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BackgroundCancer anorexia–cachexia is a debilitating condition frequently observed in NSCLC patients, characterized by decreased body weight, reduced food intake, and impaired quality of life. Anamorelin, a novel selective ghrelin receptor agonist, has anabolic and appetite-enhancing activities.Patients and methodsROMANA 3 was a safety extension study of two phase 3, double-blind studies that assessed safety and efficacy of anamorelin in advanced NSCLC patients with cachexia. Patients with preserved Eastern Cooperative Oncology Group ≤2 after completing 12 weeks (w) on the ROMANA 1 or ROMANA 2 trials (0–12 weeks) could enroll in ROMANA 3 and continue to receive anamorelin 100 mg or placebo once daily for an additional 12w (12–24 weeks). The primary endpoint of ROMANA 3 was anamorelin safety/tolerability (12–24 weeks). Secondary endpoints included changes in body weight, handgrip strength (HGS), and symptom burden (0–24 weeks).ResultsOf the 703 patients who completed ROMANA 1 and ROMANA 2, 513 patients entered ROMANA 3 (anamorelin, N = 345, mean age 62.0 years; placebo, N = 168; mean age 62.2 years). During ROMANA 3, anamorelin and placebo groups had similar incidences of treatment–emergent adverse events (TEAEs; 52.2% versus 55.7%), grade ≥3 TEAEs (22.4% versus 21.6%), and serious TEAEs (12.8% versus 12.6%). There were 36 (10.5%) and 23 (13.8%) deaths in the anamorelin and placebo groups, respectively; none were drug-related. Improvements in body weight and anorexia–cachexia symptoms observed in the original trials were consistently maintained over 12–24 weeks. Anamorelin, versus placebo, significantly increased body weight from baseline of original trials at all time points (P < 0.0001) and improved anorexia–cachexia symptoms at weeks 3, 6, 9, 12, and 16 (P < 0.05). No significant improvement in HGS was seen in either group.ConclusionDuring the 12–24 weeks ROMANA 3 trial, anamorelin continued to be well tolerated. Over the entire 0–24w treatment period, body weight and symptom burden were improved with anamorelin.Clinical trial registration numbersROMANA 1 (NCT01387269), ROMANA 2 (NCT01387282), and ROMANA 3 (NCT01395914).

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The pattern of blood flow in the large extra parenchymal pulmonary veins is pulsatile in both dog and man. This pulsatility is dominated by the changes in left atrial pressure taking place throughout the cardiac cycle. No pulsatile component of low in the large pulmonary veins could be attributed to forward transmission of a flow pulse conducted from the lung capillaries. The findings suggest that there must be a region of considerable compliance in the pulmonary venous system which can absorb pulsations from the lung capillaries and eliminate their transmission to the left atrium.

The wave form of blood flow in the large extra parenchymal pulmonary veins has an inverse relationship to the pressure wave form in the left atrium during each cardiac cycle. However, when vein flow from the lungs is separated from the left atrium by diverting it into a constant pressure reservoir, its wave form then resembles a lung capillary flow pulse, though delayed from it in time and reduced in ampliture. The pulsatility of flow in pulmonary veins separated from the left atrium is further reduced when transcapillary pressure is elevated by lung inflation. However, in the intact state, the relation between the pattern of pulmonary vein flow and left atrial pressure remains unaffected by lung inflation. It is postulated that the thin walled extraperenchymal pulmonary veins together behave as a collapsible reservoir which enables outflow from them to be determined by changes in left atrial pressure, in spite of variations of pulsatile flow into them from the lungs.