Urine hepcidin has additive value in ruling out cardiopulmonary bypass-associated acute kidney injury: an observational cohort study

This study was supported by grants from the German Heart Foundation (Deutsche Stiftung für Herzforschung) and from the Else Kröner-Fresenius-Stiftung, Germany

The DNA Damage Signal for Mdm2 Regulation, Trp53 Induction, and Sunburn Cell Formation In Vivo Originates from Actively Transcribed Genes

The stratum corneum and DNA repair do not completely protect keratinocytes from ultraviolet B. A third defense prevents cells with DNA photoproducts from becoming precancerous mutant cells: apoptosis of ultraviolet-damaged keratinocytes (“sunburn cells”). As signals for ultraviolet-induced apoptosis, some studies implicate DNA photoproducts in actively transcribed genes; other studies implicate non-nuclear signals. We traced and quantitated the in vivo DNA signal through several steps in the apoptosis-signaling pathway in haired mice. Homozygous inactivation of Xpa, Csb, or Xpc nucleotide excision repair genes directed the accumulation of DNA photoproducts to specific genome regions. Repair-defective Xpa−/− mice were 7–10-fold more sensitive to sunburn cell induction than wild-type mice, indicating that 86–90% of the ultraviolet B signal for keratinocyte apoptosis involved repairable photoproducts in DNA; the remainder involves unrepaired DNA lesions or nongenomic targets. Csb−/− mice, defective only in excising photoproducts from actively transcribed genes, were as sensitive as Xpa−/−, indicating that virtually all of the DNA signal originates from photoproducts in active genes. Conversely, Xpc−/− mice, defective in repairing the untranscribed majority of the genome, were as resistant to apoptosis as wild type. Sunburn cell formation requires the Trp53 tumor suppressor protein; 90–96% of the signal for its induction in vivo involved transcribed genes. Mdm2, which regulates the stability of Trp53 through degradation, was induced in vivo by low ultraviolet B doses but was suppressed at erythemal doses. DNA photoproducts in actively transcribed genes were involved in ≈ 89% of the Mdm2 response

Role of eHealth application Oncokompas in supporting self-management of symptoms and health-related quality of life in cancer survivors:a randomised, controlled trial

Background Knowledge about the efficacy of behavioural intervention technologies that can be used by cancer survivors independently from a health-care provider is scarce. We aimed to assess the efficacy, reach, and usage of Oncokompas, a web-based eHealth application that supports survivors in self-management by monitoring health-related quality of life (HRQOL) and cancer-generic and tumour-specific symptoms and obtaining tailored feedback with a personalised overview of supportive care options. Methods In this non-blinded, randomised, controlled trial, we recruited patients treated at 14 hospitals in the Netherlands for head and neck cancer, colorectal cancer, breast cancer, Hodgkin lymphoma, or non-Hodgkin lymphoma. Adult survivors (aged ≥18 years) were recruited through the Netherlands Cancer Registry (NCR) and invited by their treating physician through the Patient Reported Outcomes Following Initial Treatment and Long term Evaluation of Survivorship (PROFILES) registry. Participants were randomly assigned (1:1) by an independent researcher to the intervention group (access to Oncokompas) or control group (access to Oncokompas after 6 months), by use of block randomisation (block length of 68), stratified by tumour type. The primary outcome was patient activation (knowledge, skills, and confidence for self-management), assessed at baseline, post-intervention, and 3-month and 6-month follow-up. Linear mixed models (intention-to-treat) were used to assess group differences over time from baseline to 6-month follow-up. The trial is registered in the Netherlands Trial Register, NTR5774 and is completed. Findings Between Oct 12, 2016, and May 24, 2018, 625 (21%) of 2953 survivors assessed for eligibility were recruited and randomly assigned to the intervention (320) or control group (305). Median follow-up was 6 months (IQR 6−6). Patient activation was not significantly different between intervention and control group over time (difference at 6-month follow-up 1·7 [95% CI −0·8–4·1], p=0·41). Interpretation Oncokompas did not improve the amount of knowledge, skills, and confidence for self-management in cancer survivors. This study contributes to the evidence for the development of tailored strategies for development and implementation of behavioural intervention technologies among cancer survivors

