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Biomedical subjects

Michael S Gordon

Publications and source records attributed to Michael S Gordon.

At least 19 recordsLinked to original sources
PubMed2006

Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status.

PURPOSE: Ovarian cancers (OCs) frequently have HER2 activation in the absence of HER2 overexpression. Pertuzumab, a humanized antibody that prevents HER2 dimerization and inhibits multiple HER-mediated pathways, was studied in a phase II, multicenter trial in advanced, refractory OC. PATIENTS AND METHODS: Sixty-one patients (cohort 1) with relapsed OC received a loading dose of 840 mg pertuzumab intravenously followed by 420 mg every 3 weeks; 62 patients (cohort 2) received 1,050 mg every 3 weeks. Response rate was the primary end point. Fresh tumor biopsies were obtained in cohort 1 to assay for phosphorylated HER2 (pHER2). RESULTS: Median age was 57 years and median number of prior chemotherapy regimens was five. Fifty-five patients in cohort 1 and 62 patients in cohort 2 were assessable for efficacy. There were five partial responses (response rate [RR] = 4.3%; 95% CI, 1.7% to 9.4%), eight patients (6.8%) with stable disease (SD) lasting at least 6 months, and 10 patients with CA-125 reduction of at least 50% (includes two partial responses and four patients with SD > or = 6 months; total clinical activity, 14.5%). Median progression-free survival (PFS) was 6.6 weeks. Eight of 28 tumor biopsies (28.6%) were pHER2+ by enzyme-linked immunosorbent assay (ELISA; without gene amplification). Median PFS for pHER2+ patients was 20.9 weeks (n = 8) versus 5.8 weeks for pHER2- (n = 20; P = .14) and 9.1 weeks for unknown pHER2 status (n = 27). Pertuzumab was well tolerated with diarrhea in 69.1% (11.4% grade 3, no grade 4). Five patients had asymptomatic left ventricular ejection fraction decreases to less than 50% (one confirmed by central facility). CONCLUSION: Pertuzumab is well tolerated with a RR of 4.3% in heavily-pretreated OC patients. Further studies on pHER2 as a diagnostic are warranted.

Adult↗
PubMed2006

Phase II trial of subcutaneous recombinant human interleukin 11 with subcutaneous recombinant human granulocyte-macrophage colony stimulating factor in patients with acute myeloid leukemia (AML) receiving high-dose cytarabine during induction: ECOG 3997.

Randomized trials of substituting high-dose cytarabine (HiDAC) for standard dose cytarabine (SDAC) during induction therapy for newly diagnosed AML have not demonstrated an improvement in the complete remission (CR) rate. Phase II trials of the scheduled administration of HiDAC after SDAC suggest an improved outcome. The hematological complications of intensification are considerable. GM-CSF after chemotherapy improved the survival of older patients in a randomized trial. Recombinant human interleukin 11, a thrombopoietic cytokine, reduced the incidence of chemotherapy-induced thrombocytopenia in patients with solid tumors. Therefore, 34 patients were treated, with newly diagnosed AML less than 56 years of age, with daunorubicin 45 mg/m2 on days 1-3, cytarabine 100mg/m2 days 1-7 and cytarabine 2g/m2 for 12 h on days 8-10 (7+3+3). rhIL-11 (50 microg/kg/day,) and GM-CSF (250 microg/kg/day) were administered subcutaneously from day 11 until recovery. The complete remission rate was 59% (90% C.I. 43-73%). The median time to recovery of neutrophils to >500 and platelets to > or =20,000 microl(-1) was 27 days (95% C.I. 27-30 days) and 25 days (95% C.I. 24-29 days), respectively. The trial does not confirm the high CR rate observed in phase II trials, despite optimal supportive care.

Acute Disease↗
PubMed2006

A comparison of cognitive-behavioral therapy, sertraline, and their combination for adolescent depression.

