The risk of diarrhea and colitis in patients with lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (icis), including inhibitors of PD-1, PD-L1, and ctla-4, are relatively novel therapies for lung cancer, although their use might be limited by gastrointestinal toxicity. The aim of the present study was to determine the risk of diarrhea and colitis associated with icis in lung cancer and the rates of discontinuation because of those toxicities. Methods: Electronic databases were searched for prospective trials reporting the risk of diarrhea and colitis in patients with lung cancer treated with PD-1, PD-L1, and ctla-4 inhibitors. The incidences of diarrhea and colitis and their grades were assessed clinically using standardized reporting criteria. Pooled incidence and weighted relative risk estimates for diarrhea and colitis with 95% confidence intervals (cis) were estimated using a random effects model. The incidence of discontinuations for gi toxicity was also calculated. Results: Twenty-seven studies were included: sixteen studies with PD-1 inhibitors, nine studies with PD-L1 inhibitors, and four studies combining PD-based strategies with ctla-4 inhibitors. The incidence of all-grade diarrhea was 9.1% (95% ci: 7.8% to 10.5%) for anti-PD-1 therapy and 11.0% (95% ci: 7.5% to 14.5%) for anti-PD-L1 therapy. The incidence of all-grade colitis was 0.9% (95% ci: 0.4% to 1.3%) for anti-PD-1 therapy and 0.4% (95% ci: 0.0% to 0.8%) for anti-PD-L1 therapy. The relative risk for all-grade diarrhea was higher with combination anti-PD-1 and anti-ctla-4 than with anti-PD-1 monotherapy (relative risk: 1.61; 95% ci: 1.14 to 2.29). Anti-PD-1 therapy was discontinued in 4.1% of patients with diarrhea (95% ci: 0.7% to 7.4%) and in 35.7% of those with colitis (95% ci: 0.0% to 81.1%); combination therapy was discontinued in 10.1% of patients with diarrhea (95% ci: 4.8% to 15.4%) and in 39.9% of those with colitis (95% ci: 3.9% to 75.9%). Conclusions: Diarrhea is a relatively frequently encountered gi toxicity when ici therapy is used in lung cancer treatment. Colitis is less frequently encountered, although when it does occur, it often results in therapy discontinuation.

Exercises for mechanical neck disorders: A Cochrane review update.

BACKGROUND: Neck pain (NP) is disabling and costly. OBJECTIVES: To assess the effectiveness of exercise on pain, disability, function, patient satisfaction, quality of life (QoL) and global perceived effect (GPE) in adults with NP. METHODS: We searched computerised databases up to May 2014 for randomized controlled trials (RCTs) comparing exercise to a control in adults with NP with/without cervicogenic headache (CGH) or radiculopathy. Two reviewers independently conducted selection, data abstraction and assessed risk of bias. Meta-analyses were performed to establish pooled standardised mean differences (SMDp). The Grade of Recommendation, Assessment, Development and Evaluation (GRADE) was used to summarise the body of evidence. MAIN RESULTS: The following exercises (27 trials) were supported by 'Moderate GRADE' evidence: For chronic NP, 1) cervico-scapulothoracic and upper extremity (UE) strengthening for moderate to large pain reduction immediately post treatment (IP) and at short-term (ST) follow-up; 2) scapulothoracic and UE endurance training for a small pain reduction (IP/ST); 3) cervical, shoulder and scapulothoracic strengthening and stretching exercise for a small to large pain reduction in the long-term (LT) (SMDp -0.45 [95%CI: -0.72 to -0.18]) and function improvement; 4) cervico-scapulothoracic strengthening/stabilisation exercises for pain and function at intermediate-term (IT) (SMDp -14.90 [95%CI: -22.40 to -7.39]). 5) mindfulness exercises (Qigong) for minor improved function but not GPE (ST). For chronic CGH, cervico-scapulothoracic strengthening and endurance exercises including pressure biofeedback for small/moderate improvement of pain, function and GPE (IP/LT). AUTHORS' CONCLUSIONS: Specific strengthening exercises of the neck, scapulothoracic and shoulder for chronic NP and chronic CGH are beneficial. Future research should explore optimal dosage.

