground reaction forces, walking barefoot and with ankle-foot orthoses in children with Cerebral Palsy.

Clin Biomech (Bristol, Avon) 2021 Apr 23;84:105336. Epub 2021 Mar 23.

Faculty of Medicine, Institute of Health and Society, University of Oslo, Oslo, Norway; Division of Orthopaedic Surgery, Department of Research, Oslo University Hospital, Oslo, Norway.

Background: Children with cerebral palsy often have problems to support the body centre of mass, seen as increased ratio between excessive vertical ground reaction forces during weight acceptance and decreased forces below bodyweight in late stance. We aimed to examine whether increasing ankle range of motion through surgery and restraining motion with ankle-foot orthoses postoperatively would have impact on the vertical ground reaction force in weight acceptance and late stance.

Methods: Ground reaction forces were recorded from 24 children with bilateral and 32 children with unilateral cerebral palsy, each measured walking barefoot before and after triceps surae lengthening. Postoperatively, the children were also measured walking with ankle-foot orthoses. Changes in vertical ground reaction forces between the three conditions were evaluated with functional curve and descriptive peak analyses; accounting for repeated measures and within-subject correlation.

Findings: After surgery, there were decreased vertical ground reaction forces in weight acceptance and increased forces in late stance. Additional significant changes with ankle-foot orthoses involved increased vertical forces in weight acceptance, and in late stance corresponding to bodyweight (bilateral, from 92% to 98% bodyweight; unilateral, from 94% to 103% bodyweight) postoperatively.

Interpretation: Our findings confirmed that surgery affected vertical ground reaction forces to approach more normative patterns. Additional changes with ankle-foot orthoses indicated further improved ability to support bodyweight and decelerate centre of mass in late stance.
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http://dx.doi.org/10.1016/j.clinbiomech.2021.105336DOI Listing
April 2021

Slow-growing lesion on eyebrow.

J Fam Pract 2021 Mar;70(2):E13-E15

Department of Dermatology, Mayo Clinic Arizona, Scottsdale, USA.

It took a dermatoscopic examination followed by an e-consultation and shave biopsy to arrive at the diagnosis.
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http://dx.doi.org/10.12788/jfp.0163DOI Listing
March 2021

Hybrid schwannoma-perineurioma frequently harbors VGLL3 rearrangement.

Mod Pathol 2021 Mar 1. Epub 2021 Mar 1.

Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

Benign peripheral nerve tumors include schwannoma, neurofibroma, and perineurioma, as well as a recently recognized group of tumors with dual patterns of differentiation. The molecular pathogenesis of these so-called "hybrid" tumors remains poorly understood. Following identification of a novel CHD7-VGLL3 fusion gene in a hybrid schwannoma-perineurioma, we evaluated an expanded cohort of this tumor-type-as well as tumors with VGLL3 rearrangement identified from a curated molecular database-to characterize the prevalence of fusion genes among these tumors. Eighteen tumors met the inclusion criteria for this study. RNA sequencing identified VGLL3 rearrangement in 14 of these cases; the partner genes included CHD7 (ten cases), CHD9 (two cases), and MAMLD1 (two cases). Two cases possessed altogether unrelated fusions, including: DST-BRAF and SQSTM1-CDX1 fusion genes. Finally, two cases lacked identifiable fusion products. These findings highlight the molecular diversity of these neoplasms, with frequent rearrangement of VGLL3. More importantly, despite their dual pattern of differentiation, our results reveal the pathogenesis of hybrid schwannoma-perineurioma is unrelated to conventional schwannoma and perineurioma, thereby implying this tumor represents an altogether pathologically distinct entity.
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http://dx.doi.org/10.1038/s41379-021-00783-0DOI Listing
March 2021

Recurrent MEIS1-NCOA2/1 fusions in a subset of low-grade spindle cell sarcomas frequently involving the genitourinary and gynecologic tracts.

Mod Pathol 2021 Feb 11. Epub 2021 Feb 11.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Sarcomas with MEIS1-NCOA2 fusions have been so far reported in 2 cases each of primitive renal sarcomas and intraosseous pelvic rhabdomyosarcomas. Their histologic spectrum, anatomic distribution, and clinical behavior remain poorly defined. In this study, we report 6 additional spindle cell sarcomas with MEIS1-NCOA2 or NCOA1 fusions that fall into the same disease spectrum with the previously reported renal sarcomas. The patients' age range was wide (20-76 years, mean 46) and all except one were female. The tumors arose in the kidney (n = 2), and one each in the uterine corpus, vagina, scrotum, and para-rectal region. The consistent morphology was that of monomorphic spindle to ovoid cells in a storiform, whorling, or solid pattern. Alternating cellularity, myxoid stroma, and microcystic changes were seen in some cases. Mitotic activity varied greatly (<1-33/10 high power fields). The immunophenotype was nonspecific, with most cases expressing variable degrees of TLE1, WT1, cyclin D1, CD56, and CD10. Using various platforms of RNA-based targeted sequencing, MEIS1-NCOA2 fusions were recurrently identified in 5 cases, and a novel MEIS1-NCOA1 fusion was found in one renal tumor. The gene fusions were validated by fluorescence in situ hybridization using custom BAC probes. Of the 5 patients with available follow-up (5 months to 8 years), all experienced local recurrences, but no distant spread or death from disease. Our results expand the clinicopathologic spectrum of sarcomas with MEIS1-NCOA2/1 fusions, providing evidence of an undifferentiated spindle cell phenotype with nonspecific immunoprofile and low-grade clinical behavior.
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http://dx.doi.org/10.1038/s41379-021-00744-7DOI Listing
February 2021

A Poorly Differentiated Non-keratinizing Sinonasal Squamous Cell Carcinoma with a Novel ETV6-TNFRSF8 Fusion Gene.

