Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma.

BACKGROUND: Malignant melanoma, one of the most aggressive of all skin cancers, is increasing in incidence throughout the world. Surgery remains the cornerstone of curative treatment in earlier stages. Metastatic disease is incurable in most affected people, because melanoma does not respond to most systemic treatments. A number of novel approaches are under evaluation and have shown promising results, but they are usually associated with increased toxicity and cost. The combination of chemotherapy and immunotherapy has been reported to improve treatment results, but it is still unclear whether evidence exists to support this choice, compared with chemotherapy alone. No language restrictions were imposed. OBJECTIVES: To compare the effects of therapy with chemotherapy and immunotherapy (chemoimmunotherapy) versus chemotherapy alone in people with metastatic malignant melanoma. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register (14 February 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005), MEDLINE (2003 to 30 January 2006 ), EMBASE (2003 to 20 July 2005) and LILACS (1982 to 20 February 2006). References, conference proceedings, and databases of ongoing trials were also used to locate trials. SELECTION CRITERIA: All randomised controlled trials that compared the use of chemotherapy versus chemoimmunotherapy on people of any age, diagnosed with metastatic melanoma. DATA COLLECTION AND ANALYSIS: Two authors independently assessed each study to determine whether it met the pre-defined selection criteria, with differences being resolved through discussion with the review team. Two authors independently extracted the data from the articles using data extraction forms. Quality assessment included an evaluation of various components associated with biased estimates of treatment effect. Whenever possible, a meta-analysis was performed on the extracted data, in order to calculate a weighed treatment effect across trials. MAIN RESULTS: Eighteen studies met our criteria and were included in the meta-analysis, with a total of 2625 participants. We found evidence of an increase of objective response rates in people treated with chemoimmunotherapy, in comparison with people treated with chemotherapy. Nevertheless, the impact of these increased response rates was not translated into a survival benefit. We found no difference in survival to support the addition of immunotherapy to chemotherapy in the systemic treatment of metastatic melanoma, with a hazard ratio of 0.89 (95% CI 0.72 to 1.11, p=0.31). Additionally, we found increased hematological and non-hematological toxicities in people treated with chemoimmunotherapy. AUTHORS' CONCLUSIONS: We failed to find any clear evidence that the addition of immunotherapy to chemotherapy increases survival of people with metastatic melanoma. Further use of combined immunotherapy and chemotherapy should only be done in the context of clinical trials.

Colony stimulating factors for prevention of myelosupressive therapy induced febrile neutropenia in children with acute lymphoblastic leukaemia.

