Objective T2-signal intensity and somatostatin (SST) receptor expression are recognized predictors of therapy response in acromegaly. We investigated the relationship between these predictors and the hormonal and tumoral responses to long-acting pasireotide (PAS-LAR) therapy, which were also compared with responsiveness to first-generation somatostatin receptor ligands (SRLs). Design The PAPE study is a cohort study. Methods We included 45 acromegaly patients initially receiving SRLs, followed by combination therapy with pegvisomant, and finally PAS-LAR. We assessed tumor volume reduction (≥25% from baseline), IGF-1 levels (expressed as the upper limit of normal), and T2-weighted MRI signal and SST receptor expression of the adenoma. Results Patients with significant tumor shrinkage during PAS-LAR showed higher IGF-1 levels during PAS-LAR (mean (S.D.): 1.36 (0.53) vs 0.93 (0.43), P = 0.020), less IGF-1 reduction after first-generation SRLs (mean (S.D.): 0.55 (0.71) vs 1.25 (1.07), P = 0.028), and lower SST2 receptor expression (median (IQR): 2.0 (1.0–6.0) vs 12.0 (7.5–12.0), P = 0.040). Overall, T2-signal intensity ratio was increased compared with baseline (mean (S.D.): 1.39 (0.56) vs 1.25 (0.52), P = 0.017) and a higher T2-signal was associated with lower IGF-1 levels during PAS-LAR (β: −0.29, 95% CI: −0.56 to −0.01, P = 0.045). A subset of PAS-LAR treated patients with increased T2-signal intensity achieved greater reduction of IGF-1 (mean (S.D.): 0.80 (0.60) vs 0.45 (0.39), P = 0.016). Conclusions Patients unresponsive to SRLs with a lower SST2 receptor expression are more prone to achieve tumor shrinkage during PAS-LAR. Surprisingly, tumor shrinkage is not accompanied by a biochemical response, which is accompanied with a higher T2-signal intensity.

Purpose Although quality of life (QoL) is improved in patients with acromegaly after disease control, QoL correlates only weakly with traditional biomarkers. Our objective is to investigate a potential relation between the new serum biomarker soluble Klotho (sKlotho), GH and insulin-like growth factor 1 (IGF-1) levels, and QoL. Methods In this prospective cohort study, we investigated 54 acromegaly patients biochemically well-controlled on combination treatment with first-generation somatostatin receptor ligands (SRLs) and pegvisomant (PEGV) at baseline and 9 months after switching to pasireotide LAR (PAS-LAR; either as monotherapy, n = 28; or in combination with PEGV, n = 26). QoL was measured by the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and Acromegaly Quality of Life (AcroQoL) questionnaire. Results Switching to PAS-LAR treatment significantly improved QoL without altering IGF-1 levels. QoL did not correlate with GH or IGF-1 levels, but sKlotho correlated with the observed improvements in QoL by the AcroQoL global (r = −0.35, p = 0.012) and physical subdimension (r = −0.34, p = 0.017), and with PASQ headache (r = 0.28, p = 0.048), osteoarthralgia (r = 0.46, p = 0.00080) and soft tissue swelling score (r = 0.29, p = 0.041). Parallel changes in serum sKlotho and IGF-1 (r = 0.31, p = 0.023) suggest sKlotho and IGF-1 to be similarly dependent on GH. Comparing the PAS-LAR combination therapy and the monotherapy group we did not observe a significant difference in improvement of QoL. Conclusions Patients experienced improved QoL during PAS-LAR, either as monotherapy or in combination with PEGV. Soluble Klotho concentrations appear to be a useful marker of QoL in acromegaly patients but the underlying mechanisms remain to be investigated.

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Study design: A systematic review and meta-analysis of Mendelian randomization studies using Medline, Cumulative Index to Nursing and Allied Health Literature Complete, and Scopus databases.Key findings: Sixteen studies involving 34,050 patients with an abdominal aortic aneurysm (AAA) and 2,205,894 controls were included. Metaanalyses suggested that a 1 standard deviation increase in high-density lipoprotein cholesterol (HDL-C) significantly decreased, and a 1 standard deviation increase in low-density lipoprotein cholesterol (LDL-C) significantly increased, the risk of AAA. A 1 standard deviation increase in triglycerides did not significantly increase the risk of AAA.Conclusion: This meta-analysis suggested that LDL-C and HDL-C are positive and negative casual risk factors for AAA.Commentary: What factors may predispose to AAA formation and growth and what factors may be protective? Mendelian randomization may overcome biases of observational studies and may replicate results of large randomized controlled trials. The main findings of this metaanalysis were that high LDL-C and low HDL-C levels were risk factors for increased risk of AAA. Lowering LDL-C levels may decrease the risk of developing AAA, although it is unclear if this strategy slows AAA growth. Other factors have been shown to be associated with AAA development including inflammatory markers (IL-1Ra, IL-6R, sIL-6R), high diastolic blood pressure, and smoking. But diabetes is associated with a lower risk of AAA, which has been attributed to high blood glucose promoting extracellular matrix glycation and modulation of aortic wall matrix remodeling and inflammation. Thirteen previous randomized controlled trials have reported that drugs including antibiotics, beta-blockers, angiotensin-converting enzyme inhibitors, and mast cell inhibitors do not slow AAA growth.Remember when your mother told you to eat your oatmeal every morning? (Oatmeal has soluble fiber, which decreases LDL-C levels). She knew what she was talking about.