Head Neck Pathol 2021 Jan 4. Epub 2021 Jan 4.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.

Squamous cell carcinoma of the sinonasal tract is relatively rare and morphologically and genetically heterogeneous. We report the case of an adult male with a left sphenoid sinus mass. A biopsy revealed an undifferentiated carcinoma composed of sheets of epithelioid cells lacking keratinization and glandular formation. The tumor was associated with a prominent lymphoplasmacytic inflammatory infiltrate. Immunohistochemical staining demonstrated diffuse expression of pankeratin and p63; it was negative for p16. In addition, EBER was also negative. Morphologically the findings raised the possibility of non-keratinizing squamous cell carcinoma. RNA sequencing was undertaken to exclude the possibility of NUT carcinoma; interestingly, this revealed a novel ETV6-TNFRSF8 fusion transcript, which was independently confirmed by fluorescence in situ hybridization. The current case is illustrative because it broadens our understanding of the molecular pathogenesis of non-keratinizing squamous cell carcinoma and adds to the diversity of ETV6-rearranged malignancies.
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http://dx.doi.org/10.1007/s12105-020-01249-6DOI Listing
January 2021

How Relevant is the Basic Reproductive Number Computed During COVID-19, Especially During Lockdowns?

Infect Control Hosp Epidemiol 2020 Dec 14:1-7. Epub 2020 Dec 14.

Senior Health Advisor (Retd) formerly with CDC, World Bank, and USAID.

Basic reproductive numbers during COVID-19, either through standard approaches or through time-varying approaches, are key for understanding the pandemic growth. However, improper usage and interpretations and computational difficulties during lockdowns could be misleading for planning and mitigation.
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http://dx.doi.org/10.1017/ice.2020.1376DOI Listing
December 2020

A Proposed Blueprint for Operative Performance Training, Assessment, and Certification.

Ann Surg 2021 04;273(4):701-708

Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL.

Objective: The aim of this study was to propose an evidence-based blueprint for training, assessment, and certification of operative performance for surgical trainees.

Summary Background Data: Operative skill is a critical aspect of surgical performance. High-quality assessment of operative skill therefore has profound implications for training, accreditation, certification, and the public trust of the profession. Current methods of operative skill assessment for surgeons rely heavily on global assessment strategies across a very broad domain of procedures. There is no mechanism to assure technical competence for individual procedures. The science and scalability of operative skill assessment has progressed significantly in recent decades, and can inform a much more meaningful strategy for competency-based assessment of operative skill than has been previously achieved.

Methods: The present article reviews the current status and science of operative skill assessment and proposes a template for competency-based assessment which could be used to update training, accreditation, and certification processes. The proposal is made in reference to general surgery but is more generally applicable to other procedural specialties.

Results: Streamlined, routine assessment of every procedure performed by surgical trainees is feasible and would enable a more competency-based educational paradigm. In light of the constraints imposed by both clinical volume and assessment bias, trainees should be expected to become proficient and be measured against a mastery learning standard only for the most important and highest-frequency procedures. For less frequently observed procedures, performance can be compared to a norm-referenced standard and, to provide an overall trajectory of performance, analyzed in aggregate. Key factors in implementing this approach are the number of evaluations, the number of raters, the timeliness of evaluation, and evaluation items.

Conclusions: A competency-based operative skill assessment can be incorporated into surgical training, assessment, and certification. The time has come to develop a systematic approach to this issue as a means of demonstrating professional standards worthy of the public trust.
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http://dx.doi.org/10.1097/SLA.0000000000004467DOI Listing
April 2021

Choosing between isotretinoin and acitretin for epidermal growth factor receptor inhibitor and small molecule tyrosine kinase inhibitor acneiform eruptions.

J Am Acad Dermatol 2021 Mar 8;84(3):840-841. Epub 2020 Oct 8.

Department of Dermatology, Mayo Clinic, Scottsdale, Arizona. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.09.090DOI Listing
March 2021

A novel low-grade nasopharyngeal adenocarcinoma characterized by a GOLGB1-BRAF fusion gene.

Genes Chromosomes Cancer 2021 Jan 29;60(1):49-53. Epub 2020 Sep 29.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.

Nasopharyngeal adenocarcinoma is a rare malignancy that is classified into conventional/surface- and salivary-types. Herein we report the case of a 52-year-old male who presented with a right nasopharyngeal mass and right-sided hearing loss. Diagnostic imaging revealed a circumscribed 1.7 cm mass centred in the right antero-lateral aspect of the nasopharynx. A biopsy showed a gland-forming neoplasm that was in continuity with the surface epithelium. The tumor exhibited a nested to micro-papillary architecture, with mild cytologic atypia. Immunohistochemistry demonstrated diffuse staining for CK7, SOX10, and p16; the abluminal layer was highlighted by CK5 and p63, while the luminal cells expressed CD117. The tumor was not amenable to subclassification and was diagnosed as a low-grade nasopharyngeal adenocarcinoma, not otherwise specified (NOS). Subsequent RNA sequencing was performed which identified a novel GOLGB1-BRAF fusion product. Based on its unique morphology and molecular findings, this is presumed to represent a novel subtype of nasopharyngeal adenocarcinoma. In addition to being of diagnostic relevance, this fusion may ultimately represent a potential therapeutic target.
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http://dx.doi.org/10.1002/gcc.22897DOI Listing
January 2021

High prevalence of ADHD symptoms in unmedicated youths with post-H1N1 narcolepsy type 1.

