The influence of hypoxia on the relative sensitivity of human tumor cells to 62.5 MeV (p-->Be) fast neutrons and 4 MeV photons

Fast neutrons have been used in the clinical radiation therapy of tumors largely because of experimental evidence that their cytotoxic effects are much less dependent on oxygen levels than those of low-LET photons. The potential therapeutic advantage of fast neutrons based on hypoxia alone can be calculated as the "hypoxic gain factor", which is the ratio of the OERs for the fast-neutron compared to the photon beams. The hypoxic gain factor that is generally anticipated based on studies with established mammalian cell lines is about 1.6. However, surprisingly few studies have examined the influence of hypoxia on the fast-neutron radiosensitivity of human tumor cells of different histological types. For this reason, we have determined the OERs of five human tumor cell lines exposed to 62.5 MeV (p-->Be) cyclotron-generated fast neutrons or 4 MeV photons from a clinical linear accelerator. The OERs for four chemotherapy-naive cell lines, HT29/5, Hep2, HeLa and RT112, were invariably greater for photons than for neutrons, but all of these values were lower than expected on the basis of the previous literature. Despite their low OERs, these cell lines showed hypoxic gain factors that were within the range of 1.31-1.63, indicating that such effects cannot entirely explain the disappointing clinical results obtained with fast neutrons. In contrast, comparison of the surviving fractions at clinically relevant doses (1.6 Gy of neutrons and 2.0 Gy of photons) for these four tumor cell lines suggested that little benefit should result from neutron treatment. Only the cisplatin-resistant OAW42-CP line showed a significant hypoxic gain factor by this method of analysis. We conclude that, at the dose fractions used in clinical radiation therapy, there may not be a radiobiological precedent for higher local control rates after fast-neutron irradiation of hypoxic tumor cells.     

Are statins anti-inflammatory?

Large scale clinical trials demonstrate significant reductions in cardiovascular event rates with statin therapy. The observed benefit of statin therapy, however, may be larger in these trials than that expected on the basis of lipid lowering alone. Emerging evidence from both clinical trials and basic science studies suggest that statins have anti-inflammatory properties, which may additionally lead to clinical efficacy. Measurement of markers of inflammation such as high sensitivity C-reactive protein in addition to lipid parameters may help identify those patients who will benefit most from statin therapy.     

Characteristics of malignant melanoma cells in the treatment with fast neutrons

The radioresistance of malignant melanoma cells has been explained by the wide shoulder of the dose-cell-survival curve of the cells exposed to photon beams. Fast neutrons, 30 MeV d-Be, were used to treat patients who had malignant melanoma in order to confirm the biological effects of high linear energy transfer (LET) radiation for tumor control. Seventy-two patients suffering from malignant melanoma participated in the clinical trials with fast neutrons between November 1975 and December 1986. Of 72 patients, 45 had melanoma of the skin, 20 had melanoma of the head and neck, and seven had choroidal melanoma. Five-year survival rate of the patients who had previously untreated melanoma of the skin was 61% and for patients who received postoperative irradiation, it was 35.7% whereas no patients who had recurrent tumor survived over 4 years. Of 22 patients who had melanoma of the skin, stage I, local control in four cases was achieved by irradiation alone, whereas local control was achieved in 17 of 18 patients who required salvage surgery after fast-neutron therapy. The results of pathological studies performed with specimens obtained from salvage surgery have shown that melanoma cells growing in intradermal tissue are radio-resistant, compared with cells growing in intraepidermal tissue. This might suggest that melanoma cells acquire radioresistance when the connective tissue is involved. Five-year survival rate of the patients who had locally advanced melanoma of the head and neck, previously untreated, was 15.4%. Radiation therapy with accelerated protons was suitable for patients suffering from choroidal melanoma.     

