Postoperative Revision, Complication and Economic Outcomes of Patients with Reverse or Anatomic Total Shoulder Arthroplasty at One Year: A Retrospective, United States Hospital Billing Database Analysis.

BACKGROUND: Data on the one-year postoperative revision, complication, and economic outcomes in a hospital setting after total shoulder arthroplasty (TSA) are sparse. METHODS: A retrospective cohort study using the Premier Healthcare Database, a hospital-billing data source, evaluated one-year postoperative revision, complication, and economic outcomes of reverse (RTSA) and anatomic (ATSA) TSA for patients who underwent the procedure from 2015 until 2021. All-cause revisits, including revision-related events (categorized as either irrigation and débridement or revision procedures and device removals) and shoulder/non-shoulder complications were collected. The incidences and costs of these revisits were evaluated. Generalized linear models were used to evaluate the associations between patient characteristics and revision and complication occurrences and costs. RESULTS: Among 51,478 RTSA and 34,623 ATSA patients (mean [standard deviation (SD)] ages RTSA 71.5 [8.1] years, ATSA 66.8 [9.0] years), one-year adjusted incidences of all-cause revisits, irrigation/débridement, revision procedures/device removals, and shoulder/non-shoulder complications were RTSA: 45.0% (95% confidence interval (CI): 44.6%-45.5%), 0.1% (95% CI: 0.1%-0.2%), 2.1% (95% CI: 2.0%-2.2%), and 17.8% (95% CI: 17.5%-18.1%) and ATSA: 42.3% (95% CI: 41.8%-42.9%), 0.2% (95% CI: 0.1%-0.2%), 1.9% (95% CI: 1.8%-2.1%), and 14.4% (95% CI: 14.0%-14.8%), respectively; shoulder-related complications were RTSA: 12.4% (95% CI: 12.1%-12.7%) and ATSA: 9.9% (95% CI: 9.6%-10.3%). Significant factors associated with a high risk of revisions and complications included, but were not limited to, chronic comorbidities and noncommercial insurance. Per patient, the mean (SD) total one-year hospital cost was $25,225 ($15,911) and $21,520 ($13,531) for RTSA and ATSA, respectively. Revision procedures and device removals were most costly, averaging $22,920 ($18,652) and $26,911 ($18,619) per procedure for RTSA and ATSA, respectively. Patients with revision-related events with infections had higher total hospital costs than patients without this event (RTSA: $60,887 (95% CI: $56,951-$64,823) and ATSA: $59,478 (95% CI: $52,312-$66,644)), equating to a mean difference of $36,148 with RTSA and $38,426 with ATSA. Significant factors associated with higher costs of revision-related events and complications included age, race, chronic comorbidities, and noncommercial insurance. CONCLUSIONS: Nearly 45% RTSA and 42% ATSA patients returned to the hospital, most often for shoulder/non-shoulder complications (overall 17.8% RTSA and 14.4% ATSA, and shoulder-related 12.4% RTSA and 9.9% ATSA). Revisions and device removals were most expensive ($22,920 RTSA and $26,911 ATSA). Infection complications requiring revision had the highest one-year hospital costs (∼$60,000). This study highlights the need for technologies and surgical techniques that may help reduce TSA healthcare utilization and economic burden.

Lipid profiling of electrosurgical vapors for real-time assistance of soft tissue sarcoma resection.

BACKGROUND: Soft tissue sarcomas (STS) constitute a heterogeneous group of rare tumor entities. Treatment relies on challenging patient-tailored surgical resection. Real-time intraoperative lipid profiling of electrosurgical vapors by rapid evaporative ionization mass spectrometry (REIMS) may aid in achieving successful surgical R0 resection (i.e., microscopically negative-tumor margin resection). Here, we evaluate the ex vivo accuracy of REIMS to discriminate and identify various STS from normal surrounding tissue. METHODS: Twenty-seven patients undergoing surgery for STS at Maastricht University Medical Center+ were included in the study. Samples of resected STS specimens were collected and analyzed ex vivo using REIMS. Electrosurgical cauterization of tumor and surrounding was generated successively in both cut and coagulation modes. Resected specimens were subsequently processed for gold standard histopathological review. Multivariate statistical analysis (principal component analysis-linear discriminant analysis) and leave-one patient-out cross-validation were employed to compare the classifications predicted by REIMS lipid profiles to the pathology classifications. Electrosurgical vapors produced during sarcoma resection were analyzed in vivo using REIMS. RESULTS: In total, 1200 histopathologically-validated ex vivo REIMS lipid profiles were generated from 27 patients. Ex vivo REIMS lipid profiles classified STS and normal tissues with 95.5% accuracy. STS, adipose and muscle tissues were classified with 98.3% accuracy. Well-differentiated liposarcomas and adipose tissues could not be discriminated based on their respective lipid profiles. Distinction of leiomyosarcomas from other STS could be achieved with 96.6% accuracy. In vivo REIMS analyses generated intense mass spectrometric signals. CONCLUSION: Lipid profiling by REIMS is able to discriminate and identify STS with high accuracy and therefore constitutes a potential asset to improve surgical resection of STS in the future.