BACKGROUND: Acute lymphoblastic leukaemia (ALL) is the most common cancer in childhood and febrile neutropenia is a potentially life-threatening side effect of its treatment. Current treatment consists of supportive care plus antibiotics. Clinical trials have attempted to evaluate the use of colony-stimulating factors (CSF) as additional therapy to prevent febrile neutropenia in children with ALL. The individual trials do not show whether there is significant benefit or not. Systematic review provides the most reliable assessment and the best recommendations for practice. OBJECTIVES: To evaluate the safety and effectiveness of the addition of G-CSF or GM-CSF to myelosuppressive chemotherapy in children with ALL, in an effort to prevent the development of febrile neutropenia. Evaluation of number of febrile neutropenia episodes, length to neutrophil count recovery, incidence and length of hospitalisation, number of infectious disease episodes, incidence and length of treatment delays, side effects (flu-like syndrome, bone pain and allergic reaction), relapse and overall mortality (death). SEARCH STRATEGY: The search covered the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CANCERLIT, LILACS, and SciElo. We manually searched records of conference proceedings of ASCO and ASH from 1985 to 2003 as well as databases of ongoing trials. We consulted experts and scanned references from the relevant articles. SELECTION CRITERIA: We looked for randomised controlled trials (RCTs) comparing CSF with placebo or no treatment as primary or secondary prophylaxis to prevent febrile neutropenia in children with ALL. DATA COLLECTION AND ANALYSIS: Two authors independently selected, critically appraised studies and extracted relevant data. The end points of interest were:* Primary end points: number of febrile neutropenia episodes and overall mortality (death) * Secondary end points: time to neutrophil count recovery, incidence and length of hospitalisation, number of infectious diseases episodes, incidence and length of treatment delays, side effects (flu-like syndrome, bone pain and allergic reaction) and relapse. We conducted a meta-analysis of these end points and expressed the results as Peto odds ratios. For continuous outcomes we calculated a weighted mean difference and a standardised mean difference. For count data, meta-analysis of the logarithms of the rate ratios using generic inverse variance was employed. MAIN RESULTS: We scanned more than 5500 citations and included six studies with a total of 332 participants in the analysis. There were insufficient data to assess the effect on survival. The use of CSF significantly reduced the number of episodes of febrile neutropenia episodes (Rate Ratio = 0.63; 95% confidence interval (CI) 0.46 to 0.85; p =0.003, with substantial heterogeneity), the length of hospitalisation (weighted mean difference (WMD) = -1.58; 95% CI -3.00 to -0.15; p = 0.03), and number of infectious diseases episodes (Rate Ratio=0.44; 95%CI 0.24 to 0.80; p=0.002). In spite of these results, CSF did not influence the length of episodes of neutropenia (WMD = -1.11; 95% CI -3.55 to 1.32; p = 0.4) or delays in chemotherapy courses (Rate Ratio=0.77; 95%CI 0.49 to 1,23; p=0.28) . AUTHORS' CONCLUSIONS: Children with ALL treated with CSF benefit from shorter hospitalisation and fewer infections. However, there was no evidence for a shortened duration of neutropenia nor fewer treatment delays, and no useful information about survival. The role of CSF regarding febrile neutropenia episodes is still uncertain. Although current data shows statistical benefit for CSF use, substantial heterogeneity between included trials does not allow this conclusion.

Sustained coronary-risk-factor reduction after gastric bypass for morbid obesity.

Lipids and clinical changes including diabetes and hypertension were monitored in morbidly obese patients after Roux-Y gastric bypass. Total cholesterol (Chol), high-density-lipoprotein (HDL) cholesterol, and triglycerides at 1 and at 5-7 y postoperatively in 33 patients and at 1 y in 23 patients (including apolipoproteins A-I and B) were compared with preoperative concentrations. Mean concentrations of Chol and both apolipoproteins were unchanged. Elevated serum triglycerides became normal, and reduced concentrations persisted at 5-7 y in men (p less than 0.025). HDL-cholesterol concentrations increased at 1 y (p less than 0.01) and remained higher at 5-7 y in women. Ratios of Chol to HDL cholesterol were lower at 1 y (p less than 0.01) in both men and women. Diabetes (9 patients) and hypertension (22 patients) also were reduced at 1 y (p less than 0.01) and remained lower at 5-7 y. A mean 61% of excess weight was lost in 1 y whereas a 12% weight gain occurred by 5-7 y. The beneficial changes in most coronary risk factors lasted 5-7 y after surgery.

Correlation of the extent of coronary occlusion with Apo B levels. Application of a new enzyme immunoassay technique for Apo B.

A new rapid and sensitive method for measurement of apolipoprotein B (Apo B) in plasma has been developed. This method, based on a Competitive Enzyme-Linked Immunoassay (CELIA), has been used to study the association between the extent of coronary artery occlusion as measured by coronary arteriography and the levels of plasma Apo B. The correlation between Apo B levels and some other plasma lipids was also determined. Significant relationship was found between the extent of coronary artery occlusion and Apo B, as well as between Apo B and plasma total cholesterol and plasma triglyceride levels.

The effect of dehydration on the elimination of aqueous contrast media from the subarachnoid space.

The frequency of side effects and complications from aqueous myelography is increased by dehydration. To study the effect of dehydration on the elimination of water-soluble contrast medium from the lumbar subarachnoid space, we measured iodine concentrations in the cerebrospinal fluid, serum, and urine for 24 hours after myelography in "hydrated" and "dehydrated" monkeys. Dehydrated animals were fasted for 12 hours prior to and 24 hours after myelography; hydrated animals received oral fluids ad libitum and 300 ml of intravenous fluids. Dehydrated animals had a lower concentration of contrast medium in the blood than hydrated animals. Dehydration slows the elimination of aqueous contrast medium from the lumbar subarachnoid space.

