On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) kill tumor cells while causing virtually no damage to normal cells. Several novel drugs targeting TRAIL receptors are currently in clinical trials. However, TRAIL resistance is a common obstacle in TRAIL-based therapy and limits the efficiency of these drugs. In this review article we discuss different mechanisms of TRAIL resistance, and how they can be predicted and therapeutically circumvented. In addition, we provide a brief overview of all TRAIL-based clinical trials conducted so far. It is apparent that although the effects of TRAIL therapy are disappointingly modest overall, a small subset of patients responds very well to TRAIL. We argue that the true potential of targeting TRAIL DRs in cancer can only be reached when we find efficient ways to select for those patients that are most likely to benefit from the treatment. To achieve this, it is crucial to identify biomarkers that can help us predict TRAIL sensitivity.

Characterizing the phenomenon of radiation recall dermatitis.

Radiation recall represents the 'recalling' of an effect similar in appearance to that of an acute radiation reaction in a previously irradiated field. The recall is triggered by the administration of certain drugs days to years after the exposure to ionizing radiation. This review focuses almost exclusively on the skin manifestations of radiation recall to assemble the largest data base upon which to discuss this rare phenomenon. No absolute radiation dose threshold is apparent, but rather an interplay between dose and time before drug exposure seems to affect both the risk and speed of onset of recall. Recall usually occurs on first exposure to a particular recall-triggering drug. The skin reaction develops within minutes to days. The time to develop the reaction may be slightly longer for oral than intravenously administered drugs reflecting their bioavailability. Most drugs associated with recall are cytotoxics, but several other drugs may elicit the phenomenon. Individuals exposed to a number of potentially recall-triggering drugs reveal the marked drug specificity characteristic of the phenomenon. Skin reactions usually settle within a few days of stopping the triggering drug. The role of steroids or anti-histamines in affecting resolution is unclear. Drug rechallenge tends to produce either only a mild recurrence or no recurrence of recall. Steroids or dose reduction may favour uneventful rechallenge. A number of aetiological hypotheses on radiation recall exist. Using the available evidence these hypotheses are critically reviewed and a novel hypothesis based on radiation affecting local cutaneous immunological responses proposed.

An aggressive intrasinusoidal lymphoma presenting with marked systemic disturbance but normal imaging studies.

A patient with an aggressive intrasinusoidal non-Hodgkins lymphoma, presenting with marked systemic disturbance but only a mildly raised alkaline phosphatase as a localising sign is described. All imaging studies of the liver were normal and the diagnosis was delayed until a percutaneous liver biopsy was performed. Once diagnosed, the patient responded extremely well to conventional anti-lymphoma chemotherapy.