Biomedical subjects

J Houghton

Publications and source records attributed to J Houghton.

At least 19 recordsLinked to original sources

PubMed2006

Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results from the ZIPP study.

The Zoladex In Pre-menopausal Patients (ZIPP) study was designed to determine whether addition of goserelin ('Zoladex') and/or tamoxifen to adjuvant therapy (radiotherapy and/or chemotherapy), provided benefit to pre- or peri-menopausal women with operable, early breast cancer. A combined analysis of four randomised trials using a core protocol was performed. Patients (n = 2710) were randomised into a 2 x 2 factorial trial based on goserelin and tamoxifen (n = 1800) or randomised to receive goserelin or not (n = 910; some received elective tamoxifen) for 2 years. The analysis presented here compares women who did (n = 1354) or did not (n = 1356) receive goserelin. After a median follow-up of 5.5 years, goserelin provided a significant benefit for event-free survival (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.69, 0.92; P = 0.002) and overall survival (HR 0.81; 95% CI 0.67, 0.99; P = 0.038). Goserelin was well tolerated. These data show that the addition of goserelin to standard adjuvant therapy is more effective than standard therapy alone in pre-menopausal women with early breast cancer.

Adult↗

PubMed2006

Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status.

BACKGROUND: Most women with oestrogen receptor (ER) positive primary breast cancer receive adjuvant tamoxifen after surgery. The measurement of tumour biomarkers should allow better selection of patients for such treatment or for therapies such as aromatase inhibitors. PATIENTS AND METHODS: Histopathological blocks of primary breast cancer patients who had been randomized to receive 2-years tamoxifen or no adjuvant therapy in two mature randomised clinical trials were retrieved. Immunohistochemical staining for ER, progesterone receptor (PgR), HER2 and epidermal growth factor receptor (EGFR) was undertaken. The primary endpoint was relapse free survival. RESULTS: 813 patients were included in the study. Benefit from tamoxifen was seen in ER-positive patients [Relative risk (rr) 0.77, ci 0.63-0.93]. ER-negative patients also showed a strong trend to benefit from tamoxifen (rr 0.73, ci 0.52-1.02) which was largely confined to the PgR-positive group. Amongst the ER-positive group, PgR-positive and PgR-negative patients showed similar benefit (rr 0.81; ci 0.65-1.02 and 0.70; ci 0.49-0.99, respectively). Patients positive for HER2 did not benefit significantly (rr 1.14; ci 0.75-1.73) but this group was small. CONCLUSIONS: Measurement of PgR status in ER-negative patients defines a group of patients that benefit from tamoxifen but would be excluded from tamoxifen therapy on the basis of ER status alone. The data are consistent with HER2 positive tumours being resistant to tamoxifen.

Adult↗

PubMed2006

Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial.

BACKGROUND: The Arimidex (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole with tamoxifen as adjuvant treatment for postmenopausal women with early-stage breast cancer. After an extended follow-up beyond the 5 years of treatment, we aimed to assess the safety, tolerability, and risk-benefit indices of these compounds. METHODS: We analysed postmenopausal women (mean age 64 years [SD 9]) with localised breast cancer randomly assigned to anastrozole (n=3125) or tamoxifen (n=3116). Efficacy measures, including death and risk-benefit indices, were analysed by intention to treat. Safety analyses were based on treatment first received (n=3092 for anastrozole and n=3094 tamoxifen). We calculated a risk-benefit analysis using the two global indices for the Women's Health Initiative and for Disease-Free Survival and Serious Adverse Events. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. FINDINGS: At median follow-up of 68 months (range 1-93), treatment-related adverse events occurred significantly less often with anastrozole than with tamoxifen (1884 [61%] vs 2117 [68%]; p<0.0001), as did treatment-related serious adverse events (146 [5%] vs 277 [9%]; p<0.0001) and adverse events leading to withdrawal (344 [11%] vs 442 [14%]; p=0.0002). Patients given anastrozole had significantly fewer overall events for the Global Index of the Women's Health Initiative (744 [24%] vs 851 [27%]; hazard ratio 0.85 [95% CI 0.77-0.94], p=0.001) and the Global Index of Disease-Free Survival and Serious Adverse Events (1453 [46%] vs 1594 [51%]; 0.88 [0.82-0.94]; p=0.0004). INTERPRETATION: Anastrozole is tolerated better than tamoxifen by postmenopausal women with early-stage breast cancer, and results in fewer serious adverse events. Furthermore, it has a more favourable overall risk-benefit profile and lower recurrence rate than tamoxifen.

