Circadian disruption and cisplatin chronotherapy for mammary carcinoma.

Solid tumors are commonly treated with cisplatin, which can cause off-target side effects in cancer patients. Chronotherapy is a potential strategy to reduce drug toxicity. To determine the effectiveness of timed-cisplatin treatment in mammals, we compared two conditions: clock disrupted jet-lag and control conditions. Under normal and disrupted clock conditions, triple-negative mammary carcinoma cells were injected subcutaneously into eight-week-old NOD.Cg-Prkdcscid/J female mice. Tumor volumes and body weights were measured in these mice before and after treatment with cisplatin. We observed an increase in tumor volumes in mice housed under disrupted clock compared to the normal clock conditions. After treatment with cisplatin, we observed a reduced tumor growth rate in mice treated at ZT10 compared to ZT22 and untreated cohorts under normal clock conditions. However, these changes were not seen with the jet-lag protocol. We also observed greater body weight loss in mice treated with ZT10 compared to ZT22 or untreated mice in the jet-lag protocol. Our observations suggest that the effectiveness of cisplatin in mammary carcinoma treatment is time-dependent in the presence of the circadian clock.

A pragmatic effectiveness randomized controlled trial of the duration of psychiatric hospitalization in a trans-diagnostic sample of patients with acute mental illness admitted to a ward with either blue-depleted evening lighting or normal lighting conditions.

BACKGROUND: There is increasing recognition of the need to stabilize sleep-wake cycles in individuals with major mental disorders. As such, clinicians and researchers advocate the use of interventions targeted at sleep and circadian dysrhythmias as an adjunct to the standard treatments offered for acute illness episodes of a broad range of diagnoses. To determine the trans-diagnostic generalizability of chronotherapy, we explore the benefits of admitting individuals with an acute illness episode to a psychiatric inpatient unit where changes in light exposure are integrated into the therapeutic environment. METHODS/DESIGN: A two-arm, pragmatic effectiveness, randomized controlled treatment trial, where individuals admitted for acute inpatient psychiatric care will be allocated to a ward with blue-depleted evening light or to a ward with the same layout and facilities but lacking the new lighting technology. The trial will test whether the experimental lighting conditions offer any additional benefits beyond those associated with usual treatment in an acute psychiatric inpatient unit. The main objectives are to examine any differences between groups in the mean duration of hospitalization in days. Additional analyses will compare group differences in symptoms, functioning, medication usage, and side effects and whether length of stay is associated with stability of sleep-wake cycles and circadian rhythms. Ancillary investigations should determine any benefits according to diagnostic subgroups and potential drawbacks such as any adverse effects on the well-being of professionals working across both wards. DISCUSSION: This unit offers a unique opportunity to explore how exposure to different lighting conditions may modify sleep-wake cycles and how any changes in sleep-wake cycle may impact on the clinical and functional outcomes of individuals experiencing an acute episode of a severe mental disorder that requires inpatient care. The findings could influence the future design of hospital units offering care to patients with mental or physical disorders. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03788993 . Retrospectively registered on 28 December 2018.

Sleep deprivation therapy for depression.

Sleep deprivation (SD) is the most widely documented rapid-onset antidepressant therapy, targeting the broadly defined depressive syndrome. Although SD responses are transient, its effects can be sustained by concomitant medications (e.g., selective serotonin reuptake inhibitors and lithium) and circadian-related interventions (e.g., bright light and sleep phase advance). Thus, considering its safety, this technique can now be considered among the first-line antidepressant treatment strategies for patients affected by mood disorders. SD is a complex intervention and it should be considered multi-target in nature. Thus, the mechanisms explaining its antidepressant effect can be looked for on many levels, involving not only monoaminergic mechanisms but also sleep homeostatic and circadian mechanisms, glutamatergic mechanisms and synaptic plasticity.

[Chronotherapy with 5-fluorouracil folinic acid and oxaliplatin delivered over 48 hours every second week in colorectal cancer. The CHC-Liège experience (Belgium)]. / Chronochimiothérapie à base de 5-fluorouracil, acide folinique et oxaliplatine administrée en deux jours toutes les deux semaines pour le cancer colorectal. L'expérience du CHC-Liège (Belgique).

