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At least 145 records · Page 8Linked to original sources

PubMed2005

Volume-related sequence of tumor distribution pattern in prostate carcinoma: importance of posterior midline crossover in predicting tumor volume, extracapsular extension, and seminal vesicle invasion.

AIM: To evaluate intraprostatic distribution of prostate carcinoma as a function of increasing tumor size and its potential clinical relevance. METHODS: Forty-six prostates with different tumor extent were three dimensionally reconstructed and analyzed with emphasis on number of separate tumors (multifocality) and its distribution on both sides of the urethral midline (laterality). RESULTS: Three tumor distribution patterns were identified: multiple bilateral without posterior midline crossover, multiple bilateral with crossover, and single bilateral (global) tumors. Unilateral tumors were rare (2%). The pattern of tumor distribution was associated with total tumor volume, presence and volume of high grade component, presence of extracapsular extension, and seminal vesicle involvement. Bilateral tumors with crossover were larger than bilateral tumors without crossover (Spearman's rho=0,728, P<0.001) and were associated with adverse pathological features including capsular penetration, seminal vesicle invasion, and surgical margin involvement. However, only high-grade volume was independently and highly associated with seminal vesicle involvement (OR=2.64, 95%, CI=1.181-5.340, P<0.001). Total (OR=2.53 [1.23-3.74], P<0.001) and index tumor (OR=2.54 [1.31-4.93], P<0.001) volumes were independently associated with capsular penetration. CONCLUSIONS: The distribution of bilateral prostatic carcinomas with and without crossover may have clinical relevance because of their relation to total and high-grade volume.

Adenocarcinoma↗

PubMed2005

Changes in crossover distribution along a quadrivalent in a man carrier of a reciprocal translocation t(11;14).

A testicular biopsy from an infertile man carrying a heterozygous chromosome translocation t(11;14) was studied with synaptonemal complex analysis and immunolocalization of the protein MLH1 for crossover detection. A full blockage of spermatogenesis at the spermatocyte stage was related to the presence of the translocation quadrivalents at pachytene. Only 2% of the quadrivalents showed full synapsis. Most of the spermatocytes showed asynaptic free ends that frequently mingled with the XY pair. The average number of crossovers per cell was diminished from a mean of 52.7 in controls to a mean of 48 in the patient. The difference between the number of crossovers in the quadrivalent and the normal bivalents was highly significant. The distribution of crossovers over the segment of the quadrivalent corresponding to bivalent #14 was also very different from that of the control. It is concluded that in this translocation, the pattern of crossovers is changed, mainly due to a synaptic hindrance in the quadrivalent, and that the spermatogenesis arrest is mainly due to the quadrivalents that interact with the XY pair.

Chromosomes, Human, Pair 11↗

PubMed1991

Intent-to-treat analysis and the problem of crossovers. An example from the Veterans Administration coronary bypass surgery study.

In randomized clinical trials of treatment for ischemic heart disease that compare medical with surgical treatment, many persons initially assigned to medical therapy eventually receive surgical intervention. For example, in the three major trials of bypass grafting for stable angina, crossover rates from medical to surgical therapy were approximately 25% at 5 years. For this reason, the classic intent-to-treat analyses have been criticized for their inability to evaluate the "true" effect of treatment. In this article we emphasize the concept of "initial treatment" as it applies to intent-to-treat analyses and examine four proposed alternative methods of analysis based on adherence with survival data from the Veterans Administration Cooperative Study to illustrate the concepts. The alternative methods include (1) censoring crossovers when treatment changes, (2) transferring crossovers from the original to the new treatment group when treatment changes, (3) excluding all crossovers from analysis, and (4) counting crossovers from the date of randomization in the treatment ultimately received group. We point out the biases attendant on analyses based on adherence and reaffirm the validity of intent-to-treat analysis.

Actuarial Analysis↗

PubMed1990

Use of crossover trials to obtain antihypertensive dose-response curves and to study combination therapy during the development of benazepril.

