Advances in the treatment of prolactinomas

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future

EXPLORING THE MULTIFACTORAL IMPACT OF AEROBIC EXERCISE IN HYPERMOBILE EHLERS DANLOS SYNDROME

BACKGROUND: Hypermobile Ehlers Danlos Syndrome (hEDS) is a heritable connective tissue disorder that negatively impacts musculoskeletal function and psychological health yet the specific impact of hEDS on gait mechanics and muscle function is not well understood. Our pilot data demonstrated that people with hEDS ambulate with a 37% lower peak hip extensor moment (HEM) and exhibit a 40% deficit in hip extensor strength compared to healthy controls. Approximately 72% of our hEDS cohort also self-reported hip joint subluxations (i.e., increased hip instability) and may be due to altered hip extensor function and mechanics. This hip extensor dysfunction may lead to an increased risk of hip joint pain and degeneration. Although exercise is prescribed as a conservative treatment for hEDS-related joint pain, these exercise protocols lack scientific justification. Therefore, this study will assess the effects of aerobic exercise on hip mechanics and the corresponding relationship of psychological health and hip extensor muscle function with changes in hip joint mechanics and pain during exercise in hEDS. METHODS: Participants will undergo a 3D gait analysis while walking on an instrumented treadmill at a self-selected speed for 30 minutes and we will assess changes in peak HEM and hip pain (VAS). Hip extensor rate of torque development (RTD) will be assessed using isometric strength testing. All participants will complete surveys to assess psychological health (Tampa Scale, and the MHQoL). We will assess the within- and between-group differences in peak HEM using an analysis of variance (p\u3c0.05) while group differences in psychological health, hip pain and muscle function will be assessed using t-tests and non-parametric tests as needed. The relationship between psychological factors and muscle function with changes in peak HEM and hip pain will be assessed using multi-variate linear regression. A minimum of 20 total participants (f=0.35) will provide a minimum of 84% power to detect statistical differences. ANTICPATED RESULTS: We hypothesize that the hEDS group will exhibit reduced peak HEM and increased hip pain during the walking task, as well as worse psychological health and hip extensor RTD compared to controls. Our study results will identify the specific biomechanical, muscular and psychological targets for a multi-disciplinary exercise intervention to improve hip mechanics and reduce hip pain in hEDS. This research was supported in part by the University of Kentucky Department of Kinesiology and Health Promotion Graduate Student Research Funding and NIH (K01AG073698 & K01-HL149984

ALTERED TOTAL JOINT MOMENT OF THE HIP DURING WALKING IN PEOPLE WITH MARFAN SYNDROME

BACKGROUND: Marfan syndrome (MFS) is an inherited connective disorder that is associated with muscle weakness and ligamentous laxity. Despite documented ligamentous laxity and muscle weakness, the implications of altered musculoskeletal function on the high rate (46%) of self-reported hip pain in the MFS population is not well understood. Assessment of the hip joint loading patterns that occur in individuals with MFS may provide an understanding of this population’s high risk of developing hip pain. Therefore, the purpose of this study was to assess hip joint loading during walking that may help to explain the presence of hip pain in individuals with MFS. METHODS: Thirteen individuals with MFS and thirteen asymptomatic controls were used in this cross-sectional study. Participants underwent 3D gait analysis while walking at the average level ground walking speed (1.35 m/s) for males and females. Using a custom written MATLAB script, the total joint moment (TJM) of the hip joint, was calculated as the square root of the sum of the square of the internal sagittal, frontal, and transverse plane moments, at each frame of the stance phase (initial contact to toe-off). The corresponding sagittal, frontal, and transverse plane moments at the peak TJM in the first and second half of the stance phase were extracted and their percent contribution to the peak TJMs was calculated. Between-group differences in peak TJMs, moments at the TJMs and the corresponding percent moment contributions to the hip TJMs were assessed using an analysis of covariance, adjusting for age, with p\u3c0.05 used for statistical significance. RESULTS: Compared to the control group, the MFS group exhibited a 1.2x larger first peak TJM (p=0.031) and a 1.5x larger first peak abduction moment (p=0.024). Although no differences were observed in the second peak TJM, the MFS group exhibited a 1.2x larger abduction moment (p=0.021) compared to the control group. CONCLUSIONS: Higher abduction moment at the first and second peak TJM in the MFS group may contribute to altered total hip joint loading and may be associated with the high rate of hip pain in MFS. Future work will include a larger sample size as additional TJM-related parameters were underpowered to detect a statistical difference.Research Support: The Marfan Foundation, NIH (KL2-TR001996, K01-AG073698, & K01-HL149984

The efficacy and safety of S-1-based regimens in the first-line treatment of advanced gastric cancer : a systematic review and meta-analysis

BACKGROUND: S-1 is first-line therapy for advanced gastric cancer in Asia and is used with increased frequency in Western counties. We conducted a meta-analysis to investigate the efficacy and toxicity of S-1-based therapy compared with 5-fluorouracil (5-FU)/capecitabine-based therapy and S-1-based combination therapy compared with S-1 monotherapy. METHODS: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, American Society of Clinical Oncology meeting abstracts, European Society for Medical Oncology meeting abstracts and ClinicalTrials.gov were searched for randomized clinical trials until May 2015. Data were extracted for overall survival (OS), progression-free-survival (PFS), objective response rate (ORR) and grade 1-2 and grade 3-4 adverse events. Stratified OS data for subgroups were extracted. RESULTS: S-1 was not different from 5-FU (eight studies, n = 2788) in terms of OS [hazard ratio (HR) 0.93, 95 % confidence interval (CI) 0.85-1.01] and PFS (HR 0.87, 95 % CI 0.73-1.04), whereas ORR was higher (risk ratio 1.43, 95 % CI 1.05-1.96). There was no subgroup difference in efficacy among Asian and Western patients, but in Western patients S-1 was associated with a lower rate of febrile neutropenia, toxicity-related deaths and grade 3-4 stomatitis and mucositis compared with 5-FU. S-1 showed no difference in efficacy compared with capecitabine (three studies, n = 329), but was associated with a lower rate of grade 3-4 neutropenia and grade 1-2 hand-foot syndrome. S-1-combination therapy was superior to S-1 monotherapy (eight studies, n = 1808) in terms of OS (HR 0.76, 95 % CI 0.65-0.90), PFS (HR 0.68, 95 % CI 0.56-0.82) and ORR (risk ratio 1.20, 95 % CI 1.04-1.38) but was more toxic. Survival benefit of S-1 combination therapy over S-1 monotherapy was most pronounced in patients with non-measurable disease, diffuse-type histological features and peritoneal metastasis. CONCLUSIONS: S-1 is effective and tolerable as first-line therapy for advanced gastric cancer in both Asian and Western countries