Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial.

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.

Technology insight: water diffusion MRI--a potential new biomarker of response to cancer therapy.

Diffusion-weighted MRI (DW-MRI) is a functional imaging technique that displays information about the extent and direction of random water motion in tissues. Water movement in tissues is modified by interactions with hydrophobic cellular membranes, intracellular organelles and macromolecules. DW-MRI provides information on extracellular-space tortuosity, tissue cellularity and the integrity of cellular membranes. Images can be sensitive to large or small displacements of water, therefore, macroscopic water flows and microscopic water displacements in the extracellular space can be depicted. Preclinical and clinical data indicate a number of potential roles of DW-MRI in the characterization of malignancy, including determination of lesion aggressiveness and monitoring response to therapy. This Review outlines the biological basis of observations made on DW-MRI and describes how measurements are acquired and quantified, and discusses the interpretation of images and limitations of the technique. The strength of evidence for adoption of DW-MRI as a biomarker for the assessment of tumor response is presented.

Glucarpidase following high-dose methotrexate: update on development.

Glucarpidase (Carboxypeptidase G2 or Voraxaze) is a recombinant enzyme that belongs to the class of carboxypeptidases which are naturally occurring enzymes. Glucarpidase is able to cleave methotrexate (MTX) into non-cytotoxic metabolites that may help prevent or minimise subsequent toxicities such as renal failure. In this review, the authors outline the discovery of the carboxypeptidase class of enzymes and the pre-clinical data demonstrating that glucarpidase is highly effective in the rapid reduction of MTX levels. The authors summarise the compassionate use studies of glucarpidase for patients with nephrotoxicity following high dose MTX or with very high post-MTX levels and the current developmental status of the drug. In conclusion, glucarpidase has been shown to be very useful in emergency situations following administration of high-dose MTX. Glucarpidase has yet to receive marketing approval in the EU or USA, and we await further data from In conclusion, glucarpidase Phase I/II studies assessing routine prophylactic administration following high-dose methotrexate.

Controversies in the management of germ cell tumours of the ovary.

PURPOSE OF REVIEW: Ovarian germ cell tumours are rare, but curable at all stages of disease. This review gives an outline of the main controversies regarding the management of this disease. RECENT FINDINGS: Pelvic malignancies are very rare during pregnancy, which should avoid the need for radical surgery or termination in these patients. Also during pregnancy, AFP-L2 looks to be a promising tumour marker in detecting relapse. Malignant transformation of mature teratomas may be predicted by preoperative squamous cell antigen and tumour size. OCT4 immunohistochemistry has been shown to be a very useful adjunct in the diagnosis of dysgerminomas. The traditional method for grading immature teratomas is challenged by a new classification. Patients receiving cisplatin-based chemotherapy are at a higher risk of developing cardiovascular risk factors. There is a hint that high-dose chemotherapy may play a role in relapsed patients. SUMMARY: Rarity of the disease means many controversies are difficult to resolve, with much reliance on using data from testicular cancer studies. Many clinicians still advocate adjuvant chemotherapy for stage I nondysgerminomatous tumours of grade 2 and above despite good evidence that surveillance is a safe option, and increasing concerns about life-threatening long-term effects of treatment.