When a new drug is developed, one of the first requirements is to establish the correct dose. Unfortunately, in dose-determination studies, not enough lessons have been learned from the past. Pilot studies are often planned without sufficient statistical power, due to an insufficient number of patients and highly variable blood pressure measurements. In the development of the new angiotensin converting enzyme (ACE) inhibitor benazepril, crossover trials were used to obtain useful information. At the end of phase II of the benazepril development, a double-blind crossover study was carried out with 25 patients, and the results made it possible to redefine the 12- and 24-h effects of benazepril in comparison with placebo. Moreover, the crossover trial allowed an investigation of the biological effects of the treatment. In further work, the efficacy of 10 mg benazepril, administered once a day, was confirmed in comparison with captopril and enalapril, with a beta-risk of less than 20%. Since this crossover study yielded reliable data, and there was no carryover effect, a similar crossover design was used to study the interaction between benazepril and nifedipine. In the past, mistakes were made and many antihypertensive drugs were administered in high doses, with no further beneficial effect on blood pressure and an increased risk of side effects. Work described in this paper shows that fewer but better designed and implemented studies can improve the efficiency and value of dose-finding studies for antihypertensive drugs.

Antihypertensive Agents↗

PubMed1998

Role of crossover bypasses in the treatment of ischemia of the lower extremity.

AIM: To evaluate the role of crossover bypasses in the treatment of the lower extremity ischemia. METHODS: A retrospective study (1978-1997) included 51 patients with 52 femoro- or iliofemoral crossover bypasses. The most frequent indication for crossover bypass was unilateral thrombotic occlusion of the bifurcated graft or unilateral pelvic occlusion (49.0%) and the rest pain (40.4%). The main type of crossover reconstruction was "U" shaped, subcutaneous femorofemoral bypass. The first, third, and fifth year primary patency rates were evaluated using the life table analysis method. RESULTS: The cumulative patency rates were 91.3%, 73.9%, and 54.5% at 1, 3, and 5 years, respectively. Limb amputation had to be performed in five (9.6%) failed reconstructions. In four (7.7%) cases, thrombosis of reconstruction, and in one (1.9%) case, graft infection, caused the bypass occlusion. One patient (1.9%) died within 30 days after surgery from an acute myocardial attack. CONCLUSION: Crossover bypass is an attractive method because of its technical simplicity, low morbidity, and good long-term results.

Aged↗

PubMed2005

Bioequivalence trials with the incomplete 3 x 3 crossover design.

In bioequivalence trials, one often considers two or more generic products with the original one. The 3 x 3 crossover design can be adopted to evaluate the two generic candidates with a brand name drug, rather than conducting two separate 2 x 2 crossover trials. Dropouts, however, are more likely to occur due to various administrative reasons when we consider a higher order crossover design. A modified method, which was originally given by Chow and Shao (1997), is extended to compare two generic products with a reference in the incomplete 3 x 3 crossover design. A simulation study and discussion are also presented.

Computer Simulation↗

PubMedDate not supplied

Twin crossover relative potency analgesic assays in man. I. Morphine vs. morphine.

Although the four-point relative potency assay using crossover design has proven a powerful technique for the clinical evaluation of analgesics in patients with chronic pain, excessive dropouts have made this design impractical in postoperative pain. In a relative potency assay comparing single graded intramuscular doses of morphine standard and morphine test in postoperative patients, we have managed to circumvent this difficulty while preserving many of the advantages of a complete crossover by using the "twin-crossover" balanced incomplete block design, which requires that each subject receive only two of the four possible treatments. The "twin crossover" design, coupled with a sequential decision-making process that expedites choosing the doses of the test medication which are most closely equianalgesic with the standard, yielded excellent analgesic assay sensitivity and made efficient use of our population of postoperative patients.

Adult↗

PubMedDate not supplied

Crossover trials in clinical analgesic assays: studies of buprenorphine and morphine.

Analgesic studies of buprenorphine, a thebaine derivative and potent partial narcotic agonist, were carried out in patients with cancer who had postoperative or chronic pain. Intramuscular buprenorphine was compared with intramuscular morphine in a series of sequentially related, twin crossover assays and was found to be about 25 times as potent as morphine. Side effects were essentially morphine-like. In a second assay, the acceptability and analgesic activity of sublingual buprenorphine was studied in a 6-dose, balanced, incomplete block assay, a modification of the twin crossover design employed in the all-intramuscular trial. Sublingual buprenorphine was found to be about 15 times as potent as intramuscular morphine and was well accepted by our patients. The 4-dose twin crossover trial in which doses are adjusted sequentially is more flexible in that a wide range of doses may be studied, but it lacks the ability of the 6-dose design to provide estimates of the curvature of the dose-response slopes of the study drugs. When first-dose-only data were analyzed as parallel group assays, the main difference in results compared with the crossover studies was a decrease in efficiency and sensitivity.