Sleep Med 2020 11 18;75:171-180. Epub 2020 Jun 18.

Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias, Department of Rare Disorders, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Norway.

Objectives: To characterize attention deficit-hyperactivity disorder (ADHD) symptoms in unmedicated post-H1N1 narcolepsy type 1 (NT1) youths, and explore associations between ADHD symptoms and the narcolepsy phenotype.

Methods: A total of 50 consecutively enrolled post-H1N1 NT1 youths (7-20 years, 62% females, 98% HLA-DQB1∗06:02-positive, 98% CSF hypocretin-1 deficient, 88% vaccinated) were assessed after two weeks off medication for ADHD (ADHD diagnosis pre/post-narcolepsy, parent-rated ADHD symptoms) and narcolepsy-phenotyped (semi-structured interview, Stanford Sleep Questionnaire, Epworth Sleepiness Scale, polysomnography (PSG), Multiple Sleep Latency Test (MSLT)).

Results: In sum, 26 (52%) and 15 (30%) of participants had ADHD symptoms above and below the clinical significant cut-off, respectively, while 9 (18%) had no ADHD symptoms. High values were found for ADHD total score (mean (SD), 17.9 (9.5)) and ADHD subscores (inattentive score, 11.0 (6.3); hyperactive/impulsivity score, 6.9 (4.7)). These were significantly higher than previously reported in a mainly medicated narcolepsy cohort (p < 0.0001). Age, gender and disease duration did not influence scores. Two participants (4%) had ADHD diagnosis prior to narcolepsy onset. ADHD symptoms were correlated with parent-rated, but not with patient rated ESS scores, objective sleepiness (mean sleep latency), sleep fragmentation (sleep stage shift index, awakening index), or CSF hypocretin-1 level.

Conclusion: Comorbid ADHD symptoms were more prevalent in unmedicated post-H1N1 NT1 youths than previously reported in mainly medicated pediatric narcolepsy cohorts. The high prevalence was not due to pre-existing ADHD and generally not correlated with core narcolepsy sleep/wake phenotype characteristics, indicating that the ADHD symptoms were not a direct consequence of disturbed sleep or daytime sleepiness.
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http://dx.doi.org/10.1016/j.sleep.2020.06.014DOI Listing
November 2020

Beyond right or wrong: More effective feedback for formative multiple-choice tests.

Perspect Med Educ 2020 10;9(5):307-313

Department of Family & Community Medicine & The Wilson Centre, University of Toronto, Toronto, Ontario, Canada.

Introduction: The role of feedback in test-enhanced learning is an understudied area that has the potential to improve student learning. This study investigates the influence of different forms of post-test feedback on retention and transfer of biomedical knowledge within a test-enhanced learning framework.

Methods: 64 participants from a Canadian and an Australian medical school sat two single-best-answer formative multiple choice tests one week apart. We compared the effects of conceptually focused, response-oriented, and simple right/wrong feedback on a learner's ability to correctly answer new (transfer) questions. On the first test occasion, participants received parent items with feedback, and then attempted items closely related (near transfer) to and more distant (far transfer) from parent items. In a repeat test at 1 week, participants were given different near and far transfer versions of parent items. Feedback type, and near and far transfer items were randomized within and across participants.

Results: Analysis demonstrated that response-oriented and conceptually focused feedback were superior to traditional right/wrong feedback for both types of transfer tasks and in both immediate and final retention test performance. However, there was no statistically significant difference between response-orientated and conceptually focused groups on near or far transfer problems, nor any differences in performance between our initial test occasion and the retention test 1 week later. As with most studies of transfer, participants' far transfer scores were lower than for near transfer.

Discussion: Right/wrong feedback appears to have limited potential to augment test-enhanced learning. Our work suggests that item-level feedback and feedback that identifies and elaborates on key conceptual knowledge are two important areas for future research on learning, retention and transfer.
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http://dx.doi.org/10.1007/s40037-020-00606-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550480PMC
October 2020

Gene fusions characterize a subset of uterine cellular leiomyomas.

Genes Chromosomes Cancer 2020 Jul 17. Epub 2020 Jul 17.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.

