Biomedical subjects
R Grant
Publications and source records attributed to R Grant.
Lessons learned from a community hospital chest pain center.
The iterative lessons from our studies suggest that creation of a chest pain center alone will not change the practice of chest pain management by most physicians. In 1993 we established a chest pain center; in mid-1995 we established a patient management algorithm directing intermediate-risk patients to the chest pain center rather than admit them to the hospital. The creation of a chest pain center did not reduce the rate of chest pain admission by mid-1995. After the patient management algorithm was created, admittances dropped by a rate of 21% (p <0.001) and chest pain center usage increased by +1,726% (p <0.001). Among the 473 patients treated and discharged in the chest pain center after mid-1995, 333 (70%) were considered intermediate risk. No patient died after discharge from the chest pain center and there was 1 non-Q-wave myocardial infarction. We conclude that a chest pain management algorithm in a chest pain center can be safe, yet effective, for identifying high-risk patients for admission and low-risk patients for discharge.
Open-label comparison of the antiemetic efficacy of single intravenous doses of dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy.
BACKGROUND: Nausea and vomiting are among the most unpleasant adverse side effects of cancer therapy. PROCEDURE: An open-label dose-escalation study was conducted to assess the appropriate intravenous dose of dolasetron for pediatric patients undergoing chemotherapy. Patients received dolasetron in single intravenous doses of 0.6 (n = 10), 1.2 (n = 12), 1.8 (n = 12), or 2.4 (n = 12) mg/kg 30 min before receiving emetogenic chemotherapy. Pharmacokinetic parameters were evaluated at each dose level and efficacy was evaluated over the first 24 hr following the administration of dolasetron. RESULTS: A complete response was achieved in 10% of patients given 0.6 mg/kg, 25% of patients given 1. 2 mg/kg, 67% of patients given 1.8 mg/kg, and 33% of patients given 2.4 mg/kg. Peak plasma concentrations (Cmax) were observed between 0. 33 and 0.75 hr following dolasetron infusion. Cmax and area under plasma concentration-time (AUC) increased with larger doses of dolasetron, while terminal disposition half-life (t1/2) and apparent clearance (Clapp) were not significantly changed with respect to dose. For 1.8-mg/kg dolasetron, the t1/2 was 4.98 hr and the maximum plasma concentration (tmax) 0.47 hr. Adverse events were mild to moderate. No serious events occurred. Conclusions. This study suggests that a single intravenous dose of 1.8 mg/kg is the optimum single intravenous dose for controlling chemotherapy-induced emesis in pediatric patients.
Imaging features of leptomeningeal metastases.
AIMS: To assess the range of appearances, and accuracy of various methods of diagnosing leptomeningeal metastases. MATERIALS AND METHODS: In a retrospective study, the notes and imaging of all patients with a radiological and/or CSF cytological diagnosis of leptomeningeal metastasis (LM) were identified, and assessed for the following: age and sex, primary tumour type, presenting symptoms, initial radiological and cytological diagnosis, radiological appearances and length of survival following diagnosis. Discordance between the CSF cytology and radiological diagnosis of LM was also noted. RESULTS: 41 positive cases (36 female) of LM were identified over a 2.7 year period (diagnosis based on: imaging only--19 cases, cytology only--6, both--16 cases). The average age was 48 years, and the most frequent primary tumour was breast carcinoma (27/41). Two thirds of patients presented with at least one cranial or spinal nerve palsy. Where performed, contrast-enhanced CT was normal in 40% (10/25), with LM mistaken for parenchymal disease in a further 24% (6/25). CSF cytology was positive in 85% (22/26). Gadolinium-enhanced MRI was positive in all cases where it was performed (25/25). Pial enhancement and nodularity was the commonest finding (67%), but other manifestations included nodular disease, neural enhancement and white matter changes. Prognosis was uniformly poor. CONCLUSION: Leptomeningeal metastatic disease has a poor prognosis, and treatment regimen may differ from those of parenchymal CNS metastases. CT is normal or misleading in two thirds of patients, and CSF cytology may also be negative. Gadolinium-enhanced T1-weighted MRI complements CSF cytology, and is the investigation of choice in patients with a non-haematological primary tumour and suspected LM.
Evolution of viral quasispecies in interferon-treated patients with chronic hepatitis C virus infection.