Abdominal inflammatory myofibroblastic tumour: Clinicopathological and molecular analysis of 20 cases, highlighting potential therapeutic targets.

AIMS: Inflammatory myofibroblastic tumour (IMT) is a rare mesenchymal neoplasm of intermediate malignant potential, occurring at any age and at multiple sites. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of IMT, typically involving the abdomen. Most IMTs harbour kinase gene fusions, especially involving ALK and ROS1, but 20-30% of IMTs show no detectable translocations. The aim of this study is to further delineate clinicopathological and molecular characteristics of abdominal IMT and discover potential new therapeutic targets. METHODS AND RESULTS: In 20 IMTs, including four EIMS, RNA fusion analysis was performed, followed by multiplex DNA analysis if no ALK or ROS1 fusion was detected. Fourteen IMTs (70.0%) had an ALK translocation and the fusion partner was identified in 11, including a RRBP1::ALK fusion, not previously described in classical (non-EIMS) IMT. RANBP2::ALK fusion was demonstrated in all EIMS. One IMT had a ROS1 fusion. In all ALK/ROS1 translocation-negative IMTs mutations or fusions - as yet unreported in primary IMT - were found in genes related to the receptor tyrosine kinase (RTK)/PI3K/AKT pathway. Three of four patients with EIMS died of disease [mean survival 8 months (4-15 months)], whereas only one of 14 classical IMT patients succumbed to disease [mean follow-up time 52 months (2-204 months); P < 0.01]. CONCLUSION: This study shows the wide clinical spectrum of abdominal IMTs and affirms the poor prognosis of EIMS, raising discussion about its status as IMT subtype. Furthermore, the newly detected alterations of the RTK/PI3K/AKT pathway expand the molecular landscape of IMTs and provide potential therapeutic targets.

Creating Case Studies for Digital Health and Technology Competency in Nursing.

BACKGROUND: Nursing programs and their faculty must ensure that graduates have the informatics, digital health, and health care technologies competencies needed by health systems. PROBLEM: A gap exists in nursing faculty knowledge, skills, and abilities for incorporating informatics, digital health, and technologies across curricula because of low focus on this area in faculty development initiatives and rapid adoption and evolution of technologies in health care systems. APPROACH: The Nursing Knowledge Big Data Science initiative Education Subgroup used a process to create case studies for including informatics, digital health, and the concomitant clinical reasoning/critical thinking competencies across curricula. OUTCOMES: Three case study examples were created using the process. CONCLUSIONS: The process for creating case studies that incorporate required informatics, digital health, and health care technologies can be used by nursing educators for teaching across their curricula and to assess student competency.

Risk factors and healthcare costs associated with long bone fracture non-union: a retrospective US claims database analysis.

BACKGROUND: Few contemporary US-based long bone non-union analyses have recently been published. Our study was designed to provide a current understanding of non-union risks and costs, from the payers' perspective. METHODS: The Merative™ MarketScan® Commercial Claims and Encounters database was used. Patients with surgically treated long bone (femur, tibia, or humerus) fractures in the inpatient setting, from Q4 2015 to most recent, were identified. Exclusion criteria included polytrauma and amputation at index. The primary outcome was a diagnosis of non-union in the 12 and 24 months post-index. Additional outcomes included concurrent infection, reoperation, and total healthcare costs. Age, gender, comorbidities, fracture characteristics, and severity were identified for all patients. Descriptive analyses were performed. Crude and adjusted rates of non-union (using Poisson regressions with log link) were calculated. Marginal incremental cost of care associated with non-union and infected non-union and reoperation were estimated using a generalized linear model with log link and gamma distribution. RESULTS: A total of 12,770, 13,504, and 4,805 patients with femoral, tibial, or humeral surgically treated fractures were identified, 74-89% were displaced, and 18-27% were comminuted. Two-year rates of non-union reached 8.5% (8.0%-9.1%), 9.1% (8.6%-9.7%), and 7.2% (6.4%-8.1%) in the femoral, tibial, and humeral fracture cohorts, respectively. Shaft fractures were at increased risk of non-union versus fractures in other sites (risk ratio (RR) in shaft fractures of the femur: 2.36 (1.81-3.04); tibia: 1.95 (1.47-2.57); humerus: 2.02 (1.42-2.87)). Fractures with severe soft tissue trauma (open vs. closed, Gustilo III vs. Gustilo I-II) were also at increased risk for non-union (RR for Gustilo III fracture (vs. closed) for femur: R = 1.96 (1.45-2.58), for tibia: 3.33 (2.85-3.87), RR for open (vs. closed) for humerus: 1.74 (1.30-2.32)). For all fractures, younger patients had a reduced risk of non-union compared to older patients. For tibial fractures, increasing comorbidity (Elixhauser Index 5 or greater) was associated with an increased risk of non-union. The two-year marginal cost of non-union ranged from $33K-$45K. Non-union reoperation added $16K-$34K in incremental costs. Concurrent infection further increased costs by $46K-$86K. CONCLUSIONS: Non-union affects 7-10% of surgically treated long bone fracture cases. Shaft and complex fractures were at increased risk for non-union.