Anastrozole↗

PubMed2005

Patients' preferences for adjuvant endocrine therapy in early breast cancer: what makes it worthwhile?

Adjuvant endocrine therapy improves recurrence and survival rates, but has side effects and is inconvenient. The aim of this study was to determine the preferences of premenopausal women who had adjuvant endocrine therapy in a randomised trial. In all, 85 (or eighty-five) women completed semistructured interviews 6-30 months after finishing adjuvant endocrine therapy. Hypothetical scenarios based on known potential survival times (5 or 15 years) and rates (60% or 80% at 5 years) without adjuvant endocrine therapy were used to determine the smallest gains women judged necessary to make their adjuvant endocrine therapy worthwhile. Although a third of the women considered gains of 1% in survival rates or 6 months in survival times sufficient to make their adjuvant endocrine therapy worthwhile, more than half the women required gains of at least 5% in survival rates or 3 years in survival time as necessary to make adjuvant endocrine therapy worthwhile. Larger benefits were required by women who had longer treatment, worse side effects, and by those who were treated with goserelin alone. The route of administration (tablet vs injection) did not affect preferences and some women judged small benefits sufficient to make their adjuvant endocrine therapy worthwhile, but many women required larger benefits than their counterparts in similar studies of preferences for adjuvant chemotherapy.

Adult↗

PubMed2005

Isolation and characterization of a novel mouse lymphatic endothelial cell line: SV-LEC.

BACKGROUND: The lymphatic system regulates interstitial fluid and protein balance and modulates immune responses by regulating leukocyte and antigen traffic to lymph nodes. The present article describes a stable mouse lymphatic endothelial cell line from mesenteric adventitial tissue (SV-LEC) which is distinct from blood aortic (AEC) and venous (VEC) endothelial cells, based on expression of several lymphatic markers (e.g., Prox-1, LYVE-1, Flt-4). SV-LEC also expresses MAdCAM-1 in response to TNF-alpha, an effect seen in VEC, but not AEC. METHODS AND RESULTS: Lymphatic endothelial cells (SV-LEC) were isolated from mesenteric adventitia from mice expressing temperature-sensitive SV40 large T ('Immortomouse', H-2K(b)tsA58) selected with hypoxia culture in D-valine-substituted MEM supplemented with VEGFC in a low oxygen atmosphere (0% O2, 5% CO2, and 95% N2) with 5 mM thioglycolate. Expression of lymphatic-specific markers (Flt-4, LYVE-1, Prox-1) and the tight junction proteins (ZO-1) were examined by RT-PCR, immunoblotting, and fluorescent microscopy. MAdCAM-1 (a high endothelial venular marker) expression was also examined in response to TNF-alpha IL-1beta and IFN-gamma. RESULTS: Message for Flt-4 and LYVE-1 was detected on SV-LEC. Immunoblotting for LYVE-1 and Prox-1 showed strong expression on SV-LEC and VEC, but not AEC. Occludin expression was seen in all cell types, junctional ZO-1 was detected at SV-LEC and VEC junctions, not AEC. CONCLUSION: SV-LEC expresses several lymphatic endothelial markers, some of which are shared with VEC, but not AEC, and may represent a useful system for modeling lymphatic function in vitro.

Animals↗

PubMed2005

Homogeneity of mesothelial cells with lymphatic endothelium: expression of lymphatic endothelial markers by mesothelial cells.

