High Risk Of Therapeutic Failure Research Articles

Periacetabular Osteotomy for Symptomatic Acetabular Dysplasia in Patients ≥40 Years Old: Intermediate and Long-Term Outcomes and Predictors of Failure.

The Bernese periacetabular osteotomy (PAO) is controversial as a treatment for symptomatic acetabular dysplasia in patients ≥40 years of age. We conducted a retrospective study to evaluate the outcomes, measure the survival rate, and identify factors associated with PAO failure in patients ≥40 years of age. We performed a retrospective study of patients ≥40 years of age undergoing PAO. Study eligibility criteria were met by 166 patients (149 women; mean age, 44 ± 3 years), and 145 (87%) were followed for ≥4 years after PAO. We used a Kaplan-Meier curve with right-censoring to calculate survivorship, with "failure" defined as either conversion to or recommendation for total hip arthroplasty or a Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score of ≥10 at the most recent follow-up. We used simple logistic regression models to determine whether any preoperative characteristics were significantly associated with PAO failure. The median follow-up time was 9.6 years (range, 4.2 to 22.5 years). Sixty-one of 145 hips (42%, 95% confidence interval [CI] = 34% to 51%) experienced PAO failure during follow-up. The median survival time was 15.5 years (95% CI = 13.4 to 22.1 years). The median survival time was longer for hips with no or mild preoperative osteoarthritis: 17.0 years for Tönnis grade 0, 14.6 years for grade 1, and 12.9 years for grade 2. Higher preoperative Tönnis arthritis grades (p = 0.03) and worse WOMAC function scores (p < 0.001) were associated with an increased likelihood of failure. PAO is usually effective at improving function and is effective at preserving the hip in patients ≥40 years of age provided that they have good preoperative function and no or mild preoperative osteoarthritis (Tönnis grade 0 or 1). Patients who are ≥40 years old with advanced preoperative osteoarthritis (Tönnis grade 2) and those with poor preoperative dysfunction have a high risk of therapeutic failure after PAO. Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Overexpression of excision repair cross-complementing 1 gene associates with higher risk of therapeutic failure after definitive chemoradiation for unresectable non-small cell lung cancer.

Locally advanced non-small cell lung cancer (NSCLC) is typically treated with concurrent chemoradiation (CRT). Excision Repair Cross-Complementing 1 (ERCC1) is a protein involved in DNA damage repair. The objective of this study was to assess whether higher tumoral ERCC1 expression would associate with worse clinical outcomes in NSCLC treated with CRT. Twenty-five patients were included. Relative expression levels of messenger RNA (mRNA) for ERCC1 were measured with a quantitative reverse transcription polymerase chain reaction (qRT-PCR) and expressed as scaled ERCC1 mRNA gene expression value. Patients were followed every 3 months with history, physical exam, and imaging to assess clinical outcomes. We evaluated the associations between ERCC1, as well as other prognostic variables including stage, age, gender, race, histology, RT dose, performance status, and progression free survival (PFS) and overall survival (OS) with Kaplan-Meier method and Cox regression. Recursive partitioning analysis identified a GeneExp cutoff of 1.54. Higher ERCC1 expression was associated with worse PFS [hazard ratio (HR) =1.70, P=0.04] and trended towards worse OS (HR =1.53, P=0.11). Increasing tumor volume (HR =1.001, P=0.055), squamous cell (HR =7.86, P=0.008) and poorly differentiated histology (HR =5.25, P=0.06) also associated with worse OS. The cumulative incidence of local recurrence at 1 year trended higher with ERCC1 GeneExp ≥1.54 (78.1%) compared to ERCC1 GeneExp <1.54 (14.9%, P=0.08). Distant relapse at 1 year was 72% with tumor ERCC1 expression ≥1.54 and 52% with ERCC1 expression <1.54 (P=0.28). Higher ERCC1 expression by qRT-PCR appears to correlate with worse PFS in locally advanced NSCLC treated with CRT. However, the overall sample size of the population was small; thus, larger studies are warranted to integrate molecular biomarkers to identify patients who might benefit from treatment intensification.