EWSR1::POU2AF3(COLCA2) Sarcoma: An Aggressive, Polyphenotypic Sarcoma With a Head and Neck Predilection.

EWSR1::POU2AF3 (COLCA2) sarcomas are a recently identified group of undifferentiated round/spindle cell neoplasms with a predilection for the head and neck region. Herein, we report our experience with 8 cases, occurring in 5 men and 3 women (age range, 37-74 years; median, 60 years). Tumors involved the head/neck (4 cases), and one each the thigh, thoracic wall, fibula, and lung. Seven patients received multimodal therapy; 1 patient was treated only with surgery. Clinical follow-up (8 patients; range, 4-122 months; median, 32 months) showed 5 patients with metastases (often multifocal, with a latency ranging from 7 to 119 months), and 3 of them also with local recurrence. The median local recurrence-free and metastasis-free survival rates were 24 months and 29 months, respectively. Of the 8 patients, 1 died of an unknown cause, 4 were alive with metastatic disease, 1 was alive with unresectable local disease, and 2 were without disease. The tumors were composed of 2 morphologic subgroups: (1) relatively bland tumors consisting of spindled to stellate cells with varying cellularity and fibromyxoid stroma (2 cases) and (2) overtly malignant tumors composed of nests of "neuroendocrine-appearing" round cells surrounded by spindled cells (6 cases). Individual cases in the second group showed glandular, osteogenic, or rhabdomyoblastic differentiation. Immunohistochemical results included CD56 (4/4 cases), GFAP (5/8), SATB2 (4/6), keratin (AE1/AE3) (5/8), and S100 protein (4/7). RNA sequencing identified EWSR1::POU2AF3 gene fusion in all cases. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization in 5 cases. Our findings confirm the head/neck predilection and aggressive clinical behavior of EWSR1::POU2AF3 sarcomas and widen the morphologic spectrum of these rare lesions to include relatively bland spindle cell tumors and tumors with divergent differentiation.

Predicting HPV association using deep learning and regular H&E stains allows granular stratification of oropharyngeal cancer patients.

Human Papilloma Virus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) represents an OPSCC subgroup with an overall good prognosis with a rising incidence in Western countries. Multiple lines of evidence suggest that HPV-associated tumors are not a homogeneous tumor entity, underlining the need for accurate prognostic biomarkers. In this retrospective, multi-institutional study involving 906 patients from four centers and one database, we developed a deep learning algorithm (OPSCCnet), to analyze standard H&E stains for the calculation of a patient-level score associated with prognosis, comparing it to combined HPV-DNA and p16-status. When comparing OPSCCnet to HPV-status, the algorithm showed a good overall performance with a mean area under the receiver operator curve (AUROC) = 0.83 (95% CI = 0.77-0.9) for the test cohort (n = 639), which could be increased to AUROC = 0.88 by filtering cases using a fixed threshold on the variance of the probability of the HPV-positive class - a potential surrogate marker of HPV-heterogeneity. OPSCCnet could be used as a screening tool, outperforming gold standard HPV testing (OPSCCnet: five-year survival rate: 96% [95% CI = 90-100%]; HPV testing: five-year survival rate: 80% [95% CI = 71-90%]). This could be confirmed using a multivariate analysis of a three-tier threshold (OPSCCnet: high HR = 0.15 [95% CI = 0.05-0.44], intermediate HR = 0.58 [95% CI = 0.34-0.98] p = 0.043, Cox proportional hazards model, n = 211; HPV testing: HR = 0.29 [95% CI = 0.15-0.54] p < 0.001, Cox proportional hazards model, n = 211). Collectively, our findings indicate that by analyzing standard gigapixel hematoxylin and eosin (H&E) histological whole-slide images, OPSCCnet demonstrated superior performance over p16/HPV-DNA testing in various clinical scenarios, particularly in accurately stratifying these patients.

Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes.

Kabuki syndrome is a well-recognized syndrome characterized by facial dysmorphism and developmental delay/intellectual disability and in the majority of patients a germline variant in KMT2D is found. As somatic KMT2D variants can be found in 5-10% of tumors a tumor predisposition in Kabuki syndrome is discussed. So far less than 20 patients with Kabuki syndrome and a concomitant malignancy have been published. Here we report on a female patient with Kabuki syndrome and a c.2558_2559delCT germline variant in KMT2D who developed an embryonal rhabdomyosarcoma (ERMS) at 10 years. On tumor tissue we performed DNA-methylation profiling and exome sequencing (ES). Copy number analyses revealed aneuploidies typical for ERMS including (partial) gains of chromosomes 2, 3, 7, 8, 12, 15, and 20 and 3 focal deletions of chromosome 11p. DNA methylation profiling mapped the case to ERMS by a DNA methylation-based sarcoma classifier. Sequencing suggested gain of the wild-type KMT2D allele in the trisomy 12. Including our patient literature review identified 18 patients with Kabuki syndrome and a malignancy. Overall, the landscape of malignancies in patients with Kabuki syndrome was reminiscent of that of the pediatric population in general. Histopathological and molecular data were only infrequently reported and no report included next generation sequencing and/or DNA-methylation profiling. Although we found no strong arguments pointing towards KS as a tumor predisposition syndrome, based on the small numbers any relation cannot be fully excluded. Further planned studies including profiling of additional tumors and long term follow-up of KS-patients into adulthood could provide further insights.

The predictive and prognostic value of weight loss and body composition prior to and during immune checkpoint inhibition in recurrent or metastatic head and neck cancer patients.

BACKGROUND: Response rates of immune checkpoint inhibitor (ICI) therapy for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are low. PATIENTS AND METHODS: This retrospective multicentre cohort study evaluates the predictive and prognostic value of weight loss and changes in body composition prior and during therapy. Patient, tumor, and treatment characteristics of 98 patients were retrieved, including neutrophil and platelet-lymphocyte-ratio (NLR and PLR). Programmed death-ligand 1 (PD-L1) expression was determined on residual material. Cachexia was defined according to Fearon et al. (2011). Skeletal muscle (SM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were evaluated on computed tomography scans at the third lumbar vertebrae level. Univariable and multivariable regression analyses were performed for 6 months progression free survival (PFS6m) and overall survival (OS). RESULTS: Significant early weight loss (>2%) during the first 6 weeks of therapy was shown in 34 patients (35%). This patient subgroup had a significantly higher NLR and PLR at baseline. NLR and PLR were inversely correlated with SM and VAT index. Independent predictors of PFS6m were lower World Health Organization performance status (HR 0.16 [0.04-0.54] p = 0.003), higher baseline SAT index (HR 1.045 [1.02-1.08] p = 0.003), and weight loss <2% (HR 0.85 [0.74-0.98] p = 0.03). Baseline cachexia in combination with >2% early weight loss remained a predictor of OS, independent of PD-L1 expression (HR 2.09 [1.11-3.92] p = 0.02, HR 2.18 [1.13-4.21] p = 0.02). CONCLUSION: We conclude that the combination of cachexia at baseline and weight loss during ICI therapy is associated with worse OS in R/M HNSCC patients, independent of PD-L1 expression.

Insights into the quantification and reporting of model-related uncertainty across different disciplines.

Quantifying uncertainty associated with our models is the only way we can express how much we know about any phenomenon. Incomplete consideration of model-based uncertainties can lead to overstated conclusions with real-world impacts in diverse spheres, including conservation, epidemiology, climate science, and policy. Despite these potentially damaging consequences, we still know little about how different fields quantify and report uncertainty. We introduce the "sources of uncertainty" framework, using it to conduct a systematic audit of model-related uncertainty quantification from seven scientific fields, spanning the biological, physical, and political sciences. Our interdisciplinary audit shows no field fully considers all possible sources of uncertainty, but each has its own best practices alongside shared outstanding challenges. We make ten easy-to-implement recommendations to improve the consistency, completeness, and clarity of reporting on model-related uncertainty. These recommendations serve as a guide to best practices across scientific fields and expand our toolbox for high-quality research.

