Training radiology residents to evaluate deep myometrial invasion in endometrial cancer patients on MRI: A learning curve study.

PURPOSE: To evaluate the impact of a four-month training program on radiology residents' diagnostic accuracy in assessing deep myometrial invasion (DMI) in endometrial cancer (EC) using MRI. METHOD: Three radiology residents with limited EC MRI experience participated in the training program, which included conventional didactic sessions, case-centric workshops, and interactive classes. Utilizing a training dataset of 120 EC MRI scans, trainees independently assessed subsets of cases over five reading sessions. Each subset consisted of 30 scans, the first and the last with the same cases, for a total of 150 reads. Diagnostic accuracy metrics, assessment time (rounded to the nearest minute), and confidence levels (using a 5-point Likert scale) were recorded. The learning curve was obtained plotting the diagnostic accuracy of the three trainees and the average over the subsets. Anatomopathological results served as the reference standard for DMI presence. RESULTS: The three trainees exhibited heterogeneous starting point, with a learning curve and a trend to more homogeneous performance with training. The diagnostic accuracy of the average trainee raised from 64 % (56 %-76 %) to 88 % (80 %-94 %) across the five subsets (p < 0.001). Reductions in assessment time (5.92 to 4.63 min, p < 0.018) and enhanced confidence levels (3.58 to 3.97, p = 0.12) were observed. Improvements in sensitivity, specificity, positive predictive value, and negative predictive value were noted, particularly for specificity which raised from 56 % (41 %-68 %) in the first to 86 % (74 %-94 %) in the fifth subset (p = 0.16). Although not reaching statistical significance, these advancements aligned the trainees with literature performance benchmarks. CONCLUSIONS: The structured training program significantly enhanced radiology residents' diagnostic accuracy in assessing DMI for EC on MRI, emphasizing the effectiveness of active case-based training in refining oncologic imaging skills within radiology residency curricula.

Arsenite enhances ERO1α expression via ryanodine receptor dependent and independent mechanisms.

Arsenite is a potent carcinogen and toxic compound inducing an array of deleterious effects via different mechanisms, which include the Ca2+-dependent formation of reactive oxygen species. The mechanism whereby the metalloid affects Ca2+ homeostasis involves an initial stimulation of the inositol 1, 4, 5-triphosphate receptor, an event associated with an endoplasmic reticulum (ER) stress leading to increased ERO1α expression, and ERO1α dependent activation of the ryanodine receptor (RyR). Ca2+ release from the RyR is then critically connected with the mitochondrial accumulation of Ca2+. We now report that the resulting formation of mitochondrial superoxide triggers a second mechanism of ER stress dependent ERO1α expression, which however fails to impact on Ca2+ release from the RyR or, more generally, on Ca2+ homeostasis. Our results therefore demonstrate that arsenite stimulates two different and sequential mechanisms leading to increased ERO1α expression with different functions, possibly due to their different subcellular compartmentalization.

Crosstalk between ERO1α and ryanodine receptor in arsenite-dependent mitochondrial ROS formation.

Arsenite, a well-established human carcinogen and toxic compound, promotes the formation of mitochondrial superoxide (mitoO2-) via a Ca2+-dependent mechanism, in which an initial stimulation of the inositol 1, 4, 5-trisphosphate receptor (IP3R) is followed by the activation of the ryanodine receptor (RyR), critical for providing Ca2+ to the mitochondria. We now report that, under the same conditions, arsenite triggers endoplasmic reticulum (ER) stress and a threefold increase in ER oxidoreductin 1α (ERO1 α) levels in proliferating U937 cells. EN460, an inhibitor of ERO1 α, recapitulated all the effects associated with RyR inhibition or downregulation, including prevention of RyR-induced Ca2+ accumulation in mitochondria and the resulting O2-. formation. Quantitatively similar results were obtained in inhibitor studies performed in terminally differentiated wild type C2C12 cells. Moreover, ERO1 α knockout C2C12 myotubes responded to arsenite as their wild type counterpart supplemented with EN460. As a final note, arsenite enhanced the expression of ERO1 α via a mechanism mediated by Ca2+ release from both the IP3R and RyR. We therefore conclude that arsenite activates a positive feedback amplification cycle between Ca2+ levels and ERO1 α in the ER, by which IP3R-dependent Ca2+ induces ERO1 α and ERO1 α promotes Ca2+ release via RyR, thereby amplifying the initial Ca2+ load and causing the mitochondrial accumulation of the cation, critical for mitoO2- formation.

Functional organization of the endoplasmic reticulum dictates the susceptibility of target cells to arsenite-induced mitochondrial superoxide formation, mitochondrial dysfunction and apoptosis.

Arsenite induces many critical effects associated with the formation of reactive oxygen species (ROS) through different mechanisms. We focused on Ca2+-dependent mitochondrial superoxide (mitoO2-.) formation and addressed questions on the effects of low concentrations of arsenite on the mobilization of the cation from the endoplasmic reticulum and the resulting mitochondrial accumulation. Using various differentiated and undifferentiated cell types uniquely expressing the inositol-1, 4, 5-triphosphate receptor (IP3R), or both the IP3R and the ryanodine receptor (RyR), we determined that expression of this second Ca2+ channel is an absolute requirement for mitoO2-. formation and for the ensuing mitochondrial dysfunction and downstream apoptosis. In arsenite-treated cells, RyR was recruited after IP3R stimulation and agonist studies provided an indirect indication for a close apposition between RyR and mitochondria. It was also interesting to observe that arsenite fails to promote mitochondrial Ca2+ accumulation, mitoO2-. formation and mitochondrial toxicity in RyR-devoid cells, in which the IP3R is in close contact with the mitochondria. We therefore conclude that low dose arsenite-induced mitoO2- formation, and the resulting mitochondrial dysfunction and toxicity, are prerequisite of cell types expressing the RyR in close apposition with mitochondria.