Biological dosimetry for epithermal neutron beams

The radiobiological effectiveness of an epithermal neutron beam is described using cell survival as the end point. The M67 epithermal neutron beam at the Nuclear Reactor Laboratory, Massachusetts Institute of Technology, that was used for clinical trials of boron neutron capture therapy was used to irradiate Chinese hamster ovary cells at seven depths in a water-filled phantom that simulated healthy tissue. No boron was added to the samples. Therefore, this experiment evaluates the biological effectiveness of the neutron and photon components, which comprise 80-95% of the dose to healthy tissue. Cell survival was dependent upon the depth in the phantom, as a result of moderation and attenuation of the epithermal neutron beam components by the overlying water. The results were compared with 250 kVp X irradiations to determine relative biological effectiveness values. Cell survival as a function of the dose delivered was lowest at the most shallow depth of 0.5 cm, and increased at depths of 1.5, 3, 4, 5.6, 6.6 and 8.1 cm. The gradual increase in cell survival with increasing depth in the phantom is due to the exponential drop of the fast-neutron intensity of the beam. These results are applicable to clinical boron neutron capture therapy Phase I/II trials in which healthy tissue toxicity was an end point.     

A mathematical model of brain tumour response to radiotherapy and chemotherapy considering radiobiological aspects

Glioblastoma is the most frequent and malignant brain tumour. For many years, the conventional treatment has been maximal surgical resection followed by radiotherapy (RT), with a median survival time of less than 10 months. Previously, the use of adjuvant chemotherapy (given after RT) has failed to demonstrate a statistically significant survival advantage. Recently, a randomized phase III trial has confirmed the benefit of temozolomide (TMZ) and has defined a new standard of care for the treatment of patients with high-grade brain tumours. The results showed an increase of 2.5 months in median survival, and 16.1% in 2 year survival, for patients receiving RT with TMZ compared with RT alone. It is not clear whether the major benefit of TMZ comes from either concomitant administration of TMZ with RT, or from six cycles of adjuvant TMZ, or both.The objectives were to develop our original model, which addressed survival after RT, to construct a new module to assess the potential role of TMZ from clinical data, and to explore its synergistic contribution in addition to radiation. The model has been extended to include radiobiological parameters. The addition of the linear quadratic equation to describe cellular response to treatment has enabled us to quantify the effects of radiation and TMZ in radiobiological terms.The results indicate that the model achieves an excellent fit to the clinical data, with the assumption that TMZ given concomitantly with RT synergistically increases radiosensitivity. The alternative, that the effect of TMZ is due only to direct cell killing, does not fit the clinical data so well. The addition of concomitant TMZ appears to change the radiobiological parameters. This aspect of our results suggests possible treatment developments.Our observations need further evaluations in real clinical trials, may suggest treatment strategies for new trials, and inform their design.     

Endpoints,patient selection,and biomarkers in the design of clinical trials for cancer vaccines

Therapeutic cancer vaccines are an emerging and potentially effective treatment modality. Cancer vaccines are usually very well tolerated, with minimal toxicity compared with chemotherapy. Unlike conventional cytotoxic therapies, immunotherapy does not result in immediate tumor shrinkage but may alter growth rate and thus prolong survival. Multiple randomized controlled trials of various immunotherapeutic agents have shown a delayed separation in Kaplan–Meier survival curves, with no evidence of clinical benefit within the first 6–12 months of vaccine treatment. Overall survival benefit is seen in patients with lower disease burden who are not expected to die within those initial 6–12 months. The concept of improved overall survival without marked initial tumor reduction represents a significant shift from the current paradigms established by standard cytotoxic therapies. Future clinical studies of therapeutic vaccines should enroll patients with either lower tumor burden, more indolent disease or both, and must seek to identify early markers of clinical benefit that may correlate with survival. Until then, improved overall survival is the only clear, discriminatory endpoint for therapeutic vaccines as monotherapies.     