Incidence, costs and post-operative complications following ankle fracture - A US claims database analysis.

BACKGROUND: The epidemiology and payer costs for ankle fractures are not well documented. This study evaluated: (1) the incidence of ankle fracture and ankle surgery following fracture in the US population; and (2) the clinical presentation of patients presenting with ankle fractures requiring surgery, their complication rates, and payer costs. METHODS: Patients in the IBM® MarketScan® Commercial and Medicare Supplemental databases with an inpatient/outpatient diagnosis of ankle fracture from 2016 to 2019 were stratified by age group and gender, and rates of fracture per 10,000 enrollees were estimated. Surgically-treated patients between January 2016 - October 2021 were further analyzed. One-year post-surgical outcomes evaluated complication rates (e.g., infection, residual pain), reoperations, and 1-year payments. Standard descriptive statistics were calculated for all variables and outcomes. Generalized linear models were designed to estimate payments for surgical care and incremental payments associated with postoperative complications. RESULTS: Fracture cases affected 0.14% of the population; 23.4% of fractures required surgery. Pediatric and elderly patients were at increased risk. From 3 weeks to 12 months following index ankle surgery, 5.5% (5.3% - 5.7%) of commercially insured and 5.9% (5.1% - 6.8%) of Medicare patients required a new surgery. Infection was observed in 4.4% (4.2% - 4.6%) commercially insured and 9.8% (8.8% - 10.9%) Medicare patients, and residual pain 3 months post-surgery was observed in 29.5% (28.7% - 30.3%) commercially-insured and 39.3% (36.0% - 42.6%) Medicare patients. Commercial payments for index surgery ranged from $9,821 (95% CI: $9,697 - $9,945) in the ambulatory surgical center to $28,169 (95% CI: $27,780 - $28,559) in the hospital inpatient setting, and from $16,775 (95% CI: $16,668 - $16,882) in patients with closed fractures, to $41,206 (95% CI: $38,795 - $43,617) in patients with Gustilo III fractures. Incremental commercial payments for pain and infection averaged $5,200 (95% CI: $4,261 - $6,139) and $27,510 (95% CI: $21,759 - $33,261), respectively. CONCLUSION: Ankle fracture has a high incidence and complication rate. Residual pain affects more than one-third of all patients. Ankle fracture thus presents a significant societal impact in terms of patient outcomes and payer burden.

Evaluation of the Sensitivity of Metabolic Profiling by Rapid Evaporative Ionization Mass Spectrometry: Toward More Radical Oral Cavity Cancer Resections.

Radical resection for patients with oral cavity cancer remains challenging. Rapid evaporative ionization mass spectrometry (REIMS) of electrosurgical vapors has been reported for real-time classification of normal and tumor tissues for numerous surgical applications. However, the infiltrative pattern of invasion of oral squamous cell carcinomas (OSCC) challenges the ability of REIMS to detect low amounts of tumor cells. We evaluate REIMS sensitivity to determine the minimal amount of detected tumors cells during oral cavity cancer surgery. A total of 11 OSCC patients were included in this study. The tissue classification based on 185 REIMS ex vivo metabolic profiles from five patients was compared to histopathology classification using multivariate analysis and leave-one-patient-out cross-validation. Vapors were analyzed in vivo by REIMS during four glossectomies. Complementary desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) was employed to map tissue heterogeneity on six oral cavity sections to support REIMS findings. REIMS sensitivity was assessed with a new cell-based assay consisting of mixtures of cell lines (tumor, myoblasts, keratinocytes). Our results depict REIMS classified tumor and soft tissues with 96.8% accuracy. In vivo REIMS generated intense mass spectrometric signals. REIMS detected 10% of tumor cells mixed with 90% myoblasts with 83% sensitivity and 82% specificity. DESI-MSI underlined distinct metabolic profiles of nerve features and a metabolic shift phosphatidylethanolamine PE(O-16:1/18:2))/cholesterol sulfate common to both mucosal maturation and OSCC differentiation. In conclusion, the assessment of tissue heterogeneity with DESI-MSI and REIMS sensitivity with cell mixtures characterized sensitive metabolic profiles toward in vivo tissue recognition during oral cavity cancer surgeries.

Assessing the prognostic value of tumor-infiltrating CD57+ cells in advanced stage head and neck cancer using QuPath digital image analysis.