Uterine leiomyomas are the most common benign tumor of the female genital tract. Previous studies have shown that conventional leiomyomas often harbor-specific alterations including rearrangements involving HMGA2. Cellular leiomyomas are a variant of uterine leiomyoma that are less well-studied from a genomic point of view. Morphologically and immunohistochemically, cellular leiomyomas may be confused with low-grade endometrial stromal neoplasms, a group of tumors which frequently harbor a number of recurrent gene fusions. Ancillary molecular testing may be used to investigate tumors where low-grade endometrial stromal neoplasms enter into the differential diagnosis. At our institution, we identified a uterine cellular leiomyoma harboring a HMGA2-TRAF3IP2 fusion. After a retrospective review 11 additional tumors were identified. All included cases were reviewed and evaluated for immunohistochemical expression of smooth muscle actin, desmin, h-caldesmon, CD10, estrogen receptor, and progesterone receptor. RNA sequencing using the TruSight RNA Fusion Panel was performed on formalin-fixed paraffin-embedded tissue samples. In addition to the index case, two other cases harbored fusions: HMGA2-NAA11 and TPCN2-YAP1, of which the latter is novel and was confirmed with reverse transcriptase-polymerase chain reaction. In conclusion, a subset of cellular leiomyomas harbor rearrangements involving HMGA2, suggesting molecular kinship with conventional uterine leiomyomas. In addition, the prevalence of the novel TPCN2-YAP1 gene fusion in cellular leiomyomas requires further study. The fusions reported here, when identified, may be useful when the diagnosis of cellular leiomyoma is in question.
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http://dx.doi.org/10.1002/gcc.22888DOI Listing
July 2020

Contrasting DCIS and invasive breast cancer by subtype suggests basal-like DCIS as distinct lesions.

NPJ Breast Cancer 2020 17;6:26. Epub 2020 Jun 17.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

Ductal carcinoma in situ (DCIS) is a non-invasive type of breast cancer with highly variable potential of becoming invasive and affecting mortality. Currently, many patients with DCIS are overtreated due to the lack of specific biomarkers that distinguish low risk lesions from those with a higher risk of progression. In this study, we analyzed 57 pure DCIS and 313 invasive breast cancers (IBC) from different patients. Three levels of genomic data were obtained; gene expression, DNA methylation, and DNA copy number. We performed subtype stratified analyses and identified key differences between DCIS and IBC that suggest subtype specific progression. Prominent differences were found in tumors of the basal-like subtype: Basal-like DCIS were less proliferative and showed a higher degree of differentiation than basal-like IBC. Also, tumors (characterized by high correlation to the basal-like centroid) were not identified amongst DCIS as opposed to IBC. At the copy number level, basal-like DCIS exhibited fewer copy number aberrations compared with basal-like IBC. An intriguing finding through analysis of the methylome was hypermethylation of multiple protocadherin genes in basal-like IBC compared with basal-like DCIS and normal tissue, possibly caused by long range epigenetic silencing. This points to silencing of cell adhesion-related genes specifically in IBC of the basal-like subtype. Our work confirms that subtype stratification is essential when studying progression from DCIS to IBC, and we provide evidence that basal-like DCIS show less aggressive characteristics and question the assumption that basal-like DCIS is a direct precursor of basal-like invasive breast cancer.
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http://dx.doi.org/10.1038/s41523-020-0167-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299965PMC
June 2020

Estimating the Prevalence of Pseudomyxoma Peritonei in Europe Using a Novel Statistical Method.

Ann Surg Oncol 2021 Jan 2;28(1):252-257. Epub 2020 Jun 2.

Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital Oslo, Oslo, Norway.

Background: The determination of the incidence and prevalence of rare diseases is important for economists and health-care providers. Pseudomyxoma peritonei (PMP) is a rare, slow-growing abdominal cancer that represents a substantial burden on both patients and health-care systems. The incidence rate was previously approximated at 1-2 people per million per year; this incidence has never been challenged, and the prevalence has not been estimated.

Methods: Epidemiological data from Norway and England were obtained and analysed to calculate a minimum incidence rate based on the number of patients having a first surgical intervention for PMP. A novel method was then used to determine a prevalence rate for PMP, incorporating incidence, death, and cure rates in a multi-year analysis that accounted for the increasing population of Europe over a 10-year period.

Results: An incidence rate of 3.2 people per million per year was calculated, with a corresponding estimated prevalence rate of 22 people per million per year. By this calculation, 11,736 people in Europe were estimated to be living with PMP in 2018.

Conclusion: Incidence and prevalence are essential tools for assessment of the financial and human cost of a disease. For rare diseases, such as PMP, the lack of accurate registries presents a particular challenge in determining such health-related statistical parameters. Based on our calculations, a significant number of people are living with PMP in Europe, underlining the need for appropriate resource allocation to ensure that adequate health-care measures are provided.
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http://dx.doi.org/10.1245/s10434-020-08655-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752784PMC
January 2021

Middle Ear and Temporal Bone Nonkeratinizing Squamous Cell Carcinomas With DEK-AFF2 Fusion: An Emerging Entity.

Am J Surg Pathol 2020 09;44(9):1244-1250

Laboratory Medicine Program, University Health Network.

