Maternal milk feedings reduce sepsis, necrotizing enterocolitis and improve outcomes of premature infants.

OBJECTIVE: Human milk (donor milk (DM) and/or maternal milk (MM)) feedings protect against late onset sepsis (LOS), necrotizing enterocolitis (NEC) and death. However, DM lacks many anti-infective components of MM. Therefore, we studied exclusive MM feedings to evaluate the full effect of human milk on infectious and other outcomes in premature infants. STUDY DESIGN: All infants born before 33 weeks postmenstrual age (PMA) who received exclusive (>95%) MM or exclusive preterm formula (PF) were included in this prospective investigation. RESULTS: Sixty-three infants (53%) received MM and 55 infants (47%) received PF. Both groups had similar baseline characteristics. Infants in the MM group achieved full enteral nutrition sooner (14±8 vs 19±15 days, P<0.03) and required a shorter duration of central venous lines (14±10 vs 22±21, P<0.005). Fewer infants in the MM group developed LOS (9 vs 19, P<0.05) and pneumonia (8 vs 16, P<0.05) than PF infants. Only one MM and five PF infants developed NEC (Bell stage ⩾II). Logistic regression analysis using PMA and prolonged rupture of membranes as covariates demonstrated an increased rate of NEC (odds ratio=8.85, CI=1.01 to 25.17, P=0.048) in PF infants. Periventricular leukomalacia (PVL) was more common in PF (4 vs 0, P=0.04) than in MM infants. CONCLUSION: Feedings of MM advanced more rapidly and were associated with fewer infections than PF. A possible protective effect of MM against PVL, not previously described, may be related to its immune and anti-inflammatory components.

Packed red blood cell transfusion is not associated with increased risk of necrotizing enterocolitis in premature infants.

OBJECTIVE: Recent reports have posited a temporal association between blood transfusion with packed red blood cells (BT) and necrotizing enterocolitis (NEC). We evaluated the relationship between BT and NEC among infants at three hospitals who were consented at birth into a prospective observational study of NEC. STUDY DESIGN: We used a case-control design to match each case of NEC in our study population of infants born at<33 weeks postmenstrual age (PMA) to one control infant using hospital of birth, PMA, birth weight and date of birth. RESULT: The number of transfusions per infant did not differ between 42 NEC cases and their controls (4.0 ± 4.6 vs 5.4 ± 4.1, mean ± s.d., P = 0.063). A matched-pair analysis did not identify an association of transfusion with NEC in either the 48-h or 7-day time periods before the onset of NEC. Stratifying on matched-sets, the Cox proportional hazard model did not identify any difference in the total number of BTs between the two groups (hazard ratio 0.78, 95% confidence interval 0.57 to 1.07, P = 0.11). CONCLUSION: In contrast to previous studies, our case-control study did not identify a significant temporal association between BT and NEC. Additional large prospective randomized studies are needed to clarify the relationship between BT and NEC.

Temporal lobe magnetic resonance spectroscopic imaging following selective amygdalohippocampectomy for treatment-resistant epilepsy.

OBJECTIVES: Magnetic resonance spectroscopic imaging (MRSI) may show circumscribed or extensive decreased brain N-acetyl aspartate (NAA)/creatine and phosphocreatine (Cr) in epilepsy patients. We compared temporal lobe MRSI in patients seizure-free (SzF) or with persistent seizures (PSz) following selective amygdalohippocampectomy (SAH) for medically intractable mesial temporal lobe epilepsy (mTLE). We hypothesized that PSz patients had more extensive temporal lobe metabolite abnormalities than SzF patients. MATERIALS AND METHODS: MRSI was used to study six regions of interest (ROI) in the bilateral medial and lateral temporal lobes in 14 mTLE patients following SAH and 11 controls. RESULTS: PSz patients had more temporal lobe ROI with abnormally low NAA/Cr than SzF patients, including the unoperated hippocampus and ipsilateral lateral temporal lobe. CONCLUSION: Postoperative temporal lobe MRSI abnormalities are more extensive if surgical outcome following SAH is poor. MRSI may be a useful tool to improve selection of appropriate candidates for SAH by identifying patients requiring more intensive investigation prior to epilepsy surgery. Future prospective studies are needed to evaluate the utility of MRSI, a predictor of successful outcome following SAH.