One hundred and ten consecutive patients suffering from a colorectal cancer received chronotherapy infused over two days every two weeks. Each course comported 5 FU 3g/m(2), folinic acid (600 mg/m(2) - l. form or 1200 mg/m(2)--racemic form) and oxaliplatin (85/mg/m(2)--adjuvant indication or 100mg/m(2)--palliative indication). According to chronobiological concepts, 5 FU and folinic acid were infused from 10 pm to 10 am with a peak at 4 am while oxaliplatin was delivered from 10 am to 10 pm with a peak at 4 pm. The overall tolerance was excellent with a maximum of 17% patients experiencing a grade 3 toxicity. The toxicity was higher in women, in older patients (>=70) or in case of flat infusion. In adjuvant situation (60 cases), progression free and overall survivals established respectively at 76% (42+months) and 88% (45+months). Fifty-two percent response rate were recorded within the palliative group (50 cases) with an overall 68% disease control. Median progression free survival was seven months but median survival was not attained at 31+ months. Thirty percent patients could benefit from a curative surgery after chemotherapy. Older patients (>=70) experienced worsened survival. In conclusion, we think that our chrono-FOLFOX 2-12 should be proposed as standard treatment for colorectal cancer patients.

Randomised phase II study of standard versus chronomodulated CPT-11 plus chronomodulated 5-fluorouracil and folinic acid in advanced colorectal cancer patients.

In this study, a randomised phase II trial explored the effects of 6-h chronomodulated CPT-11 infusion in advanced colorectal cancer patients. Sixty-eight pre-treated patients were randomly assigned to CPT-11 administered at 180 mg/m2 on day 1, by 1-h infusion (Arm A) or 6-h sinusoidal infusion with peak timing at 5:00 a.m. (Arm B). All patients also received chronomodulated folinic acid/5-fluorouracil (FA/5-FU). Patients in Arm B obtained a 25.7% response rate for 7.0 months duration, a progression-free survival for 8.0 months and a median survival of 28 months. The same data in Arm A were 18.2%, 4.5, 6.0 and 18 months, respectively. No differences in drugs dose-intensity or increased toxicity with prolonged chronomodulated infusion were detected. Major grade 3-4 toxicity was diarrhoea: 10 patients in Arm A and 13 in Arm B. In conclusion, this study has shown that chronomodulated infusion of CPT-11 and FA/5-FU is safe, active and can be integrated with oxaliplatin (EORTC 05011) for the treatment of advanced colorectal cancer.

Are there hangover-effects on physical performance when melatonin is ingested by athletes before nocturnal sleep?

Athletes ingest melatonin in an attempt to improve sleep quality or alleviate symptoms of jet lag after transmeridian travel. It is not known whether there are residual effects of this hormone on physical performance in fit subjects. After a sample size estimation involving a meaningful effect on performance of 5%, five milligrams of melatonin or placebo were ingested by twelve physically-active subjects before sleep in a double-blind experiment. The following morning, subjective sleep quality (latency and maintenance) were measured together with intra-aural temperature, grip strength of the left and right hands, and time to complete a 4 km time trial on a cycle ergometer. The subjects also rated perceived exertion during the latter test. The null hypothesis of no effect of melatonin on either subjective sleep quality or physical performance measured the morning after administration could not be rejected on the basis of our observations (P > 0.30). The mean differences between treatments were less than 1% for the strength tests and time trial performance. The confidence intervals for these differences for left and right grip strength and the cycling test were - 2.1 to 2.8 kg, - 3.1 to 2.7 kg and -3.0 to 4.5 s, respectively. In conclusion, it is unlikely that 5 mg of melatonin would have any meaningful effects on physical performance in the morning after fit subjects ingest the hormone. There was also little evidence that it improves sleep quality in this population. Further research is needed concerning the effects of daytime and nighttime admistration of melatonin on performance, in both situations of normal and disturbed sleep.