Caregivers' perception of adults with Down syndrome willingness to participate in research.

BACKGROUND: Historically, individuals with Down syndrome have been excluded from clinical research. Our objective was to assess the degree of interest adults with Down syndrome have in participating in research from the perspective of the caregivers who care for them. METHODS: We conducted an online survey of N = 390 caregivers of adults with Down syndrome and asked about interest in research participation and demographics. RESULTS: Caregivers were mostly family members, older than 55 years, and White. Caregivers reported that the adult with Down syndrome that they cared for would be more comfortable participating in research that was physiological, such as research involving fit bits (70.2% would participate), exercise (63.3%) or diet apps (53.9%), whereas they would be less likely to participate in clinical trials involving more invasive procedures such as injections (10.9%) and laboratory exams like MRIs (32.0%). We found little difference by age or gender of the adult with Down syndrome or by caregiver education level. CONCLUSIONS: Our survey identified high interest for less invasive studies, illustrating acceptability of observational and lifestyle studies. More effort may be needed to understand fear and barriers to participation and to create tools and methods to increase interest in more invasive studies.

Three palonosetron regimens to prevent CINV in myeloma patients receiving multiple-day high-dose melphalan and hematopoietic stem cell transplantation.

BACKGROUND: Explore safety and efficacy of three palonosetron-containing regimens for emesis prevention over 7 days in multiple myeloma (MM) patients receiving melphalan (100 mg/m(2)) and hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: Randomized, double-blind pilot study in MM patients (n=73) receiving 1, 2, or 3 days of 0.25 mg palonosetron (30-s i.v. bolus) 30 min before melphalan (days -2 and -1) and HSCT (day 0). Patients received dexamethasone (20 mg i.v., days -2 and -1) immediately before or after study drug/placebo. Daily diaries recorded emesis, rescue medication, nausea duration, and adverse events (AEs). RESULTS: Seven-day complete protection (no emesis) occurred in 41.7% [95% confidence interval (CI) 22.1% to 63.4%], 41.7% (95% CI 22.1% to 63.4%), and 44.0% (95% CI 24.2% to 65.1%) of patients receiving 1, 2, or 3 days of palonosetron, respectively (P=0.43). Complete response (emesis free without rescue medication) occurred in 8.3%, 20.8%, and 20.0% (P=0.14). Common AEs (≥10%) were mild-to-moderate diarrhea, constipation, headache, insomnia, and flatulence. No serious AEs occurred. CONCLUSIONS: Palonosetron with dexamethasone was safe and effective in preventing emesis in MM patients receiving melphalan and HSCT. This pilot study with a limited number of patients suggests that multiple doses of palonosetron could be more effective than a single dose in making patients emesis free without need for rescue medication. However, even multiple doses of palonosetron resulted in only 20% of patients being emesis free without rescue medication, suggesting that further improvement will require development of more effective combination antiemetic therapy.

The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer's type.

OBJECTIVE: To evaluate the production rate of CSF in patients with differing disease states. METHODS: The authors measured the production rate of CSF in three groups of patients: five patients with PD below age 60 (aged 51 +/- 4 years, mean +/- SD), nine with PD over age 60 (aged 69 +/- 6 years, mean +/- SD), and seven with dementia of the Alzheimer's type (AD) (aged 72 +/- 9 years, mean +/- SD). This method, based on the Masserman technique, employs ventricular rather than a lumbar access to the CSF space. Furthermore, the volume of CSF removed during the procedure is only 3 mL rather than 10 mL. RESULTS: These measurements indicate that the mean rate of CSF production in patients with PD under age 60 was 0.47 +/- 0.13 mL/minute, in patients with PD aged 60 or older the mean rate was 0.40 +/- 0.12 mL/minute, and in patients with AD the mean rate was 0.20 +/- 0.06 mL/minute. CONCLUSION: These results indicate that the rate of CSF production in patients with PD is normal, and that the rate of CSF production in patients with AD is markedly reduced.

Incidence, cost, and outcomes of bleeding and chemotherapy dose modification among solid tumor patients with chemotherapy-induced thrombocytopenia.

