DNA Methylation Profiling Distinguishes Adamantinoma-Like Ewing Sarcoma From Conventional Ewing Sarcoma.

Adamantinoma-like Ewing sarcoma (ALES) has traditionally been considered a variant of Ewing sarcoma because it generally harbors EWSR1::FLI1 fusions despite showing diffuse positivity for keratins and p40. However, it has become increasingly recognized that different tumors can have identical translocations, including shared fusions between carcinomas and sarcomas, raising questions as to whether ALES might represent a separate entity. Using methylation profiling, we further explored the relationship between Ewing sarcoma and ALES. The archives of multiple institutions were searched for candidate cases of ALES. DNA methylation profiling was performed and results were compared to corresponding data from conventional Ewing sarcoma. Twelve cases of ALES (5 previously reported) were identified in 10 men and 2 women (aged 20-72 years; median age, 41.5 years). Cases included tumors arising in the parotid gland (3), sinonasal cavity (2), submandibular gland (2), thyroid gland (1), neck (1), gingiva (1), hypopharynx (1), and mandible (1). Histologic review consistently showed sheets and nests of basaloid cells within a fibromyxoid or hyalinized stroma. All tumors were positive for at least 1 keratin and CD99 expression, whereas all 10 cases tested were positive for p63 or p40; S100 protein expression was noted in 2 cases. Cases harbored either EWSR1::FLI1 fusions (n = 6), FUS::FLI1 fusions (n = 1), and/or EWSR1 rearrangements (n = 6). Methylation profiling was successful in 11/12 cases evaluated. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) of DNA methylation data revealed a distinct methylation cluster for all 11 cases, including the tumor with the FUS::FLI1 fusion, which clearly segregated them from the conventional Ewing sarcoma. Follow-up (n = 11, 1-154 months) revealed that 4 patients experienced recurrence and 6 developed metastatic disease. ALES demonstrates a distinct methylation signature from conventional Ewing sarcoma. This finding adds to the distinctive immunoprofile of ALES, suggesting that these 2 tumors should be considered distinct entities rather than histologic extremes of the same disease.

An assessment of air passenger confidence a year into the COVID-19 crisis: A segmentation analysis of passengers in Norway.

The COVID-19 crisis has become the most intense and long-lasting in the history of aviation. There is already a significant literature on the immediate impact of the outbreak, as well as on speculation on the future evolution of the industry. This paper seeks to contribute to this discussion by assessing a year into the crisis the demand related aspects and passenger behavioural impacts of the pandemic. Specifically, the paper aims to identify discrete market segments of air passengers according to their shared attitudes and preferences about air travel in light of the COVID-19 crisis, as well as past behaviour and future travel intentions. To achieve this, we analyse data from a large (n = 2096) online questionnaire survey of air passengers in Norway. The cluster analysis identifies four distinct passenger segments, with each displaying varying attitudes, behaviours, and levels of concern about air travel. One of these groups, described as the 'Apprehensive Elders', were identified as having the highest level of concern about flying, and subsequently showed a sharp decline in their intention to travel in the future. Another group, termed the 'Cautious Commuters', showed similarly enhanced levels of concerns about flying, but maintained a high propensity to fly following the pandemic despite these concerns. Regarding possible interventions to increase confidence in flying in the future, across all segments the data shows a clear preference for more 'traditional' active interventions, including wearing of face masks and enforcement of physical distancing, over and above passive or technological interventions. Norway represents a valuable case as a possible signal for future policy and practice in relation to the recovery of air travel following the pandemic. The findings have important implications for air transport managers and decision makers in terms of managing the perceptions and expectations of different passenger groups as air travel begins to return.

Ready for digital transformation? The effect of organisational readiness, innovation, airport size and ownership on digital change at airports.

This study investigates the effect of organisational readiness, innovation and airport size and ownership on digital change at airports. Data is collected from a survey of managers at 94 airports worldwide and analysed using partial least squares structural equation modelling. Organisational readiness is found to have a direct effect on digital change. Organisational readiness also has a direct effect on innovation, which subsequently affects digital change. Airport size has a direct effect on digital change while the effect of ownership is not significant. The findings show that successful development of organisational readiness can be used to speed up the rate of innovation needed for digital change at airports.

Machine Learning-Based Risk Assessment for Cancer Therapy-Related Cardiac Dysfunction in 4300 Longitudinal Oncology Patients.