This study aimed to assess the prognostic value of intratumoral CD57+ cells in head and neck squamous cell carcinoma (HNSCC) and to examine the reproducibility of these analyses using QuPath. Pretreatment biopsies of 159 patients with HPV-negative, stage III/IV HNSCC treated with chemoradiotherapy were immunohistochemically stained for CD57. The number of CD57+ cells per mm2 tumor epithelium was quantified by two independent observers and by QuPath, software for digital pathology image analysis. Concordance between the observers and QuPath was assessed by intraclass correlation coefficients (ICC). The correlation between CD57 and clinicopathological characteristics was assessed; associations with clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan-Meier curves. The patient cohort had a 3-year OS of 65.8% with a median follow-up of 54 months. The number of CD57+ cells/mm2 tumor tissue did not correlate to OS, DFS, or LRC. N stage predicted prognosis (OS: HR 0.43, p = 0.008; DFS: HR 0.41, p = 0.003; LRC: HR 0.24, p = 0.007), as did WHO performance state (OS: HR 0.48, p = 0.028; LRC: 0.33, p = 0.039). Quantification by QuPath showed moderate to good concordance with two human observers (ICCs 0.836, CI 0.805-0.863, and 0.741, CI 0.692-0.783, respectively). In conclusion, the presence of CD57+ TILs did not correlate to prognosis in advanced stage, HPV-negative HNSCC patients treated with chemoradiotherapy. Substantial concordance between human observers and QuPath was found, confirming a promising future role for digital, algorithm driven image analysis.

Surface-Enhanced Raman and Surface-Enhanced fluorescence of charged dyes based on alginate silver nanoparticles and its calcium alginate hydrogel beads.

This study shows a new SERS (Surface-enhanced Raman Scattering) and SEF (Surface-enhanced Fluorescence) platform approach, in which substrates were constructed from the silver nanoparticles stabilized by alginate polymer (AgALG) and encapsulated in hydrogel calcium alginate beads (AgALGbead). In this regard, the electrostatic repulsion or attraction concerning the charged dyes and the carboxylate groups of the alginate could define the distances between the probe molecules and metallic nanoparticles to determine the SERS or SEF effect. In this sense, the anionic dye named New Indocyanine Green (IR-820) and the cationic dye Rhodamine 6G (Rh6G) were selected to discuss the alginate's ability to quench or enhance the fluorescence and the Raman dyes signals. Furthermore, the SEF effect using the IR-820 dye can be detected for the near-infrared emission (S1 â†’ S0) using the 532 and 633 nm laser lines as well at the visible region (S2 â†’ S0) applying the excitation at 532 nm in the AgALGbead substrates. Nevertheless, the cationic dye provides the Surface-enhanced Resonance Raman Scattering (SERRS) effect and quenching of the fluorescence for the same AgALGbeads substrate at 532 nm laser line.

Sclerosing Polycystic Adenoma of Salivary Glands: A Novel Neoplasm Characterized by PI3K-AKT Pathway Alterations-New Insights Into a Challenging Entity.