Primary squamous cell carcinomas (SCCs) of the middle ear and temporal bone are rare and usually keratinizing by morphology. Nonkeratinizing, basaloid SCCs arising in this area are exceedingly rare, and, due to the anatomic proximity to the skull base, nasopharynx, and nasal sinuses, the differential diagnosis is broad. Most tumors with squamous differentiation arising in these subsites are either viral-induced (human papillomavirus/Epstein-Barr virus) or rarely may have specific molecular alterations (BRD4-NUT, EWSR1-FLI translocations). Occasional tumors are negative for these findings, and their pathogenesis is unknown. A recently discovered DEK-AFF2 fusion was clinically detected in a series of 2 cases known to the authors. This fusion has been previously reported in the literature in a patient with a base of skull tumor who was an exceptional responder to programmed cell death protein 1 inhibitor therapy. We examine here the histomorphologic and molecular findings of 2 additional cases of an emerging entity. Two male patients were identified. Each had a primary middle ear/temporal bone mass with locally advanced disease. The histology was reviewed, and immunohistochemistry was performed. RNA-based next-generation sequencing was performed for clinical detection of diagnostic or actionable fusions. Both patients had basaloid/nonkeratinizing tumors on biopsy. They were positive for markers of squamous differentiation (HMWK, CK5, and p40). By RNA sequencing, they demonstrated the presence of a DEK-AFF2 fusion and were negative for EWSR1 and NUT translocations. The DEK-AFF2 fusion may define a novel diagnostic category of middle ear and temporal bone nonkeratinizing/basaloid SCCs. This fusion also may represent a potential avenue for immunotherapy in these patients. Further studies are needed to fully explore whether this fusion defines a location-specific clinicopathologic entity.
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http://dx.doi.org/10.1097/PAS.0000000000001498DOI Listing
September 2020

Biphasic Hyalinizing Psammomatous Renal Cell Carcinoma (BHP RCC): A Distinctive Neoplasm Associated With Somatic NF2 Mutations.

Am J Surg Pathol 2020 07;44(7):901-916

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.

We report 8 cases of a distinctive, previously undescribed renal cell carcinoma associated with somatic mutations in the neurofibromin 2 (NF2) gene. All patients were adults, ranging from 51 to 78 years of age and of cases of known sex 6 of 7 were males. The carcinomas were predominantly unencapsulated, and all had a rounded, nodular interface with the native kidney. The neoplasms were all solid with papillary architecture evident in most cases (7/8), while 1 was only tubular. All cases were biphasic, characterized by larger and smaller carcinoma cells. The smaller cells clustered around basement membrane material similar to the characteristic pattern of the t(6;11) renal cell carcinoma associated with TFEB gene fusions. In 6 of 8 carcinomas, branching nodules of small cells clustered around basement membrane material within larger acini yielding a distinctive glomeruloid pattern. In 6 of 8 carcinomas, the small cells were focally spindle-shaped and unassociated with the basement membrane material. The stroma was sclerotic in all 8 carcinomas, and all 8 contained psammoma bodies that were abundant in 2. In some carcinomas, focal or predominant areas had a less distinctive appearance; 2 had areas that resembled clear cell renal cell carcinoma, 2 had high-grade eosinophilic areas, while 1 had branching tubular architecture that resembled mucinous tubular and spindle cell carcinoma. Two carcinomas demonstrated cellular necrosis. Although we have minimal clinical follow-up, 1 case presented with distant metastasis, progressed and resulted in patient death. While NF2 mutations may be found in other established renal cell carcinoma subtypes (often as secondary genetic alterations), they are potentially the genetic driver of this distinctive entity.
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http://dx.doi.org/10.1097/PAS.0000000000001467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350624PMC
July 2020

Variant WWTR1 gene fusions in epithelioid hemangioendothelioma-A genetic subset associated with cardiac involvement.

Genes Chromosomes Cancer 2020 07 20;59(7):389-395. Epub 2020 Mar 20.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

The genetic hallmark of epithelioid hemangioendothelioma (EHE) is a recurrent WWTR1-CAMTA1 fusion, which is present in most cases bearing a conventional histology. A subset of cases is characterized by a distinct morphology and harbors instead of YAP1-TFE3 fusion. Nevertheless, isolated cases lack these canonical fusions and remain difficult to classify. Triggered by an index case of a left atrial mass in a 76-year-old female with morphologic features typical of EHE, but which showed a WWTR1-MAML2 fusion by targeted RNA sequencing, we searched our files for similar cases displaying alternative WWTR1 fusions. A total of 6 EHE cases were identified with variant WWTR1 fusions, four of them presenting within the heart. There were three females and three males, with a wide age range at diagnosis (21-76 years, mean 62, median 69). The four cardiac cases occurred in older adults (mean age of 72, equal gender distribution); three involved the left atrium and one the right ventricle. One case presented in the vertebral bone and one in pelvic soft tissue. Microscopically, all tumors had morphologic features within the spectrum of classic EHE; two of the cases appeared overtly malignant. All cases were tested by FISH and four were investigated by targeted RNA sequencing. Two tumors harbored WWTR1-MAML2 fusions, one WWTR1-ACTL6A, and in three cases, no WWTR1 partner was identified. Of the four patients with follow-up, two died of disease, one was alive with lung metastases, and the only patient free of disease was s/p resection of a T11 vertebral mass. Our findings report on additional genetic variants involving WWTR1 rearrangements, with WWTR1-MAML2 being a recurrent event, in a small subset of EHE, which appears to have predilection for the heart.
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http://dx.doi.org/10.1002/gcc.22839DOI Listing
July 2020

Medical student experiences with accessing and entering patient information in electronic health records during the obstetrics-gynecology clerkship.

Am J Obstet Gynecol 2020 09 14;223(3):435.e1-435.e6. Epub 2020 Feb 14.

Indiana University School of Medicine, Indianapolis, IN.

Background: Medical school graduates should be able to enter information from patient encounters and to write orders and prescriptions in the electronic health record. Studies have shown that, although students often can access electronic health records, some students may receive inadequate preparation for these skills. Greater understanding of student exposure to electronic health records during their obstetrics and gynecology clerkships can help to determine the extent to which students receive the educational experiences that may best prepare them for their future training and practice.