An intensive monitoring of adverse drug reactions in pediatric hospitalized patients of a tertiary care hospital

Background: Children are at a higher risk of therapeutic failure due to major difference in pharmacokinetic, pharmacodynamics of drugs, off-label use and divergence of their illness from adult. The safety of drugs used in adult patients cannot be extrapolated to a pediatric age group. Hence, this study aimed to evaluate the incidence and overall pattern of adverse drug reactions in pediatric patients hospitalized in pediatric wards at a tertiary care hospital in India.Methods: Pediatric patients up to 12 years hospitalized in two randomly selected pediatric units were enrolled and followed up daily till discharge. Detailed information of patients and ADRs (adverse drug reactions) if any were recorded from case records. ADRs were assessed for incidence, onset, duration, management, outcome, causality, severity, preventability, seriousness and risk factors. Appropriateness of drug treatment in patients with ADRs was analyzed using Phadke’s criteria. Data was analyzed using student’s t test, ANOVA and Chi square test.Results: A total of 700 patients were enrolled (mean age 3.95±0.12 years). A total of 66 ADRs observed in 58 patients. Intravenous (70.4%) being most common route for ADRs. The incidence of ADRs was 8.28%. Majority of ADRs occurred within 1 day, commonly affected skin and appendages followed by (28.78%), GI (25.75%) ADRs were frequently associated with antimicrobials (69.38%) and vaccines and sera (12.24%). Majority of reactions were mild (56%%), non-serious (77.2%), not preventable (95.4%), recovered completely at discharge (83.33%) and had possible (77.2%) causal association with suspect drug. Age group 0-3 years and prescription of ≥5 drugs were risk factors for occurrence of ADRs. Semi rational drug therapy was observed in 65.5% patients.Conclusions: Clinicians should be vigilant regarding occurrence of ADRs in pediatrics especially during the first week of hospitalization. Risk factors like 0-3 years of age and multiple drugs should be taken into consideration during treatment of these patients to help minimize adverse drug reactions.

Digital PCR for Detection and Quantification of Fluoroquinolone Resistance in Legionella pneumophila.

The emergence of fluoroquinolone (FQ)-resistant mutants of Legionella pneumophila in infected humans was previously reported using a next-generation DNA sequencing (NGS) approach. This finding could explain part of the therapeutic failures observed in legionellosis patients treated with these antibiotics. The aim of this study was to develop digital PCR (dPCR) assays allowing rapid and accurate detection and quantification of these resistant mutants in respiratory samples, especially when the proportion of mutants in a wild-type background is low. We designed three dPCRgyrA assays to detect and differentiate the wild-type and one of the three gyrA mutations previously described as associated with FQ resistance in L. pneumophila: at positions 248C→T (T83I), 259G→A (D87N), and 259G→C (D87H). To assess the performance of these assays, mixtures of FQ-resistant and -susceptible strains of L. pneumophila were analyzed, and the results were compared with those obtained with Sanger DNA sequencing and real-time quantitative PCR (qPCR) technologies. The dPCRgyrA assays were able to detect mutated gyrA sequences in the presence of wild-type sequences at up to 1:1,000 resistant/susceptible allele ratios. By comparison, Sanger DNA sequencing and qPCR were less sensitive, allowing the detection of gyrA mutants at up to 1:1 and 1:10 ratios, respectively. When testing 38 respiratory samples from 23 legionellosis patients (69.6% treated with an FQ), dPCRgyrA detected small amounts of gyrA mutants in four (10.5%) samples from three (13.0%) patients. These results demonstrate that dPCR is a highly sensitive alternative to quantify FQ resistance in L. pneumophila, and it could be used in clinical practice to detect patients that could be at higher risk of therapeutic failure.

Intra-arterial chemotherapy of ENT cancers

The key element that has determined us to initiate a study concerning the benefits of intra-arterial chemotherapy is the fact that, despite progress regarding therapy, the ENT cancer prognosis is poor, especially in stages that have regional invasion, with a higher risk of therapeutic failure. ENT cancer treatment has raised many questions, the present therapeutic standard being simultaneous radio-chemotherapy with cisplatin, a quality regional control being obtained by hyper-fractionated radiotherapy, targeted on the tumour volume. The technical inconveniences that, in some cases, make impossible the accomplishment of a correct treatment, have determined us to make a retrospective analysis of the studies published in medical journals, with the aim of discerning a therapeutic method that has a role in increasing the loco-regional control of the disease. The studies speak about intra-arterial chemoinfusion with cisplatin, alongside radiotherapy, demonstrating with certainty the superiority of this method versus administrating the drug intravenously, in terms of local tumour control and tolerability. Because the benefits regarding the survival rate and the disease-free period have not reached the statistically significant level, intra-arterial chemoinfusion of cisplatin, alongside radiotherapy, remains a subject that is open to further studies. The efficacy of intra-arterial chemoinfusion of cisplatin hasn’t been studied in the case of a relapse, remaining still a subject that is worthy of being approached, seeing as this method was shown to be efficient regarding the safety profile, having a good tolerability and also having a good activity profile, leading to increase in the quality of life and an increase in survival through a local tumour control that is superior than in the case of intravenous administration of the drug.

