Clinical efficacy of first and second series of peptide receptor radionuclide therapy in patients with neuroendocrine neoplasm: a cohort study.

OBJECTIVES: Peptide receptor radionuclide therapy (PRRT) is an established treatment for metastatic neuroendocrine neoplasms (NEN). However, only limited data exists for the effect of multiple series of PRRT. The aim of this study was to investigate PFS and OS inNEN patients treated with multiple series of PRRT conforming to the ENETS treatment protocol. METHODS: We included all patients with gastrointestinal (GI), pancreatic and bronchopulmonary (BP) NEN treated with PRRT from 2008 to 2018. We used Kaplan-Meier estimation to evaluate PFS and OS with subgroup analysis of primary tumor, Ki67-index, type of radioisotope and number of PRRT series. RESULTS: 133 patients (female/male 61/72) were included, median age 70 (interquartile range 64-76) years. GI-NEN comprised 62%, pancreatic 23% and BP 11%. Median Ki67-index was 5%. After first PRRTG1- and G2-tumors had PFS of 25 and 22 months, compared to 11 months in G3-NENs (p < .05) and PFS was longer in G1/G2 GI-NENs than BP-NEN (30vs. 12 months, p < .05). After retreatment with a second series of PRRT, the overall PFS (G1-G3) was 19 months, with G1- and G2-tumors having the highest PFS of 19 and 22 months, respectively. Overall, the GI and BP tumors had an OS of 54 and 51 months. CONCLUSIONS: PRRT is an effective therapy with long-term PFS and OS, especially in G1 and G2 NENs, and with better prognosis in GI-NEN compared with BP-NENs. OS and PFS was shorter after the second series of PRRT compared with the first, however results were still encouraging.

One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial.

AIMS: To confirm, in a 26-week extension study, the sustained efficacy and safety of a fixed combination of insulin degludec and liraglutide (IDegLira) compared with either insulin degludec or liraglutide alone, in patients with type 2 diabetes. METHODS: Insulin-naïve adults with type 2 diabetes randomized to once-daily IDegLira, insulin degludec or liraglutide, in addition to metformin ± pioglitazone, continued their allocated treatment in this preplanned 26-week extension of the DUAL I trial. RESULTS: A total of 78.8% of patients (1311/1663) continued into the extension phase. The mean glycated haemoglobin (HbA1c) concentration at 52 weeks was reduced from baseline by 1.84% (20.2 mmol/mol) for the IDegLira group, 1.40% (15.3 mmol/mol) for the insulin degludec group and 1.21% (13.2 mmol/mol) for the liraglutide group. Of the patients on IDegLira, 78% achieved an HbA1c of <7% (53 mmol/mol) versus 63% of the patients on insulin degludec and 57% of those on liraglutide. The mean fasting plasma glucose concentration at the end of the trial was similar for IDegLira (5.7 mmol/l) and insulin degludec (6.0 mmol/l), but higher for liraglutide (7.3 mmol/l). At 52 weeks, the daily insulin dose was 37% lower with IDegLira (39 units) than with insulin degludec (62 units). IDegLira was associated with a significantly greater decrease in body weight (estimated treatment difference, -2.80 kg, p < 0.0001) and a 37% lower rate of hypoglycaemia compared with insulin degludec. Overall, all treatments were well tolerated and no new adverse events or tolerability issues were observed for IDegLira. CONCLUSIONS: These 12-month data, derived from a 26-week extension of the DUAL I trial, confirm the initial 26-week main phase results and the sustainability of the benefits of IDegLira compared with its components in glycaemic efficacy, safety and tolerability.

Calcium score of small coronary calcifications on multidetector computed tomography: results from a static phantom study.

