The IASLC/ITMIG thymic epithelial tumors staging project: Proposals for the T component for the forthcoming (8th) edition of the TNM classification of malignant tumors

Despite longstanding recognition of thymic epithelial neoplasms, there is no official American Joint Committee on Cancer/ Union for International Cancer Control stage classification. This article summarizes proposals for classification of the T component of stage classification for use in the 8th edition of the tumor, node, metastasis classification for malignant tumors. This represents the output of the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group Staging and Prognostics Factor Committee, which assembled and analyzed a worldwide database of 10,808 patients with thymic malignancies from 105 sites. The committee proposes division of the T component into four categories, representing levels of invasion. T1 includes tumors localized to the thymus and anterior mediastinal fat, regardless of capsular invasion, up to and including infiltration through the mediastinal pleura. Invasion of the pericardium is designated as T2. T3 includes tumors with direct involvement of a group of mediastinal structures either singly or in combination: lung, brachiocephalic vein, superior vena cava, chest wall, and phrenic nerve. Invasion of more central structures constitutes T4: aorta and arch vessels, intrapericardial pulmonary artery, myocardium, trachea, and esophagus. Size did not emerge as a useful descriptor for stage classification. This classification of T categories, combined with a classification of N and M categories, provides a basis for a robust tumor, node, metastasis classification system for the 8th edition of American Joint Committee on Cancer/Union for International Cancer Control stage classification

Automated quality control of ultrasound based on in-air reverberation patterns

Ultrasound image degradation originates primarily from transducer defects and potentially undermines reliable image interpretation. Systematic quantitative quality control is often neglected due to the limited resources available for this task. We propose a quantitative quality control based on in-air reverberation images. These images serve as an initial indication of image degradation. They are easily generated for any (curvi-)linear transducer independent of the level of expertise of the operator. Automated analysis is presented to extract quality parameters based on the in-air reverberation pattern. Static images acquired by the clinical user are transferred to a server where analysis is performed. The results are available to the sonographer prior to clinical use and transducer status can be remotely monitored with trend analysis over time. The method was evaluated for normal functioning and defect transducers. A pilot study was performed over a period of three weeks to assess reproducibility and practical feasibility. All reverberation images were successfully analysed for different transducer types and vendor-specific image presentation. The proposed quality parameters are sensitive to signal loss and allow differentiation of type and severity of image degradation. The pilot study was well received by the sonographers for the simplicity of the method and the measurements were consistent over time. The proposed automated analysis method of ultrasound quality control can monitor (curvi-)linear transducer status in the entire hospital, overcoming previous limitations for periodic quality control. Implementation of the method can reduce the number of defective transducers routinely used in clinical practice

Automated quality control of ultrasound based on in-air reverberation patterns

Ultrasound image degradation originates primarily from transducer defects and potentially undermines reliable image interpretation. Systematic quantitative quality control is often neglected due to the limited resources available for this task. We propose a quantitative quality control based on in-air reverberation images. These images serve as an initial indication of image degradation. They are easily generated for any (curvi-)linear transducer independent of the level of expertise of the operator. Automated analysis is presented to extract quality parameters based on the in-air reverberation pattern. Static images acquired by the clinical user are transferred to a server where analysis is performed. The results are available to the sonographer prior to clinical use and transducer status can be remotely monitored with trend analysis over time. The method was evaluated for normal functioning and defect transducers. A pilot study was performed over a period of three weeks to assess reproducibility and practical feasibility. All reverberation images were successfully analysed for different transducer types and vendor-specific image presentation. The proposed quality parameters are sensitive to signal loss and allow differentiation of type and severity of image degradation. The pilot study was well received by the sonographers for the simplicity of the method and the measurements were consistent over time. The proposed automated analysis method of ultrasound quality control can monitor (curvi-)linear transducer status in the entire hospital, overcoming previous limitations for periodic quality control. Implementation of the method can reduce the number of defective transducers routinely used in clinical practice

Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β₂ adrenergic agonist

Metabolic reprogramming contributes to oncogenesis, tumor growth, and treatment resistance in pancreatic ductal adenocarcinoma (PDAC). Here we report the effects of (R,S′)-4′-methoxy-1-naphthylfenoterol (MNF), a GPR55 antagonist and biased β(2)-adrenergic receptor (β(2)-AR) agonist on cellular signaling implicated in proliferation and metabolism in PDAC cells. The relative contribution of GPR55 and β(2)-AR in (R,S′)-MNF signaling was explored further in PANC-1 cells. Moreover, the effect of (R,S′)-MNF on tumor growth was determined in a PANC-1 mouse xenograft model. PANC-1 cells treated with (R,S′)-MNF showed marked attenuation in GPR55 signal transduction and function combined with increased β(2)-AR/Gα(s)/adenylyl cyclase/PKA signaling, both of which contributing to lower MEK/ERK, PI3K/AKT and YAP/TAZ signaling. (R,S′)-MNF administration significantly reduced PANC-1 tumor growth and circulating l-lactate concentrations. Global metabolic profiling of (R,S′)-MNF-treated tumor tissues revealed decreased glycolytic metabolism, with a shift towards normoxic processes, attenuated glutamate metabolism, and increased levels of ophthalmic acid and its precursor, 2-aminobutyric acid, indicative of elevated oxidative stress. Transcriptomics and immunoblot analyses indicated the downregulation of gene and protein expression of HIF-1α and c-Myc, key initiators of metabolic reprogramming in PDAC. (R,S′)-MNF treatment decreased HIF-1α and c-Myc expression, attenuated glycolysis, shifted fatty acid metabolism towards β-oxidation, and suppressed de novo pyrimidine biosynthesis in PANC-1 tumors. The results indicate a potential benefit of combined GPR55 antagonism and biased β(2)-AR agonism in PDAC therapy associated with the deprogramming of altered cellular metabolism

The effect of caffeine on glucose kinetics in humans – influence of adrenaline

While caffeine impedes insulin-mediated glucose disposal in humans, its effect on endo-genous glucose production (EGP) remains unknown. In addition, the mechanism involved in these effects is unclear, but may be due to the accompanying increase in adrenaline concentration. We studied the effect of caffeine on EGP and glucose infusion rates (GIR), and whether or not adrenaline can account for all of caffeine's effects. Subjects completed three isoglycaemic–hyperinsulinaemic clamps (with 3-[(3)H]glucose infusion) 30 min after ingesting: (1) placebo capsules (n = 12); (2) caffeine capsules (5 mg kg(−1)) (n = 12); and either (3) placebo plus a high-dose adrenaline infusion (HAdr; adrenaline concentration, 1.2 nm; n = 8) or (4) placebo plus a low-dose adrenaline infusion (LAdr; adrenaline concentration, 0.75 nm; n = 6). With caffeine, adrenaline increased to 0.6 nm but no effect on EGP was observed. While caffeine and HAdr decreased GIR by 13 (P < 0.05) and 34% (P < 0.05) versus the placebo, respectively, LAdr did not result in a significant reduction (5%) in GIR versus the placebo. Due to the fact that both caffeine and LAdr resulted in similar adrenaline concentrations, but resulted in different decreases in GIR, it is concluded that adrenaline alone does not account for the effects of caffeine and additional mechanisms must be involved

Caffeine's impairment of insulin-mediated glucose disposal cannot be solely attributed to adrenaline in humans

Caffeine (CAF) impedes insulin-mediated glucose disposal (IMGD) and increases plasma adrenaline concentrations ([ADR]; 0.6 nm). While the antagonism of ADR abolishes the CAF effect, infusion of ADR (0.75 nm) has no effect on IMGD. We have now examined CAF and ADR in concert to determine whether or not they elicit an additive response on IMGD. We hypothesized that CAF + ADR would elicit a greater effect than either CAF or ADR alone (i.e. that CAF effects would not be solely attributed to ADR). Subjects (n = 8) completed four trials in a randomized manner. An isoglycaemic–hyperinsulinaemic clamp was performed 30 min after the following treatments were administered: (1) placebo capsules and saline infusion ([ADR]= 0.29 nm) (PL trial), (2) CAF capsules (dose = 5 mg kg−1) and saline infusion ([ADR]= 0.62 nm) (CAF trial), (3) PL capsules and ADR infusion ([ADR]= 1.19 nm) (ADR trial), and (4) CAF capsules (dose = 5 mg kg−1) and ADR infusion ([ADR]= 0.93 nm) (CAF + ADR trial). As expected, CAF, ADR and CAF + ADR decreased (P ≤ 0.05) IMGD compared to PL. CAF + ADR resulted in a more pronounced decrease in IMGD versus PL (42%) compared to CAF (26%) or ADR (24%) alone; however, the effect was not fully additive (P = 0.08). Furthermore, CAF decreased IMGD to a similar magnitude as ADR despite a 50% lower [ADR]. In summary, while ADR contributes to the CAF-induced impairment in IMGD, it is not solely responsible for caffeine's effects