Elimination of aqueous myelographic contrast media from the subarachnoid space.

Elimination of aqueous contrast media from the lumbar subarachnoid space was measured. Iodine concentrations in serum and cisterna magna cerebrospinal fluid were studied in animals undergoing myelography with metrizamide, iocarmate, Iopamidol, or P-297. We found that all four contrast media were eliminated rapidly into the serum and urine, and transported slowly into the basal cisterns.

Excretion of aqueous myelographic contrast media in animals undergoing a repeat myelogram.

The rate of elimination of contrast media may be a factor in side effects and complications of aqueous myelography. The authors studied the effect of a previous myelogram and arachnoiditis on the elimination of aqueous contrast media from the subarachnoid space. Serum and cisternal CSF iodine concentrations were measured after experimental myelography in subhuman primates. The transfer of the aqueous contrast media from CSF to serum was slowed and the circulation with the cerebrospinal fluid into the intracranial cisterns was increased by a previous myelogram or arachnoiditis.

Association of dehydroepiandrosterone sulfate, body composition, and physical fitness in independent community-dwelling older men and women.

OBJECTIVES: To determine the association of dehydroepiandrosterone sulfate (DHEAS), body composition, and physical fitness in independent community-dwelling men and women aged 60 to 80 years. DESIGN: Cross sectional analysis. PARTICIPANTS: Independent men and women, 60 years of age and older, living in urban and suburban communities of Southeastern Wisconsin. MEASUREMENTS: History, physical examination, physical activity level, and anthropometrics were measured for every subject. Total adipose mass (TAM) and lean body mass were measured using dual energy X-ray absorptiometry. Dehydroepiandrosterone sulfate, insulin-like growth factor-1 (IGF-1), total testosterone (TT), and free testosterone (FT) were measured using radioimmunoassay. Physical fitness was measured as VO2max using exercise stress tests. Blood for lipids was analyzed using standard assays. RESULTS: In men, the DHEAS was significantly correlated to age (r = -.32), TAM (r = -.27), percent fat (r = -.30), HDL cholesterol (r = .34), TT (r = .30), VO2max (r = .23), and percent lean body mass (% LBM) (r = .33). In women, the DHEAS was not significantly correlated to any of the variables examined except body mass index (BMI) (r = .23). In men, after partialling out age, DHEAS was significantly correlated to HDL, % fat, TAM, % LBM, and TT. Multivariate analysis for men revealed that high density lipoprotein cholesterol (HDL) was the strongest predictor of serum DHEAS level, followed by % LBM, BMI, and age. The men in the highest quartile of serum DHEAS levels were different from those in the lowest quartile in terms of age, TT, FT, % fat, TAM, % LBM, HDL, and low density lipoprotein (LDL) cholesterol level. No such differences were found in the two groups of women. CONCLUSION: In this group of independent community-dwelling older men, several factors were found to be associated with the serum DHEAS concentration, whereas in a group of older women, no such associations were identified with the exception of BMI. Men in the highest quartile of serum DHEAS level, compared with those with a serum DHEAS level in the lowest quartile, were younger, leaner, more fit, had higher TT and FT levels, and had a favorable lipid profile. No such differences were identified between the women in the highest and the lowest quartiles of serum DHEAS level.

Platelet aggregation and the ouabain-insensitive ATPase. Ecto-ATPase, reflection of membrane integrity.

The ecto-ATPase activity of washed human platelets has been characterized by a higher-performance liquid chromatographic method. Mg++ was found to stimulate ecto-ATPase activity more strongly than Ca++. The combination of Mg++ and Ca++ at increasing concentrations caused diminishing activity levels. Elevated ecto-ATPase activity was also found in platelets incubated with prostaglandin E1 (PGE1) or potassium cyanide (KCN). It is proposed that the increase of ecto-ATPase activity is related to the extrusion or exposure of plasma membrane containing a ouabain-insensitive ATPase. The role of ecto-ATPase in platelet aggregation is discussed in light of these findings.