Randomized controlled trial of yoga and exercise in multiple sclerosis.

OBJECTIVE: To determine the effect of yoga and of aerobic exercise on cognitive function, fatigue, mood, and quality of life in multiple sclerosis (MS). METHODS: Subjects with clinically definite MS and Expanded Disability Status Score less than or equal to 6.0 were randomly assigned to one of three groups lasting 6 months: weekly Iyengar yoga class along with home practice, weekly exercise class using a stationary bicycle along with home exercise, or a waiting-list control group. Outcome assessments performed at baseline and at the end of the 6-month period included a battery of cognitive measures focused on attention, physiologic measures of alertness, Profile of Mood States, State-Trait Anxiety Inventory, Multi-Dimensional Fatigue Inventory (MFI), and Short Form (SF)-36 health-related quality of life. RESULTS: Sixty-nine subjects were recruited and randomized. Twelve subjects did not finish the 6-month intervention. There were no adverse events related to the intervention. There were no effects from either of the active interventions on either of the primary outcome measures of attention or alertness. Both active interventions produced improvement in secondary measures of fatigue compared to the control group: Energy and Fatigue (Vitality) on the SF-36 and general fatigue on the MFI. There were no clear changes in mood related to yoga or exercise. CONCLUSION: Subjects with MS participating in either a 6-month yoga class or exercise class showed significant improvement in measures of fatigue compared to a waiting-list control group. There was no relative improvement of cognitive function in either of the intervention groups.

Trafficking of superparamagnetic iron oxide particles (Combidex) from brain to lymph nodes in the rat.

Central nervous system (CNS) drainage may occur via connections to the vasculature, but in animal models up to 50% occurs via perivascular, perineural and primitive lymphatic drainage to cervical lymph nodes. We evaluated efflux of particles from the brain to cervical lymph nodes in normal rats, using Combidex iron oxide-based magnetic resonance imaging (MRI) agent. After intracerebral, intraventricular, intracarotid or intravenous injection of Combidex in normal Long Evans rats, particle localization was assessed by MRI and histochemistry for iron and the dextran coat (n = 27). Intraventricular or intracerebral injection, but not intracarotid administration of Combidex (100 micro g), resulted in MRI signal changes in the deep cervical lymph nodes around the carotid artery, and, less strongly, in the superficial cervical nodes. Within 2 h of Combidex administration, iron was histologically localized in cervical lymph nodes, with patched staining of capsule and peripheral sinus consistent with delivery via multiple afferent lymphatic vessels. Lymph node staining in groups receiving CNS Combidex was significantly different from controls (P < 0.0001) and was significantly localized in the deep vs. superficial cervical lymph nodes (P = 0.0003). The trafficking of the superparamagnetic iron particles from the CNS in the rat could be visualized by MRI and histology. Combidex provides a powerful tool to rapidly assess drainage of virus-sized particles from the CNS.

Telemedicine for the Medicare population: pediatric, obstetric, and clinician-indirect home interventions.

