Impact of acetaminophen on the efficacy of immunotherapy in cancer patients.

BACKGROUND: Acetaminophen (APAP) use has been associated with blunted vaccine immune responses. This study aimed to assess APAP impact on immunotherapy efficacy in patients with cancer. PATIENTS AND METHODS: Exposure to APAP was assessed by plasma analysis and was correlated with clinical outcome in three independent cohorts of patients with advanced cancer who were treated with immune checkpoint blockers (ICBs). The immunomodulatory effects of APAP were evaluated on a preclinical tumor model and on human peripheral blood mononuclear cells (PBMCs) from healthy donors. RESULTS: Detectable plasma APAP levels at treatment onset were associated with a significantly worse clinical outcome in ICB-treated cancer patients, independently of other prognostic factors. APAP significantly reduced ICB efficacy in the preclinical MC38 model, as well as the production of PD-1 blockade-related interferon-γ secretion by human PBMCs. Moreover, reduction of ICB efficacy in vivo was associated with significantly increased tumor infiltration by regulatory T cells (Tregs). Administration of APAP over 24 h induced a significant expansion of peripheral Tregs in healthy individuals. In addition, interleukin-10, a crucial mediator of Treg-induced immune suppression, was significantly up-regulated upon treatment with ICB in cancer patients taking APAP. CONCLUSIONS: This study provides strong preclinical and clinical evidence of the role of APAP as a potential suppressor of antitumor immunity. Hence, APAP should be used with caution in patients treated with ICB.

Chiropractic spinal manipulative therapy for migraine: a three-armed, single-blinded, placebo, randomized controlled trial.

BACKGROUND AND PURPOSE: To investigate the efficacy of chiropractic spinal manipulative therapy (CSMT) for migraineurs. METHODS: This was a prospective three-armed, single-blinded, placebo, randomized controlled trial (RCT) of 17 months duration including 104 migraineurs with at least one migraine attack per month. The RCT was conducted at Akershus University Hospital, Oslo, Norway. Active treatment consisted of CSMT, whereas placebo was a sham push manoeuvre of the lateral edge of the scapula and/or the gluteal region. The control group continued their usual pharmacological management. The RCT consisted of a 1-month run-in, 3 months intervention and outcome measures at the end of the intervention and at 3, 6 and 12 months follow-up. The primary end-point was the number of migraine days per month, whereas secondary end-points were migraine duration, migraine intensity and headache index, and medicine consumption. RESULTS: Migraine days were significantly reduced within all three groups from baseline to post-treatment (P < 0.001). The effect continued in the CSMT and placebo group at all follow-up time points, whereas the control group returned to baseline. The reduction in migraine days was not significantly different between the groups (P > 0.025 for interaction). Migraine duration and headache index were reduced significantly more in the CSMT than the control group towards the end of follow-up (P = 0.02 and P = 0.04 for interaction, respectively). Adverse events were few, mild and transient. Blinding was strongly sustained throughout the RCT. CONCLUSIONS: It is possible to conduct a manual-therapy RCT with concealed placebo. The effect of CSMT observed in our study is probably due to a placebo response.

International consensus on the most useful physical examination tests used by physiotherapists for patients with headache: A Delphi study.

BACKGROUND: A wide range of physical tests have been published for use in the assessment of musculoskeletal dysfunction in patients with headache. Which tests are used depends on a physiotherapist's clinical and scientific background as there is little guidance on the most clinically useful tests. OBJECTIVES: To identify which physical examination tests international experts in physiotherapy consider the most clinically useful for the assessment of patients with headache. DESIGN/METHODS: Delphi survey with pre-specified procedures based on a systematic search of the literature for physical examination tests proposed for the assessment of musculoskeletal dysfunction in patients with headache. RESULTS: Seventeen experts completed all three rounds of the survey. Fifteen tests were included in round one with eleven additional tests suggested by the experts. Finally eleven physical examination tests were considered clinically useful: manual joint palpation, the cranio-cervical flexion test, the cervical flexion-rotation test, active range of cervical movement, head forward position, trigger point palpation, muscle tests of the shoulder girdle, passive physiological intervertebral movements, reproduction and resolution of headache symptoms, screening of the thoracic spine, and combined movement tests. CONCLUSIONS: Eleven tests are suggested as a minimum standard for the physical examination of musculoskeletal dysfunctions in patients with headache.

[Administration of tetracycline to the intact and thyroidectomized rat: its effect on the ultrastructure of hepatocytes, lipids in the liver and plasma]. / Administration de tétracycline au rat intact et éthyroïdé: ses effets sur l'ultrastructure des hépatocytes, les lipides du foie et du plasma.

Tetracycline hydrochlorohydrate was administered to fed adult female rats. Ultrastructural hepatocytes, liver and plasmatic lipids were studied. Tetracycline administration induced a fatty liver in both euthyroid and thyroidectomized group. Blockade of formation or release of lipoproteins into plasma in thyroidectomized rats occurred earlier than in intact ones. In intoxicated thyroidectomized rats, REG was disorganized, and Golgi was poorly loaded with VLDL particles whereas in intact rats REG was regular and Golgi vesicles were hypertrophied. Serum FFA increased only in the thyroidectomized rats after tetracycline.

[Hepatic lipids of intact or thyroidectomized rats after administration of tetracycline or ethanol]. / Lipides hépatiques du rat intact ou thyroidectomisé après administration de tétracycline ou d'éthanol

The purpose of this work was to study the quantitative modifications of the hepatic lipids in adult thyroidectomized rats after administration of tetracycline or ethanol (acute dose or prolonged ingestion). 1. - Thyroidectomy did not inhibit the accumulation of fat in the liver of fed euthyroid or hypothyroid rats after intraperitoneal infusion of tetracycline (320 mg/body weight in 2 injections at an interval of 16 h, the diet containing 6% of lipids). 2. - Sixteen hours after the oral administration of a single large dose of ethanol (5 g/kg body weight), there were only found some small modifications of the lipid composition of the liver in fasting euthyroid or thyroidectomized rats, receiving a diet with 6% of lipids before the experiment; on the contrary, when the diet contained 19% of lipids, a fatty liver occurred in the intact rat, but not in the thyroidectomized rat. 3. - The prolonged ethanol intake (in a 20% solution in water) for 5 months with a diet containing 19% of lipids did not induce a fatty liver in intact rats but produced a decrease of hepatic non-phosphorus lipid and an increase of the cholesterol amounts. After the administration of L-thyroxin (10 mug/100 g body weight per day) to these alcoholic thyroidectomized rats during 2 weeks, it was found an increase of the hepatic non phosphorus lipids till an higher amount than in the euthyroid rats. 4. - The hepatic phospholipid amounts were relatively constant in the different experiments. These results accounting for this differential effects were discussed.