TNF-related apoptosis-inducing ligand cooperates with NSAIDs via activated Wnt signalling in (pre)malignant colon cells.

TNF-related apoptosis-inducing ligand (TRAIL) receptor agonistic agents and non-steroidal anti-inflammatory drugs (NSAIDs) are interesting agents for the chemoprevention and treatment of colorectal cancer. We investigated whether NSAIDs sensitize colon cancer and adenoma cell lines and ex vivo cultured human adenomas to recombinant human (rh)TRAIL. Involvement of the crucial Wnt signalling pathway in the sensitization of colon cancer cells was examined. Five colon cancer and two adenoma cell lines, human ex vivo adenomas and normal colonic epithelium were treated with aspirin or sulindac combined with rhTRAIL. Apoptosis levels, expression of intracellular proteins and TRAIL receptor membrane expression were assessed. Ls174T cells stably transfected with an inducible dominant negative TCF-4 (dnTCF-4) construct served to analyse the role of Wnt pathway activation. Both rhTRAIL-sensitive and -resistant colon cancer cell lines were strongly sensitized to rhTRAIL by aspirin (maximum enhancement ratio, 7.1). Remarkably, in adenoma cell lines sulindac enhanced rhTRAIL-induced apoptosis most effectively (maximum enhancement ratio, 2.5). Although membrane TRAIL receptor expression was not affected by NSAIDs, caspase-8 activation was enhanced by combinational treatment. Several proteins from different biological pathways were affected by NSAIDs, indicating complex mechanisms of sensitization. Elimination of TCF-4 completely blocked the sensitizing effect in colon cancer cells. In ex vivo adenomas the combination of sulindac and rhTRAIL increased apoptosis from 18.4% (sulindac) and 17.8% (rhTRAIL) to 28.0% (p = 0.003 and p = 0.005, respectively). It was concluded that NSAID-induced sensitization to rhTRAIL requires TCF-4 activity. Thus, the combination of TRAIL-receptor agonistic agents and NSAIDs is a potentially attractive treatment option for (pre)malignant tumours with constitutively active Wnt signalling, such as colorectal tumours.

Unexpected neurologic complications following a novel lymphoma treatment 'expected' to give rise to neurologic toxicity.

Chimeric antigen receptor (CAR) T-cell therapy is a novel and promising form of cellular immunotherapy using genetically engineered, tumour-specific autologous T cells. CD19-specific CAR T-cells have been shown to be very effective as a treatment for relapsed/refractory B-cell acute lymphoblastic leukaemia and aggressive B-cell non-Hodgkin's lymphoma. ICANS (immune effector cell-associated neurotoxicity syndrome) is one of the most frequently occurring toxicities of CAR T-cell treatment. We describe two cases of patients with neurologic symptoms following CAR T-cell infusion who were suspected to have ICANS, but in fact had cerebral toxoplasmosis and venous sinus thrombosis respectively. The focus on CRS and ICANS after CAR T-cell infusion may lead to less vigilance to the 'normal' threats faced by intensively pretreated patients with lymphoma such as infections and thrombosis. Both cases underscore the importance of a broad and thorough examination of patients if they experience neurologic symptoms after CAR T-cell treatment.

Total abdominal 18F-FDG uptake reflects intestinal adenoma burden in Apc mutant mice.

UNLABELLED: Apc mutant (Apc(Min)) mice develop multiple adenomas in their intestines and are widely used to study colorectal carcinogenesis and chemopreventive approaches. Molecular imaging of intestinal adenomas could potentially provide noninvasive longitudinal evaluation of these lesions in living mice. Therefore, the aim of this study was to investigate the role of (18)F-FDG PET in the Apc(Min) mouse model. METHODS: Apc(Min) mice (n = 8) fed a purified diet were imaged serially after injection of (18)F-FDG at age 9 and 12 wk using a small-animal PET scanner. Abdominal uptake of the tracer was quantified. After dissection, intestines were imaged separately, and intestinal tracer uptake was quantified. Tracer distribution was compared with results from microscopic examination regarding adenoma number and size. Thereafter, findings were validated serially in 20 Apc(Min) mice aged 6, 8, 10, and 12 wk that received standard chow to increase adenoma numbers. In vivo abdominal (18)F-FDG uptake was correlated with microscopy results. RESULTS: Microscopic examination showed that the mice developed 25-35 intestinal adenomas at age 12 wk. Ex vivo (18)F-FDG PET of the dissected intestines visualized all large adenomas and most small adenomas. Ex vivo total intestinal (18)F-FDG uptake correlated with in vivo total abdominal uptake and with the number of large adenomas at age 9 and 12 wk. At 12 wk, there was a clear correlation between in vivo abdominal tracer uptake and the number of large adenomas but not the total number of lesions. CONCLUSION: Intestinal adenomas in Apc(Min) mice are metabolically active lesions that take up (18)F-FDG. Abdominal (18)F-FDG uptake at age 12 wk serves as a readout modality for large intestinal adenomas.

Perspectives for tailored chemoprevention and treatment of colorectal cancer in Lynch syndrome.

Lynch syndrome (LS) is caused by a germline mutation in one of the mismatch repair (MMR) genes. The resulting loss of MMR gene function induces a strong mutator phenotype and predisposition to colorectal cancer (CRC). LS mutation carriers undergo regular colonoscopic surveillance and have extensive colonic resection in case of cancer because of the chance of metachronous tumors. Given the high risk and early onset of CRC, LS mutation carriers are good candidates for chemoprevention. Furthermore, evidence increases indicating that the response of MMR-deficient tumors to standard chemotherapy and radiotherapy differs from that of MMR-proficient tumors. Efforts should thus be directed at designing tailored strategies concerning both chemoprevention and medical cancer treatment for LS individuals. This review provides guidance for future studies in this field based on results from clinical and preclinical research.