Objective: The purpose of this study was to examine medical student reporting of electronic health record use during the obstetrics and gynecology clerkship.

Study Design: A Step 2 Clinical Knowledge End-of-Examination Survey about electronic health record use was administered to medical students after they completed the Step 2 Clinical Knowledge component of the United States Medical Licensing Examination. For inpatient and outpatient rotations, students were asked if they accessed a record and if they entered notes or orders into it. Descriptive statistics for a sample of 16,366 medical students who graduated from Liaison Committee on Medical Education-accredited schools from 2012-2016 summarize student interactions with electronic health records by rotation type and graduation year. Chi-square techniques were used to examine mean differences in access and entry.

Results: The survey had an overall response rate of 70%. In 2016, most survey respondents (94%) accessed electronic health records during their obstetrics and gynecology clerkship, but 26% of them reported "read-only" access. On the inpatient service, <10% of students reported any order entry; 58% of them reported entering progress notes, and 47% of them reported entering an admitting history and physical.

Conclusion: Medical school graduates who are entering obstetrics and gynecology residencies are expected to be competent in documenting clinical encounters and entering orders, including those that are unique to obstetrics and gynecology. This study shows that some students may receive less experience with entering information into electronic health records during their obstetrics and gynecology clerkships than others, which could result in unequal levels of preparedness for graduate medical education.
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http://dx.doi.org/10.1016/j.ajog.2020.02.004DOI Listing
September 2020

NTRK3 overexpression in undifferentiated sarcomas with YWHAE and BCOR genetic alterations.

Mod Pathol 2020 07 7;33(7):1341-1349. Epub 2020 Feb 7.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The BCOR family of tumors includes a number of undifferentiated sarcomas, occurring in various age groups and anatomic sites, characterized by a spindle and round cell phenotype and diffuse immunoreactivity for BCOR. Prior RNA sequencing data revealed that NTRK3 was a top-upregulated gene in BCOR-CCNB3 sarcomas. In this study, we investigate a large cohort of tumors harboring BCOR/YWHAE genetic alterations for NTRK3 upregulation at both the mRNA and protein levels, compared with other sarcoma types. Pan-Trk immunohistochemistry was assessed for intensity and extent. A correlation between NTRK3 expression and the type of BCOR alteration and BCOR immunoreactivity was also performed. Most soft tissue undifferentiated round cell sarcomas with YWHAE or BCOR rearrangements or BCOR internal tandem duplications (ITD) showed NTRK3, but not NTRK1 or NTRK2, upregulation by RNA sequencing data analysis. Cytoplasmic pan-Trk immunoreactivity was also observed in most soft tissue round cell sarcomas with YWHAE rearrangements (100%), BCOR ITD (80%), and BCOR-CCNB3 fusions (67%), as well as clear cell sarcomas of kidney (75%), another BCOR family tumor, and ossifying fibromyxoid tumors with ZC3H7B-BCOR fusion (100%), with variable staining intensity and extent. Pan-Trk staining was also seen in solitary fibrous tumors (100%) and less frequently in synovial sarcoma and Ewing sarcoma, but rarely in other sarcomas tested. Tumors harboring rare fusion variants of BCOR, such as BCOR-CHD9, a novel fusion identified by targeted RNA sequencing, and KMT2D-BCOR, were also positive for pan-Trk staining and NTRK3 overexpression. In conclusion, NTRK3 upregulation resulting in pan-Trk overexpression is common in the BCOR family of tumors as well as in subsets of BCOR-expressing sarcomas through alternative mechanisms. The therapeutic implication of this finding awaits further investigation.
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http://dx.doi.org/10.1038/s41379-020-0495-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329614PMC
July 2020

Oligohydramnios: a prospective study of fetal, neonatal and maternal outcomes in low-middle income countries.

Reprod Health 2020 Jan 30;17(1):19. Epub 2020 Jan 30.

Department of Obstetrics/Gynecology, Columbia University, New York, NY, USA.

Background: Oligohydramnios is a condition of abnormally low amniotic fluid volume that has been associated with poor pregnancy outcomes. To date, the prevalence of this condition and its outcomes has not been well described in low and low-middle income countries (LMIC) where ultrasound use to diagnose this condition in pregnancy is limited. As part of a prospective trial of ultrasound at antenatal care in LMICs, we sought to evaluate the incidence of and the adverse maternal, fetal and neonatal outcomes associated with oligohydramnios.

Methods: We included data in this report from all pregnant women in community settings in Guatemala, Pakistan, Zambia and the Democratic Republic of Congo (DRC) who received a third trimester ultrasound as part of the First Look Study, a randomized trial to assess the value of ultrasound at antenatal care. Using these data, we conducted a planned secondary analysis to compare pregnancy outcomes of women with to those without oligohydramnios. Oligohydramnios was defined as measurement of an Amniotic Fluid Index less than 5 cm in at least one ultrasound in the third trimester. The outcomes assessed included maternal morbidity and fetal and neonatal mortality, preterm birth and low-birthweight. We used pairwise site comparisons with Tukey-Kramer adjustment and multivariable logistic models using general estimating equations to account for the correlation of outcomes within cluster.