High cancer risk and increased mortality in patients with Peutz-Jeghers syndrome

Background Peutz-Jeghers syndrome (PJS) is associated with an increased cancer risk. As the determination of optimal surveillance strategies is hampered by wide ranges in cancer risk estimates and lack of data on cancer-related mortality, we assessed cancer risks and mortality in a large cohort of patients with PJS. Methods Dutch PJS patients were included in this cohort study. Patients were followed prospectively between January 1995 and July 2009, and clinical data from the period before 1995 were collected retrospectively. Data were obtained by interview and chart review. Cumulative cancer risks were calculated by Kaplan-Meier analysis and relative cancer and mortality risks by Poisson regression analysis. Results We included 133 PJS patients (48% males) from 54 families, contributing 5004 person-years of follow-up. 49 cancers were diagnosed in 42 patients (32%), including 25 gastrointestinal (GI) cancers. The median age at first cancer diagnosis was 45 years. The cumulative cancer risk was 20% at age 40 (GI cancer 12%), increasing to 76% at age 70 (GI cancer 51%). Cumulative cancer risks were higher for females than for males (p=0.005). The relative cancer risk was higher in PJS patients than in the general population (HR 8.96; 95% CI 6.46 to 12.42), and higher among female (HR 20.40; 95% CI 13.43 to 30.99) than among male patients (HR 4.76; 95% CI 2.82 to 8.04). 42 patients had died at a median age of 45 years, including 28 cancer-related deaths (67%). Mortality was increased in our cohort compared to the general population (HR 3.50; 95% CI 2.57 to 4.75). Conclusions PJS patients carry high cancer risks, leading to increased mortality. The malignancies occur particularly in the GI tract and develop at young age. These results justify surveillance in order to detect malignancies in an early phase to improve outcome

An exploration of needs and preferences for dietary support in colorectal cancer survivors : A mixed-methods study

Purpose To describe the proportion of colorectal cancer (CRC) survivors who perceive a need for dietary support; to examine which socio-demographic, cancer-related, and health-related characteristics are associated with this need; to explore reasons for (not) needing support; and to explore CRC survivors’ specific needs and preferences with regard to lifestyle (i.e., dietary, exercise, and/or weight management) support. Methods This mixed-methods study comprised a cross-sectional survey among 1774 Dutch CRC survivors and three focus groups (n = 16). To examine associations, logistic regression analyses were conducted. Focus groups were audio-taped, transcribed verbatim, and analyzed using a thematic approach. Results Of 1458 respondents (82%), 1198 (67.5%) were included for analyses. 17.5% reported a need for dietary support. Characteristics associated with this need were: being younger, living without a partner, having a stoma, having diabetes, and being overweight or obese. The main reason for needing support was being unable to initiate and maintain lifestyle changes without support. CRC survivors preferred receiving information soon after diagnosis to make an autonomous, informed decision on improving their lifestyle. They preferred to receive individually-tailored lifestyle support in an autonomy-supportive environment, preferably with involvement of their family and fellow-sufferers. Conclusions This study has provided knowledge on appropriate support for CRC survivors in need for dietary support to improve health outcomes by promoting adherence to lifestyle and body weight recommendations. Findings can be used to better identify CRC survivors in need for dietary support, and to tailor lifestyle support to their needs and preferences in order to promote uptake, adherence, and effectiveness.</p

Phenacetin acts as a weak genotoxic compound preferentially in the kidney of DNA repair deficient Xpa mice.

Chronic use of phenacetin-containing analgesics has been associated with the development of renal cancer. To establish genotoxicity as a possible cause for the carcinogenic effect of phenacetin, we exposed wild type and DNA repair deficient Xpa-/- and Xpa-/-/Trp53+/- mice (further referred as Xpa and Xpa/p53 mice, respectively), carrying a reporter lacZ gene, to 0.75% (w/w) phenacetin mixed in feed. Xpa mice completely lack the nucleotide excision repair pathway, and as such they are sensitive to some classes of genotoxic compounds. Phenacetin exposure induced a significant increase of lacZ mutations in the kidney of both Xpa and Xpa/p53 mice. A minor response was found in liver, whereas no lacZ mutation induction was observed in the spleen of these animals. Interestingly, the observed phenacetin-induced mutant frequencies were higher in male than those found in female mice. This gender difference is probably due to a difference in metabolic rate. Phenacetin-induced mutations mainly consisted of point mutations rather than deletions. The mutational spectra in the kidney of treated WT and Xpa mice were quite similar. Taken together, these results demonstrate that the human carcinogen phenacetin acts as a weak genotoxic agent in an in vivo mouse model system