BACKGROUND: Mesothelial cell monolayers cover the serous cavities and internal organs, and provide a protective low-friction interface between apposed organs and tissues. The mesothelium also regulates inflammation, fluid and cell exchange, and tissue repair in these compartments and possibly tumor metastasis. In the present study, a stable pleural mesothelial cell line (MIM) was isolated and characterized, and the expression of several lymphatic specific markers by these cells examined. METHODS AND RESULTS: MIM were isolated from mice stably expressing a temperature-sensitive SV40 large T antigen ('Immortomouse', strain: H-2K(b)-tsA58). These cells were compared with lymphatic endothelial cells (LEC) derived from the mesenteric adventitia of the Immortomouse. MIM and LEC expression of lymphatic-specific markers (Flt-4, LYVE-1, and Prox-1) was examined, and the tight junction protein (ZO-1) was studied by immunofluorescence and immunoblotting in these cells. RESULTS: LYVE-1, Prox-1, and Flt-4 were detected in both MIM and LEC, with Prox-1 and LYVE-1 more strongly expressed on LEC than MIM. Conversely, Flt-4 was more densely expressed on MIM than on LEC. Spatially, ZO-1 was prominent at MIM junctions, but was less well organized in LEC. CONCLUSION: MIM and LEC share several characteristic markers usually associated with lymphatic endothelium. MIM might be useful for studying the biology and pathology of mesothelial cells in vitro and help in the development of therapies for mesothelial-related diseases, such as mesothelioma and pleural effusion.

Animals↗

PubMed2004

N-methyl-D-aspartate receptor activation in human cerebral endothelium promotes intracellular oxidant stress.

Cerebral endothelial cells in the rat, pig, and, most recently, human have been shown to express several types of receptors specific for glutamate. High levels of glutamate disrupt the cerebral endothelial barrier via activation of N-methyl-d-aspartate (NMDA) receptors. We have previously suggested that this glutamate-induced barrier dysfunction was oxidant dependent. Here, we provide evidence that human cerebral endothelial cells respond to glutamate by generating an intracellular oxidant stress via NMDA receptor activation. Cerebral endothelial cells loaded with the oxidant-sensitive probe dihydrorhodamine were used to measure intracellular reactive oxygen species (ROS) formation in response to glutamate receptor agonists, antagonists, and second message blockers. Glutamate (1 mM) significantly increased ROS formation compared with sham controls (30 min). This ROS response was significantly reduced by 1) MK-801, a noncompetitive NMDA receptor antagonist; 2) 8-(N,N-diethylamino)-n-octyl-3,4,5-trimethoxybenzoate, an intracellular Ca(2+) antagonist; 3) LaCl(3), an extracellular Ca(2+) channel blocker; 4) diphenyleiodonium, a heme-ferryl-containing protein inhibitor; 5) itraconazole, a cytochrome P-450 3A4 inhibitor; and 6) cyclosporine A, which prevents mitochondrial membrane pore transition required for mitochondrial-dependent ROS generation. Our results suggest that the cerebral endothelial barrier dysfunction seen in response to glutamate is Ca(2+) dependent and may require several intracellular signaling events mediated by oxidants derived from reduced nicotinamide adenine dinucleotide oxidase, cytochrome P-450, and the mitochondria.

Brain↗

PubMed2004

Late follow-up of a randomized trial of surgery plus tamoxifen versus tamoxifen alone in women aged over 70 years with operable breast cancer.