BACKGROUND/AIMS: To evaluate whether interferon treatment failure/relapse is related to changes in hepatitis C virus quasispecies complexity (number of variants) or diversity (genetic relatedness of variants). METHODS: We analyzed hypervariable region heterogeneity in hepatitis C virus-infected patients by heteroduplex mobility assay and by phylogenetic analysis of sequenced clones. Sera from 11 patients were tested. Response was defined biochemically and virologically. Patients were treated with 3 or 6 MIU interferon for 6 months and followed up for 6 months. Four patients were non-responders, four were transient responders and three untreated patients served as controls. Three time points were studied for the non-responders (pre-interferon, end of interferon, end of 6 months of follow-up), two for the transient responders (pre-interferon and post follow-up) and two for the controls (1 year apart). A total of 260 clones were examined by heteroduplex mobility assay and 144 clones were sequenced. RESULTS: A linear correlation between heteroduplex mobility and nucleotide substitutions was observed, validating this method for assessment of quasispecies diversity. Although complexity at each time point was similar in all groups, diversity increased significantly with interferon treatment. The percentage of new variants in follow up was significantly higher in non-responders than in controls. These new variants exhibited a greater change in heteroduplex mobility, a higher percentage of changes in amino acids in non-responders compared to controls and were found to cluster separately from pretreatment variants when analyzed phylogenetically. These changes were less marked in transient responders. CONCLUSIONS: These mutations may allow hepatitis C virus to escape antiviral effects of interferon therapy.
Angiotropic large B-cell lymphoma with clinical features resembling subacute combined degeneration of the cord.
Angiotropic large cell lymphoma is a rare neoplastic disorder associated with a high mortality. The hallmark of the disease is lymphoid proliferation confined to the intravascular compartment without local tissue or vessel wall infiltration [1]. This feature is so striking that the disease was originally thought to arise from endothelial tissue and early cases were described as malignant angioendotheliomatosis. However, application of immunohistochemical methods for detection of lymphoid markers such as the CD45 and CD20 cell surface markers has confirmed its lymphoid origin, usually of B-cell lineage [2]. Clinical manifestations of the disease are protean and are due to multifocal medium and small vessel occlusion by tumour cells [3]. Characteristic sites of involvement are skin and central nervous system and although an ante-mortem diagnosis can be made from a biopsy specimen, it is often unsuspected [4]. We present a case of angiotropic large B-cell lymphoma in a 74-year-old man who presented with urinary symptoms and had a neurological picture resembling subacute combined degeneration of the cord.
Use of different outcome measures in randomised studies of malignant glioma can significantly alter the interpretation of time to progression: reanalysis of the MRC BR2 study.
The Medical Research Council (MRC) BR2 study [1] is a randomised trial of two doses of cranial radiation for patients with malignant glioma. We reanalysed data to examine the effect of using change in ranked scales of neurological status (MRC Neurological Status Scale) and performance (World Health Organisation Scale: WHO) to determine progression rather than clinician's impression. Four hundred and seventy four patients were studied. Where clinicians recorded no progression, ranked scales frequently documented progression (MRC 13%; WHO 13%). Where clinicians recorded progression, ranked scales frequently did not alter (MRC 33%; WHO 30%) or occasionally improved (MRC 5%; WHO 3%). When analysing time to progression based on a variety of measures, the estimated difference between treatments was most extreme (hazard ratio 0.81, logrank p = 0.04) when change in WHO status was used, and least extreme when change in MRC neurological status was used (hazard ratio 0.99, p = 0.94). This study highlights how different outcome measures can significantly alter the interpretation of randomised studies.
Phase II studies of RMP-7 and carboplatin in the treatment of recurrent high grade glioma. RMP-7 European Study Group.
