BackgroundPreclinical evidence shows that short-term fasting (STF) protects healthy cells against side effects of chemotherapy and makes cancer cells more vulnerable to it. This pilot study examines the feasibility of STF and its effects on tolerance of chemotherapy in a homogeneous patient group with early breast cancer (BC).MethodsEligible patients had HER2-negative, stage II/III BC. Women receiving (neo)-adjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) were randomized to fast 24 h before and after commencing chemotherapy, or to eat according to the guidelines for healthy nutrition. Toxicity in the two groups was compared. Chemotherapy-induced DNA damage in peripheral blood mononuclear cells (PBMCs) was quantified by the level of γ-H2AX analyzed by flow cytometry.ResultsThirteen patients were included of whom seven were randomized to the STF arm. STF was well tolerated. Mean erythrocyte- and thrombocyte counts 7 days post-chemotherapy were significantly higher (P = 0.007, 95 % CI 0.106-0.638 and P = 0.00007, 95 % CI 38.7-104, respectively) in the STF group compared to the non-STF group. Non-hematological toxicity did not differ between the groups. Levels of γ-H2AX were significantly increased 30 min post-chemotherapy in CD45 + CD3- cells in non-STF, but not in STF patients.ConclusionsSTF during chemotherapy was well tolerated and reduced hematological toxicity of TAC in HER2-negative BC patients. Moreover, STF may reduce a transient increase in, and/or induce a faster recovery of DNA damage in PBMCs after chemotherapy. Larger studies, investigating a longer fasting period, are required to generate more insight into the possible benefits of STF during chemotherapy.Trial registrationClinicalTrials.gov: NCT01304251, March 2011Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1663-5) contains supplementary material, which is available to authorized users.

ObjectiveTo determine the frequency of distinctive EGFr cysteine altering NOTCH3 mutations in the 60,706 exomes of the exome aggregation consortium (ExAC) database.MethodsExAC was queried for mutations distinctive for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), namely mutations leading to a cysteine amino acid change in one of the 34 EGFr domains of NOTCH3. The genotype‐phenotype correlation predicted by the ExAC data was tested in an independent cohort of Dutch CADASIL patients using quantified MRI lesions. The Dutch CADASIL registry was probed for paucisymptomatic individuals older than 70 years.ResultsWe identified 206 EGFr cysteine altering NOTCH3 mutations in ExAC, with a total prevalence of 3.4/1000. More than half of the distinct mutations have been previously reported in CADASIL patients. Despite the clear overlap, the mutation distribution in ExAC differs from that in reported CADASIL patients, as mutations in ExAC are predominantly located outside of EGFr domains 1–6. In an independent Dutch CADASIL cohort, we found that patients with a mutation in EGFr domains 7–34 have a significantly lower MRI lesion load than patients with a mutation in EGFr domains 1–6.InterpretationThe frequency of EGFr cysteine altering NOTCH3 mutations is 100‐fold higher than expected based on estimates of CADASIL prevalence. This challenges the current CADASIL disease paradigm, and suggests that certain mutations may more frequently cause a much milder phenotype, which may even go clinically unrecognized. Our data suggest that individuals with a mutation located in EGFr domains 1–6 are predisposed to the more severe “classical” CADASIL phenotype, whereas individuals with a mutation outside of EGFr domains 1–6 can remain paucisymptomatic well into their eighth decade.

ObjectiveTo determine the small vessel disease spectrum associated with cysteine altering NOTCH3 variants in community dwelling individuals, by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants.MethodsThe exome- and genome sequencing datasets of UK Biobank (n=50,000) and cohorts of cognitively healthy elderly (n=751) were queried for cysteine altering NOTCH3 variants. Brain MRI’s of individuals harboring such variants were scored according to STRIVE criteria and clinical information was extracted using ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex matched UK Biobank controls and clinically diagnosed patients from the Dutch CADASIL registry.ResultsWe identified 108 individuals harboring a cysteine altering NOTCH3 variant (2.2/1000), of which 75% has a variant which has been previously reported in CADASIL pedigrees. Almost all variants were located in one of the NOTCH3 protein epidermal growth factor-like repeat domains 7-34. White matter hyperintensity lesion load was higher in individuals with NOTCH3 variants than in controls (p=0.006), but lower than in CADASIL patients with the same variants (p<0.001). Almost half of the 24 individuals with brain MRI had a Fazekas score of 0 or 1 up to age 70. There was no increased risk of stroke.ConclusionsAlthough community dwelling individuals harboring a cysteine altering NOTCH3 variant have a higher small vessel disease MRI burden than controls, almost half have no MRI abnormalities up to age 70. This shows that NOTCH3 cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to non-penetrance.