Sclerosing polycystic adenoma (SPA) is a rare salivary gland neoplasm originally thought to represent a non-neoplastic lesion. Recently we have encountered an index case of apocrine intraductal carcinoma of parotid gland of 62-year-old man with invasive salivary duct carcinoma component arising from SPA, a combination of tumor entities that has never been published so far. Here, we further explore the nature of SPA by evaluating 36 cases that were identified from the authors' consultation files. The patients were 25 females and 11 males aged 11 to 79 years (mean, 47.8 y). All tumors originated from the parotid gland. Their size ranged from 11 to 70 mm (mean, 28 mm). Histologically, all cases revealed characteristic features of SPA, such as lobulated well-circumscribed growth, focal hyalinized sclerosis, presence of large acinar cells with abundant brightly eosinophilic intracytoplasmic granules, and ductal components with variable cytomorphologic characteristics, including foamy, vacuolated, apocrine, mucous, clear/ballooned, squamous, columnar and oncocyte-like cells. In all cases, there were foci of intraluminal solid and cribriform intercalated duct-like epithelial proliferations with variable dysplasia which were positive for S100 protein and SOX10, and fully enveloped by an intact layer of myoepithelial cells. In addition, 14/36 cases (39%) had focal intraductal cribriform and micropapillary apocrine-type dysplastic epithelial structures composed of cells positive for androgen receptors and negative for S100/SOX10. The intraductal proliferations of both types showed focal mild to severe dysplasia in 17 cases (17/36; 47%). Two cases showed overt malignant morphology ranging from high-grade intraductal carcinoma to invasive carcinoma with an apocrine ductal phenotype. Next generation sequencing using ArcherDX panel targeting RNA of 36 pan-cancer-related genes and/or a TruSight Oncology 170/500 Kit targeting a selection of DNA from 523 genes and RNA from 55 genes was performed. Tumor tissue was available for molecular analysis in 11 cases, and 9 (9/11; 82%) of them harbored genetic alterations in the PI3K pathway. Targeted sequencing revealed HRAS mutations c.37G>C, p.(Gly13Arg) (2 cases) and c.182A>G, p.(Gln61Arg) (2 cases), and PIK3CA mutations c.3140A>G, p.(His1047Arg) (3 cases), c.1633G>A, p.(Glu545Lys) (1 case), and c.1624G>A, p.(Glu542Lys) (1 case). Moreover, mutations in AKT1 c.49G>A, p.(Glu17Lys) and c.51dup, p.(Tyr18ValfsTer15); c.49_50delinsAG, p.(Glu17Arg) (as a double hit) were found (2 cases). In addition, germinal and somatic mutation of PTEN c.1003C>T, p.(Arg335Ter); c.445C>T, p.(Gln149Ter), respectively, were detected. Gene fusions were absent in all cases. These prevalent molecular alterations converging on one major cancer-related pathway support the notion that SPA is a true neoplasm with a significant potential to develop intraluminal epithelial proliferation with apocrine and/or intercalated duct-like phenotype. The name SPA more correctly reflects the true neoplastic nature of this enigmatic lesion.

Clinical Validity of a Prognostic Gene Expression Cluster-Based Model in Human Papillomavirus-Positive Oropharyngeal Carcinoma.

Under common therapeutic regimens, the prognosis of human papillomavirus (HPV)-positive squamous oropharyngeal carcinomas (OPCs) is more favorable than HPV-negative OPCs. However, the prognosis of some tumors is dismal, and validated prognostic factors are missing in clinical practice. The present work aimed to validate the prognostic significance of our published three-cluster model and to compare its prognostic value with those of the 8th edition of the tumor-node-metastasis staging system (TNM8) and published signatures and clustering models. METHODS: Patients with HPV DNA-positive OPCs with locoregionally advanced nonmetastatic disease treated with curative intent (BD2Decide observational study, NCT02832102) were considered as validation cohort. Patients were treated in seven European centers, with expertise in the multidisciplinary management of patients with head and neck cancer. The median follow-up was 46.2 months (95% CI, 41.2 to 50), and data collection was concluded in September 2019. The primary end point of this study was overall survival (OS). Three-clustering models and seven prognostic signatures were compared with our three-cluster model. RESULTS: The study population consisted of 235 patients. The three-cluster model confirmed its prognostic value. Two-year OS in each cluster was 100% in the low-risk cluster, 96.6% in the intermediate-risk cluster, and 86.3% in the high-risk cluster (P = .00074). For the high-risk cluster, we observed an area under the curve = 0.832 for 2-year OS, significantly outperforming TNM 8th edition (area under the curve = 0.596), and functional and biological differences were identified for each cluster. CONCLUSION: The rigorous clinical selection of the cases included in this study confirmed the robustness of our three-cluster model in HPV-positive OPCs. The prognostic value was found to be independent and superior compared with TNM8. The next step includes the translation of the three-cluster model in clinical practice. This could open the way to future exploration of already available therapies in HPV-positive OPCs tailoring de-escalation or intensification according to the three-cluster model.

Spontaneous Regression of a Middle Ear Melanoma.

OBJECTIVE: To describe a case of complete spontaneous regression of a middle ear melanoma. PATIENT: We present a case of a 68-year-old man with complaints of unilateral hearing loss and an ipsilateral facial nerve paresis. Radiological and histopathological examination revealed a cT4bN0M0 mucosal melanoma of the middle ear. INTERVENTIONS: The patient underwent a subtotal petrosectomy and postoperative radiotherapy. MAIN OUTCOME MEASURE: Computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography/computed tomography with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG-PET-CT), and histopathological examination. RESULTS: After subtotal petrosectomy, histopathological examination of the resection specimen showed only fibrosis and a histiocytic and clonal T-cell infiltration, but no residual melanoma at the primary tumor site, consistent with spontaneous tumor regression. Follow-up MRI scanning 6 and 12 months after radiotherapy showed no signs of tumor recurrence. CONCLUSIONS: This case describes the concept of spontaneous regression of a mucosal melanoma of the middle ear. Spontaneous tumor regression at this location has not been described before.

