Malignancies in Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, primarily of, but not restricted to, the gut. Association between IBD and cancer has been clearly established and is uniformly accepted. SUMMARY: IBD patients are at particular risk for intestinal and extraintestinal cancers. There are 2 underlying mechanisms: (1) IBD-related inflammation triggers initiation and progression of tumor formation. This particularly results in the development of colorectal cancer, small bowel adenocarcinoma, intestinal lymphoma, anal cancer, and cholangiocarcinoma. (2) Immunosuppressive drugs exhibit carcinogenic properties such as shown for azathioprine and anti-TNF promoting lymphoproliferative malignancies and melanoma and nonmelanoma skin cancer. However, within the last years, IBD-related cancer incidence and prevalence have been decreasing, which might be attributed to better treatment options and surveillance strategies. Moreover, novel biological drugs have been introduced in clinical practice and have dramatically changed long-term IBD management. Therefore, we sought to summarize up-to-date knowledge about (1) overall cancer risk; (2) risk and protective factors for cancer development; and (3) inflammation- and immunosuppression-related malignancies in the current anti-TNF era of IBD. Key Messages: Recent studies and meta-analyses questioned the excess rates of cancer in IBD patients. However, IBD still is associated with cancer development due to ongoing intestinal inflammation and the use of potential carcinogenic drugs. Patients should be educated about the increased risk of cancer with IBD and IBD drugs. However, they should also be informed that most malignancy subtypes are possibly preventable by controlling intestinal inflammation and by using adequate screening strategies.

Cardiovascular and metabolic determinants of quality of life in patients with cancer.

AIMS: Maintaining quality of life (QoL) in patients with cancer has gathered significant interest, but little is known about its major determinants. We sought to identify determinants of QoL in patients undergoing cancer treatment as well as in treatment-naïve patients about to commence such therapy. METHODS AND RESULTS: QoL was assessed in 283 patients with cancer using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 questionnaire. All patients underwent a battery of tests including physical examination, resting electrocardiogram, hand grip strength, and biochemistry assessment. Using multivariable logistic regression, we found that age [odds ratio (OR) 0.954, 95% confidence interval (CI) 0.916-0.994], resting heart rate (OR 1.036, 95% CI 1.004-1.068), hand grip strength (OR 0.932, 95% CI 0.878-0.990), and the presence of cachexia (OR 4.334, 95% CI 1.767-10.631) and dyspnoea (OR 3.725, 95% CI 1.540-9.010; all P < 0.05) remained independently predictive of reduced QoL. CONCLUSIONS: Therefore, it may be reasonable to address circumstances that are affecting muscle mass, body weight, and heart rate to maintaining QoL; however, prospective studies to test these endpoints are required.

Predictors of lower exercise capacity in patients with cancer.

Maintaining cancer patients' exercise capacity and therefore patients' ability to live a self-determined life is of huge importance, but little is known about major determinants. We sought to identify determinants of exercise capacity in patients with a broad spectrum of cancer types, who were already receiving cancer treatment or about to commence such therapy. Exercise capacity was assessed in 253 consecutive patients mostly suffering from advanced cancer using the 6-min walk test (6-MWT). All patients underwent echocardiography, physical examination, resting electrocardiogram, hand grip strength (HGS) measurement, and laboratory assessments. Patients were divided into two groups according to the median distance in the 6-MWT (459 m). Patients with lower exercise capacity were older, had significantly lower HGS and haemoglobin and higher values of high sensitive (hs) Troponin T and NT-proBNP (all p < 0.05). Whilst the co-morbidity burden was significantly higher in this group, no differences were detected for sex, body mass index, tumor type, or cachexia (all p > 0.2). Using multivariable logistic regression, we found that the presence of anaemia (odds ratio (OR) 6.172, 95% confidence interval (CI) 1.401-27.201, p = 0.016) as well as an increase in hs Troponin T (OR 3.077, 95% CI 1.202-5.301, p = 0.019) remained independent predictors of impaired exercise capacity. Increasing HGS was associated with a reduced risk of a lower exercise capacity (OR 0.896, 95% CI 0.813-0.987, p = 0.026). Screening patients for elevated hs troponin levels as well as reduced HGS may help to identify patients at risk of lower exercise capacity during cancer treatment.

Disruption of a nuclear NFATc2 protein stabilization loop confers breast and pancreatic cancer growth suppression by zoledronic acid.

The aminobisphosphonate zoledronic acid has elicited significant attention due to its remarkable anti-tumoral activity, although its detailed mechanism of action remains unclear. Here, we demonstrate the existence of a nuclear GSK-3ß-NFATc2 stabilization pathway that promotes breast and pancreatic cancer growth in vitro and in vivo and serves as a bona fide target of zoledronic acid. Specifically, the serine/threonine kinase GSK-3ß stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2-mediated proteolysis. Zoledronic acid disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK-3ß inhibition and induction of HDM2 activity. Upon nuclear accumulation, HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues Lys-684/Lys-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis-induced constitutive serine phosphorylation (Ser-215, Ser-219, and Ser-223) of the SP2 domain prevents NFATc2 from HDM2-mediated ubiquitination and degradation and consequently rescues cancer cells from growth suppression by zoledronic acid. In conclusion, this study demonstrates a critical role of the GSK-3ß-HDM2 signaling loop in the regulation of NFATc2 protein stability and growth promotion and suggests that double targeting of this pathway is responsible, at least to a significant part, for the potent and reliable anti-tumoral effects of zoledronic acid.

Enhancer of Zeste Homolog 2 (EZH2) Is a Marker of High-Grade Neuroendocrine Neoplasia in Gastroenteropancreatic and Pulmonary Tract and Predicts Poor Prognosis.

Tumor grading is a robust prognostic predictor in patients with neuroendocrine neoplasms (NEN) and guides therapy, especially in tumors with high proliferation. NEN can be separated into well-differentiated and poorly differentiated types. The more aggressive NEN have been further separated into neuroendocrine tumors (NET G3) with a better prognosis and neuroendocrine carcinomas (NEC) with a worse prognosis. Despite this distinction's tremendous clinical and therapeutic relevance, optimal diagnostic biomarkers are still lacking. In this study, we analyzed the protein expression and prognostic impact of Enhancer of Zeste Homolog 2 (EZH2) by immunohistochemistry in 219 tissue samples of gastroenteropancreatic (GEP-NEN) and pulmonary NEN (P-NEN). EZH2 was almost exclusively expressed in NEN with a proliferation rate above 20% (G3), while all low-grade tumors were nearly negative. Among high-grade NEN, 65% showed high and 35% low expression of EZH2. In this group, the high expression of EZH2 was significantly associated with poor overall survival and NEC histology. Interestingly, EZH2 seems to act independently of Polycomb Repressive Complex 2 (PRC2) in NEN. In conclusion, we propose EZH2 as a robust biomarker for distinguishing between NET G3 and NEC among gastroenteropancreatic and pulmonary NEN.