Background The growing awareness of cardiovascular toxicity from cancer therapies has led to the emerging field of cardio-oncology, which centers on preventing, detecting, and treating patients with cardiac dysfunction before, during, or after cancer treatment. Early detection and prevention of cancer therapy-related cardiac dysfunction (CTRCD) play important roles in precision cardio-oncology. Methods and Results This retrospective study included 4309 cancer patients between 1997 and 2018 whose laboratory tests and cardiovascular echocardiographic variables were collected from the Cleveland Clinic institutional electronic medical record database (Epic Systems). Among these patients, 1560 (36%) were diagnosed with at least 1 type of CTRCD, and 838 (19%) developed CTRCD after cancer therapy (de novo). We posited that machine learning algorithms can be implemented to predict CTRCDs in cancer patients according to clinically relevant variables. Classification models were trained and evaluated for 6 types of cardiovascular outcomes, including coronary artery disease (area under the receiver operating characteristic curve [AUROC], 0.821; 95% CI, 0.815-0.826), atrial fibrillation (AUROC, 0.787; 95% CI, 0.782-0.792), heart failure (AUROC, 0.882; 95% CI, 0.878-0.887), stroke (AUROC, 0.660; 95% CI, 0.650-0.670), myocardial infarction (AUROC, 0.807; 95% CI, 0.799-0.816), and de novo CTRCD (AUROC, 0.802; 95% CI, 0.797-0.807). Model generalizability was further confirmed using time-split data. Model inspection revealed several clinically relevant variables significantly associated with CTRCDs, including age, hypertension, glucose levels, left ventricular ejection fraction, creatinine, and aspartate aminotransferase levels. Conclusions This study suggests that machine learning approaches offer powerful tools for cardiac risk stratification in oncology patients by utilizing large-scale, longitudinal patient data from healthcare systems.

Expression of LC3B and FIP200/Atg17 in brain metastases of breast cancer.

BACKGROUND: Macroautophagy/autophagy is considered to play key roles in tumor cell evasion of therapy and establishment of metastases in breast cancer. High expression of LC3, a residual autophagy marker, in primary breast tumors has been associated with metastatic disease and poor outcome. FIP200/Atg17, a multi-functional pro-survival molecule required for autophagy, has been implicated in brain metastases in experimental models. However, expression of these proteins has not been examined in brain metastases from patients with breast cancer. METHODS: In this retrospective study, specimens from 44 patients with brain metastases of infiltrating ductal carcinoma of the breast (IDC), unpaired samples from 52 patients with primary IDC (primary-BC) and 16 matched-paired samples were analyzed for LC3 puncta, expression of FIP200/Atg17, and p62 staining. RESULTS: LC3-puncta+ tumor cells and FIP200/Atg17 expression were detected in greater than 90% of brain metastases but there were considerable intra- and inter-tumor differences in expression levels. High numbers of LC3-puncta+ tumor cells in brain metastases correlated with a significantly shorter survival time in triple-negative breast cancer. FIP200/Atg17 protein levels were significantly higher in metastases that subsequently recurred following therapy. The percentages of LC3 puncta+ tumor cells and FIP200/Atg17 protein expression levels, but not mRNA levels, were significantly higher in metastases than primary-BC. Meta-analysis of gene expression datasets revealed a significant correlation between higher FIP200(RB1CC1)/Atg17 mRNA levels in primary-BC tumors and shorter disease-free survival. CONCLUSIONS: These results support assessments of precision medicine-guided targeting of autophagy in treatment of brain metastases in breast cancer patients.

Temporal Variability of Global Longitudinal Strain in Stable Patients Undergoing Chemotherapy With Trastuzumab.

Global longitudinal strain (GLS) is used to evaluate left ventricular (LV) performance after chemotherapy. Differentiating between reduction in GLS due to clinical change and normal temporal variability in measurement remains a challenge. We quantified interobserver, test-retest variability of GLS by expert observers in relation to variability of GLS quantified for clinical assessment by sonographers in our laboratory. We examined the temporal variability of GLS in 30 patients with normal LV ejection fraction (LVEF >53%) undergoing chemotherapy in the absence of change in medications and clinical symptoms in up to 5 sequential echocardiograms. GLS was quantified using EchoPAC (GE Healthcare, Milwaukee, Wisconsin) and 2-dimensional biplane LVEF was measured from 4- and 2- chamber views. Interobserver test-retest variability of GLS measured in 10 random patients by 2 expert readers was calculated using a one-way analysis of variance. Square root of mean squared error provided the SEM for temporal variability. Baseline LVEF was 59.3 ± 5.1% and remained relatively unchanged over 12 months, p = 0.87. Temporal variability of GLS measured by sonographers was 1.28% and similar to interobserver test-retest variability of GLS measured by expert observers, 1.12% (p = 0.17). Maximum detectable difference in GLS measured by expert observers was similar to that derived from sequential measurements of GLS (3.2% vs 3.6%, respectively). Temporal variability of GLS among clinically stable patients is 1.28% and similar to interobserver test-retest variability of 1.12% measured by expert observers. In conclusion, a reduction in strain >3.2% during sequential echocardiograms under these conditions may be significant.

