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PubMed2004

Remission in major depression with two antidepressant mechanisms: results from a naturalistic study.

BACKGROUND: Since remission should be the goal of the treatment of depression, the aims of this study were to evaluate the rate of remission obtained with SSRIs in routine clinical practice and to assess alternative treatments with a combined mechanism of action. METHODS: The study involved a prospective naturalistic 6-month follow-up of 44 consecutive unipolar depressed (DSM-IV) outpatients. After 6 weeks of treatment with a SSRI, patients were classified as remitted (HAM-D-17 score <==7), partial responders (>/=50% reduction in HAM-D-17 score but still higher than 7) and non-responders. In case of non-response, an antidepressant with noradrenergic action (NaA) was added to the ongoing SSRI treatment or were switched to venlafaxine in monotherapy when NaA was contraindicated. RESULTS: At 6 weeks, eight patients (18.1%) achieved full remission, nine patients (20.5%) were partial responders and 27 (61.4%) non responders. At the end of follow-up 31.8% (n=14) of the initial sample remained remitted with SSRIs, whereas 96.2% (26/27) of previous non-responders experienced remission with the alternative treatment. Non-responders to SSRIs in monotherapy were significantly more likely to show melancholic features and to have higher HAM-D-17 scores and lower GAF scores than remitted patients with SSRIs. LIMITATIONS: the observational and naturalistic design of the study determines inherent limitations. CONCLUSIONS: this study showed a low remission rate with SSRIs in the long-term treatment of more severe and melancholic depression, and the benefit of using treatments with a combined mechanism of action.

Adult↗

PubMed2004

Pharmacokinetic-pharmacodynamic relationships and dose response to meloxicam in horses with induced arthritis in the right carpal joint.

OBJECTIVE: To determine pharmacokinetic-pharmacodynamic (PK-PD) relationships and dose effects for meloxicam in horses and to propose a suitable dosage for use in clinical studies. ANIMALS: 6 adult horses. PROCEDURE: The study was conducted by use of a randomized, Latin-square design. Arthritis was induced in the right carpal joint of each horse by administration of Freund's complete adjuvant. Various dosages of meloxicam (0, 0.25, 0.5, 1.0, and 2.0 mg/kg, IV) were then administered. Validated endpoints including stride length and overall clinical lameness score (scale of 0 to 20) were used to assess the effect of meloxicam. The dose-effect relationship was quantified by use of a maximum possible effect (Emax) model. RESULTS: For stride length (expressed as a relative percentage increase from control values), the median effective dose (ED50) was 0.120 mg/kg for an Emax of 11.15%. For clinical lameness score (expressed as an absolute increase from the control value), the ED50 was 0.265 mg/kg for an Emax of 9.16 units. The PK-PD analysis allowed calculation of a median effective concentration of 130 ng/mL for stride length and 195 ng/mL for lameness score. Use of the Emax model predicted a maximal possible increase in effect of 19.5% for stride length and 13.91 units for lameness score. For stride length and lameness score, the Hill coefficient (slope) was extremely high, which suggested a steep dose-effect relationship. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study suggest that meloxicam is a potent anti-inflammatory drug in horses. A dosage of 0.6 mg/kg/d would be appropriate for use in a clinical study.

Animals↗

PubMed2003

Pharmacokinetic dosing of aminoglycosides: a controlled trial.