Fibric acid derivatives in cardiovascular disease prevention: results from the large clinical trials

PURPOSE OF REVIEW: Results from five large placebo-controlled trials with second-generation fibrates have shown varying success in reducing cardiovascular events. This review focuses on a number of extended analyses from these trials that may relate to the success or failure of fibrate therapy and indicate who might likely benefit from this therapy. RECENT FINDINGS: Results have been far from uniform and several trials have been adversely impacted by high off-trial statin use. Collective evidence suggests, however, that fibrates have optimum cardiovascular benefit in diabetes or other manifestations of insulin resistance. Much of this evidence comes from posttrial analysis in subgroups with more sharply defined clinical characteristics than in the overall trial population. Analyses also suggest that different fibrates have a different range of favorable clinical properties, that the cardiovascular benefit of fibrates may not be readily measured or mostly predicted by changes in traditional lipid measurements, and that other nonlipid properties of fibrates as peroxisome proliferator-activated receptor agents might explain some of the benefit of these drugs. SUMMARY: Results of major clinical endpoint trials with fibrates, although not uniformly positive, provide substantial evidence for a selective therapeutic role of these drugs in cardiovascular event reduction in diabetes or insulin resistance.     

Cardiovascular disease with diabetes or the metabolic syndrome: should statins or fibrates be first line lipid therapy?

PURPOSE OF REVIEW: Subgroups with diabetes or with features of the metabolic syndrome have been increasingly highlighted in large clinical endpoint trials with lipid therapy. This review will focus on the results of trials with statins or fibrates and examine the strength of the evidence for major cardiovascular event reduction with each kind of therapy in these high-risk subgroups that typically have low-to-moderate levels of LDL cholesterol. RECENT FINDINGS: Of six statin trials in populations with moderately increased LDL cholesterol only one, the Heart Protection Study, has shown that statin therapy will significantly reduce the major coronary heart disease events of non-fatal myocardial infarction or coronary heart disease death in diabetes. None of these trials has shown that statins have a particular predilection for reducing cardiovascular events in individuals with higher levels of body weight or other features of the metabolic syndrome. There are far fewer trial data with fibrates than with statins. However, the Veterans Affairs High Density Lipoprotein Intervention Trial has shown that a fibrate can significantly reduce major cardiovascular events, most particularly coronary heart disease death, in those with diabetes as well as those without diabetes who have insulin resistance. Indeed, all fibrate trials show that this therapy appears to selectively benefit the individual with obesity and features of the metabolic syndrome. SUMMARY: Based principally on evidence from the Veterans Affairs High Density Lipoprotein Intervention Trial and the cumulative experience with statins, trial data would thus far suggest that the patient with a modest increase in LDL cholesterol who has diabetes or features of the metabolic syndrome might be likely to achieve more substantial cardiovascular benefit from fibrate than from statin therapy.     

Does Combination T4 And T3 Therapy Make Sense?

ObjectiveTo evaluate the existing evidence regarding the combined use of levothyroxine and liothyronine to treat hypothyroidism.MethodsEleven published randomized controlled trials evaluating the efficacy and safety of combined levo- thyroxine and liothyronine therapy for hypothyroidism were reviewed and summarized. Related basic and clinical research findings were also incorporated for perspective.ResultsAn initial randomized controlled trial reported symptomatic improvement in hypothyroid patients taking combined levothyroxine and liothyronine therapy compared with those taking levothyroxine therapy alone. Subsequently, multiple relatively small randomized controlled trials failed to demonstrate any subjective or objective benefit from combined levothyroxine and liothy- ronine therapy. A polymorphism (Thr92Ala) in the gene encoding the deiodinase 2 (D2) enzyme that converts thy- roxine to triiodothyronine in the brain was later identified in about 16% of hypothyroid persons. This polymorphism may impair brain deiodinase activity in the presence of low brain thyroxine levels. One randomized controlled trial found that patients with the D2 Thr92Ala polymorphism had more baseline symptoms than those with the wild type D2 and experienced significantly greater symptomatic improvement in response to combined levothyroxine and liothyronine therapy.ConclusionsMost hypothyroid patients experience rapid symptomatic relief after institution of levothyroxine replacement therapy, but persistent symptoms remain in some despite what appears to be adequate levothyroxine therapy with normalization of the serum thyrotropin level. A thorough investigation is warranted in these patients to detect and treat other responsible lifestyle issues, medical conditions, and endocrine conditions. A subset of hypo- thyroid patients has a polymorphism in the gene encoding the D2 enzyme that may prevent full resolution of symp- toms with levothyroxine therapy alone; these patients may benefit from combination levothyroxine and liothyronine therapy. (Endocr Pract. 2012;18:750-757)     