Results: Of 12,940 women enrolled in the clusters in Guatemala, Pakistan, Zambia and the DRC in the First Look Study who had a third trimester ultrasound examination, 87 women were diagnosed with oligohydramnios, equivalent to 0.7% of those studied. Prevalence of detected oligohydramnios varied among study sites; from the lowest of 0.2% in Zambia and the DRC to the highest of 1.5% in Pakistan. Women diagnosed with oligohydramnios had higher rates of hemorrhage, fetal malposition, and cesarean delivery than women without oligohydramnios. We also found unfavorable fetal and neonatal outcomes associated with oligohydramnios including stillbirths (OR 5.16, 95%CI 2.07, 12.85), neonatal deaths < 28 days (OR 3.18, 95% CI 1.18, 8.57), low birth weight (OR 2.10, 95% CI 1.44, 3.07) and preterm births (OR 2.73, 95%CI 1.76, 4.23). The mean birth weight was 162 g less (95% CI -288.6, - 35.9) with oligohydramnios.

Conclusions: Oligohydramnos was associated with worse neonatal, fetal and maternal outcomes in LMIC. Further research is needed to assess effective interventions to diagnose and ultimately to reduce poor outcomes in these settings.

Trial Registration: NCT01990625.
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http://dx.doi.org/10.1186/s12978-020-0854-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993413PMC
January 2020

A morphologic and molecular reappraisal of myoepithelial tumors of soft tissue, bone, and viscera with EWSR1 and FUS gene rearrangements.

Genes Chromosomes Cancer 2020 06 7;59(6):348-356. Epub 2020 Feb 7.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Myoepithelial tumors (MET) represent a clinicopathologically heterogeneous group of tumors, ranging from benign to highly aggressive lesions. Although MET arising in soft tissue, bone, or viscera share morphologic and immunophenotypic overlap with their salivary gland and cutaneous counterparts, there is still controversy regarding their genetic relationship. Half of MET of soft tissue and bone harbor EWSR1 or FUS related fusions, while MET arising in the salivary gland and skin often show PLAG1 and HMGA2 gene rearrangements. Regardless of the site of origin, the gold standard in diagnosing a MET relies on demonstrating its "myoepithelial immunophenotype" of positivity for EMA/CK and S100 protein or GFAP. However, the morphologic spectrum of MET in soft tissue and bone is quite broad and the above immunoprofile is nonspecific, being shared by other pathogenetically unrelated neoplasms. Moreover, rare MET lack a diagnostic immunoprofile but shows instead the characteristic gene fusions. In this study, we analyzed a large cohort of 66 MET with EWSR1 and FUS gene rearrangements spanning various clinical presentations, to better define their morphologic spectrum and establish relevant pathologic-molecular correlations. Genetic analysis was carried out by FISH for EWSR1/FUS rearrangements and potential partners, and/or by targeted RNA sequencing. Then, 82% showed EWSR1 rearrangement, while 18% had FUS abnormalities. EWSR1-POU5F1 occurred with predilection in malignant MET in children and young adults and these tumors had nested epithelioid morphology and clear cytoplasm. In contrast, EWSR1/FUS-PBX1/3 fusions were associated with benign and sclerotic spindle cell morphology. Tumors with EWSR1-KLF17 showed chordoma-like morphology. Our results demonstrate striking morphologic-molecular correlations in MET of bone, soft tissue and viscera, which might have implications in their clinical behavior.
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http://dx.doi.org/10.1002/gcc.22835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170037PMC
June 2020

Response to Letter to the Editor on "A Meta-Analysis of Outcomes in Total Hip Arthroplasty Recipients Following Pelvic Irradiation".

J Arthroplasty 2020 03 5;35(3):908. Epub 2019 Nov 5.

Department of Orthopaedic Surgery, Stony Brook University Hospital, Stony Brook, New York.

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http://dx.doi.org/10.1016/j.arth.2019.09.023DOI Listing
March 2020

Ewing sarcoma with FEV gene rearrangements is a rare subset with predilection for extraskeletal locations and aggressive behavior.

Genes Chromosomes Cancer 2020 05 3;59(5):286-294. Epub 2019 Dec 3.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

The molecular hallmark of Ewing sarcoma (ES) is a fusion involving the EWSR1 gene and a member of the ETS family of transcription factors. EWSR1-FLI1 is the most common variant, occurring in 90% of cases, followed by EWSR1-ERG. In a small subset, the FUS gene can substitute for EWSR1 in these fusions. Only rare case reports have been described to date of ES with FEV gene rearrangements. In this study, we investigate the clinicopathologic and molecular features of 10 ES patients with FEV-rearrangements, either fused to EWSR1 (n = 4) or to FUS (n = 6). The median age at diagnosis was 38 years (range, 5-61 years); occurring in six males and four females. All tumors were located at extraskeletal sites, occurring more often in the axial soft tissues. Tumors had a similar morphologic appearance and immunophenotype as ES with more common EWSR1-ETS fusions. Of six patients with follow-up data, five patients (83%) developed metastasis and two patients (33%) died of their diseases. The diagnosis was confirmed either by fluorescence in situ hybridization and/or targeted RNA sequencing. In the five cases tested by targeted sequencing, the fusion transcripts were composed of EWSR1 or FUS fused to either exon 1 or 2 of FEV, retaining the FEV ETS DNA binding domain. This is the largest study to date investigating the ES subset with EWSR1/FUS-FEV fusions showing a predilection for extraskeletal sites and aggressive behavior.
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http://dx.doi.org/10.1002/gcc.22828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135932PMC
May 2020

Obesity and other medical comorbidities among NT1 patients after the Norwegian H1N1 influenza epidemic and vaccination campaign.