Radiation Therapy in the Management of Soft Tissue Sarcoma: A Clinician's Guide to Timing, Techniques, and Targets.

Radiation therapy represents a vital component in the multidisciplinary management of soft tissue sarcomas. Combined with limb-preserving surgery, radiation therapy represents a standard of care treatment option for patients with high-grade sarcomas. Radiation therapy for soft tissue sarcoma continues to evolve with changes in timing, techniques, and targets. Over the past 2 decades, increasing data have supported the role of preoperative radiotherapy with the potential for lower total doses of radiation and improved long-term function coming at the cost of increased wound complications for certain locations. Retroperitoneal sarcomas represent a location where preoperative treatment is becoming the standard of care based on anatomic constraints and challenges with delivering postoperative radiotherapy. Multiple radiation therapy techniques exist to deliver treatment; currently both 3-dimensional conformal radiotherapy and intensity-modulated radiation therapy (IMRT) are appropriate options, although increasing data support the role of IMRT in reducing dose to critical structures (bone, bowel, kidneys, vessels) while maintaining target coverage. Traditional target volumes have included larger fields; however, recent prospective data have demonstrated that image guidance in conjunction with smaller treatment volumes may reduce toxicity while not increasing marginal failures, although follow-up is short. Because of the toxicity associated with treatment, novel radiotherapy strategies are being used such as stereotactic radiotherapy as well as the use of tumor genetics to identify patients most likely to benefit most from radiotherapy.

Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects.

Since sodium stibogluconate (SSG) inhibited phosphatases including SHP-1 and augmented anti-tumor actions of IFN-α2b in vitro and in mice, two Phase I trials of SSG/IFN-α2b combination were undertaken to evaluate safety and target inhibition. Escalating doses of SSG (200-1200 mg/m2) and fixed doses of IFN-α2b (3x106 units/m2) with or without chemotherapy (dacarbazine, vinblastine, cisplatin) were evaluated for side effects and impact on SHP-1 phospho-substrates and IFNα-stimulated-genes (ISGs) in peripheral blood in 40 patients with metastatic melanoma, soft tissue sarcomas, gastrointestinal stromal tumors, and breast or colorectal carcinomas who did not have other established treatment options. Common adverse events were bone marrow suppression, fatigue, gastrointestinal upset, and asymptomatic lipase elevation (n=13); the latter was dose related and mostly after 10d of SSG/IFN-α2b in combination. Levels of SHP-1 substrates (pSTAT1, pSTAT3, pLck and pSlp76) were increased (up to 3x) in peripheral blood cells following SSG with no potentiation by combination with IFN-α2b. Representative ISGs in peripheral blood were induced after IFN-α2b at 4 and 24 hrs with selective modulations by combination. The median time on trials was 2.3 months (10-281d) with no objective regression of disease. Alive at 1y were 17/40 (43%) patients and after 2y were 8/40 (20%) following treatment initiation. These data demonstrate that SSG impacted signal molecules consistent with PTP inhibition and was tolerated in combination with IFN-α2b. Phase II investigations of SSG could safely utilize doses of up to 1200 mg/m2 of SSG for up to 10d alone or in combination with IFN-α2b with or without chemotherapy.

The expression of the cytoskeletal focal adhesion protein paxillin in breast cancer correlates with HER2 overexpression and may help predict response to chemotherapy: a retrospective immunohistochemical study.

Paxillin, a cytoskeletal focal adhesion adaptor protein, has been shown to be transcriptionally up-regulated and phosphorylated by human epidermal growth factor receptor-2 (HER2) signaling in vitro. Paxillin expression may also correlate with HER2 amplification in breast cancer patients. In the current study, we sought to explore the relationship further between paxillin expression and clinicopathologic features and clinical outcome in breast cancer. A total of 314 primary invasive breast carcinomas were assessed for paxillin expression via immunohistochemistry. Paxillin immunoreactivity was compared with estrogen receptor/progesterone receptor status, HER2 status by silver in situ hybridization, age, tumor size, stage, Bloom-Richardson grade, nodal status, disease-free survival (DFS), and overall survival (OS). Paxillin expression was identified in 27.7% of breast carcinomas as diffuse cytoplasmic staining and the expression correlated with HER2 overexpression (p < 0.001). The influence of paxillin on clinical outcome, in particular the response to chemotherapy, appeared to differ depending on the HER2 status of the tumor. For the subset of HER2 nonamplified cases treated with chemotherapy, patients whose tumor showed a loss of paxillin expression demonstrated a significantly lengthened DFS and OS. In contrast, loss of paxillin expression in the HER2 amplified subset of patients who received chemotherapy correlated with a significantly worse outcome. These data suggest that paxillin up-regulation may be a part of the HER2 pathway in some breast cancers and, furthermore, paxillin expression may also influence the clinical response to chemotherapy, depending upon the HER2 status of a given patient's tumor. Further study of a role for paxillin expression in predicting response to cytotoxic regimens or targeted treatments is warranted.