Estrogens, lipoproteins, and cardiovascular risk factors: an update following the randomized placebo-controlled trials of hormone-replacement therapy

PURPOSE OF REVIEW: The effects of hormone-replacement therapy on cardiovascular risk factors are examined. In an attempt to explain the results of recent randomized controlled trials in which no benefit of hormone-replacement therapy for postmenopausal women has been observed, RECENT FINDINGS: Changes in lipoproteins in response to hormone-replacement therapy have now been analysed for both primary and secondary prevention studies. In none of the large randomized controlled trials was there any effect of hormone-induced changes in low-density lipoprotein, high-density lipoprotein, or triglyceride on clinical outcome. Further detailed studies of lipoprotein metabolism have not revealed any adverse effect of hormone-replacement therapy. Recent analysis of the Heart Estrogen/Progestin-Replacement Study data suggests hormone-replacement therapy reduces the risk of developing diabetes. The effect of hormone-replacement therapy on inflammatory markers and on flow-mediated dilatation is largely beneficial, although the effect on flow-mediated dilatation is modulated according to endothelial function, which is adversely affected by known risk factors, including age and presence of atherosclerosis. In this respect the work on polymorphisms of estrogen receptor-alpha may in due course help to define those women who would benefit most from use of estrogen. Crucially, oral but not transdermal hormone-replacement therapy increases activated protein C resistance independently of the presence of factor V Leiden. This effect increases the risk of venous thromboembolic events, which is reflected in the results of a hospital case control study of thromboembolism. SUMMARY: Despite the outcome of the hormone-replacement therapy trials, recent work has confirmed the putative antiatherogenic effects of hormone-replacement therapy on lipoprotein metabolism. Metabolic differences of route of administration of estrogen, particularly on haemostatic variables, may explain this clinical paradox, which continues to be an important research area.     

The appropriate use of carotid endarterectomy

FOR THE FIRST 30 YEARS AFTER CAROTID ENDARTERECTOMY WAS FIRST DEVELOPED, anecdotal evidence was used to identify patients with internal carotid artery disease for whom this procedure would be appropriate. More recently, the appropriateness of carotid endarterectomy for symptomatic patients and asymptomatic subjects has emerged from 7 randomized trials. Risk of stroke and benefit from the procedure are greatest for symptomatic patients with at least 70% stenosis of the internal carotid artery. Within this group, carotid endarterectomy is most beneficial for the following patients: otherwise healthy elderly patients, those with hemispheric transient ischemic attack, those with tandem extracranial and intracranial lesions and those without evidence of collateral vessels. Risk of perioperative stroke and death is higher in the following groups, although they still benefit: patients with widespread leukoaraiosis, those with occlusion of the contralateral internal carotid artery and those with intraluminal thrombus. Patients with 50% to 69% stenosis experience lesser benefit, and some other groups may even be harmed by carotid endarterectomy, including women and patients with transient monocular blindness only. The procedure is indicated for patients presenting with lacunar stroke and for those with a nearly occluded internal carotid artery, but the benefit is muted. Patients with less than 50% stenosis do not benefit. In the largest randomized trial of asymptomatic subjects, the perioperative risk of stroke and death was very low (1.5%), but the results indicated that a prohibitively high number of subjects (83) must be treated to prevent one stroke in 2 years. The subsequent literature reported higher perioperative risks (2.8% to 5.6%). In asymptomatic individuals nearly half of the strokes that occur may be due to heart and small-vessel disease. These limitations counter any potential benefit. Another trial is in progress and may identify subgroups of asymptomatic subjects who would benefit. Meanwhile, most individuals without symptoms fare better with medical care.The prevention of ischemic stroke by surgical means goes back half a century. After initial endorsement of carotid endarterectomy, confusion arose as to the appropriate selection of patients and the allowable risk from the procedure. In the past 2 decades large randomized trials have been used to evaluate the benefit of the procedure for patients with symptomatic and asymptomatic disease of the internal carotid artery. Sufficient time has now passed since the publication of these trials to analyze their impact on practice and to make recommendations about the application of carotid endarterectomy. There is strong evidence of benefit in some symptomatic patients, whereas other patients will not benefit and may even face harm. There is weak statistical and weaker clinical evidence that asymptomatic subjects will survive longer without experiencing stroke if they undergo endarterectomy than if they do not. The evidence supporting carotid angioplasty and stenting remains anecdotal and conflicting.The purpose of the present report is to provide a clinical roadmap to which symptomatic patients and asymptomatic subjects with carotid stenosis are candidates for endarterectomy. The risks and complications of endarterectomy are also reported. The outlook and benefit for symptomatic patients and asymptomatic subjects are so different that the evidence supporting appropriate use of endarterectomy in these 2 groups will be presented separately.     