INTRODUCTION: Multi detector computed tomography (MDCT) underestimates the coronary calcium score as compared to electron beam tomography (EBT). Therefore clinical risk stratification based on MDCT calcium scoring may be inaccurate. The aim of this study was to assess the feasibility of a new phantom which enables establishment of a calcium scoring protocol for MDCT that yields a calcium score comparable to the EBT values and to the physical mass. MATERIALS AND METHODS: A phantom containing 100 small calcifications ranging from 0.5 to 2.0mm was scanned on EBT using a standard coronary calcium protocol. In addition, the phantom was scanned on a 320-row MDCT scanner using different scanning, reconstruction and scoring parameters (tube voltage 80-135 kV, slice thickness 0.5-3.0mm, reconstruction kernel FC11-FC15 and threshold 110-150 HU). The Agatston and mass score of both modalities was compared and the influence of the parameters was assessed. RESULTS: On EBT the Agatston and mass scores were between 0 and 20, and 0 and 3mg, respectively. On MDCT the Agatston and mass scores were between 0 and 20, and 0 and 4 mg, respectively. All parameters showed an influence on the calcium score. The Agatston score on MDCT differed 52% between the 80 and 135kV, 65% between 0.5 and 3.0mm and 48% between FC11 and FC15. More calcifications were detected with a lower tube voltage, a smaller slice thickness, a sharper kernel and a lower threshold. Based on these observations an acquisition protocol with a tube voltage of 100 kV and two reconstructions protocols were defined with a FC12 reconstruction kernel; one with a slice thickness of 3.0mm and a one with a slice thickness of 0.5mm. This protocol yielded an Agatston score as close to the EBT as possible, but also a mass score as close to the physical phantom value as possible, respectively. CONCLUSION: With the new phantom one acquisition protocol and two reconstruction protocols can be defined which produces Agatston scores comparable to EBT values and to the physical mass.

High-intensity resistance and cardiovascular training improve physical capacity in cancer patients undergoing chemotherapy.

The purpose of the study was to examine the effects of a supervised high- and low-intensity structured training program in cancer patients concurrently undergoing chemotherapy. Seventy patients, in different stages of the disease and with different diagnoses (48 females, 22 males), between 18 and 65 years of age (mean age 42.8) participated in a 9-h weekly training program over 6 weeks. The intervention involved physical exercise, relaxation, massage, and body-awareness training. Physical capacity (one-repetition maximum tests (1RM), VO2max) and body composition (weight, skin-fold) were compared before and after the exercise intervention. The average increase in muscular strength was 41.3% (P<0.001) and 14.5% in aerobic fitness (pre: 2.27+/-0.597 L/min, post: 2.56+/-0.644 L/min, (P<0.001). The exercise intervention significantly increased the weight of the subjects by 1% (pre: 72.62+/-13.42 kg, post: 73.25+/-13.44 kg, P=0.016). There was a significant decrease in skin-fold measurements by 3% (P=0.031). The exercise intervention was well tolerated, provided that daily screening criteria were adhered to. The effects of resistance and cardiovascular training observed in this short-term study support the theory that exercise is a beneficial intervention strategy for increasing muscle strength and aerobic fitness during antineoplastic chemotherapy. This type of exercise program can be an important component of complementary treatment for cancer patients undergoing chemotherapy.

Patients with severe muscle wasting are prone to develop hypoglycemia during fasting.

The authors investigated whether hypoglycemia develops during 23 hours of fasting in patients with Duchenne dystrophy (7 patients), spinal muscular atrophy (4 patients), and congenital myopathy (2 patients), all with residual muscle mass <10% of body weight. All patients with spinal muscular atrophy and congenital myopathy and one patient with Duchenne dystrophy, but none of six healthy subjects, developed hypoglycemia. Skeletal muscle is an important source of gluconeogenic substrates during fasting. Hypoglycemia must be considered in patients with low muscle mass, especially during surgery and febrile episodes.

Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running.

1. This study was performed to test the hypothesis that inflammatory cytokines are produced in skeletal muscle in response to prolonged intense exercise. Muscle biopsies and blood samples were collected from runners before, immediately after, and 2 h after a marathon race. 2. The concentration of interleukin (IL)-6 protein in plasma increased from 1.5 +/- 0.7 to 94.4 +/- 12.6 pg ml-1 immediately post-exercise and to 22.1 +/- 3.8 pg ml-1 2 h post-exercise. IL-1 receptor antagonist (IL-1ra) protein in plasma increased from 123 +/- 23 to 2795 +/- 551 pg ml-1, and increased further to 4119 +/- 527 pg ml-1 2 h post-exercise. 3. The comparative polymerase chain reaction technique was used to evaluate mRNA for IL-6, IL-1ra, IL-1beta and tumour necrosis factor (TNF)-alpha in skeletal muscle and blood mononuclear cells (BMNC) (n = 8). Before exercise, mRNA for IL-6 could not be detected either in muscle or in BMNC, and was only detectable in muscle biopsies (5 out of 8) after exercise. Increased amounts of mRNA for IL-1ra were found in two muscle biopsies and five BMNC samples, and increased amounts of IL-1beta mRNA were found in one muscle and four BMNC samples after exercise. TNF-alpha mRNA was not detected in any samples. 4. This study suggests that exercise-induced destruction of muscle fibres in skeletal muscles may trigger local production of IL-6, which stimulates the production of IL-1ra from circulating BMNC.