OBJECTIVE: To evaluate cognitive-behavioral therapy, antidepressant medication alone, and combined CBT and antidepressant medication in the treatment of depressive disorders in adolescents. METHOD: Seventy-three adolescents (ages 12-18 years) with a primary diagnosis of DSM-IV major depressive disorder, dysthymic disorder, or depressive disorder not otherwise specified were randomly allocated to one of three treatments. Treatment outcome measures were administered before and after acute treatment, and at a 6-month follow-up. Depression diagnosis was the primary outcome measure; secondary measures were self- and other report and clinician rating of global functioning. The trial was conducted at three community-based clinics between July 2000 and December 2002. Data analyses used an intent-to-treat strategy. RESULTS: Following acute treatment, all treatment groups demonstrated statistically significant improvement on outcome measures (depressive diagnosis, Reynolds Adolescent Depression Scale, Revised Children's Manifest Anxiety Scale, Suicidal Ideation Questionnaire), and improvement was maintained at follow-up. Combined cognitive-behavioral therapy and antidepressant medication was not found to be superior to either treatment alone. Compared with antidepressant medication alone, participants receiving cognitive-behavioral therapy alone demonstrated a superior acute treatment response (odds ratio = 6.86; 95% confidence interval 1.12-41.82). Although cognitive-behavioral therapy was found to be superior to antidepressant medication alone for the acute treatment of mild to moderate depression among youth, this may have stemmed from the relatively low dose of sertraline used. CONCLUSIONS: All treatments led to a reduction in depression, but the advantages of a combined approach were not evident.

Adolescent↗
PubMed2006

Effects of the PPAR-gamma agonist rosiglitazone on renal haemodynamics and the renin-angiotensin system in diabetes.

BACKGROUND: Thiazolidinediones (TZD) have been reported to improve early stages of diabetic nephropathy independent of glycaemic control. Since blockade of the renin-angiotensin system (RAS) is known to reduce the risk of nephropathy, we hypothesised that the renal effect of TZDs might be related to a favourable effect on the intrarenal RAS. We aimed to determine if the TZD rosiglitazone could reduce RAS activation. METHODS: We studied adult type 2 diabetic patients and placed them on rosiglitazone for three months. We have previously used the renal haemodynamic response to angiotensin-converting enzyme (ACE) inhibition to demonstrate the state of RAS activation, and thus measured renal plasma flow (RPF) and glomerular filtration rate (GFR) before and after administration of captopril at 0 month and at three months. Plasma renin activity (PRA), active renin, aldosterone and natriuretic peptides were analysed. RESULTS: The RPF response to ACE inhibition was not altered. There was no change in GFR, PRA, active renin and aldosterone levels. Two patients developed oedema one had an elevated baseline active renin and another had an elevated baseline aldosterone level. CONCLUSION: The favourable effects of TZDs on diabetic nephropathy is likely not related to an influence on the RAS.

Adult↗
PubMed2006

Overview of anti-VEGF therapy and angiogenesis. Part 1: Angiogenesis inhibition in solid tumor malignancies.

Several new agents that target the vascular endothelial growth factor (VEGF) pathway and inhibit angiogenesis are emerging as promising therapies in multiple cancer types. Bevacizumab, a humanized monoclonal antibody to VEGF-A, is currently approved in combination with intravenous 5-fluorouracil-containing regimens for the first-line treatment of metastatic colorectal cancer and recently demonstrated clinically important results in combination with chemotherapy in patients with non-small cell lung cancer and metastatic breast cancer. Other anti-VEGF agents that have shown benefit in various cancer types will be discussed in this monograph. Despite the often striking results observed with anti-VEGF agents, several unanswered questions remain, such as the optimal duration of therapy and patient selection criteria. These other issues, including the biologic rationale for anti-VEGF therapy, as well as recent clinical trial data with anti-VEGF agents in colorectal, pancreatic, lung, kidney, and brease cancers, are discussed.

Antibodies, Monoclonal↗
PubMed2005

Managing patients treated with bevacizumab combination therapy.