New paradigms for advanced prostate cancer

In men with metastatic hormone-refractory prostate cancer, androgen blockade produces dramatic and rapid declines in prostate-specific antigen (PSA), bone pain, and urinary tract obstruction. Nevertheless, there have been limited options with at best palliative results for patients who progress despite a castrate testosterone level. This paradigm changed in 2004 with the publication of 2 randomized clinical trials that demonstrated a 20% to 24% survival benefit for docetaxel-based therapy when compared to mitoxantrone and prednisone, data that supported US Food and Drug Administration approval of docetaxel-based therapy for the treatment of metastatic hormone-refractory prostate cancer. This article reviews the preliminary data and the timing and sequencing implications of ongoing clinical trials. Studies are evaluating the combination of docetaxel with agents that target bone, tumor vasculature, and the vitamin D receptor as well as second-line agents, such as satraplatin. The role of immune therapy is also evolving, and further studies will define the optimal timing of chemotherapy with immune therapy.     

Paradigm shifts in cancer vaccine therapy

Cancer vaccines constitute a unique therapeutic modality in that they initiate a dynamic process involving the host's immune response. Consequently, (a) repeated doses (vaccinations) over months may be required before patient clinical benefit is observed and (b) there most likely will be a "dynamic balance" between the induction and maintenance of host immune response elements to the vaccinations vs. host/tumor factors that have the potential to diminish those responses. Thus "patient response" in the form of disease stabilization and prolonged survival may be more appropriate to monitor than strictly adhering to "tumor response" in the form of Response Criteria In Solid Tumors (RECIST) criteria. This can be manifested in the form of enhanced patient benefit to subsequent therapies following vaccine therapy. This article will review these phenomena unique to cancer vaccines with emphasis on prostate cancer vaccines as a prototype for vaccine therapy. The unique features of this modality require the consideration of paradigm shifts both in the way cancer vaccine clinical trials are designed and in the way patient benefit is evaluated.     

Analysis of pre-treatment markers predictive of treatment benefit for the therapeutic cancer vaccine MVA-5T4 (TroVax)

Cancer vaccines such as MVA-5T4 (TroVax^?) must induce an efficacious immune response to deliver therapeutic benefit. The identification of biomarkers that impact on the clinical and/or immunological efficacy of cancer vaccines is required in order to select patients who are most likely to benefit from this treatment modality. Here, we sought to identify a predictor of treatment benefit for renal cancer patients treated with MVA-5T4. Statistical modeling was undertaken using data from a phase III trial in which patients requiring first-line treatment for metastatic renal cell carcinoma were randomized 1:1 to receive MVA-5T4 or placebo alongside sunitinib, IL-2 or IFN-??. Numerous pre-treatment factors associated with inflammatory anemia (e.g., CRP, hemoglobin, hematocrit, IL-6, ferritin, platelets) demonstrated a significant relationship with tumor burden and patient survival. From these prognostic factors, the pre-treatment mean corpuscular hemoglobin concentration (MCHC) was found to be the best predictor of treatment benefit (P?<?0.01) for MVA-5T4 treated patients and also correlated positively with tumor shrinkage (P?<?0.001). Furthermore, MCHC levels showed a significant positive association with 5T4 antibody response (P?=?0.01). The latter result was confirmed using an independent data set comprising phase II trials of MVA-5T4 in patients with colorectal, renal and prostate cancers. Retrospective analyses demonstrated that RCC patients who had very large tumor burdens and low MCHC levels received little or no benefit from treatment with MVA-5T4; however, patients with smaller tumor burdens and normal MCHC levels received substantial benefit from treatment with MVA-5T4.     