PURPOSE: To evaluate whether individualized pharmacokinetic dosing of aminoglycosides can reduce nephrotoxicity and improve the outcome of patients with gram-negative sepsis. METHODS: We conducted a prospective controlled trial at a tertiary care university hospital. Eighty-one patients with suspected or documented gram-negative infections were enrolled. All were treated with either gentamicin or amikacin, according to clinical judgement. Patients were allocated to one of two groups based on the last digit (odd/even) of their identification number. In the study group (pharmacokinetic dosing) of 43 patients, plasma aminoglycoside levels were determined 1 hour after initiation of drug infusion and 8 to 16 hours later to estimate the elimination half-life and volume of distribution, from which the subsequent dosage schedule was calculated. Target peak plasma levels were 20 microg/mL for gentamicin and 60 microg/mL for amikacin. Target trough levels were <1 microg/mL for both drugs. The control group (fixed once-daily dosing) consisted of 38 patients who were prescribed single daily doses of gentamicin or amikacin. The primary endpoints were renal toxicity (> or = 25% increase in serum creatinine level or a serum creatinine level > or = 1.4 mg/dL) and 28-day mortality. RESULTS: The two study groups were similar in age, sex, indications for therapy, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and clinical assessment at baseline. Although the pharmacokinetic group received significantly greater doses of aminoglycosides than did the once-daily group, the incidence of nephrotoxicity was significantly lower in the pharmacokinetic group (5% [2/43] vs. 21% [8/38], P = 0.03). There was no statistically significant difference in 28-day mortality (27% [12/43] vs. 22% [8/38], P = 0.3). CONCLUSION: These results suggest that individualized pharmacokinetic dosing of aminoglycosides reduces the incidence of nephrotoxicity and allows the use of greater doses of aminoglycosides.

Adolescent↗

PubMedDate not supplied

Hospitalization costs of total knee arthroplasty with a continuous femoral nerve block provided only in the hospital versus on an ambulatory basis: a retrospective, case-control, cost-minimization analysis.

BACKGROUND AND OBJECTIVES: After total knee arthroplasty (TKA), hospitalization may be shortened by allowing patients to return home with a continuous femoral nerve block (CFNB). This study quantified the hospitalization costs for 10 TKA patients receiving ambulatory CFNB versus a matched cohort of 10 patients who received CFNB only during hospitalization. METHODS: We examined the medical records (n = 125) of patients who underwent a unilateral, primary, tricompartment TKA with a postoperative CFNB by 1 surgeon at one institution in an 18-month period beginning January 2004. Each of the 10 patients discharged home with an ambulatory CFNB (cases) was matched with a patient with a hospital-only CFNB (controls) for age, gender, body mass index, and health status. Financial data were extracted from the hospital microcosting database. RESULTS: Nine patients with ambulatory CFNB (cases) were discharged home on postoperative day (POD) 1 and 1 on POD 4. Of the controls, 3 were discharged home on POD 3, 6 on POD 4, and 1 on POD 5. The median (range) costs of hospitalization (excluding implant and professional fees) was US dollars 5,292 (US dollars 4,326-US dollars 7,929) for ambulatory cases compared with US dollars 7,974 (US dollars 6,931-US dollars 9,979) for inpatient controls (difference = US dollars 2,682, 34% decrease, P < .001). The total charges for hospitalization, the implant, and professional fees was US dollars 33,646 (US dollars 31,816-US dollars 38,468) for cases compared with US dollars 39,100 (US dollars 36,096-US dollars 44,098) for controls (difference = US dollars 5,454, 14% decrease, P < .001). CONCLUSIONS: This study provides evidence that ambulatory CFNB for selected patients undergoing TKA has the potential to reduce hospital length of stay and associated costs and charges. However, the current study has significant inherent limitations based on the study design. Additional research is required to replicate these results in a prospective, randomized, controlled trial and to determine whether any savings exceed additional CFNB costs such as from complications, having caregivers provide care at home, and additional hospital/health care provider visits.

Aged↗

PubMedDate not supplied

Lack of integration of automated external defibrillators with EMS response may reduce lifesaving potential of public-access defibrillation.

