High-dose-rate intraoperative radiation therapy: the nuts and bolts of starting a program.

High-dose-rate intraoperative radiation therapy (HDR-IORT) has historically provided effective local control (LC) for patients with unresectable and recurrent tumors. However, IORT is limited to only a few specialized institutions and it can be difficult to initiate an HDR-IORT program. Herein, we provide a brief overview on how to initiate and implement an HDR-IORT program for a selected group of patients with gastrointestinal and pelvic solid tumors using a multidisciplinary approach. Proper administration of HDR-IORT requires institutional support and a joint effort among physics staff, oncologists, surgeons, anesthesiologists, and nurses. In order to determine the true efficacy of IORT for various malignancies, collaboration among institutions with established IORT programs is needed.

Clinicopathologic Comparison of High-Dose-Rate Endorectal Brachytherapy versus Conventional Chemoradiotherapy in the Neoadjuvant Setting for Resectable Stages II and III Low Rectal Cancer.

Purpose. To assess for differences in clinical, radiologic, and pathologic outcomes between patients with stage II-III rectal adenocarcinoma treated neoadjuvantly with conventional external beam radiotherapy (3D conformal radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT)) versus high-dose-rate endorectal brachytherapy (EBT). Methods. Patients undergoing neoadjuvant EBT received 4 consecutive daily 6.5 Gy fractions without chemotherapy, while those undergoing 3DRT or IMRT received 28 daily 1.8 Gy fractions with concurrent 5-fluorouracil. Data was collected prospectively for 7 EBT patients and retrospectively for 25 historical 3DRT/IMRT controls. Results. Time to surgery was less for EBT compared to 3DRT and IMRT (P < 0.001). There was a trend towards higher rate of pathologic CR for EBT (P = 0.06). Rates of margin and lymph node positivity at resection were similar for all groups. Acute toxicity was less for EBT compared to 3DRT and IMRT (P = 0.025). Overall and progression-free survival were noninferior for EBT. On MRI, EBT achieved similar complete response rate and reduction in tumor volume as 3DRT and IMRT. Histopathologic comparison showed that EBT resulted in more localized treatment effects and fewer serosal adhesions. Conclusions. EBT offers several practical benefits over conventional radiotherapy techniques and appears to be at least as effective against low rectal cancer as measured by short-term outcomes.

Aspirin for the older person: report of a meeting at the Royal Society of Medicine, London, 3rd November 2011.

On November 23rd 2011, the Aspirin Foundation held a meeting at the Royal Society of Medicine in London to review current thinking on the potential role of aspirin in preventing cardiovascular disease and reducing the risk of cancer in older people. The meeting was supported by Bayer Pharma AG and Novacyl.

My health: whose responsibility? A jury decides.

BACKGROUND: Medicines are likely to assume an increasingly important role in helping people to remain healthy. But there are few indications as to what information and other support people want when assessing the risks and benefits of medicines; what role they feel government and healthcare professionals should play in informing, advising and encouraging healthy people on the potential benefits and possible risks of prophylactic medicines; and, ultimately, where does the responsibility for maintaining a person's health lie? METHODS: A Citizens' Jury was convened in October 2006 to consider these issues against the background of healthy living in general. The Jury was a broadly representative group of 16 people drawn from the community. A number of experts in clinical medicine, pharmacology and public health gave evidence and were questioned by the jurors. Vascular prophylaxis by a daily low-dose of aspirin was used as a case study throughout the discussions. RESULTS: The judgements of the jury included a clear demand for more information on health issues in general and on prophylactic medicines in particular, together with a desire that the public be more closely and openly involved in decision-taking in all matters relevant to health. The jurors were generally receptive to the possible role of medicines in the maintenance of health and a majority argued that people should be presented with evidence on medicines with possible health benefits, even when there is disagreement between experts about efficacy. CONCLUSION: The strategy of the Citizens' Jury, alongside other deliberative methods, could clearly have an important and valuable role in the formulation of public health and social policy.

Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

A novel process for introducing a new intraoperative program: a multidisciplinary paradigm for mitigating hazards and improving patient safety.

BACKGROUND: Since the Institute of Medicine's report, To Err is Human, was published, numerous interventions have been designed and implemented to correct the defects that lead to medical errors and adverse events; however, most efforts were largely reactive. Safety, communication, team performance, and efficiency are areas of care that attract a great deal of attention, especially regarding the introduction of new technologies, techniques, and procedures. We describe a multidisciplinary process that was implemented at our hospital to identify and mitigate hazards before the introduction of a new technique: high-dose-rate intraoperative radiation therapy, (HDR-IORT). METHODS: A multidisciplinary team of surgeons, anesthesiologists, radiation oncologists, physicists, nurses, hospital risk managers, and equipment specialists used a structured process that included in situ clinical simulation to uncover concerns among care providers and to prospectively identify and mitigate defects for patients who would undergo surgery using the HDR-IORT technique. RESULTS: We identified and corrected 20 defects in the simulated patient care process before application to actual patients. Subsequently, eight patients underwent surgery using the HDR-IORT technique with no recurrence of simulation-identified or unanticipated defects. CONCLUSION: Multiple benefits were derived from the use of this systematic process to introduce the HDR-IORT technique; namely, the safety and efficiency of care for this select patient population was optimized, and this process mitigated harmful or adverse events before the inclusion of actual patients. Further work is needed, but the process outlined in this paper can be universally applied to the introduction of any new technologies, treatments, or procedures.

Emergent combined intracranial thrombolysis and carotid stenting in the hyperacute management of stroke patients with severe cervical carotid stenosis.

BACKGROUND AND PURPOSE: The timely re-establishment of intracranial perfusion, the effective prevention of early recurrent strokes, and the limitation of the incidence of reperfusion injury are the major factors that are key to successful treatment of patients with hyperacute stroke who had severe ipsilateral cervical internal carotid artery (ICA) stenosis. In an effort to reduce both the extent of the ongoing neurologic injury and the risk of early recurrent stroke, we have adopted an aggressive combined endovascular approach of intracranial thrombolysis and cervical carotid stent placement during the hyperacute phase. We report on the results of 5 such consecutive patients who presented to our center from January 2003 through January 2005. MATERIALS AND METHODS: From January 2003 through January 2005, 5 consecutive patients presented to our center with hyperacute strokes and severe ipsilateral cervical ICA stenosis. All were treated with emergent carotid stent placement and intra-arterial thrombolysis. The medical records were reviewed and summarized. RESULTS: One patient died. The remaining 4 patients had an average hospital stay of 4 days (range, 3-5 days) and a mean National Institutes of Health Stroke Scale (NIHSS) score of 2 (range, 0-3) at the time of discharge. With a mean clinical follow-up of 11 months (range, 6-24 months), all had excellent functional outcome with a modified Rankin score of 0 or 1. CONCLUSIONS: Data on emergent carotid stent placement in the hyperacute management of stroke are limited. The summarized experience in these 5 patients demonstrates the feasibility of this aggressive therapeutic strategy that may bring about a good outcome.

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein.