Administration, Oral↗

PubMed1993

Analysis of crossover designs with multivariate response.

Crossover designs involve observing the same response variate under different experimental conditions for each subject. Univariate methods are commonly used for analysis of data arising in these designs, but multivariate procedures offer a more general approach. The general multivariate linear model provides a natural framework for the simplest data structure as well as more complex settings with two or more response variates and measurements repeated over time. Multivariate models for crossover designs provide a unified approach that clarifies specification of hypotheses, assumptions required, and testing procedures in a wide class of applications that include longitudinal data as a special case. We focus on the 2 x 2 crossover design, but also describe models for analysing more complex crossover designs.

Adolescent↗

PubMed1994

Fitting multivariate polynomial growth curves in two-period crossover designs.

We discuss the statistical analysis of data from two clinical trials using crossover designs. In both studies, response was observed repeatedly over time in each treatment period. The first study involves repeated measurements of a single response variable whereas the second involves bivariate response. Methods are described for fitting polynomial growth curves to achieve data reduction in a two-stage approach to the analysis of crossover designs. Thus, a multivariate parametric analysis frequently can be conducted even when the sample sizes are somewhat small as is the case in many crossover designs. Hypotheses that are usually of interest in crossover designs can be tested in the second stage of the analysis. Methods for testing the multivariate general linear hypothesis as a basis for statistical inference in such problems are discussed.

Allium↗

PubMed1991

Femorofemoral crossover bypass for noninfective complications of aortoiliac surgery.

Between 1973 and 1989, 39 femorofemoral crossover bypasses were performed to treat unilateral noninfective complications of aortoiliac surgery. The initial revascularization procedure, performed an average of 79.5 months previously, was an aortobifemoral bypass in 29 cases, an aorto- or iliofemoral bypass in six cases, an inlay graft for abdominal aortic aneurysm and aortoiliac endarterectomy in two cases each. The indications for femorofemoral crossover bypass included prosthetic occlusion in 35 cases, thrombosed false aneurysm in two, and further degradation after endarterectomy (iliac stenosis and occlusion in one case each). There was no operative mortality. One patient with acute ischemia upon admission and another with distal gangrene required below-knee and forefoot amputations, respectively. No amputations were required during the rest of the follow-up period. Three repeat aortobifemoral bypasses were performed because of occurrence of aortic or inflow vessel lesions. Primary and secondary actuarial five year patency rates for femorofemoral crossover bypasses were 59.7% and 78.4%, respectively. Femorofemoral crossover bypass can extend the benefits derived from direct aortoiliac surgery with low mortality and morbidity in the absence of associated aortic pathology (false aneurysm at the aortic implantation site or severe obstructive lesions).

Aged↗

PubMed2005

Applying a case-crossover study design to examine transient exposures in the transmission of N. meningitidis.

BACKGROUND: Meningococcal disease is a serious public health problem with a case fatality of about 10%. Recent acquisition of the bacteria is generally regarded as an important risk factor for developing the invasive disease. A case-crossover study to examine the effect of transient exposures on the acute outcome, which is the acquisition of Neisseria meningitidis, was undertaken. METHODS: In the case-crossover design each case serves as its own matched control while case-times are compared to earlier time periods. Data from a longitudinal study was used for a case-crossover analysis. About 1910 students aged 14-19 were tested for meningococcal carriage and interviewed about potential risk factors. About 121 matched pairs of students who were non-carriers in the first survey and became carriers in the second were analysed. Mantel Haenszel Odds Ratios were calculated and a conditional logistic regression analysis was done. RESULTS: Both bivariate and multivariate analysis showed a significant association between meningococcal carriage and the predicting variables rhinitis, visits to cinema, and travelling abroad. While the adjusted results for rhinitis (OR: 0.33; 95% CI: 0.13-0.82) and cinema visits (OR: 0.17; 95% CI: 0.05-0.65) indicate a protective association, travelling abroad (OR: 3.50; 95% CI: 1.45-8.34) turned out as a risk factor. CONCLUSIONS: Transient exposures that trigger the infection with N. meningitidis are generally difficult to study. This case crossover study allows new insights in this process. For the interpretation of the results methodological issues and potential confounding (e.g., seasonal variation) need to be taken into account, especially while comparing the results with those from studies with traditional designs.

