Liver transplantation plus chemotherapy versus chemotherapy alone in patients with permanently unresectable colorectal liver metastases (TransMet): results from a multicentre, open-label, prospective, randomised controlled trial.

Background: Despite the increasing efficacy of chemotherapy, permanently unresectable colorectal liver metastases are associated with poor long-term survival. We aimed to assess whether liver transplantation plus chemotherapy could improve overall survival.

Methods: TransMet was a multicentre, open-label, prospective, randomised controlled trial done in 20 tertiary centres in Europe.

Why does circadian timing of administration matter for immune checkpoint inhibitors' efficacy?

Background: Tolerability and antitumour efficacy of chemotherapy and radiation therapy can vary largely according to their time of administration along the 24-h time scale, due to the moderation of their molecular and cellular mechanisms by circadian rhythms. Recent clinical data have highlighted a striking role of dosing time for cancer immunotherapy, thus calling for a critical evaluation.

Methods: Here, we review the clinical data and we analyse the mechanisms through which circadian rhythms can influence outcomes on ICI therapies.

Safety and feasibility of chemotherapy followed by liver transplantation for patients with definitely unresectable colorectal liver metastases: insights from the TransMet randomised clinical trial.

Background: Despite the increasing efficacy of chemotherapy (C), the 5-year survival rate for patients with unresectable colorectal liver metastases (CLM) remains around 10%. Liver transplantation (LT) might offer a curative approach for patients with liver-only disease, yet its superior efficacy compared to C alone remains to be demonstrated.

Methods: The TransMet randomised multicentre clinical trial (NCT02597348) compares the curative potential of C followed by LT versus C alone in patients with unresectable CLM despite stable or responding disease on C.

Association between endocrine adjuvant therapy intake timing and disease-free survival in patients with high-risk early breast cancer: results of a sub-study of the UCBG- UNIRAD trial.

Background: Circadian rhythms regulate cellular physiology and could influence the efficacy of endocrine therapy (ET) in breast cancer (BC). We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271).

Methods: 1278 patients with high-risk hormonal receptor positive (HR+)/HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus.

Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis.

Background: Recent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and non-small cell lung cancer. These data are in line with growing preclinical evidence that the adaptive immune response may be more effectively stimulated earlier in the day. We sought to determine the impact of time-of-day ICI infusions on outcomes among patients with metastatic renal cell carcinoma (mRCC).

TimeTeller: A tool to probe the circadian clock as a multigene dynamical system.

Recent studies have established that the circadian clock influences onset, progression and therapeutic outcomes in a number of diseases including cancer and heart diseases. Therefore, there is a need for tools to measure the functional state of the molecular circadian clock and its downstream targets in patients. Moreover, the clock is a multi-dimensional stochastic oscillator and there are few tools for analysing it as a noisy multigene dynamical system.

Circadian Regulation of Drug Responses: Toward Sex-Specific and Personalized Chronotherapy.

Today's challenge for precision medicine involves the integration of the impact of molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements of tolerability and/or efficacy of medications through proper administration timing have been confirmed over the past decade for immunotherapy and chemotherapy against cancer, as well as for commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, and neurological conditions. Experimental and human studies have recently revealed sexually dimorphic circadian drug responses.

International e-Delphi Consensus Recommendations for the Assessment and Diagnosis of Circadian rest-Activity Rhythm Disorders (CARDs) in Patients with Cancer.

Purpose: Circadian rest-Activity Rhythm Disorders (CARDs) are common in patients with cancer, particularly in advanced disease. CARDs are associated with increased symptom burden, poorer quality of life, and shorter survival. Research and reporting practices lack standardization, and formal diagnostic criteria do not exist.

Multicentre, interventional, single-arm study protocol of telemonitored circadian rhythms and patient-reported outcomes for improving mFOLFIRINOX safety in patients with pancreatic cancer (MultiDom, NCT04263948).

Introduction: Circadian clocks regulate cellular proliferation and drug effects. Tolerability and/or efficacy of anticancer therapies have been improved by their administration according to circadian rhythms, while being predicted by circadian robustness. The combination of leucovorin, fluorouracil, irinotecan and oxaliplatin (mFOLFIRINOX) is a standard treatment for pancreatic ductal adenocarcinoma (PDAC), that generates grades 3-4 adverse events in the majority of patients and an estimated 15%-30% emergency admission rate.

Diurnal Changes in Capecitabine Clock-Controlled Metabolism Enzymes Are Responsible for Its Pharmacokinetics in Male Mice.

The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics.

Immune disruptions and night shift work in hospital healthcare professionals: The intricate effects of social jet-lag and sleep debt.

Objectives: We aimed to examine the effects of circadian and sleep rhythm disruptions on immune biomarkers among hospital healthcare professionals working night shifts and rotating day shifts.