Resistance to apoptosis is a hallmark of many solid tumors, including pancreatic cancers, and may be the underlying basis for the suboptimal response to chemoradiation therapies. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. We determined the therapeutic efficacy of recently described small-molecule antagonists of the X-linked IAP (XIAP) in preclinical models of pancreatic cancer. Primary pancreatic cancers were assessed for XIAP expression by immunohistochemistry, using a pancreatic cancer tissue microarray. XIAP small-molecule antagonists ("XAntag"; compounds 1396-11 and 1396-12) and the related compound 1396-28 were tested in vitro in a panel of human pancreatic cancer cell lines (Panc1, Capan1, and BxPC3) and in vivo in s.c. xenograft models for their ability to induce apoptosis and impede neoplastic growth. In addition, pancreatic cancer cell lines were treated with XAntags in conjunction with either tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or with radiation to determine potential synergy for such dual targeting of the apoptotic machinery. XIAP was overexpressed in 14 of 18 (77%) of primary pancreatic cancers. The XAntags1396-11 and 1396-12, but not the inactive isomer 1396-28, induced profound apoptosis in multiple pancreatic cancer cell lines tested in vitro, with a IC(50) in the range of 2 to 5 mumol/L. Mechanistic specificity of the XAntags for the baculoviral IAP repeat-2 domain of XIAP was shown by preferential activation of downstream "effector" caspases (caspase-3 and caspase-7) versus the upstream "initiator" caspase-9. S.c. BxPC3 xenograft growth in athymic mice was significantly inhibited by monotherapy with XAntags; treated xenografts showed marked apoptosis and increased cleavage of caspase-3. Notably, striking synergy was demonstrable when XAntags were combined with either TRAIL or radiation therapy, as measured by growth inhibition in vitro and reduced colony formation in soft agar of pancreatic cancer cell lines, at dosages where these therapeutic modalities had minimal to modest effects when used alone. Finally, XAntags in combination with the standard-of-care agent for advanced pancreatic cancer, gemcitabine, resulted in significantly greater inhibition of in vitro growth than gemcitabine alone. Our results confirm that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death and also show synergy when combined with proapoptotic ligands (TRAIL), with radiation, and with a conventional antimetabolite, gemcitabine. These preclinical results suggest that targeting of the apoptotic machinery in pancreatic cancers with XAntags is a promising therapeutic option that warrants further evaluation.

The heat shock response: role in radiation biology and cancer therapy.

Since prehistoric times, elevated temperatures have been used to treat cancer in a variety of forms. In modern times (the last 40 years) efforts have concentrated on combining heat with other anti-tumour modalities, principally ionizing radiation and some chemotherapeutic drugs. Despite the emphasis on combined therapy, rodent data relating to heat sensitivity and thermal tolerance development assumed principal importance. These considerations suggested treating at 43 degrees C as a target temperature and fractionation schemes emphasizing thermal tolerance avoidance. Concomitantly crucial data on heat-induced tumour reoxygenation and its temperature dependence were largely ignored. In reality these were unrealistic and undesirable goals. The preponderance of evidence now suggests that lower temperatures (40-42 degrees C) administered more frequently, optimally immediately before and during each administration of ionizing radiation, are likely to yield optimal results. Factoring in trimodality therapy and other combinations of chemotherapeutic drugs will require some modifications of such fractionation schemes.

Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.

CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.

Platelet aggregation in whole blood is a paradoxical predictor of ischaemic stroke: Caerphilly Prospective Study revisited.

The Caerphilly Prospective Study demonstrates a paradoxical association of increased ischaemic stroke risk with decreased whole blood adenosine diphosphate (ADP) induced platelet sensitivity. A reanalysis of this association examines whether other haematological indices and prevalent disease at baseline may explain this finding. There were 1506 men free of clinical cardiovascular disease at baseline, with 85 men manifesting a first ischaemic stroke event over 8.3 years of follow-up in this population-based prospective cohort study. Using two different approaches, the paradoxical findings are confirmed and associations are slightly stronger after accounting for red cell, platelet, and white cell indices. A U-shaped relation of stroke with platelet count is noted. These findings are consistent with the existence of sub-clinical endothelial disease and compensatory mechanisms down-regulating ADP-induced aggregation sensitivity. They support an allostasis model of causality for understanding the paradox. A public health approach to prevention could have measurable impact if intervention strategies can be developed to alter early stages of disease appropriate to such mechanisms of causation.

Milk consumption, stroke, and heart attack risk: evidence from the Caerphilly cohort of older men.