BACKGROUND: This report is a supplement to an earlier evidence report, Telemedicine for the Medicare Population, which was intended to help policymakers weigh the evidence relevant to coverage of telemedicine services under Medicare. That report focused on telemedicine programs and clinical settings that had been used with or were likely to be applied to Medicare beneficiaries. While we prepared that report, it became apparent that there are also telemedicine studies among non-Medicare beneficiaries--e.g., children and pregnant women--that could inform policymakers and provide more comprehensive evidence of the state of the science regarding telemedicine applications. In addition, the first evidence report only partially included a class of telemedicine applications (called self-monitoring/testing telemedicine) in which the beneficiary used a home computer or modern-driven telephone system to either report information or access information and support from Internet resources and indirectly interact with a clinician. Self-monitoring/testing applications in the first report required direct interaction with a clinician. The goal of this report is to systematically review the evidence in the clinical areas of pediatric and obstetric telemedicine as well as home-based telemedicine where there is indirect involvement of the health care professional. (In this report, we will refer to the latter as clinician-indirect home telemedicine.) Specifically, the report summarizes scientific evidence on the diagnostic accuracy, access, clinical outcomes, satisfaction, and cost-effectiveness of services provided by telemedicine technologies for these patient groups. It also identifies gaps in the evidence and makes recommendations for evaluating telemedicine services for these populations in the future. The evidence is clustered according to three categories of telemedicine service defined in our original report: store-and-forward, self-monitoring/testing, and clinician-interactive services. The three clinical practice areas reviewed in this report are defined as follows. The term pediatric applies to any telemedicine study in which the sample consisted wholly or partially of persons aged 18 or younger, including studies with neonatal samples. The term obstetric applies to any telemedicine study in which the sample consisted entirely of women seeking pregnancy-related care. The term clinician-indirect home telemedicine applies to home-based telemedicine (called self-monitoring/testing in our original report) where a telemedicine application used in the home has only indirect involvement by the health care professional. Interactive home telemedicine was applied in this report to all patient populations. KEY QUESTIONS: The key questions that served as a guide for reviewing the literature in the evaluation of pediatric, obstetric, and clinician-indirect home telemedicine applications were derived by consensus among the evidence-review team based on the analytic framework established for the original evidence report. For the current report, the questions were applied to studies in all three practice areas as a whole group within each of the three categories of telemedicine services: store-and-forward; self-monitoring/testing; and clinician-interactive. The specific key questions were: 1. Does telemedicine result in comparable diagnosis and appropriateness of recommendations for management? 2. Does the availability of telemedicine provide comparable access to care? 3. Does telemedicine result in comparable health outcomes? 4. Does telemedicine result in comparable patient or clinician satisfaction with care? 5. Does telemedicine result in comparable costs of care and/or cost-effectiveness? METHODS: We searched for peer-reviewed literature using several bibliographic databases. In addition, we conducted hand searches of leading telemedicine journals and identified key papers from the reference lists of journal articles. For our original evidence report on telemedicine for the Medicare population, we designed a search to find any publications about telemedicine and used it to search the MEDLINE, CINAHL, and HealthSTAR databases for all years the databases were available. Through this process, we captured studies of pediatric, obstetric, and clinician-indirect home telemedicine; however, they were excluded from the original report since they were outside its scope. For this supplemental report, we reviewed our original search results and identified studies relevant to this report. We identified additional studies from the reference lists of included papers and from hand searching two peer-reviewed telemedicine publications, the Journal of Telemedicine and Telecare and Telemedicine Journal. We critically appraised the included studies for each study area and key question and discussed the strengths and limitations of the most important studies at weekly meetings of the research team. We also developed recommendations for research to address telemedicine knowledge gaps. To match these gaps with the capabilities of specific research methods, we classified the telemedicine services according to the type of evidence that would be needed to determine whether the specific goals of covering such services had been met. We emphasized the relationship between the type and level of evidence found in the systematic review of effectiveness and the types of studies that might be funded to address the gaps in knowledge in this growing field of research. FINDINGS: We identified a total of 28 eligible studies. In the new clinical areas, we found few studies in store-and-forward telemedicine. There is some evidence of comparable diagnosis and management decisions made using store-and-forward telemedicine from the areas of pediatric dental screening, pediatric ophthalmology, and neonatalogy. In self-monitoring/testing telemedicine for the areas of pediatrics, obstetrics, and clinician-indirect home telemedicine, there is evidence that access to care can be improved when patients and families have the opportunity to receive telehealth care at home rather than in-person care in a clinic or hospital. Access is particularly enhanced when the telehealth system enables timely communication between patients or families and care providers that allows self-management and necessary adjustments that may prevent hospitalization. There is some evidence that this form of telemedicine improves health outcomes, but the study sample sizes are usually small, and even when they are not, the treatment effects are small. There is also some evidence for the efficacy of clinician-interactive telemedicine, but the studies do not clearly define which technologies provide benefit or cost-efficiency. Some promising areas for diagnosis include emergency medicine, psychiatry, and cardiology. Most of the studies measuring access to care provide evidence that it is improved. Although none of these studies were randomized controlled trials, they provide some evidence of access improvement over prior conditions. Clinician-interactive telemedicine was the only area for which any cost studies were found. The three cost studies did not adequately demonstrate that telemedicine reduces costs of care (except comparing only selected costs). No study addressed cost-effectiveness. CONCLUSIONS: This supplemental report covering the areas of pediatrics, obstetrics, and indirect-clinician home telemedicine echoes the findings of our initial report for the Medicare domain, which is that while the use of telemedicine is small but growing, the evidence for its efficacy is incomplete. Many of the studies are small and/or methodologically limited, so it cannot be determined whether telemedicine is efficacious. Future studies should focus on the use of telemedicine in conditions where burden of illness and/or barriers to access for care are significant. Use of recent innovations in the design of randomized controlled trials for emerging technologies would lead to higher quality studies. Journals publishing telemedicine evaluation studies must set high standards for methodologic quality so that evidence reports need not rely on studies with marginal methodologies.