The anti-angiogenic agent bevacizumab (Avastin) has been rationally designed to target vascular endothelial growth factor (VEGF), a key mediator of tumor angiogenesis. Based on its limited roles in adults, VEGF inhibition using bevacizumab would be expected to have limited side effects. Furthermore, because its mechanism of action is different to that of standard chemotherapeutic agents, bevacizumab would not be expected to cause typical cytotoxic agent-related toxicity or to exacerbate the toxicity of concomitant chemotherapy. We have reviewed clinical trials published to date, primarily in metastatic colorectal cancer, and describe the safety profile of bevacizumab. The review focuses on hypertension, proteinuria, arterial thrombosis, effects on wound healing, bleeding and gastrointestinal (GI) perforation, which are the principal bevacizumab-related events seen in clinical trials. These events are for the most part mild to moderate in severity and clinically manageable (hypertension, proteinuria, minor bleeding) or occur uncommonly (wound healing complications, GI perforations and arterial thrombosis). The side-effect profile of bevacizumab makes it a suitable adjunct to standard chemotherapy in settings where efficacy has been demonstrated, and it is now approved for use in the USA, the European Union and other markets worldwide.

Angiogenesis Inhibitors↗
PubMed2005

Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer.

PURPOSE: Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy. PATIENTS AND METHODS: Patients with incurable, locally advanced, recurrent or metastatic solid tumors that had progressed during or after standard therapy were recruited to a dose-escalation study of pertuzumab (0.5 to 15 mg/kg) given intravenously every 3 weeks. RESULTS: Twenty-one patients received pertuzumab and 19 completed at least two cycles. Pertuzumab was well tolerated. Overall, 365 adverse events were reported and 122 considered to be possibly drug related. Of these, 116 were of grade 1 to 2 intensity. The pharmacokinetics of pertuzumab were similar to other humanized immunoglobulin G antibodies, supporting a 3-week dosing regimen. Trough plasma concentrations were in excess of target concentrations at doses greater than 5 mg/kg. Two patients, one with ovarian cancer (5.0 mg/kg) and one with pancreatic islet cell carcinoma (15.0 mg/kg), achieved a partial response. Responses were documented by Response Evaluation Criteria in Solid Tumors after 1.5 and 6 months of pertuzumab therapy, and lasted for 11 and 10 months, respectively. Stable disease lasting for more than 2.5 months (range, 2.6 to 5.5 months) was observed in six patients. CONCLUSION: These results demonstrate that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active, suggesting that inhibition of dimerization may be an effective anticancer strategy.

Adult↗
PubMed2005

Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma.

PURPOSE: The Cytokine Working Group conducted a randomized phase III trial to determine the value of outpatient interleukin-2 (IL-2) and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m(2) subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m(2) subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks. RESULTS: One hundred ninety-two patients were enrolled between April 1997 and July 2000. Toxicities were as anticipated for these regimens. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (nine of 91 patients) for IL-2/IFN (P = .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and IFN (P = .082). The median response durations were 24 and 15 [corrected] months (P = .18) [corrected] and median survivals were 17.5 and 13 months (P = .24). For patients with bone or liver metastases (P = .001) or a primary tumor in place (P = .040), survival was superior with HD IL-2. CONCLUSION: This randomized phase III trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic renal cell carcinoma.

Adult↗
PubMed2005

Abnormal prorenin processing in growth hormone deficiency.

Growth hormone deficiency (GHD) is associated with increased premature cardiovascular (CV) mortality. Abnormal cardiac structure and function, including autonomic adrenergic dysfunction as detected by heart rate variability analysis, have been described in GHD. Abnormal prorenin processing resulting in a reduced renin/prorenin ratio has been correlated with cardiac autonomic dysfunction, an established risk factor for CV mortality, in diabetic patients. We investigated renin/prorenin ratios in untreated GHD patients (n=31) and in a group of GHD patients treated with GH (n=23) and compared both groups to a group of 59 normal control subjects. The treated GHD group was replaced with GH for a mean duration of 49.4+/-6.7 months. The mean renin/prorenin ratios were 0.0765+/-0.0089 in the untreated GHD group, 0.113+/-0.018 in the treated GHD group, and 0.304+/-0.029 in the control group (P<0.01, untreated GHD or treated GHD vs. normal controls; P=NS, untreated GHD vs. treated GHD). These results demonstrate that GHD is characterized by abnormal prorenin processing implicating concomitant cardiac autonomic adrenergic dysfunction, a risk factor for increased CV mortality. GH treatment resulted in a non-significant trend towards normalizing this defect.