PURPOSE: To describe the incidence and outcomes of bleeding and chemotherapy dose modifications associated with chemotherapy-induced thrombocytopenia (platelets < 50,000/microL). PATIENTS AND METHODS: Six hundred nine patients with solid tumors or lymphoma were followed-up during 1,262 chemotherapy cycles complicated by thrombocytopenia for development of bleeding, delay or dose reduction of the subsequent cycle, survival, and resource utilization. The association between survival and bleeding or dose modification was examined using the Cox proportional hazards model. Predisposing factors were identified by logistic regression. RESULTS: Bleeding occurred during 9% of cycles among patients with previous bleeding episodes (P <.0001), baseline platelets less than 75,000/microL (P <.0001), bone marrow metastases (P =.001), poor performance status (P =.03), and cisplatin, carboplatin, carmustine or lomustine administration (P =.0002). Major bleeding episodes resulted in shorter survival and higher resource utilization (P <.0001). Chemotherapy delays occurred during 6% of cycles among patients with more than five previous cycles (P =.003), radiotherapy (P =.03), and disseminated disease (P =.04). They experienced similar clinical outcomes but used significantly more resources. Dose reductions occurred during 15% of cycles but were not associated with poor clinical outcomes or excess resource utilization. Significantly shorter survival and higher resource utilization were observed among the 20% of patients who failed to achieve an adequate response to platelet transfusion. CONCLUSION: The incidence of bleeding is low among solid tumor patients overall but exceeds 20% in some subgroups. These subgroups are easily identifiable using routinely available clinical information. A clinical prediction rule is being developed. Poor response to platelet transfusion is a clinically and financially significant downstream effect of thrombocytopenia and warrants further investigation.

Identifying risk factors for imminent death in cancer patients with acute dyspnea.

A substantial proportion of cancer patients presenting to an emergency center (EC) or clinic with acute dyspnea survives fewer than 2 weeks. If these patients could be identified at the time of admission, physicians and patients would have additional information on which to base decisions to continue therapy to extend life or to refocus treatment efforts on palliation and/or hospice care alone. The purpose of this study was to identify risk factors for imminent death (survival

Colony stimulating factors in patients with fever and neutropenia.

Colony stimulating factors (CSFs), are essential for the regulation of the hematopoietic system and were developed by the pharmaceutical biotechnology industry in the early 1990s for the prevention of serious neutropenic complication after myelosuppressive chemotherapy. Both G-CSF and GM-CSF consistently lead to an increase in circulating white blood cells and a reduction in the incidence of fever and neutropenia after myelosuppressive chemotherapy in patients with solid tumors, hematologic malignancies, and those undergoing stem-cell transplantation. Their role in improving response rates to chemotherapy and overall survival is less clear.

Time to clinical response: an outcome of antibiotic therapy of febrile neutropenia with implications for quality and cost of care.

PURPOSE: To determine whether antibiotic regimens with similar rates of response differ significantly in the speed of response and to estimate the impact of this difference on the cost of febrile neutropenia. METHODS: The time point of clinical response was defined by comparing the sensitivity, specificity, and predictive values of alternative objective and subjective definitions. Data from 488 episodes of febrile neutropenia, treated with either of two commonly used antibiotics (coded A or B) during six clinical trials, were pooled to compare the median time to clinical response, days of antibiotic therapy and hospitalization, and estimated costs. RESULTS: Response rates were similar; however, the median time to clinical response was significantly shorter with A-based regimens (5 days) compared with B-based regimens (7 days; P =.003). After 72 hours of therapy, 33% of patients who received A but only 18% of those who received B had responded (P =.01). These differences resulted in fewer days of antibiotic therapy and hospitalization with A-based regimens (7 and 9 days) compared with B-based regimens (9 and 12 days, respectively; P <.04) and in significantly lower estimated median costs ($8,491 v $11,133 per episode; P =.03). Early discharge at the time of clinical response should reduce the median cost from $10,752 to $8,162 (P <.001). CONCLUSION: Despite virtually identical rates of response, time to clinical response and estimated cost of care varied significantly among regimens. An early discharge strategy based on our definition of the time point of clinical response may further reduce the cost of treating non-low-risk patients with febrile neutropenia.

The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients.