Oregon physicians' attitudes about and experiences with end-of-life care since passage of the Oregon Death with Dignity Act.

CONTEXT: The Oregon Death with Dignity Act, passed by ballot measure in 1994 and enacted in October 1997, legalized physician-assisted suicide for competent, terminally ill Oregonians, but little is known about the effects of the act on clinical practice or physician perspective. OBJECTIVE: To examine Oregon physicians' attitudes toward and practices regarding care of dying patients since the passage of the Death with Dignity Act. DESIGN, SETTING, AND PARTICIPANTS: A self-administered questionnaire was mailed in February 1999 to Oregon physicians eligible to prescribe under the act. Of 3981 eligible physicians, 2641 (66%) returned the questionnaire by August 1999. MAIN OUTCOME MEASURES: Physicians' reports of their efforts to improve care for dying patients since 1994, their attitudes, concerns, and sources of information about participating in the Death with Dignity Act, and their conversations with patients regarding assisted suicide. RESULTS: A total of 791 respondents (30%) reported that they had increased referrals to hospice. Of the 2094 respondents who cared for terminally ill patients, 76% reported that they made efforts to improve their knowledge of the use of pain medications in the terminally ill. Nine hundred forty-nine responding physicians (36%) had been asked by a patient if they were potentially willing to prescribe a lethal medication. Seven percent of all survey participants reported that 1 or more patients became upset after learning the physician's position on assisted suicide, and 2% reported that 1 or more patients left their care after learning the physician's position on assisted suicide. Of the 73 physicians who were willing to write a lethal prescription and who had received a request from a patient, 20 (27%) were not confident they could determine when a patient had less than 6 months to live. CONCLUSION: Most Oregon physicians who care for terminally ill patients report that since 1994 they have made efforts to improve their ability to care for these patients and many have had conversations with patients about assisted suicide.

Association of total dose intensity of chemotherapy in primary central nervous system lymphoma (human non-acquired immunodeficiency syndrome) and survival.

OBJECTIVE: The importance of enhanced drug delivery in patients with central nervous system (CNS) malignancies has not yet been demonstrated conclusively. Intra-arterial chemotherapy in combination with osmotic bloodbrain barrier disruption (BBBD) increases drug delivery to tumor by 2- to 5-fold and to surrounding brain tissue by 10- to 100-fold as compared with intravenous administration of chemotherapy. Primary CNS lymphoma (PCNSL) is an excellent model for studying dose intensity because PCNSL is a highly infiltrative, chemosensitive, primary CNS malignancy in which the integrity of the blood-brain barrier is highly variable. METHODS: Survival time was assessed in 74 non-acquired immunodeficiency syndrome patients with PCNSL who underwent a total of 1047 BBBD procedures. Total dose intensity is estimated by using the number of intraarterial infusions or a cumulative degree of BBBD score. RESULTS: Using proportional hazards multivariable analyses to adjust for baseline characteristics, survival was significantly associated with the total intensity of BBBD (P < 0.05). Additional statistical analyses demonstrate that survival bias does not fully explain these associations. Even when only patients who attained a complete response are considered, increased dose intensity resulted in increased survival. CONCLUSION: In patients with PCNSL, a chemotherapy-responsive tumor type, survival time is highly associated with total drug dose delivered, even in analyses designed to control for potential survival biases. These results probably constitute the strongest evidence to date of the importance of total dose intensity in treating CNS malignancies.