Factors involved in continuance of atazanavir-based regimens: Results from a cohort of HIV1-positive patients

We evaluated predictive factors involved in durability and therapeutic failure of atazanavir (ATV)-based antiretroviral regimens with or without ritonavir (r) in real life setting. This retrospective study of HIV-1-positive patients evaluated the factors related to ATV continuance and the time-dependent probability of therapeutic failure (HIV-RNA >200 copies/mL and concomitant discontinuation of ATV). We also investigated the rate of therapeutic failure and the variations in total bilirubin levels from starting unboosted ATV-based regimens. The study involved 1030 patients: 183 treatment-naïve patients (17.8%) started ATV/r (17 subsequently switched to unboosted ATV); 653 (63.4%) switched to ATV/r from previous antiretroviral regimens (121 subsequently switched to unboosted ATV); and 194 (18.8%) switched to unboosted ATV from previous ATV-free regimens. The median ATV follow-up was 28 months (interquartile range 7–56). The risk of ATV discontinuation was significantly lower in patients switched to unboosted ATV from ATV/r (HR 0.45; p < 0.0001). The discontinuation of ATV correlated with female gender (HR 1.26; p = 0.035), use of a zidovudine/didanosine/stavudine containing backbone (HR 1.8; p = 0.004), and a baseline CD4+ cell counts of <200/μL (HR 1.54; p = 0.003), the last of which was also associated with a higher risk of therapeutic failure (HR 2.42; p = 0.001). Total bilirubin levels were significantly lower in the patients switching from ATV/r to unboosted ATV. Unboosted ATV-based therapies are safe and effective options in patients whose immuno-virological conditions are stable, and allow the long-term survival of ATV-containing regimeans.

Advances in therapy for Philadelphia-positive acute lymphoblastic leukaemia of childhood and adolescence.

The presence of the BCR/ABL1 fusion gene in childhood acute lymphoblastic leukaemia (ALL) is a rare finding and has been an adverse prognostic factor associated with a high risk of therapeutic failure. The current key components of treatment are intensive polychemotherapy and a BCR/ABL1 kinase domain inhibitor. This treatment approach has been applied in a few clinical trials by paediatric leukaemia study groups. Thus, this subtype of ALL serves as the first model system for truly targeted treatment. The role of haematopoietic stem cell transplantation (HSCT) is increasingly called into question, at least in a favourable, though not yet clearly defined, subset of patients. Currently, the choice of the most effective tyrosine kinase inhibitor is not yet settled, in particular, in view of potential reduction of overall treatment intensity.

The -174G/C Interleukin-6 Gene Promoter Polymorphism as a Genetic Marker of Differences in Therapeutic Response to Methotrexate and Leflunomide in Rheumatoid Arthritis.

Objective. To evaluate the association of -174G/C IL-6 polymorphism with failure in therapeutic response to methotrexate (MTX) or leflunomide (LEF). This prospective, observational cohort included 96 Mexican-Mestizo patients with moderate or severe rheumatoid arthritis (RA), initiating MTX or LEF, genotyped for IL-6 -174G/C polymorphism by PCR-RFLP. Therapeutic response was strictly defined: only if patients achieved remission or low disease activity (DAS-28 < 3.2). Results. Patients with MTX or LEF had significant decrement in DAS-28 (p < 0.001); nevertheless, only 14% and 12.5% achieved DAS-28 < 3.2 at 3 and 6 months. After 6 months with any of these drugs the -174G/G genotype carriers (56%) had higher risk of therapeutic failure compared with GC (RR: 1.19, 95% CI: 1.07–1.56). By analyzing each drug separately, after 6 months with LEF, GG genotype confers higher risk of therapeutic failure than GC (RR = 1.56; 95% CI = 1.05–2.3; p = 0.003), or CC (RR = 1.83; 95% CI = 1.07–3.14; p = 0.001). This risk was also observed in the dominant model (RR = 1.33; 95% CI = 1.03–1.72; p = 0.02). Instead, in patients receiving MTX no genotype was predictor of therapeutic failure. We concluded that IL-6 -174G/G genotype confers higher risk of failure in therapeutic response to LEF in Mexicans and if confirmed in other populations this can be used as promissory genetic marker to differentiate risk of therapeutic failure to LEF.