OBJECTIVES: Automated external defibrillators (AEDs) used for public-access defibrillation (PAD) allow for rapid defibrillation, particularly if the AEDs are incorporated into an organized response plan. This project was undertaken to determine how many PAD AEDs were in North Carolina, how many were properly registered, and how many were integrated into the emergency medical services (EMS) response. METHODS: Data were collected for this prospective, descriptive study via phone survey, e-mail survey, and/or direct personal interview. Four sources were utilized: 1) state office of EMS AED registration database, 2) AED sales representatives, 3) county EMS agency representatives, and 4) American Heart Association (AHA) training center instructors and regional faculty. The primary endpoint was determining the proportion of AEDs placed in unregistered locations. RESULTS: The state EMS office provided the state registry of AED locations. One-hundred percent of state-recognized AED vendors and county EMS agencies provided data. Twelve of 55 (22%) AHA personnel provided data. Eight hundred eighty-one unique locations were identified. Although AED sales are required by law to be registered, the office of EMS database contained only 99 of the 552 (18%) unique PAD locations identified by the study. CONCLUSIONS: A large number of unregistered AEDs are being placed in communities. AEDs placed as part of an organized PAD program improve the rates of survival from sudden cardiac death. In the absence of registration, it is difficult to determine the extent to which these AEDs are part of an organized PAD program.

Commerce↗

PubMed1989

The isolation and sequence of missense and nonsense mutations in the cloned bacteriophage P22 tailspike protein gene.

Twenty-seven new mutations in the structural gene for the Salmonella typhimurium bacteriophage P22 tailspike protein have been isolated, mapped using a powerful plasmid-based genetic system and their DNA sequence changes determined. The mutations were generated by hydroxylamine treatment of the cloned gene on a plasmid expression vector. Assaying the activity of the tailspike protein produced from this plasmid and screening for plasmid mutants were accomplished by the in situ complementation of P22 capsids imbedded in soft agar to produce infectious phage. Deletion mutations in the cloned gene have been constructed by a two step procedure involving oligonucleotide linker insertion and in vitro deletion by restriction endonuclease digestion. The deletions, whose physical endpoints were determined by DNA sequencing, define 12 genetic and physical intervals into which the new mutations were mapped by marker rescue experiments. These deletions were transferred to phage P22 by recombination and used to map mutations carried on plasmids. Following mapping, the nucleotide change for each of the mutations was determined by DNA sequencing. The majority were absolute missense mutations although both amber and ochre nonsense mutations were also identified in the protein coding portion of the gene. The suppression pattern of the nonsense mutations was determined on several nonsense suppressors. Four of the mutations cause severely depressed levels of tailspike protein expression from both the cloned gene on the plasmid expression vector and from P22 phage carrying these mutations. These mutations were identified as nucleotide changes in what is probably the P22 late operon transcription terminator which immediately follows the tailspike protein coding sequence.

Amino Acid Sequence↗

PubMed1994

HIV-1 immunogen induction of HIV-1-specific delayed-type hypersensitivity: results of a double-blind, adjuvant-controlled, dose-ranging trial.

OBJECTIVE: To investigate the capacity of an HIV-1 immunogen to induce or augment HIV-1-specific delayed-type hypersensitivity (DTH) over a range of doses in asymptomatic HIV-1-seropositive adults. DESIGN: A single center, double-blind, adjuvant-controlled, dose-ranging trial involving 48 HIV-1-seropositive asymptomatic patients. Each dose group consisted of 12 subjects, eight receiving HIV-1 immunogen and four incomplete Freund's adjuvant (IFA). The doses studied were 50, 100, 200, or 400 micrograms (total protein). The HIV-1 immunogen was administered intramuscularly every 4 weeks for 36 weeks, with dosing contingent on the lack of an HIV-1 immunogen DTH response. A maximum of six doses was permitted. METHODS: Immunogenicity was assessed every 4 weeks by DTH skin testing to the inactivated HIV-1 antigen in saline with > 9 mm induration representing a response to immunization. Changes in p24-antibody levels were determined by endpoint titration using an enzyme-linked immunosorbent assay and Western blot. RESULTS: At doses of > or = 100 micrograms, all treated patients demonstrated significant differences in the ability to mount an HIV-1-specific cell-mediated response relative to adjuvant controls. Dose-related response patterns were observed in the period between doses and the occurrence of rises in HIV-1 DTH. Treatment appeared to increase p24-antibody titers as well as reactivities to other HIV-1 antigens as determined by Western blots. The HIV-1 immunogen was well tolerated. CONCLUSIONS: The minimum dose of the HIV-1 immunogen in IFA required to induce HIV-1 DTH relative to the IFA control group was 100 micrograms in this patient population.