Cost effectiveness of HMG-CoA reductase inhibition in Canada.

OBJECTIVE: To assess the cost effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor therapy, particularly atorvastatin, in primary and secondary prevention of coronary artery disease (CAD) in Canada. METHODS: A Markov model was developed in which costs and effectiveness of atorvastatin were compared with those of other statins and with no drug therapy in primary and secondary prevention of CAD. PATIENTS: Cost effectiveness was assessed for cohorts of patients with risk profiles defined by CAD status, age, sex, pretreatment low density lipoprotein cholesterol level and presence of sentinel coronary risk factors. Coronary risk was estimated by using initial and subsequent event coronary risk equations from the Framingham Heart Study, and risk factors were estimated by using Canadian population survey data. Recent estimates of the costs of CAD-related medical care in Canada were used to assign costs to health states and acute coronary events. INTERVENTIONS: Interventions included atorvastatin 10 mg, simvastatin 10 mg, pravastatin 20 mg, fluvastatin 20 mg, lovastatin 20 mg and no pharmacological therapy. RESULTS: Incremental cost effectiveness ratios (CDN$/year of life gained) relative to no therapy were lowest for atorvastatin and highest for pravastatin across all risk profiles. Atorvastatin was less costly and more effective than lovastatin, pravastatin and simvastatin in primary and secondary prevention, and conferred additional health benefits at a reduced cost per year of life gained compared with fluvastatin. CONCLUSIONS: Atorvastatin was found to be the most cost effective statin in primary and secondary prevention of CAD.

Delayed sodium thiosulfate as an otoprotectant against carboplatin-induced hearing loss in patients with malignant brain tumors.

Carboplatin is effective in the treatment of malignant brain tumors. However, when administered in conjunction with osmotic opening of the blood-brain barrier (BBB), carboplatin is ototoxic. The purpose of this study was to determine whether delayed administration of sodium thiosulfate (STS), given after BBB closure, provided protection against carboplatin ototoxicity. Patients underwent monthly treatment with intra-arterial carboplatin (200 mg/m2/day x 2) in conjunction with osmotic opening of the BBB, for up to 1 year. Audiological assessment was conducted at baseline and within 24 h before each monthly treatment. STS was administered i.v. as one (20 g/m2) or two (20 g/m2 and 16 g/m2) 15-min doses, depending on baseline hearing status. The initial group received the first STS dose 2 h (or 2 and 6 h) after carboplatin (STS2) and a subsequent group received STS 4 h (or 4 and 8 h) after carboplatin (STS4). Audiological data were compared with a historical comparison group (HCG) treated with carboplatin without STS. Spearman correlation coefficients comparing STS 2 (n = 24), STS4 (n = 17), and HCG (n = 19) indicated significantly lower rates of ototoxicity with increased delay in STS (P = 0.0006). On the basis of the analysis of hearing levels, there were significant differences among the two STS groups and HCG at 8000 Hz (P = 0.0010) and at 4000 Hz (P = 0.0075). The log-rank test for time to ototoxicity indicated a significant difference between STS4 and HCG (P = 0.0018). Delayed STS was effective in protecting against carboplatin-induced hearing loss. STS delayed to 4 h after carboplatin significantly decreased time to development of ototoxicity and rate of ototoxicity when compared with HCG.

A comparison of stereoscopic fluorescein angiography with indocyanine green videoangiography in age-related macular degeneration.