Rapid Capture Targeted Next Generation Sequencing (NGS) for Detection of Genomic Kinase- and Cytokine-Receptor Rearrangements in B-Precursor Acute Lymphoblastic Leukemia

Background: Next generation sequencing (NGS) applications have recently identified various recurrent kinase and cytokine receptor rearrangements in a subgroup of B-progenitor acute lymphoblastic leukemia (BPC-ALL) that is characterized by a Ph-like gene expression signature. Implementation of whole genome applications into diagnostics have so far been hampered by high costs and long turnover times. Therefore we developed a custom-made NGS based capture panel without the need for gene specific PCR amplification steps. With a rapid turnover time, pooling of multiple samples and standardized bioinformatics, this approach can be implemented in molecular diagnostics of BCP-ALL to identify patients who may benefit from an add-on therapy with specific tyrosine kinase inhibitors. Moreover, genomic breakpoints can be used as an additional patient specific target for minimal residual disease (MRD) monitoring. Here we report a feasible approach for the identification of kinase and kinase-dependent pathway aberrations in BPC-ALL utilizing a customized sequence enrichment capture panel for NGS.Patients and Methods: Ninety three samples from BCP-ALL patients with detectable minimal residual disease (MRD) levels (≥ 5x10-4) after induction therapy from COALL studies 07-03 or 08-09 were applied to the NGS custom panel. Genomic capture probes were specific for exonic and complete intronic regions of ABL1, JAK2, PDGFRB, CRLF2, EPOR, and for the IgH-JH region on chromosome 14. JAK1, JAK3, IKZF1 and SH2B3 were analysed for exonic mutations only. These predefined genomic regions from recurrently mutated or rearranged kinase and cytokine receptor genes were enriched from 50 ng of initial genomic DNA without gene specific PCR amplification steps, followed by paired end sequencing of the captured genomic fragments (Nextera Rapid Capture Custom enrichment protocol with paired end sequencing on a MiSeq benchtop sequencing platform; Illumina). Six positive controls with known rearrangements (BCR-ABL1 and ID4-JH) were included to verify this method.Results: All breakpoints from 6 positive controls were successfully identified and verified by patient specific amplification of the genomic fusion sites. ABL1 and JH specific capture probes allowed the "fishing" of the genomic fusion partner gene, here BCR and ID4, by paired end sequencing of overlapping, breakpoint spanning reads. In addition we identified a genomic breakpoint for CRLF2, PDGFRB, EPOR, ABL1 and JAK2 in 19/93 BCP-ALL patient samples. One additional patient showed a SH2B3 5 bp insertion in exon 5 that leads to a premature stop codon. The 11 patients with either EBF1-PDGFRB (4), EPOR-JH (4), or CRLF2-JH (3) rearrangements showed the highest levels of MRD (≥ 1x10-2) at the end of induction. MRD monitoring using the genomic breakpoint in 3 cases showed highly concordant data to our standardized IgH/TCR quantification assays. For the 3 patients tested so far, our breakpoint specific MRD assays clearly showed the association of these rearrangements with the dominant leukemic clone.Discussion: In summary, we identified kinase- or cytokine receptor rearrangements in 20/93 patients analyzed with our NGS based custom enrichment panel. The majority of patients had high MRD level at EOI therapy and an age of onset ≥ 10 years. Rapid identification of kinase- or cytokine receptor rearrangements in BCP-ALL is necessary for timely therapeutic intervention with target specific tyrosine kinase inhibitors. Short turnaround times of less than 2 weeks and processing of multiple samples followed by a standardized bioinformatical workflow allows the identification of unknown fusions partners from frequently rearranged kinase- and cytokine receptor genes, providing the exact breakpoint location, irrespective of the gene expression signature. MRD guided NGS panel analysis is a feasible strategy for identification of patients with a high risk of therapeutic failure or relapse suitable for targeted TKI intervention. Table 1Age at DxFusionMRD at EOI13EBF1-PDGFRB1,0E+009EBF1-PDGFRB9,0E-0113EBF1-PDGFRB3,0E-019EBF1-PDGFRB7,0E-0216EPOR-IGH6,0E-017EPOR-IGH3,0E-0116EPOR-IGH1,0E-0118EPOR-IGH9,0E-0211CRLF2-IGH9,0E-0211CRLF2-IGH4,7E-0216CRLF2-IGH4,0E-0215PAX5-JAK27,0E-0411RCSD1-ABL15,0E-0210SH2B3-INS3,0E-0310PAR15,0E-0110PAR17,0E-021PAR11,8E-025PAR17,0E-038PAR12,0E-032,5PAR11,5E-03 DisclosuresNo relevant conflicts of interest to declare.