Adolescent↗

PubMed2004

Use of the case-crossover design to study prolonged drug exposures and insidious outcomes.

PURPOSE: The case-crossover design was originally intended to study brief exposures with immediate and transient effects, and acute outcomes with abrupt onsets. We investigated whether case-crossover methods can be used to study prolonged exposures and insidious outcomes. METHODS: We conducted a case-crossover study of 8220 patients aged > or = 65 years enrolled in several health benefits programs in New Jersey during the period between 1991 and 1995. All had episodes of central nervous system (CNS) adverse events (e.g., delirium). Drug exposures were assessed during case time periods and control time periods lasting 1, 2, 3, or 4 months. Exposures included 3 active regimens with established deleterious CNS effects (corticosteroids, digoxin, and opiates) and 2 inactive regimens without such effects (multivitamins and statins). RESULTS: In conditional logistic regression models, significantly elevated risks were observed for all three active drugs, regardless of which time windows were used. The magnitude of these risks generally increased with longer time windows. No significantly increased risks were observed for the 2 inactive drugs, regardless of the window duration. CONCLUSIONS: These results suggest that with lengthened exposure assessment windows, case-crossover methods may be useful for studying exposures with prolonged effects and outcomes with insidious onsets.

Adrenal Cortex Hormones↗

PubMed2004

Giving patients a choice improves quality of life: a multi-centre, investigator-blind, randomised, crossover study comparing letrozole with anastrozole.

AIMS: Although the third-generation aromatase inhibitors are generally well tolerated, side-effects still occur in up to 40% of women. As more women are taking these drugs for longer, the issue as to which version is better tolerated is now a significant patient concern. This study aimed to assess whether tolerance for either letrozole or anastrozole can differ for each individual in terms of early quality of life (QoL), whether patients welcome being given a preference and whether this correlated with formal toxicity scoring. MATERIALS AND METHODS: A single-blind, crossover trial, with 72 women with breast cancer who had experienced tamoxifen failure. Randomised to either letrozole 2.5 mg or anastrozole 1 mg, for 4 weeks, 1 week off, then crossover for 4 weeks. RESULTS: Patients were confidently able to choose which drug suited them best (letrozole 68%, anastrozole 32%; P < 0.01). Fewer patients, when taking letrozole, experienced adverse events than when taking anastrozole (43% vs 65%; P = 0.0028). QoL was better when patients were taking letrozole than when they took anastrozole (P = 0.02). CONCLUSIONS: As toxicity and QoL strongly correlated with patient preference for either drug, albeit with a tendency towards letrozole, this suggests that patient preference is now a legitimate and useful end point for future crossover studies. In routine practice, women would warmly welcome extra involvement in the decision-making process via a crossover manoeuvre if side-effects develop, whichever aromatase inhibitor is prescribed initially.

Administration, Oral↗

PubMed2002

Negative selection of Plasmodium falciparum reveals targeted gene deletion by double crossover recombination.

The genome sequence of Plasmodium falciparum, the causative agent of the most severe form of malaria in humans, rapidly approaches completion, but our ability to genetically manipulate this organism remains limited. Chromosomal integration has only been achieved following the prolonged maintenance of circularised episomal plasmids which selects for single crossover recombinants. It has not been possible to construct genetic deletions via double crossover recombination, presumably due to the low frequency of this event. We have used the Herpes simplex virus thymidine kinase gene and the Escherichia coli cytosine deaminase gene for negative selection of P. falciparum. Parasites were transformed with plasmids expressing the thymidine kinase and cytosine deaminase genes by positive selection for the human dihydrofolate reductase gene. Parasites expressing thymidine kinase are susceptible to the pro-drug ganciclovir while those expressing cytosine deaminase are sensitive to 5-fluorocytosine. Parental parasites were inherently resistant to these drugs. A significant 'bystander effect' was evident in cultures with either ganciclovir or 5-fluorocytosine. Positive and negative selection of the thymidine kinase transformants with both ganciclovir and WR99210 resulted in the selection of parasites containing a genetic deletion of the Pfrh3 gene, the first targeted double crossover deletions in P. falciparum. The use of negative selection for gene disruptions via double crossover recombination will dramatically improve our ability to analyse protein function and opens the possibility of using this strategy for a variety of gene deletion and modification experiments in the analysis of this important infectious agent.