PURPOSE: Febrile neutropenia remains a potentially life-threatening complication of anticancer chemotherapy, but some patients are at low risk for serious medical complications. The purpose of this study was to develop an internationally validated scoring system to identify these patients. MATERIALS AND METHODS: Febrile neutropenic cancer patients were observed in a prospective multinational study. Independent factors assessable at fever onset, predicting low risk of complications, on a randomly selected derivation set, were assigned integer weights to develop a risk-index score, which was subsequently tested on a validation set. RESULTS: On the derivation set (756 patients), predictive factors were a burden of illness indicating absence of symptoms or mild symptoms (weight, 5; odds ratio [OR], 8.21; 95% confidence interval [CI], 4.15 to 16.38) or moderate symptoms (weight, 3; OR, 3.70; 95% CI, 2.18 to 6.29); absence of hypotension (weight, 5; OR, 7.62; 95% CI, 2.91 to 19.89); absence of chronic obstructive pulmonary disease (weight, 4; OR, 5. 35; 95% CI, 1.86 to 15.46); presence of solid tumor or absence of previous fungal infection in patients with hematologic malignancies (weight, 4; OR, 5.07; 95% CI, 1.97 to 12.95); outpatient status (weight, 3; OR, 3.51; 95% CI, 2.02 to 6.04); absence of dehydration (weight, 3; OR, 3.81; 95% CI, 1.89 to 7.73); and age less than 60 years (weight, 2; OR, 2.45; 95% CI, 1.51 to 4.01). On the validation set, a Multinational Association for Supportive Care in Cancer risk-index score >/= 21 identified low-risk patients with a positive predictive value of 91%, specificity of 68%, and sensitivity of 71%. CONCLUSION: The risk index accurately identifies patients at low risk for complications and may be used to select patients for testing therapeutic strategies that may be more convenient or cost-effective.

Biologic effects of and clinical disorders caused by nonprotein amino acids.

Despite the fact that nonprotein amino acids are present in many commonly eaten foods, the biologic and clinical significance of this class of molecules has been largely overlooked. This is owing in part to their relatively low concentrations and their negligible nutritive value. Many of these compounds have the ability to interfere with a wide range of fundamental biochemical processes and cause disease. It is likely that the clinical effects of the ingestion of some nonprotein amino acids are yet to be described. Serious disorders in humans have followed the ingestion of these compounds as the result of food faddism, prodded by the commercial promotion of inadequately tested products. In view of the current popularity of herbal remedies and alternative medicine, these facts serve as another reminder to health care providers and the public at large about the need for critical analysis of the alleged benefits and the risks of exotic remedies and nutritional supplements. Beyond the public health issues they raise, non-protein amino acids take on significance because their misincorporation into proteins can trigger vigorous autoimmune attacks. To what extent this mechanism is responsible for highly prevalent diseases of autoimmunity remains to be determined.

Extraterrestrial handedness: a reply.

Recent investigations of stable isotope ratios of amino acids from the Murchison meteorite have shown them to be of unambiguous extraterrestrial origin, and examinations of their enantiomeric compositions, where terrestrial contamination can be excluded, have found a consistent excess of L-enantiomers. One explanation for this observation has been the asymmetric photolysis of racemic extraterrestrial amino acids by circularly polarized light (CPL) in the synchrotron radiation from orbiting electrons around the pulsar remnants of supernovae. Mason (1997) has attempted to discredit this mechanism on the grounds that circular dichroism (CD) bands for optically active molecules alternate in sign and sum to zero over the entire spectrum, and hence enantioselective photochemical reactions cannot be induced by broad band CPL. We submit arguments disputing this conclusion and present reasons for expecting that broad band CPL synchrotron radiation would be quite capable of inducing asymmetric photolysis, particularly in aliphatic amino acids.

The extraterrestrial origin of the homochirality of biomolecules--rebuttal to a critique.

Having concluded that abiotic terrestrial mechanisms would have been ineffectual for the origin of terrestrial homochirality, we have proposed an alternative extraterrestrial scenario involving stereoselective ultraviolet photolysis of the racemic constituents of interstellar grain mantles by circularly polarized synchrotron radiation from neutron stars, followed by terrestrial accretion of the resulting chiral molecules via cometary impact. Recently L. Keszthelyi (1995) has reviewed a number of our arguments and advanced several erroneous calculations and conclusions purporting to negate them. We offer here points of rebuttal to Keszthelyi's criticisms, and support our inferences with recent data regarding indigenous enantiomeric excesses of L-amino acids in the Murchison meteorite.