A DNA hypermethylation profile reveals new potential biomarkers for prostate cancer diagnosis and prognosis.

DNA hypermethylation has emerged as a novel molecular biomarker for the evaluation of prostate cancer diagnosis and prognosis. Defining the specific gene hypermethylation profile for prostate cancer could involve groups of genes that specifically discriminate patients with indolent and aggressive tumors. Genome-wide methylation analysis was performed on 83 tumor and 10 normal prostate samples using the GoldenGate Methylation Cancer Panel I (Illumina, Inc.). All clinical stages of disease were considered. We found 41 genes hypermethylated in more than 20% of the tumors analyzed (P < 0.01). Of these, we newly identified GSTM2 and PENK as being genes that are hypermethylated in prostate cancer and that were simultaneously methylated in 40.9% of the tumors analyzed. We also identified panels of genes that are more frequently methylated in tumor samples with clinico-pathological indicators of poor prognosis: a high Gleason score, elevated Ki-67, and advanced disease. Of these, we found simultaneous hypermethylation of CFTR and HTR1B to be common in patients with a high Gleason score and high Ki-67 levels; this might indicate the population at higher risk of therapeutic failure. The DNA hypermethylation profile was associated with cancer-specific mortality (log-rank test, P = 0.007) and biochemical recurrence-free survival (log-rank test, P = 0.0008). Our findings strongly indicate that epigenetic silencing of GSTM2 and PENK is a common event in prostate cancer that could be used as a molecular marker for prostate cancer diagnosis. In addition, simultaneous HTR1B and CFTR hypermethylation could help discriminate aggressive from indolent prostate tumors.

Acute exacerbation of chronic bronchitis: expanding short-course therapy

Recent management guidelines for acute exacerbation of chronic bronchitis (AECB) have provided antimicrobial options for different classes of patients according to varying disease severity or risk of treatment failure. In a pivotal, double-blind, double-dummy study comparing azithromycin microspheres (2 g single dose) with the respiratory quinolone levofloxacin (500 mg once daily × 7 days) for the treatment of AECB, the two regimens were equally effective and well tolerated in patients with mild-to-moderate disease (clinical cure rate 93.6% vs. 92.7%, respectively [95% confidence interval (CI) for difference, −3.4,5.5] and overall bacteriological eradication rate 91.9% vs. 94.4%, respectively (95% CI for difference, −8.8, 3.8). Interestingly, additional post hoc analyses suggest that a single dose of azithromycin also provides comparable clinical efficacy to levofloxacin in patients with a forced expiratory volume in 1 s (FEV 1) of less than 70% of the predicted value, a risk factor that would place them in a more severe stratum. These data support azithromycin microspheres as an appropriate option in patients with mild-to-moderate AECB. The potential role of this preparation and other macrolides in patients at higher risk of therapeutic failure requires additional prospective data.

Efficacy of chloroquine in the treatment of Plasmodium vivax malaria in Turkey.