Carcinoembryonic antigen and L-fucose in malignant and benign mammary disease.

A prospective study of 123 patients was undertaken to determine whether carcinoembryonic antigen (CEA) or L-fucose could be used as "tumor markers" to distinguish patients who had mammary cancer (41) from patients who had benign mammary disease (41) and patients who did not have mammary cancer (41). The predictive value of positive test results for both L-fucose and CEA was lower for patients who smoked than for those who did not. The sensitivities of CEA and L-fucose indicators are both below 55%. There were frequent false-positive and false-negative results. A substantial overlap in the levels of CEA and L-fucose was found for the patients who had mammary cancer and those who had benign mammary disease. CEA and L-fucose performed similarly in distinguishing cancer from benign disease. For patients who smoked, however, the predictive value of L-fucose was only 44%. The effect of smoking on L-fucose levels may account for discrepancies in L-fucose data reported in previous studies of mammary cancer. Neither CEA nor L-fucose were found to be of value in screening for mammary cancer.

Elevated salivary cortisol in the evening in healthy elderly men and women: correlation with bone mineral density.

BACKGROUND: Aging is associated with a loss of bone mineral density (BMD) in men and women. Loss of BMD can also be caused by hypercortisolemia in men or women at any age. This study measured salivary cortisol at 2300 h and 0700 h as indices of cortisol secretory activity in 228 elderly, community-dwelling subjects. Salivary cortisol results were correlated with BMD. We hypothesized that salivary cortisol is elevated at 2300 h in elderly people, and that salivary cortisol will correlate negatively with BMD. METHODS: Saliva was sampled at 2300 h (nadir in circadian rhythm) and 0700 h (peak in circadian rhythm) in 130 men (70.7 +/- 0.4 years old) and 98 women (70.0 +/- 0.4 years old); approximately half of the women were receiving hormone replacement therapy (HRT). BMD was measured by dual energy x-ray absorptiometry. RESULTS: Salivary cortisol at 2300 h was significantly elevated in men (2.3 +/- 0.1 nmol/L) and women (2.1 +/- 0.1 nmol/L) as compared to 73 younger controls (1.2 +/- 0.1 nmol/L; 37 +/- 1 year old). Salivary cortisol at 0700 h was not different between older subjects and younger controls. There was a significant negative correlation of lumbar (L2-4) BMD and 2300 h salivary cortisol in older women (r = -0.20, p = .05; n = 98); this correlation was significant only in women not on HRT. There was a highly significant negative correlation of lumbar (L2-4) BMD and 0700 h salivary cortisol in older men (r = -0.31, p = .0003). CONCLUSIONS: Salivary cortisol is a simple, nonstressful method for assessing activity of the hypothalamic-pituitary-adrenal (HPA) axis in the elderly population. A major finding was an elevation in the late night nadir in cortisol secretion. We also suggest that elevated cortisol secretion in elderly people may contribute to the age-related loss in bone mineral density and that this effect is prevented by HRT.

Probability of prostate cancer detection based on results of a multicenter study using the AxSYM free PSA and total PSA assays.