OBJECTIVE: To examine associations between milk consumption and incident heart disease and stroke. DESIGN: A representative population sample of men was asked to weigh and record their food intake for seven days. The total consumption of milk was obtained from these records. Details of all deaths and vascular events were collected during the following 20 years. Incident ischaemic strokes and heart disease events were diagnosed by standard criteria. SETTING: The Caerphilly cohort, a representative population sample of men in South Wales, aged 45-59 when first seen in 1979-83. PARTICIPANTS: A representative 3:10 subsample of the men in the cohort. MAIN RESULTS: 665 men (87% of those approached) returned satisfactory seven day diet diaries. After adjustment, the relative odds of an event in the men whose milk consumption was the median or higher, relative to those with lower intakes of milk, were 0.52 (0.27 to 0.99) for an ischaemic stroke and 0.88 (0.56 to 1.40) for an ischaemic heart disease event. Deaths from all causes were similar in the two milk consumption groups (relative odds 1.08; 0.74 to 1.58). CONCLUSIONS: These results give no convincing evidence of an increased risk of vascular disease from milk drinking. Rather, the subjects who drank more than the median amount of milk had a reduced risk of an ischaemic stroke, and possibly a reduced risk of an ischaemic heart disease event. These conclusions are in agreement with the results of a previously reported overview of 10 large, long term cohort studies based on food frequency intake records.

Long term effect of breast feeding: cognitive function in the Caerphilly cohort.

STUDY OBJECTIVE: There is evidence suggesting that artificial feeding is associated with a reduction in cognitive function in infants and children, in contrast with breast feeding, but the available evidence suffers from confounding by social and educational factors. An opportunity arose in the Caerphilly cohort study to examine relations between cognitive function in older men and their feeding as infants, when breast feeding was usual. DESIGN: A prospective cohort study. SETTING: Caerphilly, South Wales, UK, was a deprived coal mining community when the men had been born in 1920-35. Most had been breast fed as infants. PARTICIPANTS: 779 men aged 60-74 years when tested. The men had earlier been asked to obtain from their mothers their birth weight, and how they had been fed as infants. RESULTS: Complete data were obtained for 779 men. In those whose birth weight had been at or above the median, the adjusted mean cognitive function was only slightly and non-significantly lower in those who had been artificially fed. In the men whose birth weight had been below the median, having been artificially fed was associated with significantly lower results in both a test of reasoning (the AH4) and word power (the national adult reading test (NART)). Two standard deviations below the median birth weight, artificial feeding was associated with a reduction of six points (70% of a SD) on word power (the NART). CONCLUSIONS: In men whose birth weight had been low, having been artificially fed is associated with poorer cognitive function in late adult life.

Sorting of the human folate receptor in MDCK cells.

The human folate receptor (hFR) is a glycosylphosphatidy-linositol (GPI) linked plasma membrane protein that mediates delivery of folates into cells. We studied the sorting of the hFR using transfection of the hFR cDNA into MDCK cells. MDCK cells are polarized epithelial cells that preferentially sort GPI-linked proteins to their apical membrane. Unlike other GPI-tailed proteins, we found that in MDCK cells, hFR is functional on both the apical and basolateral surfaces. We verified that the same hFR cDNA that transfected into CHO cells produces the hFR protein that is GPI-linked. We also measured the hFR expression on the plasma membrane of type III paroxysmal nocturnal hemoglobinuria (PNH) human erythrocytes. PNH is a disease that is characterized by the inability of cells to express membrane proteins requiring a GPI anchor. Despite this defect, and different from other GPI-tailed proteins, we found similar levels of hFR in normal and type III PNH human erythrocytes. The results suggest the hypothesis that there may be multiple mechanisms for targeting hFR to the plasma membrane.

Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.