Circulating progesterone and obesity in men.

Progesterone can be detected in male plasma and has been considered to originate mainly from the adrenals. We have examined the association between circulating progesterone and obesity in a sample of thirty-eight lean to morbidly obese men aged 44.5 +/- 9.9 years (BMI: 44.3 +/- 12.8 kg/m (2)). Plasma concentrations of progesterone, 17-OH-progesterone as well as androstenedione, testosterone, DHT and DHEA-S were determined. Negative correlations were observed between plasma progesterone levels and body weight (r = - 0.47, p < 0.05), BMI (r = - 0.56, p < 0.001), waist circumference (r = - 0.58, p < 0.001), as well as subcutaneous adipocyte diameter (r = - 0.50, p < 0.05). Plasma levels of 17-OH-progesterone, DHEA-S, androstenedione, testosterone and DHT were also negatively associated with body weight, BMI and waist circumference. However, the ratio of 17-OH-progesterone-to-progesterone and androstenedione-to-17-OH-progesterone were not related to these variables. A positive correlation was found between circulating progesterone and DHEA-S levels (r = 0.50, p < 0.002 after adjustment for age). Accordingly, using multivariate regression analyses, the best steroid predictor of progesterone level was plasma DHEA-S. Waist circumference was the best predictor of progesterone levels in a multivariate model including steroid concentrations as well as waist circumference, BMI and subcutaneous adipocyte diameter. In conclusion, plasma progesterone was negatively associated with markers of obesity such as BMI, waist circumference and subcutaneous adipocyte diameter in this sample of men. Circulating DHEA-S level was the best steroid correlate of plasma progesterone. We suggest that the low progesterone levels observed in obese men may reflect decreased adrenal C(19) steroid production in the adrenal cortex. Further research is needed to confirm this hypothesis.

Thiols prevent H2O2-mediated loss of sperm motility in cryopreserved bull semen.

We previously showed that cryopreservation of bull spermatozoa in egg yolk Tris extender (EYTG) significantly reduced the intracellular level of thiols. Other studies showed the beneficial effects of adding antioxidants to cryopreserved bull spermatozoa. These studies led us to investigate the effects of various thiols, an important class of antioxidants, on sperm motility of cryopreserved bull semen in a commonly used extender, EYTG. Sperm motility was analyzed by computer-assisted semen analysis (CASA). After thawing, a diluted pool of bull semen was incubated at 38.5 degrees C in airtight tubes with the following thiols for 6 hours: glutathione (GSH/GSSG), cysteine, N-acetyl-L-cysteine (NAC) and 2-mercaptoethanol in the presence or absence of oxidative stress. The oxidative stress was caused by adding H2O2 (100 microM) to diluted semen. Incubation of diluted bull semen in EYTG at 38.5 degrees C over a period of 6 h decreased sperm motility by approximately 9 fold from the start (72 +/- 3, mean +/- SEM, n=4) to the end (9 +/- 4, n=4) of the incubation. We found that all thiols to a concentration above 0.5 mM maintained high sperm motility for 6 h in the absence of an external source of oxidative stress (52 +/- 4, for 4 thiols). However, one mM of each thiol was required to efficiently protect sperm motility in the presence of 100 microM of H2O2 for 6 h. We also found that the GSH concentration in diluted semen was too low (microM) to adequately supply exogenous addition of 72 U/mL of glutathione peroxidase (GPx), an enzyme that detoxifies H2O2 and hydroperoxides using GSH as a cofactor. In fact, a better protection of sperm motility could be achieved with only 5 U/mL of GPx and 0.1 mM of GSH added to diluted semen. Our results also demonstrated that added GSSG (0.5 mM) in diluted semen was not regenerated efficiently to GSH over 6 h. The latter result indicated in the extender that the glutathione redox-cycle was deficient. Therefore, deleterious effects sperm motility after cryopreservation in EYTG can be counteracted by adding various thiols at mM concentration.