In most regions of the world, chloroquine (CQ) has been the standard treatment for Plasmodium vivax malaria for more than 40 years. Recently, however, CQ-resistant P. vivax has been reported from Oceania, several parts of Asia, and South America. The therapeutic efficacy of CQ in the treatment of acute, P. vivax malaria has now been assessed in two areas of the Turkish province of Sanliurfa: the towns of Karacadag and Sekerli. On admission and on days 2, 3, 7, 14, 21, and 28, all 112 patients investigated were examined clinically and blood samples were collected and smeared. Treatment consisted of 10 mg CQ/kg on day 0, the same dose on day 1, and 5 mg CQ/mg on day 2, each dose being supervised. Worryingly, 14.7% of the patients from Karacadag and 10.3% of those from Sekerli showed apparent treatment failure between days 3 and 28. In Sanliurfa province, in south-eastern Turkey, there therefore seems to be a high risk of therapeutic failure in patients given CQ to cure P. vivax malaria, probably because of CQ resistance.

Dihydrofolate reductase mutations in Plasmodium vivax from Indonesia and therapeutic response to sulfadoxine plus pyrimethamine.

The target enzyme of pyrimethamine is dihydrofolate reductase (DHFR), but little is known about allelic variants of dhfr in Plasmodium vivax populations. Still less is known about associations between specific alleles and the failure of sulfadoxine/pyrimethamine (S/P) to clear the erythrocytic stages of P. vivax in vivo. We studied P. vivax dhfr mutations in 24 patients who received S/P therapy in Papua or Central Java, Indonesia, and we measured the resistance of the alleles in vitro in a dhfr yeast expression assay. Fourteen (58%) of 24 patients had an inadequate therapeutic response. Two of 6 alleles that were identified were novel. One allele that expressed 4 point mutations (57L+58R+61M+117T) correlated with a high risk of therapeutic failure. The 9 patients infected by P. vivax carrying this allele proved 23 times more likely to experience early therapeutic failure, compared with patients infected by P. vivax carrying other alleles (P=.003; 95% confidence interval, 2-450). This allele also conferred high levels of pyrimethamine resistance in vitro. The experimental antifolate WR99210 inhibited the allele in this system. The present study identified a strong correlation between specific mutations in P. vivax dhfr and S/P treatment failure. Our results suggest that WR99210 could provide effective therapy for S/P-resistant P. vivax.

Prediction of therapeutic failure in patients with bleeding peptic ulcer treated with endoscopic injection.

Endoscopic injection therapy was performed in a consecutive series of 233 patients admitted for a bleeding peptic ulcer with active arterial hemorrhage or a nonbleeding visible vessel disclosed at emergency endoscopy. Further bleeding occurred in 57 cases (24.5%). The present study was conducted to evaluate whether any clinical or endoscopic features could identify the patients at high risk of therapeutic failure. Multiple logistic regression analysis showed that failure was significantly related to: (1) the ulcer location on the posterior wall (P = 0.004) or superior wall (P = 0.003) of the duodenal bulb, (2) the ulcer size (P = 0.011), and (3) the existence of associated diseases (P = 0.012). The validity of the prediction rule based on these factors was evaluated by receiver-operating characteristic curves and was confirmed and prospectively validated in an independent sample of 81 patients with a bleeding peptic ulcer treated by endoscopic injection. We conclude that once the initial control of bleeding has been achieved by injection therapy, the present prediction rule can be used to identify candidates for alternative treatment.

Controversy I: Patients or healthy volunteers for pharmacokinetic studies?

Many factors should be considered when choosing an appropriate population for a pharmacokinetic trial. Although there are some generalities that apply to most studies, each investigation must be judged separately, since the relevant considerations will vary depending on the particular study, the nature of the drug, and the population that will receive it for therapeutic benefit. Some of the most important information that is generated from pharmacokinetic studies concerns the pharmacokinetic variability among patients and the factors that can influence this variability under the conditions that the drug will be used. This information can best be obtained from a combination of baseline studies to define the variability within the patient population(s) and comparative studies to determine the impact of specific variables on the disposition of the drug and its pharmacokinetic variability. These data can provide valuable information to the clinician that can be used to individualize drug dosage and optimize therapy as well as to identify populations who may be at high risk of therapeutic failure or drug toxicity. It is our feeling that baseline studies in patients are necessary for understanding the pharmacokinetics of a drug, whereas the objectives of most comparative studies can be achieved using healthy volunteers. For most comparative studies, the data obtained from healthy volunteers will reflect what will occur in patients, especially if the variable of interest is drug absorption. This is particularly important when practical and ethical considerations preclude the use of patients. When considering studies in the elderly, one must decide whether the variable of interest may be influenced by age.(ABSTRACT TRUNCATED AT 250 WORDS)