Sleep 2020 05;43(5)

Department of Rare Disorders, Division of Paediatric and Adolescent Medicine, Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom), Oslo University Hospital, Norway.

Study Objectives: Narcolepsy type 1 (NT1) may be complicated by comorbidities. We aimed to study the extent of obesity and other medical comorbidities in a Norwegian population of NT1 patients with debut of symptoms after the 2009 H1N1 influenza epidemic and vaccination campaign. We also aimed to explore factors associated with obesity.

Methods: Ninety-one patients (48 children and 43 adults) were included in this cross-sectional study, 80 of whom were H1N1-vaccinated. All participants were hospitalized and underwent sleep investigation and physical examination, and completed a semi-structured clinical interview.

Results: In children, 16 females (70%) and 10 males (40%) were classified as overweight or obese. Twenty children (42%) had a co-existing medical disorder. Medical comorbidity was significantly positively associated with BMI in children (p = .032). In adults, 19 females (58%) and 7 males (70%) were classified as overweight or obese. Twenty-six adults (61%) had a co-existing medical disorder. We found no factors significantly associated with BMI in adults. On a fatigue scale from 0 to 100, lower scores indicating more fatigue, we found a mean (SD) total fatigue score of 50 (17) in children and 39 (16) in adults.

Conclusion: In a cohort of predominantly H1N1-vaccinated NT1 patients, we found a high prevalence of overweight or obesity. Half of the cohort presented with one or more additional medical comorbidities, and patients reported a clinically relevant degree of fatigue. Our findings highlight the importance of carefully monitoring patients with NT1 with regard to the development of obesity, which is a significant risk factor for cardiovascular disorders.
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http://dx.doi.org/10.1093/sleep/zsz277DOI Listing
May 2020

Clinical and molecular characterization of primary sclerosing epithelioid fibrosarcoma of bone and review of the literature.

Genes Chromosomes Cancer 2020 04 15;59(4):217-224. Epub 2019 Nov 15.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare sarcoma subtype characterized by monomorphic epithelioid cells embedded in a densely sclerotic collagenous matrix. The overwhelming majority of tumors arise in soft tissues; however, rare cases have been documented to occur primarily in bone. The hallmarks of soft tissue SEF include MUC4 immunoreactivity and the presence of an EWSR1-CREB3L1 fusion. Rare cases with alternative fusions have also been reported such as EWSR1-CREB3L2 and FUS-CREB3L2 transcripts. The molecular alterations of skeletal SEF have not been well-defined, with only rare cases analyzed to date. In this study we investigated the clinicopathologic and molecular features of seven patients presenting with primary osseous SEF. There were 3 males and 4 females, with a mean age at diagnosis of 38 years. All cases had microscopic features within the histologic spectrum of SEF and showed strong and diffuse MUC4 positivity, while lacking SATB2 expression. However, due to its unusual presentation within bone, four cases were initially misinterpreted as either osteosarcoma, Ewing sarcoma or chondroblastoma. Half of the patients with follow-up data developed metastasis. The cases were tested by targeted RNA sequencing, MSK-IMPACT, and/or fluorescence in situ hybridization, showing EWSR1-CREB3L1 in six cases and EWSR1-CREB3L2 in one case. The fusion transcripts were composed of EWSR1 exon 11 to either exon 6 of CREB3L1 or CREB3L2. In summary, due to their rarity in the bone, skeletal SEF are often misdiagnosed, resulting in inadequate treatment modalities. Similar to their soft tissue counterpart, bone SEF follow an aggressive clinical behavior and show similar EWSR1-CREB3L1/CREB3L2 fusions.
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http://dx.doi.org/10.1002/gcc.22822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082133PMC
April 2020

Novel SS18-NEDD4 gene fusion in a primary renal synovial sarcoma.

Genes Chromosomes Cancer 2020 03 21;59(3):203-208. Epub 2019 Oct 21.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

We report a primary renal synovial sarcoma with a novel gene fusion and unusual morphology. The patient was a 35-year-old female who was found to have a 5 cm hypocellular, myxoid spindle cell renal neoplasm that subtly permeated amongst native renal tubules. The tumor cells showed elongated hyperchromatic nuclei with ill-defined pale cytoplasm, lacking significant mitotic activity or necrosis. Based on its deceptively bland morphology, the differential diagnosis included mainly benign entities, such as metanephric stromal tumor, mixed epithelial stromal tumor (MEST), and myxoid peripheral nerve sheath tumors. A definitive diagnosis of synovial sarcoma was made only subsequently to RNA-sequencing, which revealed a novel SS18-NEDD4 gene fusion. These results were further confirmed by fluorescence in situ hybridization using custom design break-apart probes for both genes. This case illustrates the utility of targeted RNA-sequencing in the classification of challenging tumors with deceptive morphology and identification of novel gene fusion variants. Apart from the canonical SS18-SSX fusion, this is only the second alternative gene fusion variant described in synovial sarcoma to date, in addition to two cases harboring the SS18L1-SSX1 fusion.
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http://dx.doi.org/10.1002/gcc.22814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086378PMC
March 2020