B. van der Vegt

Coping styles in animals: current status in behavior and stress-physiology

This paper summarizes the current views on coping styles as a useful concept in understanding individual adaptive capacity and vulnerability to stress-related disease. Studies in feral populations indicate the existence of a proactive and a reactive coping style. These coping styles seem to play a role in the population ecology of the species. Despite domestication, genetic selection and inbreeding, the same coping styles can, to some extent, also be observed in laboratory and farm animals. Coping styles are characterized by consistent behavioral and neuroendocrine characteristics, some of which seem to be causally linked to each other. Evidence is accumulating that the two coping styles might explain a differential vulnerability to stress mediated disease due to the differential adaptive value of the two coping styles and the accompanying neuroendocrine differentiation.

Long-lasting deficient dexamethasone suppression of hypothalamic-pituitary-adrenocortical activation following peripheral CRF challenge in socially defeated rats

The present study focuses on the long‐term changes in the regulation of the hypothalamic‐pituitary‐adrenocortical (HPA) axis following two short‐lasting episodes of intensive stress in the rat stress model of social defeat and the possible similarities with HPA functioning in human affective disorders. Male Wistar rats experienced social defeats on 2 consecutive days by an aggressive male conspecific. The long‐term effect of these defeats on resting and ovine corticotropin‐releasing factor (oCRF; intravenous (i.v.) 0.5 μg/kg) induced levels of plasma ACTH and corticosterone (CORT) were measured 1 and 3 weeks later. In a second experiment the glucocorticoid feedback regulation of HPA function was tested in a combined dexamethasone (DEX)/CRF test (DEX; 25 μg/kg s.c., 90 min before oCRF injection, 0.5 μg/kg). The oCRF challenges were performed between 11.00 and 13.00 h (about three hours after start of the light phase). One week after defeat the ACTH response to CRF was significantly enhanced in defeated rats as compared to controls. Three weeks after defeat the ACTH response was back to control levels. The increased ACTH response 1 week after the stressor was not reflected in higher CORT levels. Neither were baseline ACTH and CORT levels affected by the prior stress exposure. DEX pretreatment inhibited pituitary adrenocortical activity, reflected both in reduced baseline and response values of ACTH and CORT. The ACTH response to CRF following DEX administration was significantly higher in defeated rats as compared to controls both at one and three weeks after defeat. A reduced DEX suppression of baseline secretion of ACTH appeared 3 weeks after defeat. The same tendency was apparent in response and baseline values of CORT. The differences in CORT between socially stressed and control treated rats, however, did not reach significance. The possible role of changes in glucocorticoid‐(GR) and mineralocorticoid receptor (MR) binding in the altered regulation of HPA activity following defeat were studied in brain and pituitary of male Wistar rats 1 and 3 weeks after defeat. One week after defeat GR‐binding decreased in hippocampus and hypothalamus. No changes were observed in GR‐binding in the pituitary nor in MR‐binding in any of the regions analysed. Three weeks after defeat GR‐binding recovered in hippocampus and hypothalamus but at this time MR‐binding in hippocampal tissue was seriously decreased. In a fourth experiment vasopressin (AVP) and CRF stores in the external zone of the median eminence (ZEME) were measured by quantitative immunocytochemistry one and three weeks after defeat and compared with controls. Social defeat failed to induce a change in the immunocytochemical stores of AVP or CRF. The present findings show that in rats short‐lasting stressors like defeat induce long‐lasting, temporal dynamic changes in the regulation of the HPA axis. Since these changes in time are reflected in GRs and MRs in different brain areas an altered corticosteroid receptor binding might play an important role in the affected HPA activity following defeat.

The expression pattern of MUC1 (EMA) is related to tumour characteristics and clinical outcome of invasive ductal breast carcinoma

Aims:  To clarify MUC1 patterns in invasive ductal breast carcinoma and to relate them to clinicopathological parameters, coexpression of other biological markers and prognosis.

Targeting breast cancer through its microenvironment: current status of preclinical and clinical research in finding relevant targets.