Antibiotic treatment of atherosclerosis

PURPOSE OF REVIEW: Several lines of evidence have demonstrated an association between a variety of chronic bacterial infections and atherosclerotic cardiovascular disease. This has led to the proposal that antibiotic therapy might be helpful in the secondary prevention of atherosclerosis. A variety of smaller pilot studies have been reported testing this hypothesis and several large multicenter trials are also underway. The purpose of this review is to summarize the results of these studies and comment on their implications for the treatment of atherosclerosis. RECENT FINDINGS: Most of the antibiotic studies to date have been secondary prevention studies that have targeted patients exposed to Chlamydia pneumoniae. Most have used either azithromycin or roxithromycin with treatment courses ranging from a few days to 3 months. Several small studies of coronary artery disease patients have shown significant promise for reducing cardiovascular events such as death, myocardial infarction, or admission for unstable angina. However, other studies have not been so positive. Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders, WIZARD, the largest study to date, in which stable post-myocardial infarction patients were randomized to receive a 3-month course of azithromycin or placebo, demonstrated a significant reduction in death and myocardial infarction by 6 months, but this benefit was not sustained throughout the remaining course of follow-up. The Azithromycin and Coronary Events (ACES) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trials are ongoing and are testing the effect of more prolonged treatment duration. SUMMARY: A variety of antibiotic trials for the secondary prevention of atherosclerosis have been performed. Several pilot studies have shown significant positive clinical effects, but, thus far, no large randomized trial has confirmed those findings. Some concerns over the antibiotics chosen and the duration of treatment have been raised. Other trials are underway to address some of those concerns. In the meantime, no recommendation for the use of antibiotic therapy for the secondary prevention of atherosclerosis can yet be made.     

Statin therapy in heart failure

PURPOSE OF REVIEW: The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors, or statins, have been shown to reduce cardiovascular morbidity and mortality among a wide spectrum of patients with established atherosclerotic vascular disease. Mounting experimental and clinical evidence also suggest a potential benefit as well as theoretical harm of statin therapy in patients with heart failure. RECENT FINDINGS: This article briefly summarizes the therapeutic properties of statins that may be of benefit to patients with heart failure and the theoretical adverse effects of cholesterol reduction in this group of patients. A number of nonrandomized clinical studies over the past several years have shown an association between statin use and reduced overall mortality. Several large-scale randomized studies designed to confirm these findings are currently under way. SUMMARY: Statin therapy appears to improve clinical outcomes in patients with both ischemic and nonischemic cardiomyopathy independently of their cholesterol-lowering properties. The theoretical adverse properties of statins in heart failure patients have not been substantiated in small to medium-sized clinical trials. Although the encouraging results of these preliminary studies suggest a role for statin therapy in heart failure, larger studies are needed to validate these findings. Several ongoing randomized trials are currently under way to evaluate the effect of statin therapy on cardiovascular outcomes in heart failure patients. The results of these studies, expected in the next several years, should provide scientific evidence for the role of statins in the treatment of failure.     