PURPOSE: To correlate features of indocyanine green (ICG) videoangiography with stereo film fluorescein angiography (FA) in the analysis of age-related macular degeneration (AMD). DESIGN: A retrospective study with concurrent comparison of two methods of assessment on one set of patients with AMD undergoing sequential FA-ICG videoangiography. METHODS: One hundred four patients with AMD who had undergone immediately sequential FA-ICG videoangiography were selected in a consecutive fashion from the photographic files of the Casey Eye Institute. Three interpreters independently graded in an unbiased fashion the FA features of AMD. These were compared with ICG videoangiography features of hypocyanescence (ICG videoangiography hypofluorescence), moderate or intense hypercyanescence (ICG videoangiography hyperfluorescence), or absence of fluorescence over background (ICG videoangiography isocyanescence). We also assessed ICG videoangiography features in the opposite eye of those with choroidal neovascularization (CNV) by FA in one eye by examining an additional 96 FA-ICG videoangiography scans. MAIN OUTCOME MEASURES: Outcomes were the ICG videoangiography characteristics of classic and occult CNV, serous pigment epithelial detachments (SPEDs) both with and without CNV, macular hemorrhage, and the comparative size of these features. RESULTS: There were 25 eyes that had significant macular hemorrhage by FA. Of these, the FA revealed CNV in its entirety under or near the hemorrhage in 11. The ICG examination revealed all 11 plus an additional 12 hypercyanescent features that were not visible by FA. Although 26 of 32 SPEDs had CNV by FA analysis, 31 of 32 had well-defined hypercyanescence under or at the SPED edge by ICG videoangiography. Eighty-seven percent of eyes with classic choroidal neovascular membranes (CCNV; 20 of 23) and 93% of eyes with fibrovascular pigment epithelial detachments (FVPED; 66 of 71) were hypercyanescent with distinct edges. Fifty percent of eyes with only late leakage of undetermined source (LLUS) were hypercyanescent, whereas 50% were isocyanescent on ICG videoangiography. There were four of 104 eyes in which ICG videoangiography revealed poorly defined hypercyanescent areas when, by FA, there were only drusen or elevated blocked fluorescence. Indocyanine green videoangiography revealed only three eyes with poorly defined hypercyanescence of 200 fellow eyes in patients with unilateral AMD. CONCLUSIONS: Indocyanine green videoangiography correlated fairly well with stereoscopic FA for the presence of CCNV or FVPED, but correlated poorly when LLUS was present. In certain cases where CNV was associated with SPED or macular hemorrhage, ICG videoangiography demonstrated features not apparent on FA.

Physicians' experiences with the Oregon Death with Dignity Act.

BACKGROUND: Physician-assisted suicide was legalized in Oregon in October 1997. There are data on patients who have received prescriptions for lethal medications and died after taking the medications. There is little information, however, on physicians' experiences with requests for assistance with suicide. METHODS: Between February and August 1999, we mailed a questionnaire to physicians who were eligible to prescribe lethal medications under the Oregon Death with Dignity Act. RESULTS: Of 4053 eligible physicians, 2649 (65 percent) returned the survey. Of the respondents, 144 (5 percent) had received a total of 221 requests for prescriptions for lethal medications since October 1997. We received information on the outcome in 165 patients (complete information for 143 patients and partial for on an additional 22). The mean age of the patients was 68 years; 76 percent had an estimated life expectancy of less than six months. Thirty-five percent requested a prescription from another physician. Twenty-nine patients (18 percent) received prescriptions, and 17 (10 percent) died from administering the prescribed medication. Twenty percent of the patients had symptoms of depression; none of these patients received a prescription for a lethal medication. In the case of 68 patients, including 11 who received prescriptions and 8 who died by taking the prescribed medication, the physician implemented at least one substantive palliative intervention, such as control of pain or other symptoms, referral to a hospice program, a consultation, or a trial of antidepressant medication. Forty-six percent of the patients for whom substantive interventions were made changed their minds about assisted suicide, as compared with 15 percent of those for whom no substantive interventions were made (P<0.001). CONCLUSIONS: Our data indicate that in Oregon, physicians grant about 1 in 6 requests for a prescription for a lethal medication and that 1 in 10 requests actually result in suicide. Substantive palliative interventions lead some--but not all--patients to change their minds about assisted suicide.

Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma.

OBJECTIVE: Patients with non-acquired immunodeficiency syndrome-related primary central nervous system lymphomas have the potential to achieve durable complete responses without radiotherapy, with treatment using enhanced chemotherapy delivery with blood-brain barrier disruption (BBBD). Reported 5-year survival rates with combined chemotherapy and radiotherapy were generally only 9 to 22% and were associated, in one study, with an overall 32% incidence of overt dementia and ataxia, which are dramatically increased among patients more than 60 years of age. METHODS: At the Oregon Health Sciences University, 111 consecutive patients with non-acquired immunodeficiency syndrome-related central nervous system lymphomas were prospectively treated with methotrexate-based, BBBD-enhanced chemotherapy and underwent formal neuropsychological evaluations. Of those, 74 patients had no systemic lymphoma and had received no prior irradiation; those 74 patients are described in this report. RESULTS: The estimated 5-year survival rate for this group was 42%, and the median survival time was 40.7 months. Overall, 48 patients (65%) exhibited complete responses and 36 patients continued to exhibit complete responses after 1 year of BBBD-enhanced chemotherapy. Of those 36 patients, none demonstrated evidence of cognitive loss in neuropsychological tests and/or clinical examinations. CONCLUSION: BBBD-enhanced chemotherapy delivery, without subsequent radiotherapy, resulted in favorable survival and cognitive outcomes for patients with primary central nervous system lymphomas who had not previously undergone irradiation. A cooperative multicenter study of intravenous chemotherapy without radiotherapy versus BBBD-enhanced chemotherapy would address the feasibility and necessity of performing a Phase III study for these rare central nervous system malignancies.

Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors.

BACKGROUND: The aim of this study was to determine the safety and efficacy of intraarterial chemotherapy with osmotic opening of the blood-brain barrier (BBB) for the treatment of malignant brain tumors when administered across multiple centers. METHODS: Patients with primary central nervous system lymphoma (PCNSL), primitive neuroectodermal tumor (PNET), germ cell tumor, cancer metastasis to the brain, or low or high grade glioma were eligible. Prior to entry, magnetic resonance imaging or computed tomography brain scan, medical history, neurologic status, and Karnofsky performance status were reviewed at the coordinating center. Standardized anesthesia and intraarterial catheterization guidelines were followed by a multidisciplinary team at each center. Between March 1994 and November 1997, 5 universities treated 221 adult patients with intraarterial chemotherapy with or without osmotic opening of the BBB (2464 procedures). RESULTS: Of evaluable patients with PCNSL, 40 of 53 (75%) achieved complete response (CR). All evaluable patients with PNET (n = 17), metastatic disease (n = 12), or germ cell tumor (n = 4) achieved stable disease (SD) or better. Of 57 evaluable patients with glioblastoma multiforme, 45 (79%) achieved SD or better. Asymptomatic subintimal tear occurred in 11 of 221 patients (5%), pulmonary embolism in 6 of 221 (2.7%), and renal toxicity in 4 of 221 (1.8%). One patient with extensive glioma expired within 48 hours after treatment. CONCLUSIONS: Using standard guidelines and protocols, intraarterial chemotherapy with or without osmotic opening of the BBB is feasible across multiple centers with a low incidence of catheter-related complications. In patients with chemotherapy-sensitive tumors, such as PCNSL, PNET, germ cell tumor, and cancer metastasis to the central nervous system, enhanced delivery results in a high degree of tumor response, with an efficacy profile that is reproducible across multiple centers.

Cost-effectiveness of statins.