The selective bradykinin analogue, RMP-7, transiently increases the permeability of the blood brain barrier and the delivery of hydrophilic agents into brain tumours. In 87 recurrent glioma patients (WHO Grade III/IV, median age 46, Karnofsky 70%) clinical and Magnetic Resonance Imaging (MRI) responses to i.v. cycles (q 28 days) of RMP-7 (300 ng/kg given as a 10 min infusion) and carboplatin (AUC 4-9) were assessed. 45 of these patients were chemotherapy naive (CN-RMP) and 42 had received one prior course of chemotherapy (CP-RMP). Neurological impairment, performance status and steroid use were measured prior to dosing at each cycle and tumour volume by 3-D MRI at the end of cycles 2, 4, 6, 9 and 12. Clinical evaluation of response demonstrated that 61% of CN-RMP patients were either stable or improved whilst this was 39% for CP-RMP patients, of which 37% and 8% improved respectively. Radiological evaluation showed 79% of CN-RMP patients were either stable, partial or complete responses and 24% for CP-RMP patients, of which 32% and 5% were CR or PR respectively. The median duration of response was 30.3 weeks in CN-RMP patients and 19.6 weeks in the CP-RMP group. Lack of response was associated with substantial baseline tumour volume. Drug toxicity was as previously reported for carboplatin. 11 patients had treatment-associated transient focal seizures. These results indicate that RMP-7 and carboplatin have significant activity in recurrent malignant glioma following radiotherapy.
Health, valuation of life, and the wish to live.
This research investigated the relationship of an affective-cognitive schema, valuation of life (VOL), to older people's responses to a set of health utility (years of desired life) questions. Six hundred healthy and chronically ill elders aged 70 and older were interviewed to measure quality of life (QOL), mental health, and VOL. Valuation of life was significantly correlated with longer Years of Desired Life under 8 of 10 health conditions when background, health, QOL, and mental health states were controlled. We concluded that VOL is an internal representation of the many positive and negative features of the person and her everyday life that is necessary to comprehend how people may cling to life or welcome its end.
Use of adjuvant ICE chemotherapy in the treatment of anaplastic ependymomas.
Despite the improved outcome for patients with ependymoma treated by surgery and radiotherapy, their prognosis remains relatively poor. To assess the impact of adjuvant chemotherapy, we reviewed the overall survival of consecutive patients with anaplastic ependymoma treated over a 10-year period with surgery and ICE (ifosfamide+ VP 16+carboplatin) chemotherapy with or without radiation at our institution. There were 11 patients (6 male, 5 female), with a median age of 3.4 years (range 1.2-1 1.1): 4 under 2 years and 7 were over 2 years old. Overall, 5 had gross total resections: 4 are alive, 2 in continuous complete remission and 2 in second complete remission. One patient who was less than 2 years old died. Among the 6 with subtotal resection, 2 achieved a complete remission after chemotherapy. However, 5 of the 6 patients have since died of progressive disease, with a median overall survival of 75 months. Overall survival was 24% and progression-free survival was 39%. In 2 of 6 patients with residual postoperative disease a temporary objective response was noted with adjuvant ICE chemotherapy. This regimen did not confer an overall survival advantage.
Comparison of survival outcomes in patients with intracranial germinomas treated with radiation alone versus reduced-dose radiation and chemotherapy.
Concern about long-term sequelae of irradiation has led to the use of adjuvant chemotherapy with lower dose irradiation in the treatment of intracranial germinomas. To assess the feasibility of this approach versus radiation only, the survival of 16 evaluable patients (13 boys, 3 girls) with biopsy-proven intracranial germinomas treated at the Hospital for Sick Children was assessed. Between 1977 and 1988, 8 patients were treated with radiation only: 7 received tumour doses between 4000 and 5100 cGy and spinal prophylaxis; 1 received 3060 cGy to the tumour with no prophylaxis. After a median follow-up of 84 months, 7 are in continuous first CR and 1 is in second CR. Between 1988 and 1996, 8 patients received adjuvant platinum- and etoposide-based chemotherapy for two or three cycles followed by local irradiation to the tumour (2500-3500 cGy). After a median follow-up of 40 months, 6 are in continuous first CR and 1 in second CR; 1 has died of progression. Survival outcomes in the two groups are similar. Prospective trials to assess event-free survivals, neurocognitive and neuroendocrine outcomes are needed before definitive treatment recommendations can be made.
Incidence studies of primary and secondary intracranial tumors: a systematic review of their methodology and results.