It is increasingly evident that not only breast cancer cells, but also the tissue embedding these cells: the tumor microenvironment, plays an important role in tumor progression, metastasis formation and treatment sensitivity. This review focuses on the current knowledge of processes by which the microenvironment affects breast cancer, including formation of the metastatic niche, metabolic stimulation, stimulation of tumor cell migration, immune modulation, angiogenesis and matrix remodeling. The number of drugs targeting key factors in these processes is expanding, and the available clinical data is increasing. Therefore current strategies for intervention and prediction of treatment response are outlined. At present, targeting the formation of the metastatic niche and metabolic stimulation by the breast cancer microenvironment, are already showing clinical efficacy. Intervening in the stimulation of tumor cell migration and immune modulation by the microenvironment upcoming fields of great research interest. In contrast, targeting microenvironmental angiogenesis or matrix remodeling appears to be of limited clinical relevance in breast cancer treatment so far. Further research is warranted to optimize intervention strategies and develop predictive tests for the relevance of targeting involved factors within the microenvironment in order to optimally personalize breast cancer treatment.

Associate editor: B. TeicherTargeting breast cancer through its microenvironment: Current status of preclinical and clinical research in finding relevant targets

It is increasingly evident that not only breast cancer cells, but also the tissue embedding these cells: the tumor microenvironment, plays an important role in tumor progression, metastasis formation and treatment sensitivity. This review focuses on the current knowledge of processes by which the microenvironment affects breast cancer, including formation of the metastatic niche, metabolic stimulation, stimulation of tumor cell migration, immune modulation, angiogenesis and matrix remodeling. The number of drugs targeting key factors in these processes is expanding, and the available clinical data is increasing. Therefore current strategies for intervention and prediction of treatment response are outlined. At present, targeting the formation of the metastatic niche and metabolic stimulation by the breast cancer microenvironment, are already showing clinical efficacy. Intervening in the stimulation of tumor cell migration and immune modulation by the microenvironment upcoming fields of great research interest. In contrast, targeting microenvironmental angiogenesis or matrix remodeling appears to be of limited clinical relevance in breast cancer treatment so far. Further research is warranted to optimize intervention strategies and develop predictive tests for the relevance of targeting involved factors within the microenvironment in order to optimally personalize breast cancer treatment.

Local control of 151 head and neck cutaneous squamous cell carcinoma after radiotherapy: a retrospective study on efficacy and prognostic factors

after radiotherapy: a retrospective study on efficacy and prognostic factors Terra, J.B.,* Gaster, M.B.,* Halmos, G.B., Roodenburg, J.L., van der Vegt, B., Romeijn, T.R. & Bijl, H.P. *Departments of Dermatology, Otorhinolaryngology, Head and Neck Surgery, Oral andMaxillofacial Surgery, Pathology, Radiation Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

RAB25 expression is epigenetically downregulated in oral and oropharyngeal squamous cell carcinoma with lymph node metastasis

ABSTRACT Oral and oropharyngeal squamous cell carcinoma (OOSCC) have a low survival rate, mainly due to metastasis to the regional lymph nodes. For optimal treatment of these metastases, a neck dissection is required; however, inaccurate detection methods results in under- and over-treatment. New DNA prognostic methylation biomarkers might improve lymph node metastases detection. To identify epigenetically regulated genes associated with lymph node metastases, genome-wide methylation analysis was performed on 6 OOSCC with (pN+) and 6 OOSCC without (pN0) lymph node metastases and combined with a gene expression signature predictive for pN+ status in OOSCC. Selected genes were validated using an independent OOSCC cohort by immunohistochemistry and pyrosequencing, and on data retrieved from The Cancer Genome Atlas. A two-step statistical selection of differentially methylated sequences revealed 14 genes with increased methylation status and mRNA downregulation in pN+ OOSCC. RAB25, a known tumor suppressor gene, was the highest-ranking gene in the discovery set. In the validation sets, both RAB25 mRNA (P = 0.015) and protein levels (P = 0.012) were lower in pN+ OOSCC. RAB25 mRNA levels were negatively correlated with RAB25 methylation levels (P < 0.001) but RAB25 protein expression was not. Our data revealed that promoter methylation is a mechanism resulting in downregulation of RAB25 expression in pN+ OOSCC and decreased expression is associated with lymph node metastasis. Detection of RAB25 methylation might contribute to lymph node metastasis diagnosis and serve as a potential new therapeutic target in OOSCC.