BACKGROUND: Breast cancer has been considered a more indolent disease in the elderly, who are less tolerant of aggressive therapy. This trial tested the hypothesis that tamoxifen without surgery would provide adequate control of breast cancer for the remainder of life in elderly women, thereby sparing them surgery. METHOD: Women aged over 70 years with operable, invasive breast cancer were randomized to receive either tamoxifen alone or surgery plus tamoxifen. Time to treatment failure (TTF), indicating initial primary treatment failure, was the primary endpoint. Overall mortality, and death from breast cancer were also compared between the two groups. RESULTS: Between 1984 and 1991, 455 patients were included in the trial. The analysis was based on a median follow-up of 12.7 years. The TTF was significantly shorter in the tamoxifen alone group: hazard ratio (HR) 4.41 (95 per cent confidence interval (c.i.) 3.31 to 5.88). Ninety-three (40.4 per cent) of 230 patients randomized to tamoxifen alone underwent surgery for the management of their disease. Both overall mortality and mortality from breast cancer were significantly increased in the tamoxifen alone group, although the survival curves did not diverge for the first 3 three years: HR 1.29 (95 per cent c.i. 1.04 to 1.59) and 1.68 (95 per cent c.i. 1.15 to 2.47) respectively. CONCLUSION: Omission of primary surgery in unselected elderly women with operable breast cancer who were fit for the procedure resulted in an increased rate of progression, therapeutic intervention and mortality.

Aged↗

PubMed2003

Human neuroepithelial cells express NMDA receptors.

L-glutamate, an excitatory neurotransmitter, binds to both ionotropic and metabotropic glutamate receptors. In certain parts of the brain the BBB contains two normally impermeable barriers: 1) cerebral endothelial barrier and 2) cerebral epithelial barrier. Human cerebral endothelial cells express NMDA receptors; however, to date, human cerebral epithelial cells (neuroepithelial cells) have not been shown to express NMDA receptor message or protein. In this study, human hypothalamic sections were examined for NMDA receptors (NMDAR) expression via immunohistochemistry and murine neuroepithelial cell line (V1) were examined for NMDAR via RT-PCR and Western analysis. We found that human cerebral epithelium express protein and cultured mouse neuroepithelial cells express both mRNA and protein for the NMDA receptor. These findings may have important consequences for neuroepithelial responses during excitotoxicity and in disease.

Animals↗

PubMed2003

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses.

BACKGROUND: The first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow-up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer, anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC). In the current article, the results of the first efficacy update, based on a median follow-up period of 47 months, are reported along with the results of an updated safety analysis, performed 7 months after the first analysis (median duration of treatment, 36.9 months). METHODS: DFS, TTR, CLBC incidence, and safety were assessed in the same patient group as in the first analysis of the ATAC trial. RESULTS: DFS estimates at 4 years remained significantly more favorable (86.9% vs. 84.5%, respectively) for patients receiving anastrozole compared with those receiving tamoxifen (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76-0.99; P = 0.03). The benefit generated by anastrozole in terms of DFS was even greater in patients with hormone receptor-positive tumors (HR, 0.82; 95% CI, 0.70-0.96; P = 0.014). The HR for TTR also indicated a significant benefit for patients receiving anastrozole compared with those receiving tamoxifen (HR, 0.83; 95% CI, 0.71-0.96; P = 0.015), with additional benefit for patients with hormone receptor-positive tumors (HR, 0.78; 95% CI, 0.65-0.93; P = 0.007). CLBC incidence data also continued to favor anastrozole (odds ratio [OR], 0.62; 95% CI, 0.38-1.02; P = 0.062), and statistical significance was achieved in the hormone receptor-positive subgroup (OR, 0.56; 95% CI, 0.32-0.98; P = 0.042). The updated safety analysis also confirmed the findings of the first analysis, in that endometrial cancer (P = 0.007), vaginal bleeding and discharge (P < 0.001 for both), cerebrovascular events (P < 0.001), venous thromboembolic events (P < 0.001), and hot flashes (P < 0.001) all occurred less frequently in the anastrozole group, whereas musculoskeletal disorders and fractures (P < 0.001 for both) continued to occur less frequently in the tamoxifen group. These results indicated that the safety profile of anastrozole remained consistent. CONCLUSIONS: After an additional follow-up period, anastrozole continues to show superior efficacy, which is most apparent in the clinically relevant hormone receptor-positive population. Furthermore, anastrozole has numerous noteworthy advantages in terms of tolerability compared with tamoxifen. These findings suggest that the benefits of anastrozole are likely to be maintained in the long term and provide further support for the status of anastrozole as a valid treatment option for postmenopausal women with hormone-sensitive early-stage breast cancer.