OBJECTIVE: To test the hypothesis that milk drinking increases the risk of ischaemic heart disease (IHD) and ischaemic stroke in a prospective study. DESIGN: In the Caerphilly Cohort Study dietary data, including milk consumption, were collected by a semiquantitative food frequency questionnaire in 1979-1983. The cohort has been followed for 20-24 y and incident IHD and stroke events identified. SUBJECTS: A representative population sample in South Wales, of 2512 men, aged 45-59 y at recruitment. MAIN OUTCOME MEASURES: In total, 493 men had an IHD event and 185 an ischaemic stroke during follow-up. RESULTS: After adjustment, the hazard ratio in men with a milk consumption of one pint (0.57 l) or more per day, relative to men who stated that they consumed no milk, is 0.71 (0.40-1.26) for IHD and 0.66 (0.24-1.81) for ischaemic stroke. At baseline, 606 men had had clinical or ECG evidence of vascular disease, and in these the vascular risk was even lower (0.37; 0.15-0.90). The hazard ratio for IHD and ischaemic stroke combined is 0.64 (0.39-1.06) in all men and 0.37 (0.15-0.90) in those who had had a prior vascular event. CONCLUSION: The data provide no convincing evidence that milk consumption is associated with an increase in vascular disease risk. Evidence from an overview of all published cohort studies on this topic should be informative. SPONSORSHIP: : The Medical Research Council, the University of Wales College of Medicine and Bristol University. Current support is from the Food Standards Agency.

Milk drinking, ischaemic heart disease and ischaemic stroke II. Evidence from cohort studies.

OBJECTIVE: Milk consumption is considered a risk factor for vascular disease on the basis of relevant biological mechanisms and data from ecological studies. The aim was to identify published prospective studies of milk drinking and vascular disease, and conduct an overview. DESIGN: The literature was searched for cohort studies, in which an estimate of the consumption of milk, or the intake of calcium from dairy sources, has been related to incident vascular disease. MAIN OUTCOME MEASURES: Ischaemic heart disease and ischaemic stroke. RESULTS: In total, 10 studies were identified. Their results show a high degree of consistency in the reported risk for heart disease and stroke, all but one study suggesting a relative risk of less than one in subjects with the highest intakes of milk. A pooled estimate of relative odds in these subjects, relative to the risk in subjects with the lowest consumption, is 0.87 (95% CI 0.74-1.03) for ischaemic heart disease and 0.83 (0.77-0.90) for ischaemic stroke. The odds ratio for any vascular event is 0.84 (0.78-0.90). CONCLUSIONS: Cohort studies provide no convincing evidence that milk is harmful. While there still could be residual confounding from unidentified factors, the studies, taken together, suggest that milk drinking may be associated with a small but worthwhile reduction in heart disease and stroke risk. SPONSORSHIP: The University of Wales College of Medicine and Bristol University. Current support is from the Food Standards Agency.

Venous ligation of dural arteriovenous fistulae.

This study evaluated the clinical outcomes following venous ligation for the treatment of dural arteriovenous fistulas (DAVF) with leptomeningeal or cortical venous drainage. The authors conducted a single-centre, retrospective study of 15 patients with DAVF treated consecutively between 1990 and 2000. There were eight female patients of mean age 60 years (range 36-71). Eight patients presented with haemorrhage, two with mass affect, two with headaches, one with seizures and two patients were asymptomatic. Four fistulas were located in the petrosal region, three at the torcula, three in the transverse sigmoid region, three in the parasagittal region and two at the foramen magnum. Leptomeningeal or cortical veins drained all DAVF. Eight patients underwent preoperative embolization of the arterial feeders. Venous ligation resulted in obliteration of all fistula confirmed by direct visualization of the thrombosed veins and/or radiographic follow up. Mean follow up period was 37 months with a range of 1-112 months. All symptomatic patients improved and there was no surgical morbidity. These results indicated that venous ligation to obliterate DAVF with leptomeningeal or cortical drainage is safe and effective. With appropriate neuroradiological diagnosis and preoperative neuroendovascular intervention, this technique resulted in obliteration of DAVF in 15 patients without significant morbidity.