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.
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.
Twenty primary abdominal inflammatory myofibroblastic tumours, including four epithelioid inflammatory myofibroblastic sarcomas, were analysed showing mostly kinase fusions, including a novel RRBP1::ALK fusion and FGFR1 translocation. In kinase fusion‐negative IMTs, we expand the molecular profile to genes related to the RTK/PI3K/AKT pathway, rendering further opportunities for targeted therapy.
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.
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.
Abstract
While a rapid sea ice retreat in the Arctic has become ubiquitous, the potential weakening of the Atlantic meridional overturning circulation (AMOC) in response to global warming is still ...under debate. As deep mixing occurs in the open ocean close to the sea ice edge, the strength and vertical extent of the AMOC is likely to respond to ongoing and future sea ice retreat. Here, we investigate the link between changes in Arctic sea ice cover and AMOC strength in a long simulation with the EC-Earth–Parallel Ice Sheet Model (PISM) climate model under the emission scenario RCP8.5. The extended duration of the experiment (years 1850–2300) captures the disappearance of summer sea ice in 2060 and the removal of winter sea ice in 2165. By introducing a new metric, the Arctic meridional overturning circulation (ArMOC), we document changes beyond the Greenland–Scotland ridge and into the central Arctic. We find an ArMOC strengthening as the areas of deep mixing move north, following the retreating winter sea ice edge into the Nansen Basin. At the same time, mixing in the Labrador and Greenland Seas reduces and the AMOC weakens. As the winter sea ice edge retreats farther into the regions with high surface freshwater content in the central Arctic Basin, the mixing becomes shallower and the ArMOC weakens. Our results suggest that the location of deep-water formation plays a decisive role in the structure and strength of the ArMOC; however, the intermittent strengthening of the ArMOC and convection north of the Greenland–Scotland ridge cannot compensate for the progressive weakening of the AMOC.
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.
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.
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.
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.
Highlights ► The automatic detection of HFOs is crucial to propel the clinical use of HFOs as biomarkers of epileptogenic tissue. ► A comparison of existing detectors on the same dataset is presented ...to analyze their performance and to emphasize the issues involved in validation. ► Optimizing on a particular type of data could improve performance in any detector.
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.
The prognostic value of weight loss prior to and during ICI therapy for R/M HNSCC
This study aims to identify if oscillations at frequencies higher than the traditional EEG can be recorded on the scalp EEG of patients with focal epilepsy and to analyze the association of these ...oscillations with interictal discharges and the seizure onset zone (SOZ).
The scalp EEG of 15 patients with focal epilepsy was studied. We analyzed the rates of gamma (40-80 Hz) and ripple (>80 Hz) oscillations, their co-occurrence with spikes, the number of channels with fast oscillations inside and outside the SOZ, and the specificity, sensitivity, and accuracy of gamma, ripples, and spikes to determine the SOZ.
Gamma and ripples frequently co-occurred with spikes (77.5% and 63% of cases). For all events, the proportion of channels with events was consistently higher inside than outside the SOZ: spikes (100% vs 70%), gamma (82% vs 33%), and ripples (48% vs 11%); p < 0.0001. The mean rates (events/min) were higher inside than outside the SOZ: spikes (2.64 ± 1.70 vs 0.69 ± 0.26, p = 0.02), gamma (0.77 ± 0.71 vs 0.20 ± 0.25, p = 0.02), and ripples (0.08 ± 0.12 vs 0.04 ± 0.09, p = 0.04). The sensitivity to identify the SOZ was spikes 100%, gamma 82%, and ripples 48%; the specificity was spikes 30%, gamma 68%, and ripples 89%; and the accuracy was spikes 43%, gamma 70%, and ripples 81%.
The rates and the proportion of channels with gamma and ripple fast oscillations are higher inside the SOZ, indicating that they can be used as interictal scalp EEG markers for the SOZ. These fast oscillations are less sensitive but much more specific and accurate than spikes to delineate the SOZ.
Abstract
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.
PDF
