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.

WITHDRAWN: Radioisotopes for metastatic bone pain.

BACKGROUND: This is an update of the review published in Issue 4, 2003. Bone metastasis cause severe pain as well as pathological fractures, hypercalcaemia and spinal cord compression. Treatment strategies currently available to relieve pain from bone metastases include analgesia, radiotherapy, surgery, chemotherapy, hormone therapy, radioisotopes and bisphosphonates. OBJECTIVES: To determine efficacy and safety of radioisotopes in patients with bone metastases to improve metastatic pain, decrease number of complications due to bone metastases and improve patient survival. SEARCH METHODS: We sought randomised controlled trials (RCTs) in MEDLINE, EMBASE, CENTRAL, and the PaPaS Trials Register up to October 2010. SELECTION CRITERIA: Studies selected had metastatic bone pain as a major outcome after treatment with a radioisotope, compared with placebo or another radioisotope. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias of included studies by their sequence generation, allocation concealment, blinding of study participants, researchers and outcome assessors, and incomplete outcome data. Two review authors extracted data. We performed statistical analysis as an "available case" analysis, and calculated global estimates of effect using a random-effects model. We also performed an intention-to-treat (ITT) sensitivity analysis. MAIN RESULTS: This update includes 15 studies (1146 analyzed participants): four (325 participants) already included and 11 new (821 participants). Only three studies had a low risk of bias. We observed a small benefit of radioisotopes for complete relief (risk ratio (RR) 2.10, 95% CI 1.32 to 3.35; Number needed to treat to benefit (NNT) = 5) and complete/partial relief (RR 1.72, 95% CI 1.13 to 2.63; NNT = 4) in the short and medium term (eight studies, 499 participants). There is no conclusive evidence to demonstrate that radioisotopes modify the use of analgesia with respect to placebo. Leucocytopenia and thrombocytopenia are secondary effects significantly associated with the administration of radioisotopes (RR 5.03; 95% CI 1.35 to 18.70; Number needed to treat to harm (NNH) = 13). Pain flares were not higher in the radioisotopes group (RR 0.74; 95% CI 0.27 to 2.06). There are scarce data of moderate quality when comparing Strontium-89 (89Sr) with Samarium-153 (153Sm), Rhenium-186 (186Re) and Phosphorus-32 (32P). We observed no significant differences between treatments. Similarly, we observed no differences when we compared different doses of 153Sm (0.5 versus 1.0 mCi). AUTHORS' CONCLUSIONS: This update adds new evidence on efficacy of radioisotopes versus placebo, 89Sr compared with other radioisotopes, and dose-comparisons of 153Sm and 188Re. There is some evidence indicating that radioisotopes may provide complete reduction in pain over one to six months with no increase in analgesic use, but severe adverse effects (leucocytopenia and thrombocytopenia) are frequent.

Radioisotopes for metastatic bone pain.

BACKGROUND: This is an update of the review published in Issue 4, 2003. Bone metastasis cause severe pain as well as pathological fractures, hypercalcaemia and spinal cord compression. Treatment strategies currently available to relieve pain from bone metastases include analgesia, radiotherapy, surgery, chemotherapy, hormone therapy, radioisotopes and bisphosphonates. OBJECTIVES: To determine efficacy and safety of radioisotopes in patients with bone metastases to improve metastatic pain, decrease number of complications due to bone metastases and improve patient survival. SEARCH STRATEGY: We sought randomised controlled trials (RCTs) in MEDLINE, EMBASE, CENTRAL, and the PaPaS Trials Register up to October 2010. SELECTION CRITERIA: Studies selected had metastatic bone pain as a major outcome after treatment with a radioisotope, compared with placebo or another radioisotope. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias of included studies by their sequence generation, allocation concealment, blinding of study participants, researchers and outcome assessors, and incomplete outcome data. Two review authors extracted data. We performed statistical analysis as an "available case" analysis, and calculated global estimates of effect using a random-effects model. We also performed an intention-to-treat (ITT) sensitivity analysis. MAIN RESULTS: This update includes 15 studies (1146 analyzed participants): four (325 participants) already included and 11 new (821 participants). Only three studies had a low risk of bias. We observed a small benefit of radioisotopes for complete relief (risk ratio (RR) 2.10, 95% CI 1.32 to 3.35; Number needed to treat to benefit (NNT) = 5) and complete/partial relief (RR 1.72, 95% CI 1.13 to 2.63; NNT = 4) in the short and medium term (eight studies, 499 participants). There is no conclusive evidence to demonstrate that radioisotopes modify the use of analgesia with respect to placebo. Leucocytopenia and thrombocytopenia are secondary effects significantly associated with the administration of radioisotopes (RR 5.03; 95% CI 1.35 to 18.70; Number needed to treat to harm (NNH) = 13). Pain flares were not higher in the radioisotopes group (RR 0.74; 95% CI 0.27 to 2.06). There are scarce data of moderate quality when comparing Strontium-89 ((89)Sr) with Samarium-153 ((153)Sm), Rhenium-186 ((186)Re) and Phosphorus-32 ((32)P). We observed no significant differences between treatments. Similarly, we observed no differences when we compared different doses of (153)Sm (0.5 versus 1.0 mCi). AUTHORS' CONCLUSIONS: This update adds new evidence on efficacy of radioisotopes versus placebo, (89)Sr compared with other radioisotopes, and dose-comparisons of (153)Sm and (188)Re. There is some evidence indicating that radioisotopes may provide complete reduction in pain over one to six months with no increase in analgesic use, but severe adverse effects (leucocytopenia and thrombocytopenia) are frequent.