We reviewed the incidence studies of intracranial tumors to compare their methodology and identify whether there was evidence of true differences in incidence by time, place, age, or sex. Studies were identified from Medline (1966-95), bibliographies of relevant articles, and personal knowledge. For each study, various methodological details were recorded, along with the age-standardized incidence of all primary tumors and the crude and age/sex-specific incidences of different types of intracranial tumor. Methodological factors which significantly influenced the reported incidence were identified and the results of different studies were compared and combined in a meta-analysis if appropriate. Twenty studies (over 20,000 primary tumors) were included. Higher incidences of primary tumors were found in studies that: used many methods to identify cases (odds ratio [OR] 1.92); included a high percentage of asymptomatic patients (OR 2.03); did not require histologic confirmation of the diagnosis (OR 1.69). Studies from the 1980's reported higher incidences than in previous decades (OR 1.51), probably because of improved methodology. Comparable studies from the 1980's gave widely different incidence rates for all primary tumors (7.1-18.6 per 100,000 per year). In all studies, the incidence of neuroepithelial and meningeal tumors increased dramatically with age. Neuroepithelial tumors were 40% more common in men, whilst meningeal and cranial nerve tumors were about 80% and 40% more common in women, respectively. Further incidence studies are required to establish geographical and secular variations in the incidence of primary intracranial tumors but these must use comparable methodologies. Provisional guidelines for future studies are given.
Significant change in tests of neurological impairment in patients with brain tumours.
There is a need for valid objective tests of neurological improvement or deterioration to more accurately define response or progression in phase II studies of malignant glioma. The Edinburgh Functional Impairment Tests (EFIT) incorporate objective measures of upper and lower limb function, memory and a rating scale for dysphasia. We examined the intra-observer repeatability of the (EFIT) 24 hours apart in 55 patients with brain tumors and stable neurological disease and the inter-rater repeatability in 33 patients in the perioperative period (54 dual assessments). Intra-observer studies of the four subtests, failed to demonstrate any learning effect and showed close agreement. Inter-rater studies were affected by a treatment effect (steroids) and identified slight inter-rater bias for the ten meter walk. Altman-Bland plots showed that the level of agreement was less good in patients with more severe impairment. Correction for the severity of handicap was possible using a simple formulae: (timed tests: [rater 1 - rater 2]/[rater 1 + rater 2], Williams Delayed Recall Test [WDRT] (rater 1 - 2/81). Using this correction, all intra- and inter-rater variance of patients tested within 12 hours were < 0.2. A change of > or = 0.2 for the timed tests and WDRT, and a change in dysphasia score of > or = 2, represent a significant change in impairment using the EFIT. The EFIT should be a useful addition in phase II studies where objectively recording response or time to progression is important.
Expression of human bone morphogenic protein 7 in primary rabbit periosteal cells: potential utility in gene therapy for osteochondral repair.
A commonly encountered problem in orthopedics is bone and cartilage tissue injury which heals incompletely or without full structural integrity. This necessitates development of improved methods for treatment of injuries which are not amenable to treatment using current therapies. An already large and growing number of growth factors which play significant roles in bone remodeling and repair have been identified in the past few years. It is well established that bone morphogenic proteins induce the production of new bone and cartilage. An efficient method of delivery of these growth factors by conventional pharmacological means has yet to be elucidated. We wished to evaluate the use of retroviral vector-mediated gene transfer to deliver genes of therapeutic relevance for bone and cartilage repair. To determine the feasibility of using amphotropically packaged retroviral vectors to transduce primary rabbit mesenchymal stem cells of periosteal origin, primary periosteal cells were isolated from New Zealand white rabbits, transduced in vitro with a retroviral vector bearing both the nuclear localized lacZ marker gene and the neo(r) gene, and selected in G418. We used a convenient model for analysis of in vivo stability of these cells which were seeded on to polymer scaffold grafts and implanted into rabbit femoral osteochondral defects. The nuclear localized beta-galactosidase protein was expressed in essentially 100% of selected cells in vitro and was observed in the experimental explants from animals after both 4 and 8 weeks in vivo, while cells transduced with a retroviral vector bearing only the neo(r) gene in negative control explants showed no blue staining. We extended our study by delivering a gene of therapeutic relevance, human bone morphogenic protein 7 (hBMP-7), to primary periosteal cells via retroviral vector. The hBMP-7 gene was cloned from human kidney 293 cell total RNA by RT-PCR into a retroviral vector under control of the CMV enhancer/promoter. Hydroxyapatite secretion, presumably caused by overexpression of hBMP-7, was observed on the surface of the transduced and selected periosteal cells, however, this level of expression was toxic to both PA317 producer and primary periosteal cells. Subsequently, the strong CMV enhancer/promoter driving the hBMP-7 gene was replaced in the retroviral vector by a weaker enhancer/promoter from the rat beta-actin gene. Nontoxic levels of expression of hBMP-7 were confirmed at both the RNA and protein levels in PA317 producer and primary periosteal cell lines and cell supernatants. This work demonstrates the feasibility of using a gene therapy approach in attempts to promote bone and cartilage tissue repair using gene-modified periosteal cells on grafts.