Adult↗

PubMed2005

Determination of apoptosis, uracil incorporation, DNA strand breaks, and sister chromatid exchanges under conditions of thymidylate deprivation in a model of BER deficiency.

Thymidylate synthase (TS) is an important target of several chemotherapeutic agents. During TS inhibition, dTTP levels decrease with a subsequent increase in dUTP. Uracil incorporated into the genome is removed by base excision repair (BER). BER has been hypothesized to play a role in the response to thymidylate deprivation, despite a lack of direct evidence. We previously found that beta-pol null murine fibroblasts were approximately six-fold more resistant than wild-type cells to raltitrexed, a folate-based inhibitor specific for TS. In this study, a number of endpoints were determined to understand the influence of BER and beta-pol during raltitrexed treatment. Raltitrexed induced apoptosis in wild-type cells to a greater extent than in beta-pol null cells. A PARP inhibitor decreased the sensitivity to raltitrexed, although the extent was not different between wild-type and beta-pol null cells. No evidence was seen for extensive strand break formation that preceded apoptosis, although raltitrexed induced more sister chromatid exchanges in wild-type cells. Increased levels of uracil in DNA were detected following treatment in wild-type and beta-pol null cells. However, uracil levels were only approximately two-fold higher in DNA from treated cells compared to untreated. Uracil DNA glycosylase activity was slightly higher in beta-pol null cells, although not sufficiently different to explain the difference in sensitivity to raltitrexed. Taken together, the data suggest that the sensitivity of the wild-type cells to raltitrexed is not associated with activation of PARP-1 dependent BER, extensive uracil incorporation into DNA and persistent strand breaks, but rather with changes suggestive of DNA recombination.

Animals↗

PubMed2006

Rebeccamycin analog for refractory breast cancer: a randomized phase II trial of dosing schedules.

Rebeccamycin analog (NSC 655649) is a synthetic antibiotic cytotoxic agent thought to inhibit topoisomerase function. We sought to determine the response rate to rebeccamycin analog among patients with refractory advanced breast cancer using two different treatment schedules. Eligible patients had measurable disease, central venous access, and one or two prior chemotherapy regimens for advanced cancer, or recurrence within 12 months of adjuvant chemotherapy. Patients were randomized to rebeccamycin analog on one of two treatment schedules: arm 1, 500 mg/m2 IV bolus every 21 days; arm 2, 140 mg/m2 IV bolus daily x 5 days, every 21 days. The primary study endpoint was response rate; a two stage accrual design evaluated each schedule separately. Forty-two women entered the trial, 21 on each arm. Prior chemotherapy regimens for metastatic breast cancer were: 0, n=4; 1, n=21; 2, n=17. Prior treatments (including adjuvant therapy) anthracyclines: 88%, taxanes 67%, 5FU-based therapy, 50%. There were 5 partial responses (overall response rate 12%), two in arm 1 and 3 in arm 2, all in patients with prior anthracycline-based adjuvant chemotherapy. Median time to progression was 2.1 months (range 1-14+ months). An additional 9 patients had stable disease as best response. Grade 3 or 4 toxicity rates were: anemia 5%, neutropenia 33%, thrombocytopenia 12%, RBC transfusion 14%, nausea/vomiting 10%. Toxicity profiles were similar between the treatment arms. Rebeccamycin analog is reasonably well tolerated on two different treatment schedules for advanced breast cancer, with modest clinical activity in this heavily pretreated population.