Animals↗

PubMed1997

Normalizing the crossover effect: enhancement of cognitive attentional processing in schizophrenia.

Thirty male schizophrenic subjects and 20 male control subjects were administered both the classic Rodnick and Shakow reaction time (RT) procedure and a modified experimental procedure using a balanced design in an attempt to enhance cognitive attentional processing and inhibit the crossover effect in schizophrenic patients. The experimental procedure increased the number of predictable trials, provided more information about the task and presented the regular trials in a simple ascending order. Analysis of the RT data showed the typical early schizophrenic crossover and late normal crossover on the standard task, while schizophrenic patients in the experimental condition showed a new finding of statistically significant normalization of the early crossover effect. The results support Shakow's theory of attentional set deficit in schizophrenia and in conjunction with previous findings suggest that separate neuropsychological mechanisms of cognitive preparatory attention and a more automatic form of vigilance attention may, respectively, underlie the regular and irregular procedures of the traditional RT task.

Adolescent↗

PubMed1998

Positive and negative schizotypal symptoms relate to different aspects of crossover reaction time task performance.

Although the expressions of both positive and negative symptoms in schizophrenia spectrum illnesses can each occur with varying degrees of severity, researchers have often dichotomized patients as generally positive or negative subtypes. Studies of schizophrenia and schizotypal personality disorder (SPD) have not typically controlled for the severity of the other symptom types when examining the relationship between positive and negative symptom subtypes and cognitive impairment. The present study investigated the relationship between the severity of both symptom types and reaction time crossover task performance in SPD in groups made equivalent on the severity of the other type of symptom. Fifty-eight out of 458 undergraduates were screened into one of four groups (high negative-high positive, low negative-low positive, high negative-low positive or low negative-high positive) by the Schizotypal Personality Questionnaire and assessed with the reaction time crossover task. The results indicated that negative schizotypal symptoms were associated with the early crossover pattern, while positive schizotypal symptoms related to longer overall reaction time. Therefore, different cognitive mechanisms involved in crossover task performance appeared to be associated with different symptom subtypes.

Adult↗

PubMed2002

Randomized, placebo-controlled, parallel group versus crossover study designs for the study of dementia in Parkinson's disease.

In studies of dementia, crossover designs are controversial, reflecting concerns about temporal stability of disease, confounding of treatment effects with period by treatment interactions and/or carryover effects. Carryover effects are differences in the lingering effect of treatments (placebo) into subsequent periods. In the context of a trial to study the effect of donepezil on dementia in patients with Parkinson's disease, we examine two-sequence crossover studies with two or four periods, and a four-sequence design with two periods. We quantify bias in estimated treatment effects due to carryover effects and explore the use of biased estimators in hypothesis testing. For hypothesis testing, type I error rates are valid if (1) repeated administration of treatment alters the outcome only for effective treatments and (2) carryover effects due to placebo following treatment periods are nonzero only for effective treatments. For crossover and parallel group designs, sample sizes are adjusted for reduced statistical power due to carryover effects and temporal changes in variance. For the proposed clinical study, we estimate that a single-period parallel group design with baselines would require 104 patients and take about 23 months to complete. A two-sequence, four-period parallel group design with baselines would require about 80 patients and about 20 months to complete. We conservatively assume a carryover effect of 50% of the treatment effect for a two-sequence four-period crossover design. The estimated treatment effect for this model may underestimate the true treatment effect by up to 13%. The sample size/study length requirements are 28 patients or 12.4 months, respectively, a substantial saving over either parallel group design. The cost of allowing for carryover in the sample size calculation is about 1.2 months of study time.

Bias↗