Anastrozole↗

PubMed2003

Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor.

l-Glutamate is a major excitatory neurotransmitter that binds ionotropic and metabotropic glutamate receptors. Cerebral endothelial cells from many species have been shown to express several forms of glutamate receptors; however, human cerebral endothelial cells have not been shown to express either the N-methyl-D-aspartate (NMDA) receptor message or protein. This study provides evidence that human cerebral endothelial cells express the message and protein for NMDA receptors. Human cerebral endothelial cell monolayer electrical resistance changes in response to glutamate receptor agonists, antagonists, and second message blockers were tested. RT-PCR and Western blot analysis were used to demonstrate the presence of the NMDA receptor. Glutamate and NMDA (1 mM) caused a significant decrease in electrical resistance compared with sham control at 2 h postexposure; this response could be blocked significantly by MK-801 (an NMDA antagonist), 8-(N,N-diethylamino)-n-octyl-3,4,5-trimethyoxybenzoate (an intracellular Ca2+ antagonist), and N-acetyl-L-cystein (an antioxidant). Trans(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid, a metabotropic receptor agonist (1 mM), did not significantly decrease electrical resistance. Our results are consistent with a model where glutamate, at excitotoxic levels, may lead to a breakdown in the blood brain barrier via activation of NMDA receptors.

Biological Transport↗

PubMed2003

Malignancy-associated changes in lactiferous duct epithelium.

OBJECTIVE: To determine whether cells from histologically normal appearing epithelium of the lactiferous duct from women with a remote ductal lesion in the breast provide any clues indicating the existence of such a lesion. STUDY DESIGN: Tissue sections cut to 4 microns and stained with hematoxylin and eosin were prepared from duct tissue of 20 women with breast lesions and of 20 women free of any such lesion who had undergone mammoplastic procedures or resection for benign reasons. One hundred nuclei were measured from each case. Measures of nuclear deviation from normal were computed, discriminant functions were derived, and multivariate significance tests were conducted. RESULTS: Nuclei from histologically normal appearing regions of lactiferous duct epithelium from women harboring distant lesions exhibited changes in the distribution pattern of their nuclear chromatin, indicating the presence of these lesions. The statistical significance of these changes was documented. The changes were clearly evident in all 20 subjects with lesions and were not observed in 19 of the 20 subjects without lesions. CONCLUSION: The results suggest that studies aimed at detecting malignancy-associated changes in cells collected by ductal lavage might lead to a minimally invasive screening procedure for breast lesions.

Adult↗

PubMed2002

Trends in the incidence of childhood diabetes in south Asians and other children in Bradford, UK.

AIMS: To investigate incidence rates and time trends, over 21 years, of Type 1 diabetes in a migrant population of south Asian children in Bradford, UK. METHODS: Children (0-14 years) living in the city of Bradford and diagnosed with Type 1 diabetes were selected from a population-based region-wide register. Between 1978 and 1998, 289 new-onset cases were registered and classified as south Asian (Indian, Pakistani, Bangladeshi) or not, based on their full name using two different computer algorithms and visual inspection. RESULTS: Sixty-six children (22.8%) were designated as south Asian with 223 (77.2%) remaining. The overall age-sex standardized incidence for south Asian and non-south Asian children was 13.0 per 100,000 person years (95% confidence interval 9.9-16.2) and 12.9 (11.2-14.6), respectively. Rates were similar for south Asians at all ages, whereas for the mainly Caucasian children incidence differed significantly by age group (P < 0.001). An average annual increase in incidence of 4.3% (P = 0.001) was seen for all children compared with 6.5% in south Asians (P = 0.002) and 2.4% (P = 0.128) in non-south Asians. CONCLUSIONS: Children in south Asia have a low incidence of Type 1 diabetes but migrants to the UK have similar overall rates to the indigenous population. However, a more steeply rising incidence is seen in the south Asian population, and our data suggest that incidence in this group may eventually outstrip that of the non-south Asians. Genetic factors are unlikely to explain such a rapid change, implying an influence of environmental factors in disease aetiology. The similarity in rates by age group in the south Asian population is notable.