Adult↗

PubMed2004

The monosodium iodoacetate model of osteoarthritis: a model of chronic nociceptive pain in rats?

Osteoarthritis (OA) is a widespread condition affecting the elderly population. One of the most prominent features but least studied symptoms is chronic pain associated with OA. The study objective was to determine pain endpoints in rats with monosodium iodoacetate (MIA) induced OA, and to investigate the efficacy of common nociceptive agents. Sprague-Dawley rats received an intraarticular injection of either 25 microl 80 mg/ml MIA or 25 microl 0.9% sterile saline into the right knee joint. Changes in von Frey thresholds and latencies to stroking with a cotton bud (punctate and dynamic allodynia, respectively) were measured pre- and for up to 10 weeks post-intraarticular injection. Changes in hind paw weight distribution were also determined. Both punctate allodynia and a weight bearing deficit were observed in MIA-treated rats for up to 10 weeks. Interestingly, dynamic allodynia was not detected at any time point tested. Morphine (0.3-3 mg/kg, s.c.) and tramadol (3-100 mg/kg, p.o.) dose-dependently inhibited punctate allodynia and partially reversed weight bearing deficit. In conclusion, the MIA model of OA is reproducible and mimics OA pain in humans. Analgesic drug studies indicate this model may be useful for investigating chronic nociceptive pain.

Analysis of Variance↗

PubMed2001

A three-arm phase III randomised trial assessing, in patients with extensive-disease small-cell lung cancer, accelerated chemotherapy with support of haematological growth factor or oral antibiotics.

The European Lung Cancer Working Party (ELCWP) designed a 3-arm phase III randomised trial to determine the role of accelerated chemotherapy in extensive-disease (ED) small-cell lung cancer (SCLC). Eligible patients were randomised between the 3 following arms: (A) Standard chemotherapy with 6 courses of EVI (epirubicin 60 mg m(-2), vindesine 3 mg m(-2), ifosfamide 5 g m(-2); all drugs given on day 1 repeated every three weeks. (B) Accelerated chemotherapy with EVI administered every 2 weeks and GM-CSF support. (C) Accelerated chemotherapy with EVI and oral antibiotics (cotrimoxazole). Primary endpoint was survival. 233 eligible patients were randomised. Chemotherapy could be significantly accelerated in arm B with increased absolute dose-intensity. Best response rates, in the population of evaluable patients, were, respectively for arm A, B and C, 59%, 76% and 70%. The response rate was significantly higher in arm B in comparison to arm A (P = 0.04). There was, however, no survival difference with respective median duration and 2-year rate of 286 days and 5% for arm A, 264 days and 6% for arm B and 264 days and 6% for arm C. Severe thrombopenia occurred more frequently in arm B but without an increased rate of bleeding. Non-severe infections were more frequent in arm B and severe infections were less frequent in arm C. Our trial failed to demonstrate, in ED-SCLC, a survival benefit of chemotherapy acceleration by using GM-CSF support.

Administration, Oral↗

PubMed2002

What do patients with migraine want from acute migraine treatment?

Migraine is a common chronic condition with an ever-expanding therapeutic armamentarium. As therapeutic options multiply, it is increasingly important to understand patients' attitudes and preferences regarding various treatment characteristics. Several strategies have evolved to establish treatment priorities in migraine and rationalize and prioritize end points and outcomes to meet the needs of patients. A survey of a population-based sample of migraineurs indicated that an overwhelming majority of patients consider complete relief of head pain, no recurrence, and rapid onset of action as important or very important attributes of acute migraine therapy. An analysis of the relationship between clinical end points and satisfaction found that more than 90% of patients who were pain-free at 2 hours were at least somewhat satisfied with treatment, but satisfaction was dependent on relatively rapid relief. Using a "willingness-to-pay" approach, results indicated that while patients will pay more for migraine treatment that produces rapid, consistent relief without adverse effects or recurrence, speed of complete relief is the most valued attribute. By assessing physician preferences and practices, degree of pain relief and rapid onset were identified as the most important attributes of acute therapy. Based on results from preference studies of triptans, 50% of patients cited more rapid pain relief as the most important determinant of treatment preference. Based on these various approaches, the consensus view is that both clinicians and patients desire a broad range of positive migraine treatment attributes, but rapid onset of complete pain relief is a particularly important priority.

