Quality of Regional Nodal Irradiation Plans in Breast Cancer Patients Across a Large Network—Can We Translate Results From Randomized Trials Into the Clinic?

PurposeRegional nodal irradiation (RNI) improved disease-free survival by 3% to 5% in 2 large randomized trials, but this small absolute advantage relies on accurate contouring and dose delivery. We audited our network to determine compliance on regional nodal coverage, contouring, and dosimetric parameters with respect to accepted guidelines.Methods and MaterialsIn our network, we have established a clinical pathway for patients with node-positive breast cancer that guides indications for RNI and dosimetric goals. We reviewed records of 183 patients with nodal macrometastases after upfront surgery or involved nodes of any size after neoadjuvant chemotherapy. Radiation treatment plans were examined to determine lymph node volumes treated, whether nodes were contoured, quality of nodal contours, and whether target coverage and normal organ dosimetric constraints were met when RNI was delivered.ResultsDespite the presence of macrometastases on sentinel lymph node biopsy, no lymph nodes were treated in 2.2% (4 of 183). Of 179 patients who received nodal irradiation, 18 received radiation to axillary levels 1 and 2 only, and 161 patients received RNI. Overall, regional nodes were not treated despite strong indications in 7.6% (14 of 183). Treated nodes were not contoured for 2.2% (4 of 179), and lymph node contours were unacceptable in 15.4% (27 of 175). Of patients receiving RNI, 14.9% (24 of 161) did not have adequate nodal target volume coverage, mean heart dose was >4 Gy for 3.1% (5 of 161), and lung V20 Gy was >35% for 8.7% (14 of 161).ConclusionsAdherence to indications for regional nodal treatment was high, but nodes were either not contoured or had unacceptable contour quality in 18% of plans, and coverage was inadequate in 15%. Because the small disease-free survival advantage seen in trials may be decreased with these deviations, routine clinical practice requires detailed peer review to fully translate results of clinical trials.     

Premature Ticagrelor Discontinuation in Secondary Prevention of Atherosclerotic CVD: JACC Review Topic of the Week

Ticagrelor is a cornerstone of modern antithrombotic therapy alongside aspirin in patients with acute coronary syndrome and after percutaneous coronary intervention. Adverse effects such as bleeding and dyspnea have been associated with premature ticagrelor discontinuation, which may limit any potential advantage of ticagrelor over clopidogrel. The randomized trials of ticagrelor captured adverse events, offering the opportunity to more precisely quantify these effects across studies. Therefore, a meta-analysis of 4 randomized clinical trials of ticagrelor conducted between January 2007 and June 2017 was performed to quantify the incidence and causes of premature ticagrelor discontinuation. Among 66,870 patients followed for a median 18 months, premature ticagrelor discontinuation was seen in 25%; bleeding was the most common cause of discontinuation followed by dyspnea. Versus the comparators, the relative risk of dyspnea-related discontinuation during follow-up was 6.4-fold higher, the relative risk of bleeding was 3.2-fold higher, and the relative risk of discontinuation due to any adverse event was 59% higher for patients receiving ticagrelor. Understanding these potential barriers to adherence to ticagrelor is crucial for informed patient-physician decision making and can inform future efforts to improve ticagrelor adherence. This review discusses the incidence, causes, and biological mechanisms of ticagrelor-related adverse effects and offers strategies to improve adherence to ticagrelor.     

Serial circulating vasopressin levels in children with septic shock.

BACKGROUND: Septic shock is an important cause of death in pediatric intensive care units. Initial evaluations have shown that vasopressin may have a role in catecholamine refractory shock in adults. It is important to determine whether children with septic shock have deficiency of vasopressin. This will help in defining the role of vasopressin in septic shock. DESIGN: Prospective cohort study. SETTING: Pediatric intensive care unit of a tertiary care hospital in north India. PATIENTS: Patients were children with septic shock, and controls were children with sepsis but no shock. STUDY DESIGN: Vasopressin levels in plasma were determined by enzyme-linked immunosorbent assay for children with septic shock at diagnosis (baseline) and thereafter at 24, 48, and 96 hrs to determine the time trends. The baseline vasopressin values for children with septic shock were compared with those for children without shock. RESULTS: The median (95% confidence interval) vasopressin level at baseline in children with septic shock was 116 (63.3-130.7) pg/mL, and in children with sepsis but no shock it was 106 (61.7-131.77) pg/mL. The median value for survivors was 76 (44.6-130.9) pg/mL, and for nonsurvivors, 118 (81.7-259) pg/mL (p = .16). The serial values also did not show any significant changes; the values at 24 hrs (n = 17), 48 hrs (n = 16), and 96 hrs (n = 15) were 105 (76.1-125.9), 105 (41.4-155.5), and 109.5 (54.9-154.8) pg/mL, respectively. CONCLUSIONS: The results of our study suggest that vasopressin levels are elevated in children with septic shock and that serial values up to 96 hrs do not show any decline.     

Sleep-related neurons in the central nucleus of the amygdala of rats and their modulation by the dorsal raphe nucleus

The amygdala (AMY) plays an important role in initiating appropriate neurobehavioral responses to emotionally arousing events. Its major efferents from the central nucleus (Ace) to the basal forebrain, hypothalamus and brainstem permit it to influence sleep mechanisms. To characterize further the neuronal activity of AMY during sleep and wakefulness, we recorded single neuronal activity in Ace across behavioral states in freely moving, normally behaving rats. Of the 49 neurons recorded from Ace, 24 neurons had firing patterns related to sleep-wakefulness (S-W). Of these, 50% (n = 12) had a high firing frequency during wakefulness (W) or both W and REM sleep (REM), 12% (n = 3) were non-REM (NREM)-related, 17% (n = 4) had a high firing rate in REM (REM-ON), and 20% (n = 5) fired at a low rate during REM. Because serotonin introduced into AMY during REM induces short-latency changes of state, we also studied the effects of low frequency (1 Hz) electrical stimulation of the dorsal raphe nucleus (DRN) on Ace neurons. All REM-ON neurons recorded from Ace were inhibited by DRN stimulation, and other cell types were unaffected. Thus, we found that the majority of cells in Ace related to S-W fired slowly during NREM and increased their discharge during W and/or REM, and that the DRN has the potential for modulating the spontaneous activity of REM-ON cells in rats.