Adolescent↗

PubMed2001

A phase I trial of amsalog (CI-921) administered by intravenous infusion using a 5-day schedule.

PURPOSE: Amsalog, a derivative of 9-aminoacridine, is an inhibitor of topoisomerase II. Early studies of intravenous amsalog administered either once weekly, or daily for 3 days repeated every 3 weeks, showed that myelosuppression is the dose-limiting toxicity (DLT). Phase II studies showed only limited activity in breast, head and neck, and non-small-cell lung cancer. The activity of other topoisomerase inhibitors is schedule-dependent. We therefore performed a phase I study to evaluate the use of amsalog on a more prolonged schedule. METHODS: A group of 19 patients with refractory malignancies were treated in six cohorts using 2-h infusions of amsalog daily for 5 days, repeated every 3 weeks. RESULTS: Myelosuppression was seen as DLT at 200 mg/m2 per day. Other toxicities included nausea and vomiting, fatigue, and, when administered via a peripheral venous line, severe phlebitis necessitating administration via an indwelling central venous catheter for doses greater than 100 mg/m2. Pharmacokinetic studies showed a linear relationship between Cmax and AUC, and dose. The terminal half-life was 2 h, consistent with previous studies. CONCLUSION: We conclude that amsalog can be safely given on a 5-day schedule every 3 weeks at doses up to 200 mg/m2. The dose recommended for further studies is 180 mg/m2 per day for 5 days repeated every 3 weeks. However, in view of the phlebitis, which necessitated the use of central venous catheters for administration, other routes of administration, for example oral formulations, should be explored.

Adult↗

PubMed2001

Tolerability of hormone therapies for breast cancer: how informative are documented symptom profiles in medical notes for 'well-tolerated' treatments?

Hormonal therapies for cancer are often viewed as a gentler option than many other cancer treatments, but is low toxicity an accurate perception of patients' experiences? Side effects tend to be described as minimal or well tolerated, yet published symptoms from hormonal therapy vary considerably in their descriptions and frequencies. Previous research has highlighted under-reporting of side effects by clinical staff so as part of a wider study examining tamoxifen and goserelin treatment as adjuvant therapy for breast cancer, treatment-related symptoms documented in medical notes were compared with those that patients reported during a research interview. There was a significant difference in the frequency of many side effects reported by the two methods in this study. Sixty four out of 72 (89%) women who had received adjuvant tamoxifen or goserelin had side effects recorded in their medical notes, compared with 74/75 (99%) reporting side effects at interview. We compared the published frequencies of commonly reported symptoms with those found ourselves. The discrepancies between patient-reported and clinician-recorded (usually from clinical trial data) symptom profiles were similar to those found in our study. Without accurate comprehensive side effect profiles for hormone therapies, prospective patients cannot make informed judgements on proposed treatments.

Adult↗

PubMed2001

Vigam-S, a solvent/detergent-treated intravenous immunoglobulin, in idiopathic thrombocytopenic purpura.