Methods: Hospital nurses working either as permanent night shifters (n=95) or as day shifters rotating between morning and afternoon shifts (n=96) kept a daily diary on their sleep and work schedules over a full working week. Blood samples were collected at the beginning and end of the last shift during the week, and participants were categorized into three groups based on work shift: morning shift (39 day shifters sampled at 7:00 and 14:00), afternoon shift (57 day shifters sampled at 14:00 and 21:00), and night shift (95 night shifters sampled at 21:00 and 7:00).

Digital circadian and sleep health in individual hospital shift workers: A cross sectional telemonitoring study.

Background: Telemonitoring of circadian and sleep cycles could identify shift workers at increased risk of poor health, including cancer and cardiovascular diseases, thus supporting personalized prevention.

Methods: The Circadiem cross-sectional study aimed at determining early warning signals of risk of health alteration in hospital nightshifters (NS) versus dayshifters (DS, alternating morning and afternoon shifts). Circadian rhythmicity in activity, sleep, and temperature was telemonitored on work and free days for one week.

Time-Dependent Efficacy of Checkpoint Inhibitor Nivolumab: Results from a Pilot Study in Patients with Metastatic Non-Small-Cell Lung Cancer.

Hypothesis: Prior experimental and human studies have demonstrated the circadian organization of immune cells' proliferation, trafficking, and antigen recognition and destruction. Nivolumab targets T(CD8) cells, the functions, and trafficking of which are regulated by circadian clocks, hence suggesting possible daily changes in nivolumab's efficacy. Worse progression-free survival (PFS), and overall survival (OS) were reported for malignant melanoma patients receiving more than 20% of their immune checkpoint inhibitor infusions after 16:30 as compared to earlier in the day.

Sex differences and sex bias in human circadian and sleep physiology research.

Growing evidence shows that sex differences impact many facets of human biology. Here we review and discuss the impact of sex on human circadian and sleep physiology, and we uncover a data gap in the field investigating the non-visual effects of light in humans. A virtual workshop on the biomedical implications of sex differences in sleep and circadian physiology led to the following imperatives for future research: i) design research to be inclusive and accessible; ii) implement recruitment strategies that lead to a sex-balanced sample; iii) use data visualization to grasp the effect of sex; iv) implement statistical analyses that include sex as a factor and/or perform group analyses by sex, where possible; v) make participant-level data open and available to facilitate future meta-analytic efforts.

Model learning to identify systemic regulators of the peripheral circadian clock.

Motivation: Personalized medicine aims at providing patient-tailored therapeutics based on multi-type data toward improved treatment outcomes. Chronotherapy that consists in adapting drug administration to the patient's circadian rhythms may be improved by such approach. Recent clinical studies demonstrated large variability in patients' circadian coordination and optimal drug timing.

Telemonitored Human Circadian Temperature Dynamics During Daily Routine.

Background: Circadian rhythms in body temperature coordinate peripheral molecular clocks, hence they could potentially predict optimal treatment timing (chronotherapy) in individual patients. Circadian parameters in chest surface body temperature (Chesttemp) were recorded remotely and in real time through the use of wearable sensors.

Methods: The dynamics of circadian oscillations in Chesttemp and core body temperature (Coretemp) and their moderation by sex and age were analysed in 38 men and 50 women, aged 21-78 years.

Impact of assessment frequency of patient-reported outcomes: an observational study using an eHealth platform in cancer patients.

Background And Aim: The evaluation of patient-reported outcomes (PRO) in cancer has proven relevant positive clinical impact on patients' communication with healthcare professionals, decision-making for management, well-being, and overall survival. However, the optimal frequency of PRO assessment has yet to be defined. Based on the assumption that more frequent sampling would enhance accuracy, we aimed at identifying the optimal sampling frequency that does not miss clinically relevant insight.

Dose- and time-dependent tolerability and efficacy of organo-osmium complex FY26 and its tissue pharmacokinetics in hepatocarcinoma-bearing mice.

The organo-osmium complex [OsII(ɳ6-p-cym)(PhAzPy-NMe2)I]+ (FY26) exhibits promising in vitro antitumour activity against mouse hepatocarcinoma Hepa1-6 and other mouse or human cancer cell lines. Here, we drastically enhance water solubility of FY26 through the replacement of the PF6- counter-anion with chloride using a novel synthesis method. FY26⋅PF6 and FY26⋅Cl displayed similar in vitro cytotoxicity in two cancer cell models.

Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5-fluorouracil and leucovorin combination as first- or second-line treatment against metastatic colorectal cancer: Results from the International EORTC 05011 Trial.

The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian-based administration (chronoIFLO5) as either first- or second-line treatment, within the time-finding EORTC 05011 trial. Five-day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2.