Influence of data display formats on physician investigators' decisions to stop clinical trials: prospective trial with repeated measures.

OBJECTIVE: To examine the effect of the method of data display on physician investigators' decisions to stop hypothetical clinical trials for an unplanned statistical analysis. DESIGN: Prospective, mixed model design with variables between subjects and within subjects (repeated measures). SETTING: Comprehensive cancer centre. PARTICIPANTS: 34 physicians, stratified by academic rank, who were conducting clinical trials. INTERVENTIONS: PARTICIPANTS were shown tables, pie charts, bar graphs, and icon displays containing hypothetical data from a clinical trial and were asked to decide whether to continue the trial or stop for an unplanned statistical analysis. MAIN OUTCOME MEASURE: Percentage of accurate decisions with each type of display. RESULTS: Accuracy of decisions was affected by the type of data display and positive or negative framing of the data. More correct decisions were made with icon displays than with tables, pie charts, and bar graphs (82% v 68%, 56%, and 43%, respectively; P=0.03) and when data were negatively framed rather than positively framed in tables (93% v 47%; P=0.004). CONCLUSIONS: Clinical investigators' decisions can be affected by factors unrelated to the actual data. In the design of clinical trials information systems, careful consideration should be given to the method by which data are framed and displayed in order to reduce the impact of these extraneous factors.

Evaluating cost-effectiveness in outpatient management of medical complications in cancer patients.

It has been estimated that 85% to 90% of all cancer patient care occurs in the outpatient setting, and the vast majority of chemotherapy is administered in the outpatient setting either in physician offices or hospital clinics. With the introduction of white blood cell growth factors in the early 1990s, dose-intensive regimens either for curative or palliative therapy became more common. Since that time, major dose-limiting toxicities have become gastrointestinal mucositis and chemotherapy-induced thrombocytopenia. Patient-reported symptoms have also become important as the changing financing and reimbursement for health care shifts the focus to a patient-centered, value-oriented approach in hematology and medical oncology. This paper will examine advances in the management of three common complications of antineoplastic therapy, mucositis, thrombocytopenia, and fatigue, with a particular emphasis on cost-effectiveness as it relates to value in health care.

Costs of blood transfusion: a process-flow analysis.

PURPOSE: To determine the cost of transfusing 2 units (U) of packed RBCs at a comprehensive cancer center. METHODS: We performed a process-flow analysis to identify all costs of transfusing 2 U of allogeneic packed RBCs on an outpatient basis to patients with either (1) solid tumor who did not undergo bone marrow transplantation (BMT), (2) solid tumor who underwent BMT, (3) hematologic malignancy who did not undergo BMT, (4) hematologic malignancy who underwent allogeneic BMT, or (5) hematologic malignancy who underwent autologous BMT. We conducted structured interviews to determine the personnel time used and physical resources necessary at all steps of the transfusion process. RESULTS: The mean cost of a 2-U transfusion of allogeneic packed RBCs was $548, $565, $569, $569, and $566 for patients with non-BMT solid tumor, BMT solid tumor, non-BMT hematologic malignancy, allogeneic BMT hematologic malignancy, and autologous BMT hematologic malignancy, respectively. Sensitivity analysis showed that total transfusion costs were sensitive to variations in the amount of clinician compensation and overhead costs, but were relatively insensitive to reasonable variations in the direct costs of blood tests and the blood itself, or the probability or extent of transfusion reaction. CONCLUSION: The costs of the transfusion of packed RBCs are greater than previously analyzed, particularly in the cancer care setting.

Relationship of senescence of cerebrospinal fluid circulatory system to dementias of the aged.