OBJECTIVES: The determination of the percentage of free prostate-specific antigen (%fPSA) enhances the specificity of prostate cancer (CaP) detection. This study was undertaken to assess the performance of %fPSA in differentiating benign prostate disease from CaP and to determine the CaP probability estimates using the AxSYM Free PSA and AxSYM Total PSA assays. METHODS: In this prospective study, 297 men, 50 years old or older, with a total PSA level between 4 and 10 ng/mL and a nonsuspicious digital rectal examination were enrolled at 10 clinical sites. All subjects underwent at least sextant prostate biopsies to establish the diagnosis. fPSA and total PSA (tPSA) levels were determined using the AxSYM Free PSA and AxSYM Total PSA assays. Percent fPSA values were compared with tPSA values to determine the appropriate cutoffs for prostate biopsy and to calculate the CaP probability estimates. RESULTS: The strongest predictor of CaP in a logistic regression model was %fPSA (odds ratio 2.29), which contributed significantly more than age or tPSA to the predictive model. In this study population, a %fPSA cutoff of 26.4% would have detected 96% of subjects with CaP (sensitivity) and would have eliminated 27.4% of unnecessary biopsies (specificity). CaP probability estimates ranged from 9% to 69% and increased as the %fPSA value decreased. Men with a %fPSA level of 10% or lower had a 69% probability of CaP, and men with a %fPSA level of greater than 26% had a 9% probability of CaP. CONCLUSIONS: Percent fPSA values can help differentiate CaP from benign prostate disease and reduce unnecessary biopsies in 27% of men 50 years old or older whose digital rectal examination was normal and whose tPSA level was between 4 and 10 ng/mL. A %fPSA result can assist the physician and patient in determining the probability of CaP and assessing the need for prostate biopsy.

Examination of a competitive enzyme-linked immunoassay (CELIA) technique and a laser nephelometric immunoassay technique for the measurement of apolipoprotein B.

A competitive enzyme-linked immunoassay (CELIA) technique for quantitative measurement of apolipoprotein B (Apo B) was developed. The method is a non-isotopic immunoassay that utilizes a soluble enzyme/antibody complex as a universal labeling reagent. The method was characterized according to precision, sensitivity, recovery and parallelism. The CELIA Apo B method was compared to a commercially available laser nephelometric immunoassay. We found that the nephelometric results were highly correlated with triglyceride levels and the nephelometric assay was susceptible to interference from lipemia or turbidity. The range of values obtained on 56 apparently healthy, fasting young adults was 0.35-1.25 g/l by the CELIA method and 0.40-1.00 g/l by the nephelometric immunoassay. The nephelometric method was more precise (coefficient of variation 5%) than the CELIA technique (CV 10%); however, the CELIA method seems to be less sensitive to interferences.

Plasma dopamine-beta-hydroxylase in uremia--increase in enzyme activity after renal transplantation.

Plasma dopamine-beta-hydroxylase in uremia. Plasma dopamine-beta-hydroxylase (DBH) activity was found to be low in 26 uremic patients when compared with 56 normal individuals (p less than 0.001). Hemodialysis caused only a slight increase in plasma DBH levels in the uremic group. In contrast, a group of kidney transplanted patients with a return of good renal function had DBH values similar to the normal group (p greater than 0.1). The mean plasma DBH activity in eight patients measured pre- and post-transplantation increased from 4.5 to 28 International Units/l (p less than 0.01). No evidence was found to indicate that the depressed levels of plasma DBH in uremia were secondary to genetic or enzyme inhibiting factors. It is suggested that low levels of DBH activity in patients with renal failure may be a consequence of altered sympathetic nervous activity which is known to occur in the uremic state.

Pharmacokinetic evaluation of a new oral cyclosporine formulation.

STUDY OBJECTIVE: To compare the pharmacokinetics of a new oral cyclosporine preparation with those of cyclosporine solution diluted in Isocal and the intravenous formulation. DESIGN: Randomized, crossover trial. SETTING: Tertiary care referral center. PATIENTS: Seven pediatric liver transplant recipients who were receiving oral cyclosporine as part of their immunosuppressive regimen. All patients completed the study. INTERVENTIONS: Pharmacokinetic studies were performed with the intravenous and oral dosage forms. Patients received one dose of intravenous cyclosporine, and then were randomized to receive their usual oral cyclosporine dose incorporated into a chocolate wafer or mixed with Isocal. After a minimum of 3 days, the alternative preparation was administered. Serial cyclosporine blood samples were collected at predetermined intervals for 12 hours after the third dose for each regimen. Concentrations were determined by high-performance liquid chromatography. The data for the three dosage forms were fit simultaneously with a two-compartment model. MEASUREMENTS AND MAIN RESULTS: No difference was seen in F, ka, Cmax, and tmax between the two oral cyclosporine preparations (p > 0.05). No new rejection episodes occurred during the study period. CONCLUSIONS: We conclude there is no difference in the bioavailability of the oral solution and the chocolate formulation. We believe the new preparation may increase patient compliance and ensure administration of a complete dose compared with the currently marketed solution.