Currently, 6 hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are marketed in the United States (US). Given the wide variation in the prices and efficacy of statins, formal cost-effectiveness analysis may improve drug selection decisions. To assess the cost-effectiveness of statin therapy in primary and secondary prevention of coronary heart disease, we developed a model of the costs and consequences of lipid-regulating therapy and estimated the incremental cost-effectiveness of 5 statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) at usual starting doses versus no therapy. Drug effects on serum lipids were assessed using data approved by the US Food and Drug Administration for product labeling. Annual risks of coronary event occurrence were estimated using Framingham Heart Study coronary risk equations developed for use in this model. Current estimates of direct medical costs of coronary heart disease were used to assign costs to health states and acute coronary events. Main outcome measurements were net cost (statin therapy minus savings in coronary heart disease treatment), gain in life expectancy, and cost per life-year saved. The maximum gain in life expectancy was achieved with atorvastatin, which also had a lower net cost than lovastatin, pravastatin, and simvastatin. Compared with fluvastatin, atorvastatin's greater effectiveness is attained at a lower cost per life-year saved. The cost-effectiveness of HMG-CoA reductase inhibition in primary and secondary prevention of coronary heart disease has been improved with the introduction of atorvastatin.

Tacrine hydrochloride treatment IND: methods for rapid physician and patient enrollment and data retrieval.

A Treatment IND (TIND) is a mechanism available to the Food and Drug Administration (FDA) in the United States by which promising new drugs can be provided to patients with life-threatening illnesses. In many instances, the illness is life-threatening but of relatively low incidence, making the demand for the new treatment limited. However, if the disease is more prevalent and incidence is increasing, the demand for access to an experimental therapy may be substantially greater. Novel approaches and technologies would help manage recruitment of physicians, enrollment of patients and retrieval and timely analysis of data. Such was the case in the TIND for tacrine hydrochloride (Cognex), a cholinesterase inhibitor which was under development for the treatment of patients with Alzheimer's Disease (AD). There were an estimated 4 million prevalent cases of AD in the US for which no approved therapeutic option was available at the time this TIND was initiated. We anticipated that there could be a large demand by both physicians and patients to enroll in the TIND. Therefore, to meet this demand, various mechanisms were employed to allow rapid enrollment and drug shipments to the patient. In addition, physicians who participated in the TIND were able to use a telephone touch-tone data entry system for reporting data and ordering new supplies of tacrine for their patients. Serious adverse events were reported directly to trained operators and summarized on a weekly basis for reporting to the FDA. At the time the programme was terminated, nearly 2000 physicians had enrolled to participate in the TIND and nearly 10,000 patients had received tacrine under the programme. The methods employed in this study to collect clinic visit and safety data met both regulatory and good clinical practice guidelines. In summary, a large volume of data was handled rapidly and efficiently in this programme.

Prediction of bone marrow iron findings from tests performed on peripheral blood.

After evaluating multiple tests, the authors have devised a scheme to predict bone marrow iron findings from tests performed on peripheral blood. They examined bone marrows from 97 consecutive patients with anemia who were divided into five marrow morphologic groups: (1) iron deficiency; (2) anemia of chronic disease; (3) abnormal sideroblasts; (4) ring sideroblasts; and (5) other. Tests of peripheral blood included hemoglobin, hematocrit, red blood cell count and red blood cell indices, reticulocyte count, sedimentation rate or zetacrit, ferritin, iron, iron binding capacity, free erythrocyte protoporphyrin, and tests of hepatic and renal function. Cluster analysis, multidimensional scaling, and logistic discriminant analysis were used to derive a graph of serum ferritin with the sedimentation rate, allowing accurate confirmation or exclusion of iron deficiency in most patients. Percent saturation of serum transferrin and serum ferritin allowed identification of only 50 percent of patients with abnormal or ring sideroblasts while excluding 100 percent of patients without abnormal or ring sideroblasts. In three years of follow-up, two of 19 patients with abnormal or ring sideroblast have developed the dysmyelopoietic syndrome or ANLL, respectively. With the aid of the two parameter graphs described, the authors believe the differential diagnosis of the hypoproliferative anemias relating to iron metabolism can frequently be made without examination of the bone marrow.