Adolescent↗
PubMed2005

Stroke training of prehospital providers: an example of simulation-enhanced blended learning and evaluation.

Since appropriate treatment of patients in the first few hours of ischemic stroke may decrease the risk of long-term disability, prehospital providers should recognize, assess, manage and communicate about stroke patients in an effective and time-efficient manner. This requires the instruction and evaluation of a wide range of competencies including clinical skills, patient investigation and management and communication skills. The authors developed and assessed the effectiveness of a simulation-enhanced stroke course that incorporates several different learning strategies to evaluate competencies in the care of acute stroke patients. The one-day, interactive, emergency stroke course features a simulation-enhanced, blended-learning approach that includes didactic lectures, tabletop exercises, and focused-examination training and small-group sessions led by paramedic instructors as standardized patients portraying five key neurological syndromes. From January to October 2000, 345 learners were assessed using multiple-choice tests as were randomly selected group of 73 learners using skills' checklists during two pre- and two post-course simulated patient encounters. Among all learners there was a significant gain in knowledge (pre: 53.9%+/-13.9 and post: 85.4%+/-8.5; p<0.001), and for the 73 learners a significant improvement in their clinical and communication skills (p<0.0001 for all). By using a simulation-enhanced, blended-learning approach, pre-hospital paraprofessionals were successfully trained and evaluated in a wide range of competences that will lead to the more improved recognition and management of acute stroke patients.

Brain Ischemia↗
PubMed2005

Effects of intrastimulus modality change on audiovisual time-to-arrival judgments.

In this research, anticipatory perception of an approaching vehicle was examined. By varying the availability of visual and acoustic media, conditions occurred in which the input to the modalities was repetitively interrupted while the presentation of the approach event continued. In these conditions, the audio and the visual signals were presented either in short and concurrent segments at regular intervals or in alternation (interleaved) at regular intervals. It was found that interrupting the signal within a single modality did not affect performance if the approach information was available in the alternate modality. These results are consistent with a modally flexible detection mechanism for the perception of approaching objects. This modal flexibility may provide some evidence that information is detected using a modality-neutral strategy.

Adult↗
PubMed2004

Novel antiangiogenic therapies for renal cell cancer.

Renal cell cancer remains a disease for which highly effective therapy for the majority of patients with metastatic disease is lacking. The biology of clear cell carcinomas and their association with mutations of the von Hippel-Lindau gene and its resultant increased expression of vascular endothelial growth factor (VEGF) make angiogenesis a potentially pathophysiologic mechanism for tumor development. As a result, the use of antiangiogenic therapy is an intriguing concept for the treatment of renal cell cancer. Various agents, aside from the inhibitors of VEGF, have been studied, including thalidomide, low-dose interferon, and novel antiangiogenic agents such as the thrombospondin-1 mimetics. Use of these agents has been associated with some degree of objective response or prolonged stabilization of disease, and their true value needs to be assessed in ongoing prospective studies. Combinations of antiangiogenic agents either with other similarly acting drugs or as a component of a "cocktail" with other noncytotoxic therapies should be explored in this patient population.

Angiogenesis Inhibitors↗
PubMed2004

Predicting retention of adolescents in substance abuse treatment.

Because retention of adolescents in substance abuse treatment is critical to treatment effectiveness, factors that predict length of time in treatment were examined among youth (N=173) admitted to five outpatient clinics. At admission, youth received a comprehensive psychosocial assessment. Relevant predictors of length of treatment were determined using Poisson regression analyses. Factors positively associated with treatment duration included use of drugs in addition to alcohol and marijuana, having less deviant peers, absence of substance-caused emotional problems, and viewing counselor's skills more positively. In contrast, pressure to enter treatment was unrelated to treatment duration. Results suggest that the counselor-client relationship and peer influences be explicitly considered in treatment.

