Circadian clock genes regulate 10-15% of the transcriptome, and might function as tumor suppressor genes. Relatively little is known about the circadian clock in tumors and its effect on surrounding healthy tissues. Therefore, we compared the 24-hr expression levels of key circadian clock genes in liver and kidney of healthy control mice with those of mice bearing C26 colorectal tumor metastases in the liver. Metastases were induced by injection of C26 colorectal carcinoma cells into the spleen. Subsequently, tumor, liver and kidney tissue was collected around the clock to compare circadian rhythmicity. Expression levels of five clock genes (Rev-Erba, Per1, Per2, Bmal1 and Cry1) and three clock-controlled genes (CCGs; Dbp, p21 and Wee1) were determined by qRT-PCR. Liver and kidney tissue of healthy control mice showed normal 24-hr oscillations of all clock genes and CCGs, consistent with normal circadian rhythmicity. In colorectal liver metastases, however, 24-hr oscillations were completely absent for all clock genes and CCGs except Cry1. Liver and kidney tissue of tumor-bearing mice showed a shift in clock periodicity relative to control mice. In the liver we observed a phase advance, whereas in the kidney the phase was delayed. These data show that hepatic metastases of C26 colon carcinoma with a disrupted circadian rhythm phase shift liver and kidney tissue clocks, which strongly suggests a systemic effect on peripheral clocks. The possibility that tumors may modify peripheral clocks to escape from ordinary circadian rhythms and in this way contribute to fatigue and sleep disorders in cancer patients is discussed.The circadian timing system plays an essential role in the development of cancer. Cancer cells carry a similar machinery of increased proliferation rate, reduced apoptotic sensitivity and escaping cell-cycle control. These parameters are controlled by the circadian clock. [1][2][3][4] Circadian rhythms are generated by a molecular oscillator composed of a set of clock genes that act in a cellautonomous way and are present in all cell types. These clocks are coordinated by a master clock in the neurons of the suprachiasmatic nuclei (SCN), which is located in the anterior hypothalamus. 5 Peripheral clocks are regulated by the SCN through both the autonomic nervous system and neuroendocrine systems. Clocks in the SCN neurons and peripheral cells make use of the same set of clock genes. 6 The positive branch of the mammalian clock machinery consists of CLOCK (Circadian Locomotor Output Cycles Kaput) and BMAL1 (Brain-Muscle Arnt-Like protein 1). CLOCK and BMAL1 are transcription factors that heterodimerize and activate transcription of the Cryptochrome (Cry1 and Cry2) and Period (Per1 and Per2) genes by binding to E-box elements in their promoters. After being synthesized in the cytoplasm, CRY and PER proteins heterodimerize and enter the nucleus where they inhibit CLOCK-BMAL1-mediated transcription and accordingly close the negative feedback loop. 7 The core mechanism is more complex than a single autor...

BACKGROUNDThe main limitation to the use of irinotecan in the treatment of colorectal cancer is the severity of side effects, including neutropaenia and diarrhoea. Here, we explored the effects of 3 days of fasting on irinotecan-induced toxicities, on plasma, liver and tumour pharmacokinetics and on anti-tumour activity in mice. EXPERIMENTAL APPROACHMale BALB/c mice received C26 colon carcinoma cells subcutaneously. They were randomized 1:1 into equally sized ad libitum fed and fasted groups after which they were treated with irinotecan. Weight and adverse side effects were recorded daily. At the end of the experiment, tumours were resected and weighed, and concentrations of irinotecan and its active metabolite SN-38 were determined in plasma and tumour. KEY RESULTSFasting prevented the diarrhoea and visible signs of discomfort induced by irinotecan. Ad libitum fed animals developed leucopenia compared with untreated controls, whereas fasted mice did not. Irinotecan suppressed tumour growth equally in both treated groups, compared with untreated controls. Levels of the active irinotecan metabolite SN-38 9 (calculated as AUC values) were significantly lower in fasted mice in both plasma and liver, but not in tumour tissue. CONCLUSIONS AND IMPLICATIONSFasting protected against irinotecan-induced side effects without interfering with its anti-tumour efficacy. Fasting induced a lower systemic exposure to SN-38, which may explain the absence of adverse side effects, while tumour levels of SN-38 remained unchanged. These data offer important new approaches to improve treatment with irinotecan in patients. AbbreviationsCES, carboxylesterase; DR, dietary restriction; IGF-1, insulin-like growth factor 1; PK, pharmacokinetic; SN-38, 7-ethyl-10-hydroxycamptothecin (active metabolite of irinotecan); SN-38G, SN-38 glucuronide; UGT1A, uridine diphosphate glucuronosyltransferase 1A

Irinotecan is a widely used topoisomerase-I-inhibitor with a very narrow therapeutic window because of its severe toxicity. In the current study we have examined the effects of fasting prior to irinotecan treatment on toxicity and anti-tumor activity. FabplCre;Apc(15lox/+) mice, which spontaneously develop intestinal tumors, of 27 weeks of age were randomized into 3-day fasted and ad libitum fed groups, followed by treatment with a flat-fixed high dose of irinotecan or vehicle. Side-effects were recorded until 11 days after the start of the experiment. Tumor size, and markers for cell-cycle activity, proliferation, angiogenesis, and senescence were measured. Fasted mice were protected against the side-effects of irinotecan treatment. Ad libitum fed mice developed visible signs of discomfort including weight loss, lower activity, ruffled coat, hunched-back posture, diarrhea, and leukopenia. Irinotecan reduced tumor size in fasted and ad libitum fed groups similarly compared to untreated controls (2.4 ± 0.67 mm and 2.4 ± 0.82 mm versus 3.0 ± 1.05 mm and 2.8 ± 1.08 mm respectively, P < 0.001). Immunohistochemical analysis showed reduced proliferation, a reduced number of vascular endothelial cells, and increased levels of senescence in tumors of both irinotecan treated groups. In conclusion, 3 days of fasting protects against the toxic side-effects of irinotecan in a clinically relevant mouse model of spontaneously developing colorectal cancer without affecting its anti-tumor activity. These results support fasting as a powerful way to improve treatment of colorectal carcinoma patients.

Lipoedema is a disorder of adipose tissue that is characterized by abnormal subcutaneous fat deposition, leading to swelling and enlargement of the lower limbs as well as the trunk. This entity is often misdiagnosed as lymphoedema or obesity and, therefore, may be overlooked and missed in patients scheduled for bariatric surgery. Patients with lipoedema who undergo bariatric surgery may have to continue to have extensive lower extremity and trunk adiposity despite adequate weight loss. In this report, we present two patients who had extensive trunk and lower extremity adiposity, one of them before and the other after the bariatric surgery.