Application of the MRC brain tumour prognostic index to patients with malignant glioma not managed in randomised control trial.
OBJECTIVES: The MRC brain tumour prognostic index, which uses clinical variables to place patients in different outcome categories, has not been evaluated on a cohort outside a randomised controlled trial. The aims of this study were to (a) determine in a large cohort of patients, derived solely from one centre and not in a clinical trial, whether the MRC prognostic index stratified patients for outcome; (b) compare actual outcomes with those obtained in the original studies; and (c) examine whether neuropathological diagnosis was an independent prognostic variable. METHODS: The MRC prognostic index was calculated for 236 patients with either glioblastoma or anaplastic astrocytoma managed at a dedicated neuro-oncology clinic in Edinburgh between 1989 and 1995. RESULTS: For this mixed population of malignant glioma the median survival was 8.6 months. Two year survival was 72.2% for patients with an MRC index score of 1-10; 36.3% for those with an index score of 11-15; 25.1% for those scoring 16-20; 20.4% with those scoring 21-25; 4.8% with those scoring 26-33; and 0% for those scoring 34-38. Exclusion of 79 patients who would not have been eligible for the MRC studies from which the index was derived, because they were either too old or did not receive radiotherapy, still resulted in a similar pattern of stratification but with significantly improved median survival times for the lowest two categories. Multivariate analysis of prognostic variables in the Edinburgh cohort showed that patients with anaplastic astrocytoma did significantly better than those with glioblastoma (p<0.001). CONCLUSIONS: Although there were some differences in median survival times between the patients in the original MRC studies and the Edinburgh cohort in similar prognostic categories and a tendency to improved two year survivorship in the Edinburgh cohort these differences have arisen because (a) the Edinburgh cohort was accrued about 10 years later than the study has shown that even outside the setting of a prospective controlled trial and with relaxed inclusion criteria the Medical Research Council (MRC) prognostic index is a robust predictor of outcome in patients with malignant glioma. Survival clearly declines as the prognostic index increases. Moreover, the prognostic model can be substantially improved by the addition of histology data, although there is some evidence that this will require complex modelling procedures.
Metastatic renal cell carcinoma in a child: 11-year disease-free survival following surgery.
A child with metastatic renal cell carcinoma (RCC) is presented. This case is unusual in that the patient has remained disease free for 11 years following surgery and only one course of chemotherapy prior to thoracotomy. The management of metastatic RCC is reviewed and the genetic mechanisms leading to its development briefly discussed.
Acute low back pain secondary to retroperitoneal hemorrhage in an elderly man.
Acute low back pain is a common complaint heard in the emergency room and in a physiatrist's practice. It is important to rule out occult pathology in patients with an atypical presentation. In the case presented here, the patient was elderly, developed back pain without preceding trauma or lifting, had a history of easy bruisability, had a large ecchymosis, and had worsening back pain with bedrest. An abdominal aortic aneurysm was ruled out and the patient was discovered to have a large retroperitoneal hemorrhage. He was diagnosed with acquired hemophilia secondary to factor VIII inhibitors. This has implications for physicians who treat patients with acute low back pain. They must be alert to potentially life-threatening causes of low back pain.
Neonatal oncology: diagnostic and therapeutic dilemmas.
Tumors are a rare but important cause of mortality and morbidity in the neonate. There is a wide spectrum of benign and malignant tumors that can occur, some of which have a unique presentation and behavior in this age group. It is important to recognize that tumors such as stage IVS neuroblastoma, which have a good prognosis in older children, may be rapidly fatal in the newborn and constitute an oncological emergency. Other tumors behave in a less aggressive fashion at this age than in the older child, and should not be overtreated. An increasing number of tumors are being detected by prenatal screening, and understanding of their natural history and management is important. Management of neonatal cancer requires knowledge also of the developmental biology of the neonate, of the way in which they handle drugs, and the increased potential for acute toxicity and long-term morbidity from chemotherapy and radiation therapy.