The efficacy of Vigam-S, a highly purified intravenous immunoglobulin, was investigated by an open, noncomparative study in 20 adults with chronic idiopathic thrombocytopenic purpura (ITP). Fifteen patients responded to the initial 3-day infusion of 0.4 g kg(-1) day(-1) by exhibiting an incremental increase in platelet count of >or= 30 x 10(9) L(-1), in eight of whom platelet count normalized (> 150 x 10(9) L(-1)). The peak platelet count for responders on day 4 was 163 x 10(9) L(-1) (baseline = 18 x 10(9) L(-1)). No benefit was derived from an extra 2 days infusion in nonresponders. Further treatment (either a single 0.8 g kg(-1) dose or another 3-day infusion) given to responders when platelet counts fell below 30 x 10(9) L(-1) was effective on eight of 14 occasions. Increases in total serum IgG concentration (to a mean peak of 25.3 g L(-1)) were not correlated with platelet response. There was no evidence of seroconversion to virus markers, or of alteration in renal function, following Vigam-S infusion. Most adverse events were mild and transient; however, three patients had severe headache and vomiting (possible aseptic meningitis syndrome) and one had marked superficial thrombophlebitis. Therefore Vigam-S provides effective and well tolerated therapy in the management of adults with ITP although individual patient response remains difficult to predict.

Adolescent↗

PubMed2001

Monitoring a clinical trial conducted under the Food and Drug Administration regulations allowing a waiver of prospective informed consent: the diaspirin cross-linked hemoglobin traumatic hemorrhagic shock efficacy trial.

In 1996, the US Food and Drug Administration (FDA) enacted Rule 21 CFR section 50.24, which allows a narrow exception to the requirement for prospective informed consent from human research subjects in clinical trials investigating potentially beneficial therapies for acute, life-threatening conditions. The first clinical trial to be conducted under this rule was sponsored by Baxter Healthcare Corporation and approved by the FDA on November 21, 1996. This large, multicenter, randomized clinical trial was designed to compare the addition of diaspirin cross-linked hemoglobin (DCLHb) with standard care in the initial resuscitation of adults experiencing severe, uncompensated, traumatic hemorrhagic shock. Before the first planned interim analysis of the data, review of fatal adverse events revealed an imbalance in mortality between the 2 treatment groups. The Data Monitoring Committee (DMC) recommended suspension of patient enrollment 24 days later. Additional data collection and analyses confirmed the excess number of deaths in patients treated with DCLHb but failed to reveal the cause of these deaths. The trial was formally terminated after only 112 of the planned 850 patients had been enrolled. We review the events leading up to and the rationale behind the DMC recommendations for suspension of patient enrollment and trial termination. Although the DCLHb trial was unsuccessful in achieving its goals, the monitoring process worked well. Emergency research was facilitated by DMC oversight, and the interests of research subjects were protected by the actions of the DMC.

Aspirin↗

PubMed2001

Fecal occult blood testing in a noncompliant inner city minority population: increased compliance and adherence to screening procedures without loss of test sensitivity using stool obtained at the time of in-office rectal examination.

OBJECTIVES: Fecal occult blood screening is cost-effective, is easily administered to large groups of patients, and reduces mortality associated with colorectal cancer. Within our predominant African American and Latino inner city clinic populations, compliance with common screening procedures is suboptimal. A procedure with increased compliance is needed to adequately screen this population at high risk for colorectal cancer. The objective of this study was to compare the results of the 3-day at-home hemoccult test for occult blood to those of a hemoccult test performed from stool obtained at rectal examination in the office. METHODS: A total of 350 consecutive patients referred to the GI clinic of University Hospital or Jersey City Medical Center for colorectal cancer screening had both the 3-day at-home hemoccult test and an in-office hemoccult examination performed, followed by either sigmoidoscopy (for negative results) or by colonoscopy (for positive results). RESULTS: Patients were noncompliant with dietary restrictions, 3-day card return, follow-up appointments, and endoscopy with conventional screening methods. Decisions based on the in-office examination with direct scheduling of endoscopy significantly improved compliance with follow-up. There was no statistical difference between the two detection methods, suggesting that the in-office examination was the more effective screening test. CONCLUSIONS: Endoscopy based on an in-office hemoccult examination is an acceptable alternative to using the 3-day at-home stool collection to govern endoscopic choices. In a noncompliant inner city population, use of the in-office examination increased compliance with follow up, potentially allowing more patients exposure to screening.

Black or African American↗