A decision aid to assist in adjuvant therapy choices for breast cancer.

BACKGROUND: Decision aids are tools that help patients make specific and deliberative choices among options. This study was a group randomized controlled trial of a novel decision aid to help patients with breast cancer make adjuvant therapy (AT) decisions. METHODS: Fourteen oncology practices (n=58 physicians) were randomized to receive the decision aid or a control pamphlet. Complete data were obtained from 405 patient-oncologist pairs. Eligible patients had stage I-III disease and had completed their primary treatment. The decision aid is a simple to use computer program, titled Adjuvant!, that provides estimates of outcome with and without AT. Graphical representations of outcome are shared with patients. Consultations were audiotaped, patients interviewed, and physicians completed a self-administered survey. RESULTS: In a multivariable model, the 54 patients (13.3%) who took no AT were more likely to have received the decision aid (p=0.02). A differential effect of the Adjuvant! Decision Guide was noted between node negative and positive patients. It was stated by 86.2% of patients that the decision aid was influential when making their treatment decision. Over 95% of patients reported that the Adjuvant Decision Guide was easy to understand and 75% of physicians believed that it helped them understand their patient's treatment preferences and 81.4% reported the information as useful for themselves. CONCLUSIONS: This study showed that a decision aid made a difference in the choice of whether or not to take AT. The decision aid allowed patients and physicians to consider the benefits of AT in an easy to understand format. Treatment decisions were more individualized for patients in the intervention than in the control group. The use of the decision aid was acceptable to both patients and physicians.

The expression of fascin, an actin-bundling motility protein, correlates with hormone receptor-negative breast cancer and a more aggressive clinical course.

The invasion and metastasis of tumor cells is a major cause of mortality in cancer patients. In the current study, we investigated the expression of fascin, an actin-bundling motility-associated protein, in 210 invasive breast carcinomas with corresponding 5-year clinical follow-up. Fascin expression was compared with hormone receptor (ER/PR) status, HER2 status, cancer grade, cancer stage, metastasis pattern, disease-free survival, and overall survival. Fascin expression was seen in 16% (33/210) of the cases and correlated with ER negativity (22/33, P < 0.001), PR negativity (21/33, P < 0.001), Bloom-Richardson grade 3 (19/29, P < 0.001), and advanced stage (stage 3 or 4, P = 0.04). There was no correlation between fascin expression and HER2 status or pattern of metastases. Patients whose tumors were positive for fascin showed both a decreased mean disease-free survival (74.44 versus 100.52 months, P = 0.002) and mean overall survival (77.58 versus 98.98 months, P = 0.002), independent of tumor stage and HER2 status, but not independent of ER/PR status or cancer grade. Given fascin's role in altering cell motility, overexpression may contribute to a more aggressive clinical course in ER/PR-negative breast cancers. If so, then fascin may represent a new molecular target for therapeutic intervention in patients with ER-negative breast cancer.

Heterogeneous patterns of pH regulation in glial cells in the dorsal and ventral medulla.

We examined pH regulation in two chemosensitive areas of the brain, the retrotrapezoid nucleus (RTN) and the nucleus tractus solitarius (NTS), to identify the proton transporters involved in regulation of intracellular pH (pHi) in medullary glia. Transverse brain slices from young rats [postnatal day 8 (P8) to P20] were loaded with the pH-sensitive probe 2',7'-bis (2-carboxyethyl)-5,6-carboxyfluorescein after kainic acid treatment removed neurons. Cells were alkalinized when they were depolarized (extracellular K+ increased from 6.24 to 21.24 mM) in the RTN but not in the NTS. This alkaline shift was inhibited by 0.5 mM DIDS. Removal of CO2/HCO3- or Na+ from the perfusate acidified the glial cells, but the acidification after Na+ removal was greater in the RTN than in the NTS. Treatment of the slice with 5-(N-ethyl-N-isopropyl)amiloride (100 microM) in saline containing CO2/HCO3- acidified the cells in both nuclei, but the acidification was greater in the NTS. Restoration of extracellular Cl- after Cl- depletion during the control condition acidified the cells. Immunohistochemical studies of glial fibrillary acid protein demonstrated much denser staining in the RTN compared with the NTS. We conclude that there is evidence of Na+-HCO3- cotransport and Na+/H+ exchange in glia in the RTN and NTS, but the distribution of glia and the distribution of these pH-regulatory functions are not identical in the NTS and RTN. The differential strength of glial pH regulatory function in the RTN and NTS may also alter CO2 chemosensory neuronal function at these two chemosensitive sites in the brain stem.