Seizure outcome after epilepsy surgery in tuberous sclerosis complex: Results and analysis of predictors from a multicenter study.

Epilepsy surgery is recommended in selected patients with Tuberous Sclerosis Complex (TSC). However, reports on predictive factors of seizure outcome are variable. Here we report on seizure and cognitive outcome of 35 TSC patients who received surgery for refractory epilepsy in 7 Italian centers over a period of 22 years (1997-2019). The rate of seizure-free individuals at last follow-up (mean 7.5 years, range 1-21 years) was 51%. Patients with longer follow-up (≥10 years) had a lower rate of Engel I outcome (11.1%) than those who received surgery in the last 10 years (65.4%, p = 0.003). Factors associated with Engel II, III, IV outcome in our cohort included: high number of cortical tubers (≥5); presence of subependymal nodules (SENs); seizure onset before age 1 year; and multifocal interictal epileptic discharges (IEDs) on electroencephalogram (EEG). A subset of patients evaluated with Vineland Adaptive Behaviour Scales (VABS) showed developmental gains, in line with their developmental trajectories, but no improvement in standard scores after surgery was noted. Our study demonstrates that the rates of successful seizure outcome of epilepsy surgery in TSC have improved in the last 10 years. More than half of the patients achieved seizure freedom, and a high proportion of affected individuals experienced a reduction in seizure burden and in antiseizure medications. A comprehensive assessment after surgery should be performed in TSC patients to evaluate the overall neurodevelopmental outcome, as measures that are based only on seizure control do not adequately identify the benefits of surgery on global functioning in these patients.

Real-time lipid patterns to classify viable and necrotic liver tumors.

Real-time tissue classifiers based on molecular patterns are emerging tools for fast tumor diagnosis. Here, we used rapid evaporative ionization mass spectrometry (REIMS) and multivariate statistical analysis (principal component analysis-linear discriminant analysis) to classify tissues with subsequent comparison to gold standard histopathology. We explored whether REIMS lipid patterns can identify human liver tumors and improve the rapid characterization of their underlying metabolic features. REIMS-based classification of liver parenchyma (LP), hepatocellular carcinoma (HCC), and metastatic adenocarcinoma (MAC) reached an accuracy of 98.3%. Lipid patterns of LP were more similar to those of HCC than to those of MAC and allowed clear distinction between primary and metastatic liver tumors. HCC lipid patterns were more heterogeneous than those of MAC, which is consistent with the variation seen in the histopathological phenotype. A common ceramide pattern discriminated necrotic from viable tumor in MAC with 92.9% accuracy and in other human tumors. Targeted analysis of ceramide and related sphingolipid mass features in necrotic tissues may provide a new classification of tumor cell death based on metabolic shifts. Real-time lipid patterns may have a role in future clinical decision-making in cancer precision medicine.

Comparison of three PD-L1 immunohistochemical assays in head and neck squamous cell carcinoma (HNSCC).

Expression of programmed cell death-ligand 1 (PD-L1) is being used as predictive biomarker for immunotherapy in head and neck squamous cell carcinoma (HNSCC). Several antibodies are available for PD-L1 testing and multiple staining and scoring methods are used. This study aimed to compare the performance of two PD-L1 standardized assays (SP263 and 22C3 pharmDx) and one laboratory-developed test (LDT) (22C3) in HNSCC using the tumor proportion score (TPS) and the combined positive score (CPS). Pretreatment biopsies from 147 HNSCC patients were collected in a tissue-microarray (TMA). Serial sections of the TMA were immunohistochemically stained for PD-L1 expression using 22C3 pharmDx on the Dako Link 48 platform, SP263 on the Ventana Benchmark Ultra platform, and 22C3 as an LDT on the Ventana Benchmark Ultra. Stained slides were assessed for TPS and CPS. Cutoffs of ≥1% and ≥50% for TPS and ≥1 and ≥20 for CPS were used. Concordance between the different staining assays was moderate to poor for TPS (intraclass correlation coefficient (ICC) 0.46) as well as for CPS (ICC 0.34). When stratifying patients by clinically relevant cutoffs, considerable differences between the assays were observed: concordance was poor for both TPS and CPS. Generally, SP263 stained a higher percentage of cells than the other assays, especially when using the CPS. Moderate concordance was shown between three different PD-L1 immunohistochemical assays and considerable differences in PD-L1 positivity were observed when using clinically relevant cutoffs. This should be taken into account when using PD-L1 expression to guide clinical practice.