In common with other organ systems, the cerebrospinal fluid circulatory system is subject to senescence. Cerebrospinal fluid production and turnover rates decline. The choroid plexus calcifies and its blood supply falters. Microvascular disease violates the integrity of the blood-brain barrier. The arachnoid membranes thicken. Arachnoid villi occlude and degenerate. The consequent functional losses are exacerbated by the deterioration of other interacting organ systems. Eventually, the cerebrospinal fluid circulatory system may fail, resulting in stagnation, contamination, compositional deficiencies, and impaired clearance of noxious substances. The hypothesis is that senescence of the cerebrospinal fluid circulatory system plays a part in some dementias of the aged.

Ambulatory management of varicella-zoster virus infection in immunocompromised cancer patients.

Immunocompromised patients with varicella-zoster virus (VZV) infection are at greater risk for dissemination and the development of complications than immunocompetent individuals. Consequently, they are generally hospitalized in strict isolation rooms and treated with parenterally administered acyclovir. Although effective, this approach is expensive and creates logistic difficulties in the hospital. We treated 38 immunosuppressed cancer patients presenting to our ambulatory treatment center with VZV infections with intravenous acyclovir (500 mg/m2 8-hourly) in an ambulatory/home setting. Patients were monitored for success or failure of therapy, progression of infection, development of complications or drug toxicity, and satisfaction/compliance with therapy. Most patients (33, or 87%) responded to therapy. Among the failures, 2 patients had progressive VZV infection, 2 were hospitalized due to renal toxicity, and 1 developed a superinfection. All patients eventually responded and there were no deaths on this study. Two patients relapsed within 1 month of initial response. Both responded to retreatment with acyclovir, without hospitalization. The median duration of parenteral therapy with acyclovir was 7.5 days. Seven patients (18%) had to be switched to oral acyclovir (800 mg, 5 times a day) before complete response, owing to problems with venous access. All 7 completed therapy successfully. Overall, patients expressed a high level of satisfaction with outpatient therapy, and there were no instances of noncompliance or patient requests for withdrawal from study. The results of this study indicate that VZV infections in clinically stable immunosuppressed cancer patients are relatively benign and do not require hospitalization. Parenterally administered acyclovir in an ambulatory setting is effective therapy for such infections.

Mississippi mud in the 1990s: risks and outcomes of vancomycin-associated toxicity in general oncology practice.

BACKGROUND: Discrepancies between the severity of toxicities reported in early clinical trials and recent clinical experience with vancomycin have led to confusion regarding the need for routine serum vancomycin level monitoring and discontinuation of vancomycin when toxicities occur. Therefore, the authors examined the incidence, outcomes, and predictive factors of vancomycin-associated toxicities in general oncology practice with the goal of developing clinically relevant prediction rules and guidelines. METHODS: All 742 consecutive cancer patients who received vancomycin at a comprehensive cancer center during a 3-month period were followed prospectively for the development and outcome of phlebitis, rash, ototoxicity, and nephrotoxicity. Logistic regression was used to derive a multiple variable model of the risk of nephrotoxicity. A clinical prediction rule, the Nephrotoxicity Risk Score, was developed from the risk model and validated prospectively. RESULTS: Phlebitis occurred in 3% of patients (95% confidence interval [95% CI], 2-4%), predominantly those with recently inserted central venous catheters. Rashes occurred in 11% of patients (95% CI, 9-13%); however, all but 4 patients also were receiving beta-lactam antibiotics. Clinical evidence of ototoxicity developed in 6% of patients (95% CI, 4-9%) who were receiving vancomycin plus other ototoxic agents and only 3% of patients (95% CI, 2-5%) not receiving other ototoxic agents (P = 0.08). Nephrotoxicity occurred in 17% of patients (95% CI, 15-20%). Logistic regression revealed that factors associated with an increased risk of nephrotoxicity included administration of other mild to moderate (P = 0.01) or severely nephrotoxic agents (P < 0.001) or an acute physiology and chronic health evaluation (APACHE) score > 40 (P = 0.002). Elevated serum vancomycin peak levels did not reliably predict subsequent nephrotoxicity. CONCLUSIONS: Vancomycin-associated toxicities usually are mild and self-limiting. Some patients are at a significantly higher risk of nephrotoxicity but the authors believe these individuals can be identified reliably with the Nephrotoxicity Risk Index using information available at vancomycin initiation. Further testing of the Nephrotoxicity Risk Index is ongoing.