Acute Disease↗

PubMed1995

A behaviorally selective class of thiophene-containing benzodiazepine receptor ligands.

In a continued effort to probe the role of the aromatic rings in classical 1,4-benzodiazepine (BDZ) ligand pharmacology, a series of new thiophene-containing benzodiazepine receptor (BDZR) ligands were synthesized. As a first step in determining the binding profile and selectivity to BDZR functional subtypes, the affinities in two central nervous system (CNS) regions, cerebellum, in which a single 'Type I' BDZR could be labeled; and spinal cord, in which we have previously demonstrated some receptor heterogeneity, were determined. These compounds were also assessed for their compliance with a recently developed three dimensional pharmacophore for recognition and activation of the 'Type I' BDZR, using the techniques of computational chemistry. The computations showed all ligands synthesized fulfilled the minimum requirements for recognition, further validating the current pharmacophore. Using the criteria for activation, the new ligands were all predicted to be agonists at the cerebellar 'Type I' BDZR. Since the compounds showed reasonable affinity, the behavioral profile of one of them at five in vivo endpoints was determined. This compound demonstrated more behavioral selectivity than the typical 1,4-BDZ ligand. While they fulfilled the requirements for agonist activity at the 'Type I' BDZR, these ligands showed significantly greater delocalization in the electron density distribution in the lowest unoccupied molecular orbital (LUMO), so that either aromatic ring could serve as an electron accepting site, not just the one comparable to the more classical BDZR agonist, flunitrazepam. It is possible that the ability of the second ring in the tested compound (5a) to also function as an electron acceptor can affect the recognition and activation of other receptor types leading to the more discriminate behavioral profile of this thiophene analog compared to flunitrazepam.

Animals↗

PubMed2006

Health status measurement in COPD: the minimal clinically important difference of the clinical COPD questionnaire.

BACKGROUND: Patient-reported outcomes (PRO) questionnaires are being increasingly used in COPD clinical studies. The challenge facing investigators is to determine what change is significant, ie what is the minimal clinically important difference (MCID). This study aimed to identify the MCID for the clinical COPD questionnaire (CCQ) in terms of patient referencing, criterion referencing, and by the standard error of measurement (SEM). METHODS: Patients were > or = 40 years of age, diagnosed with COPD, had a smoking history of >10 pack-years, and were participating in a randomized, controlled clinical trial comparing intravenous and oral prednisolone in patients admitted with an acute exacerbation of COPD. The CCQ was completed on Days 1-7 and 42. A Global Rating of Change (GRC) assessment was taken to establish the MCID by patient referencing. For criterion referencing, health events during a period of 1 year after Day 42 were included in this analysis. RESULTS: 210 patients were recruited, 168 completed the CCQ questionnaire on Day 42. The MCID of the CCQ total score, as indicated by patient referencing in terms of the GRC, was 0.44. The MCID of the CCQ in terms of criterion referencing for the major outcomes was 0.39, and calculation of the SEM resulted in a value of 0.21. CONCLUSION: This investigation, which is the first to determine the MCID of a PRO questionnaire via more than one approach, indicates that the MCID of the CCQ total score is 0.4.

Administration, Oral↗

PubMed2007

Biometrical aspects of drug development.

Once the activity of a compound has been established in the laboratory (usually by use of experimental animals) the next stage of development is to bring this forward to humans in early-phase clinical trials. A pharmacokinetic study aims to establish an effective dosing regimen for the compound in order to reach concentrations within the therapeutic window as quickly as possible. The aim of the phase I trials is typically to determine a maximal safe dose with which more rigorous investigation of activity in a phase II trial can be conducted. This chapter deals with statistical issues related to the design of phase I studies.