Effect of adjuvant radiotherapy on the local recurrence of oral squamous cell carcinoma with perineural invasion: a systematic review

The decision whether to include postoperative radiotherapy on patients with oral squamous cell carcinoma depends on the risk of local recurrence. The objectives of this study were to systematically review literature on whether perineural invasion in oral squamous cell carcinoma patients is associated with higher local recurrence rates and whether local recurrence is influenced by the administration of postoperative radiotherapy in patients presenting with perineural invasion.

High sensitivity and negative predictive value of sentinel lymph node biopsy in a retrospective early stage oral cavity cancer cohort in the Northern Netherlands

In cT1‐2N0, oral squamous cell carcinoma (OSCC) occult metastases are detected in 23%‐37% of cases. Sentinel lymph node biopsy (SLNB) was introduced in head and neck cancer as a minimally invasive alternative for an elective neck dissection in neck staging. Meta‐analyses of SLNB accuracy show heterogeneity in the existing studies for reference standards, imaging techniques and pathological examination. The aim of this study was to assess the sensitivity and negative predictive value (NPV) of the SLNB in detecting occult metastases in cT1‐2N0 OSCC in a well‐defined cohort.

Clinical value of Zr-89-trastuzumab PET in HER2-positive breast cancer patients with a clinical dilemma

Background: Information on human epidermal growth factor receptor 2 (HER2) is essential for management of metastatic breast cancer (mBC). In patients suspected of HER2-positive mBC, standard work up may fail to clarify whole body HER2 status. We aimed to assess whether 89Zr-trastuzumab PET can support treatment decisions in patients posing this clinical dilemma. Methods: 89Zr-trastuzumab PET was performed as described earlier (Gaykema et al, Clin Cancer Res 2014) in patients in whom standard work up with bone scan, FDG PET, CT and if feasible a biopsy, failed to evaluate HER2 status of their disease. 89Zr-trastuzumab PET was defined positive, when at least a dominant part of the tumor load showed substantial tracer uptake (Gebhart et al, Ann Oncol 2015), when tumor tracer uptake in single lesions (except brain) was ≥ normal liver uptake or when brain metastases had a tracer uptake > background. Circulating tumor cell (CTC) analysis prior to tracer injectionwas performed using the CellSearch System (Janssen Diagnostics LLC) and CTC HER2 status was assessed immunofluorescently. Questionnaires about treatment decisions were completed before, directly after and ≥3 months after 89Zr-trastuzumab PET. Results: Twenty patients were enrolled: 8 with two primary cancers (HER2-positive and HER2-negative BC or BC and non-BC), 7 with metastases inaccessible for biopsy, 4 with prior HER2-positive and HER2-negative metastases, 1 with primary BC with equivocal HER2 status (average 4.23 HER2 gene copies/nucleus). 89Zr-trastuzumab PET was positive in 12 patients, negative in 7 and equivocal in one patient. In 15/20 patients 89Zr-trastuzumab PET supported treatment decision. The scan altered treatment of 8 patients, increased physicians9 confidence without affecting treatment in 10, and improved physicians9 understanding of disease in 18 patients. Ten patients had 1-99 CTCs, 6 with HER2 expression. There was no correlation between HER2 expression by CTCs and 89Zr-trastuzumab PET results or subsequent treatment decision. Conclusion: 89Zr-trastuzumab PET, but not CTC analysis, supports clinical decision making in BC patients in whom standard work up fails to evaluate HER2 status. (Funded by the Dutch A Sister9s Hope). Citation Format: Schroder CP, Bensch F, Brouwers AH, Lub-de Hooge MN, de Jong JR, van der Vegt B, Sleijfer S, de Vries EG. Clinical value of 89Zr-trastuzumab PET in HER2-positive breast cancer patients with a clinical dilemma [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-03-06.