Predictors of lean body mass and total adipose mass in community-dwelling elderly men and women.

As part of an ongoing longitudinal study, we analyzed cross-sectional data to identify the predictors of lean body mass (LBM) and total adipose mass (TAM) in community-dwelling elderly men and women. Body composition analysis was done using dual energy x-ray absorptiometry. A total 262 subjects (118 women and 144 men), 60 to 80 years of age, from the urban and suburban communities of southeastern Wisconsin were studied. In women, the age (r = -.18), body mass index (BMI) (r = .43), and waist-to-hip ratio (WHR) (r = .30), and in men, BMI (r = .45) and insulin-like growth factor-1 (IGF-1) (r = .32) were identified as predictors (P < .05) of LBM. In women, the BMI (r = .87), WHR (r = .21), and functional work capacity (VO2 max) (r = -.47), and in men, the BMI (r = .83), WHR (r = .52), dehydroepiandrosterone sulfate (DHEAS) (r = -.27), total testosterone (TT) (r = -.35), free testosterone (FT) (r = -.23), physical activity (LTE) (r = -.32), and VO2 peak (r = -.59) were identified as predictors of TAM. After partialling out age in addition to the predictors identified earlier, the VO2 peak was identified as a predictor (P < .05) of LBM in both women and men, and TT, FT, and LTE as predictors (P < .05) of LBM in men. We conclude that the BMI, WHR, and VO2 peak influences LBM and TAM in both women and men. Additionally, in men LBM and TAM is influenced by hormone profile.

Determination of reference intervals in the clinical laboratory using the proposed guideline National Committee for Clinical Laboratory Standards C28-P.

The Subcommittee on Reference Intervals of the National Committee for Clinical Laboratory Standards (NCCLS) has recently completed a proposed guideline, NCCLS Document C28-P, entitled "How to Define, Determine, and Utilize Reference Intervals in the Clinical Laboratory." This guideline document is an attempt to combine a concise set of procedures and recommendations, largely taken from the original literature, to form a standard, uniform, and reasonable protocol for determining population-based reference intervals. The intent of the guideline is to set forth the minimum requirements for the determination of a reliable and clinically useful reference interval. The subcommittee hopes the document will set a standard that upgrades the quality of reference intervals to a level worthy of their use in clinical medicine.

Human platelet aggregation and cAMP system--cAMP level, adenyl cyclase, phosphodiesterase.

The possibility of a direct and casual relationship between various parameters of the adenosine 3',5'-cyclic monophosphate (cAMP) system, e.g., the level of cAMP, adenyl cyclase activity and phosphodiesterase activity, and platelet aggregation was studied by measuring the effects of various environmental conditions, as well as metabolic inhibitors, aggregating agents and aggregation inhibitors upon these parameters. A competitive binding technique using 3H labeled cAMP was used to determine the level of cAMP in intact platelets, and a high performance liquid chromatographic method was developed to measure the adenyl cyclase and phosphodiesterase activities in the platelet membrane fraction. Although the availability of substrate adenosine triphosphate (ATP) correlated well with the amount of cAMP produced, and in turn the availability of cAMP seemed to have a direct effect upon the reversibility of shape changes induced by the various stimuli, the only effect upon aggregation concerned the extent to which it occurred. No direct correlation of the level of cAMP with either the actual inhibition or activation of the aggregation mechanism was observed.

Determination of erythrocyte adenosine triphosphate by liquid chromatography.

A method for measuring erythrocyte adenosine triphosphate utilizing anion exchange high-pressure liquid chromatography is described. The method is not subject to interferences inherent in methods involving hexokinase or the firefly system. The method is highly sensitive, reproducible and rapid. Adenosine diphosphate and adenosine monophosphate can also be analyzed if desired.