Perceptions of non-Western immigrant women on having breast cancer and their experiences with treatment-related changes in body weight and lifestyle:A qualitative study

BACKGROUND: The number of non-Western immigrants with breast cancer in the Netherlands has increased over the past decades and is expected to triple by 2030. Due to insufficient representation in clinical studies, it is unclear what the specific experiences and needs of these women are. Understanding how culture and religion affect these women's experience of breast cancer and how they deal with chemotherapy and treatment-related changes in body weight and lifestyle is crucial for health care professionals to be able to provide effective support. METHODS: A qualitative study was conducted using semi-structured interviews with 28 immigrant women with a history of breast cancer treated with chemotherapy. RESULTS: Women often associated breast cancer with taboo, death or bad luck. Religion offered these women guidance, strength and meaning to the disease, but also limited the women to openly talk about their disease. Women perceived lifestyle factors to have little influence on the development and treatment of cancer. After treatment, however, their thinking changed and these lifestyle factors became of paramount importance to them. They realised that they missed out on information about managing their own diet, exercise and body weight and were eager to share their experiences with other women in their culture with newly diagnosed breast cancer. CONCLUSION: Women became aware during and after breast cancer treatment that it was difficult for them to actively deal with their illness under the influence of their culture and religion. Based on their own experiences and acquired knowledge, they would like to give advice to newly diagnosed women on how to deal with breast cancer within their own culture and religion. Their recommendations could be used by mosques, churches, support groups and health care professionals, to ensure interventions during breast cancer treatment meet their religious and cultural needs and thus improve their quality of life

CXCR4 expression in glioblastoma tissue and the potential for PET imaging and treatment with [68Ga]Ga-Pentixafor /[177Lu]Lu-Pentixather

Purpose: CXCR4 (over)expression is found in multiple human cancer types, while expression is low or absent in healthy tissue. In glioblastoma it is associated with a poor prognosis and more extensive infiltrative phenotype. CXCR4 can be targeted by the diagnostic PET agent [68Ga]Ga-Pentixafor and its therapeutic counterpart [177Lu]Lu-Pentixather. We aimed to investigate the expression of CXCR4 in glioblastoma tissue to further examine the potential of these PET agents. Methods: CXCR4 mRNA expression was examined using the R2 genomics platform. Glioblastoma tissue cores were stained for CXCR4. CXCR4 staining in tumor cells was scored. Stained tissue components (cytoplasm and/or nuclei of the tumor cells and blood vessels) were documented. Clinical characteristics and information on IDH and MGMT promoter methylation status were collected. Seven pilot patients with recurrent glioblastoma underwent [68Ga]Ga-Pentixafor PET; residual resected tissue was stained for CXCR4. Results: Two large mRNA datasets (N = 284; N = 540) were assesed. Of the 191 glioblastomas, 426 cores were analyzed using immunohistochemistry. Seventy-eight cores (23 tumors) were CXCR4 negative, while 18 cores (5 tumors) had both strong and extensive staining. The remaining 330 cores (163 tumors) showed a large inter- and intra-tumor variation for CXCR4 expression; also seen in the resected tissue of the seven pilot patients—not directly translatable to [68Ga]Ga-Pentixafor PET results. Both mRNA and immunohistochemical analysis showed CXCR4 negative normal brain tissue and no significant correlation between CXCR4 expression and IDH or MGMT status or survival. Conclusion: Using immunohistochemistry, high CXCR4 expression was found in a subset of glioblastomas as well as a large inter- and intra-tumor variation. Caution should be exercised in directly translating ex vivo CXCR4 expression to PET agent uptake. However, when high CXCR4 expression can be identified with [68Ga]Ga-Pentixafor, these patients might be good candidates for targeted radionuclide therapy with [177Lu]Lu-Pentixather in the future