Tumor-biological factors uPA and PAI-1 as stratification criteria of a multicenter adjuvant chemotherapy trial in node-negative breast cancer

In axillary node-negative primary breast cancer, 70% of the patients will be cured by locoregional treatment alone. Therefore, adjuvant systemic therapy is only needed for those 30% of node-negative patients who will relapse after primary therapy and eventually die of metastases. Traditional histomorphological and clinical factors do not provide sufficient information to allow accurate risk group assessment in order to identify node-negative patients who might benefit from adjuvant systemic therapy. In the last decade various groups have reported a strong and statistically independent prognostic impact of the serine protease uPA (urokinase-type plasminogen activator) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1) in node-negative breast cancer patients. Based on these data, a prospective multicenter therapy trial in node-negative breast cancer patients was started in Germany in June 1993, supported by the German Research Association (DFG). Axillary node-negative breast cancer patients with high levels of either or both proteolytic factors in the tumor tissue were randomized to adjuvant CMF chemotherapy versus observation only. Recruitment was continued until the end of 1998, by which time 684 patients had been enrolled. Since then, patients have been followed up in order to assess the value of uPA and PAI-1 determination as an adequate selection criterion for adjuvant chemotherapy in node-negative breast cancer patients. This paper reports on the rationale and design of this prospective multicenter clinical trial, which may have an impact on future policies in prognosis-oriented treatment strategies.     

Characterization of neutron beams for boron neutron capture therapy: in-air radiobiological dosimetry

The survival curves and the RBE for the dose components generated in boron neutron capture therapy (BNCT) were determined separately in neutron beams at Japan Research Reactor No. 4. The surviving fractions of V79 Chinese hamster cells with or without 10B were obtained using an epithermal neutron beam (ENB), a mixed thermal-epithermal neutron beam (TNB-1), and a thermal (TNB-2) neutron beam; these beams were used or are planned for use in BNCT clinical trials. The cell killing effect of the neutron beam in the presence or absence of 10B was highly dependent on the neutron beam used and depended on the epithermal and fast-neutron content of the beam. The RBEs of the boron capture reaction for ENB, TNB-1 and TNB-2 were 4.07 +/- 0.22, 2.98 +/- 0.16 and 1.42 +/- 0.07, respectively. The RBEs of the high-LET dose components based on the hydrogen recoils and the nitrogen capture reaction were 2.50 +/- 0.32, 2.34 +/- 0.30 and 2.17 +/- 0.28 for ENB, TNB-1 and TNB-2, respectively. The RBEs of the neutron and photon components were 1.22 +/- 0.16, 1.23 +/- 0.16, and 1.21 +/- 0.16 for ENB, TNB-1 and TNB-2, respectively. The approach to the experimental determination of RBEs outlined in this paper allows the RBE-weighted dose calculation for each dose component of the neutron beams and contributes to an accurate inter-beam comparison of the neutron beams at the different facilities employed in ongoing and planned BNCT clinical trials.     

Anticoagulants for nonvalvular atrial fibrillation (NVAF)--drug review

Vitamin K-inhibiting anticoagulants, especially warfarin, have become standard treatment for reducing the incidence of strokes and systemic emboli in patients with nonvalvular atrial fibrillation (NVAF). The randomized controlled trials that form the scientific basis for the efficacy of anticoagulants in prophylaxis of embolic events show small but statistically significant benefit with warfarin and other vitamin K inhibitors. The generalizability of these randomized trials to clinical practice is highly questionable because of the low percentage of NVAF patients from the participating institutions that entered the trials, the relatively young age of the patients, and the superior anticoagulation monitoring compared with that in general practice. Indirect comparisons of warfarin with aspirin by looking at separate meta-analyses of placebo-controlled randomized trials give potentially biased results. The meta-analyses of trials directly comparing warfarin with aspirin have diametrically opposing conclusions. In contrast to observational studies of general medical practice, randomized trials significantly underestimate the bleeding risks of warfarin. Anticoagulants for stroke prophylaxis for NVAF cause about 17,000 major bleeds in the United States per year, of which about 4000 are fatal. In 5 randomized trials with follow-up periods of 1.3-2.3 years, 10% to 38% of patients permanently discontinued anticoagulants. The 2-year average follow up of patients in the randomized trials is too short to predict the long-term impact of anticoagulation on the natural history of NVAF. Aspirin should be preferred over anticoagulants in prophylaxis against cardiogenic embolism in NVAF patients.