Animals↗

PubMed2002

Weighing the evidence of ecological risk from chemical contamination in the estuarine environment adjacent to the Portsmouth Naval Shipyard, Kittery, Maine, USA.

In characterizing ecological risks, considerable consensus building and professional judgments are required to develop conclusions about risk. This is because how to evaluate all the factors that determine ecological risk is not well defined and is subject to interpretation. Here we report on the application of a procedure to weigh the evidence of ecological risk and develop conclusions about risk that will incorporate the strengths and weaknesses of the assessment. The procedure was applied to characterize ecological risk of chemical contamination in nearshore areas adjacent to the Portsmouth Naval Shipyard, located at the mouth of the Great Bay Estuary, New Hampshire and Maine, USA. Measures of exposure and effect were used to interpret the magnitude of risk to the assessment endpoints of pelagic species, epibenthic species, the benthic community, eelgrass plants, the salt marsh community, and avian receptors. The evidence of chemical exposure from water, sediment, and tissue and the evidence of biological effects to representative pelagic, epibenthic, benthic, eelgrass, salt marsh, and avian species were weighed to characterize ecological risk. Individual measures were weighted by the quality and reliability of their data and risk was estimated from the preponderance, magnitude, extent, and strength of causal relationships between the data on exposure and effects. Relating evidence of risk to hypothesized pathways of exposure made it possible to estimate the magnitude of risk from sediment and water and express the confidence associated with the findings. Systematically weighing the evidence of risk rendered conclusions about risk in a manner that was clearly defined, objective, consistent, and did not rely solely on professional judgment.

Ecosystem↗

PubMed2005

Adaptive signature design: an adaptive clinical trial design for generating and prospectively testing a gene expression signature for sensitive patients.

PURPOSE: A new generation of molecularly targeted agents is entering the definitive stage of clinical evaluation. Many of these drugs benefit only a subset of treated patients and may be overlooked by the traditional, broad-eligibility approach to randomized clinical trials. Thus, there is a need for development of novel statistical methodology for rapid evaluation of these agents. EXPERIMENTAL DESIGN: We propose a new adaptive design for randomized clinical trials of targeted agents in settings where an assay or signature that identifies sensitive patients is not available at the outset of the study. The design combines prospective development of a gene expression-based classifier to select sensitive patients with a properly powered test for overall effect. RESULTS: Performance of the adaptive design, relative to the more traditional design, is evaluated in a simulation study. It is shown that when the proportion of patients sensitive to the new drug is low, the adaptive design substantially reduces the chance of false rejection of effective new treatments. When the new treatment is broadly effective, the adaptive design has power to detect the overall effect similar to the traditional design. Formulas are provided to determine the situations in which the new design is advantageous. CONCLUSION: Development of a gene expression-based classifier to identify the subset of sensitive patients can be prospectively incorporated into a randomized phase III design without compromising the ability to detect an overall effect.

Antineoplastic Agents↗

PubMed2004

Serum tumor markers in patients with breast cancer.

Several serum tumor markers have been investigated in patients with breast cancer for assessing outcome, predicting recurrence and monitoring the therapeutic response. There is a general consensus concerning their limited application in diagnosing malignancy; however, serum tumor markers can be considered for the early detection of recurrence. The most effective markers for this indication are cancer antigens (CA)15-3 and 27.29, and c-erbB-2, although their efficacy in establishing disease progression has not been determined to date. In terms of evaluating prognosis and predicting response to therapy, only the expression of c-erbB-2 has clinical evidence. To conclude, at present, no serum tumor marker is cost effective, and none can be used with confidence in the decision making regarding breast cancer patients.

Antigens, Tumor-Associated, Carbohydrate↗