Evidence-based review: quality of life following head and neck intensity-modulated radiotherapy.

Inverse planned Intensity modulated radiotherapy (IMRT) can minimize the dose to normal structures and therefore can reduce long-term radiotherapy-related morbidity and may improve patients' long-term quality of life. Despite overwhelming evidence that IMRT can reduce late functional deficits in patients with head and neck cancer, treated with radiotherapy, a review of the published literature produced conflicting results with regard to quality of life outcomes. Following a critical appraisal of the literature, reasons for the discrepant outcomes are proposed.

The role of radiotherapy in multimodal treatment of pancreatic carcinoma.

Pancreatic ductal carcinoma is one of the most lethal malignancies, but in recent years a number of positive developments have occurred in the management of pancreatic carcinoma. This article aims to give an overview of the current knowledge regarding the role of radiotherapy in the treatment of pancreatic ductal adenocarcinoma (PDAC). The results of meta-analyses, phase III-studies, and phase II-studies using chemoradiotherapy and chemotherapy for resectable and non-resectable PDAC were reviewed. The use of radiotherapy is discussed in the neoadjuvant and adjuvant settings as well as in the locally advanced situation. Whenever possible, radiotherapy should be performed as simultaneous chemoradiotherapy. Patients with PDAC should be offered entry into clinical trials to identify optimal treatment results.

Mosaicism for mitochondrial DNA polymorphic variants in placenta has implications for the feasibility of prenatal diagnosis in mtDNA diseases.

Women who have had a child with mitochondrial DNA (mtDNA) disease need to know the risk of recurrence, but this risk is difficult to estimate because mutant and wild-type (normal) mtDNA coexist in the same person (heteroplasmy). The possibility that a single sample may not reflect the whole organism both impedes prenatal diagnosis of most mtDNA diseases, and suggests radical alternative strategies such as nuclear transfer. We used naturally occurring mtDNA variants to investigate mtDNA segregation in placenta. Using large samples of control placenta, we demonstrated that the level of polymorphic heteroplasmic mtDNA variants is very similar in mother, cord blood and placenta. However, where placental samples were very small (< 10 mg) there was clear evidence of variation in the distribution of mtDNA polymorphic variants. We present the first evidence for variation in mutant load, that is, mosaicism for mtDNA polymorphic variants in placenta. This suggests that mtDNA mutants may segregate in placenta and that a single chorionic villous sample (CVS) may be unrepresentative of the whole placenta. Duplicates may be necessary where CVS are small. However, the close correlation of mutant load in maternal, fetal blood and placental mtDNA suggests that the average load in placenta does reflect the load of mutant mtDNA in the baby. Provided that segregation of neutral and pathogenic mtDNA mutants is similar in utero, our results are generally encouraging for developing prenatal diagnosis for mtDNA diseases. Identifying mtDNA segregation in human placenta suggests studies of relevance to placental evolution and to developmental biology.