Adolescent↗
PubMed2004

Renal cell carcinoma: rationale and development of therapeutic inhibitors of angiogenesis.

Inhibition of tumor angiogenesis is a promising therapeutic approach to treat cancer; translation of this concept into clinical practice requires an understanding of the molecular events that are responsible for the development of tumor vasculature. Renal cell carcinoma is characterized by the frequent loss of the von Hippel-Lindau tumor suppressor gene which results in the loss of one of the critical mechanisms for regulating the level of hypoxia inducible factor 1 and leads to the overproduction of vascular endothelial growth factor (VEGF) by the tumor cell. Therapeutic strategies to inhibit the function of these important pathways have been effective in preventing tumor angiogenesis in preclinical models of kidney cancer, and more recently, in the clinical setting. Strategies to treat renal cell carcinoma with agents that are designed to prevent angiogenesis have included interruption of the VEGF signaling pathway, mimics of endogenous angiogenesis inhibitors, prevention of destruction of the basement membrane, and direct inhibition of endothelial cells by a variety of agents with complex, novel, or undetermined mechanisms. Recent clinical studies of bevacizumab, the first anti-VEGF agent to be marketed for the treatment of cancer, have provided proof for the concept that these strategies can lead to tangible benefits for patients who have advanced renal cell carcinoma and likely will be applicable broadly to the treatment of cancer.

Angiogenesis Inhibitors↗
PubMed2004

Evaluation of a group-based substance abuse treatment program for adolescents.

The effectiveness of adolescent substance abuse treatment has been repeatedly demonstrated, but specific treatment approaches have rarely been sufficiently documented to permit replication. This study evaluated the effectiveness of a manual-guided, outpatient, group-based treatment program for adolescents (N = 194) who were mild-to-moderate substance abusers. In addition to evaluating the group-based treatment model, the study was designed to compare the effectiveness of two approaches to preparing youth to engage in treatment, whereby adolescents received one of two types of treatment induction, either motivational interviewing or counseling overview. Self-reported pretreatment substance use and criminal behaviors were compared with these behaviors 6 and 12 months following treatment entry using a General Linear Mixed Model analytic approach that controlled for the effects of potential confounding variables and examined individual and program factors that might explain treatment response. Participants significantly reduced marijuana use at 6 months, and these reductions were largely sustained at 12 months. No changes in alcohol use or criminal involvement were obtained. Further examination of marijuana use indicated differential treatment response based on participants' emotional abuse history, family satisfaction, school adjustment, and pretreatment substance use frequency. This treatment approach appears promising for marijuana-abusing youth.

Adolescent↗
PubMed2004

Pretreatment illegal activities of a nationwide sample of adolescent substance abuse clients.

While much is known about criminal behavior patterns of general population and delinquent youth, little is known about the pretreatment criminality of adolescent substance abuse treatment clients. This information is important because of substantial increases in adolescent substance abuse treatment admissions and because adolescents who use substances regularly are more likely than nonusers to be criminally involved. Descriptive information is presented on the lifetime patterns of substance abuse, criminal activity, and justice system involvement of 1,122 youth admitted to nine adolescent treatment programs located throughout the United States, including short- and long-term residential and outpatient programs. Study findings indicate that involvement in illegal activities, other than use and possession of substances, is common among adolescents entering treatment. Most clients in each modality were involved with the justice system prior to treatment, and pressure from the justice system to enter treatment was widely reported. While the severity and frequency of offenses committed by short- and long-term residential clients were considerably greater than outpatient clients, a sizable minority of outpatient clients had also committed serious offenses. In addition to differences among modalities, considerable variation in criminal involvement was found among programs within the same modality. Implications for treatment and research are discussed.

Adolescent↗