Exercise-induced immunomodulation--possible roles of neuroendocrine and metabolic factors.

Acute muscular exercise induces an increased neutrophil count concomitant with recruitment of natural killer (NK), B and T cells to the blood as reflected by an elevation in the total lymphocyte count. Meanwhile, following intense exercise of long duration the lymphocyte count declines, non-MHC-restricted cytotoxicity is suppressed, but the neutrophil concentration increases. In relation to eccentric exercise involving muscle damage, the plasma concentrations of interleukin-1, interleukin-6 and the tumor necrosis factor are elevated. In this review we will propose a model based on the possible roles that stress hormones play a mediating the exercise- related immunological changes: adrenaline and to a lesser degree noradrenaline are responsible for the immediate effects of exercise on lymphocyte subpopulations and cytotoxic activities. The increase in catecholamines and growth hormone mediate the acute effects of exercise on neutrophils, whereas cortisol may be responsible for maintaining lymphopenia and neutrocytosis after exercise of long duration. Lastly, the role of beta-endorphin is less clear, but the cytokine response is closely related to muscle damage and stress hormones do not seem to be directly involved in the elevated cytokine level. Other possible mechanisms of exercise-induced immunomodulation may include the so-called glutamine hypothesis, which is based on the fact that skeletal muscle is an important source of glutamine production and that lymphocytes are dependent on glutamine for optimal growth. Furthermore, physiological changes during exercise, e.g. increased body temperature and decreased oxygen saturation may also in theory contribute to the exercise-induced immunological changes.

Dynamics of the martial arts high front kick.

Fast unloaded movements (i.e. striking, throwing and kicking) are typically performed in a proximo-distal sequence, where initially high proximal segments accelerate while distal segments lag behind, after which proximal segments decelerate while distal segments accelerate. The aims of this study were to examine whether proximal segment deceleration is performed actively by antagonist muscles or is a passive consequence of distal segment movement, and whether distal segment acceleration is enhanced by proximal segment deceleration. Seventeen skilled taekwon-do practitioners were filmed using a high-speed camera while performing a high front kick. During kicking, EMG recordings were obtained from five major lower extremity muscles. Based on the kinematic data, inverse dynamics computations were performed yielding muscle moments and motion-dependent moments. The results indicated that thigh deceleration was caused by motion-dependent moments arising from lower leg motion and not by active deceleration. This was supported by the EMG recordings. Lower leg acceleration was caused partly by a knee extensor muscle moment and partly by a motion-dependent moment arising from thigh angular velocity. Thus, lower leg acceleration was not enhanced by thigh deceleration. On the contrary, thigh deceleration, although not desirable, is unavoidable because of lower leg acceleration.

Immunity in athletes.

It has become clear that the immune system responds to increased physical activity and may be given some of the credit for exercise-related reduction in illness. In contrast, it has repeatedly been shown that intense exercise causes immunosuppression. In essence the immune system is enhanced during moderate and severe exercise, and only intense long-duration exercise is followed by immunodepression. The latter include suppressed concentration of lymphocytes, suppressed natural killer and lymphokine activated killer cytotoxicity and secretory IgA in mucosa. Whether or not the "open window" in the immune system occurs is dependent on the intensity and duration of exercise. One reason for the "overtraining effect" seen in elite athletes could be that this window of opportunism for pathogens is longer and the degree of immunosuppression more pronounced. It is being hypothesized that severe immunodepression may occur if athletes does not allow the immune system to recover, but initiate a new bout of exercise while still immunodepressed. It has also been suggested that neutrophils serve as a last line of defence. The removal of this back-up system following extreme activity would be compatible with the propensity of "overtrained" individuals to develop upper respiratory tract infections.