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M Atkins

Publications and source records attributed to M Atkins.

At least 19 recordsLinked to original sources
PubMed2001

Outpatient biochemotherapy with interleukin-2 and interferon alfa-2b in patients with metastatic malignant melanoma: results of two phase II cytokine working group trials.

PURPOSE: The Cytokine Working Group performed a randomized phase II trial of two outpatient biochemotherapy regimens to identify an outpatient regimen with high antitumor activity and less toxicity than inpatient regimens which might be compared with chemotherapy or inpatient biochemotherapy regimens in future phase III trials. PATIENTS AND METHODS: Eighty-one patients with metastatic malignant melanoma received dacarbazine 250 mg/m(2)/d intravenously (IV) and cisplatin 25 mg/m(2)/d IV on days 1, 2, and 3, plus interferon (IFN) alfa-2b 5 mU/m(2) subcutaneously (SC) on days 6, 8, 10, 13, and 15, given every 28 days. Interleukin-2 (IL-2) was given daily on days 6 to 10 and 13 to 15. In group 1, IV IL-2 was given at 18.0 MU/m(2), and in group 2, SC IL-2 was given at 5.0 mU/m(2). RESULTS: In group 1 (IV IL-2), there were five complete responses (CRs) and 11 partial responses (PRs) among 44 patients (objective response rate [ORR], 36%; 95% confidence interval [CI], 22% to 51%). In group 2 (SC IL-2), there was one CR and five PRs among the 36 patients (ORR, 17%; 95% CI, 4% to 29%). The median survival was 10.7 months in group 1 and 7.3 months in group 2. Eleven patients in group 1 and four patients in group 2 remain alive as of the last follow-up. Toxicities in both groups were similar. No patient required hospitalization for neutropenic fever. CONCLUSION: Biochemotherapy has activity in these outpatient regimens with acceptable toxicity. The antitumor activity observed with the IV IL-2 regimen seems similar to that of inpatient biochemotherapy regimens. If inpatient biochemotherapy regimens develop an established role in the management of melanoma, future phase III trial comparisons with this outpatient IV IL-2 regimen would be appropriate.

Adult↗
PubMed2001

Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation.

BACKGROUND/AIMS: The long-term prophylaxis of hepatitis B after liver transplantation requires further optimization. In a randomized trial we investigated a regimen where the initially given hepatitis B immunoglobulin (HBIg) is replaced by long-term lamivudine treatment. METHODS: Twenty-four liver transplant recipients (all HBsAg-positive/HBV DNA-negative before transplantation), who had received HBIg for at least 6 months without HBV recurrence, were randomized to receive lamivudine (n = 12) or HBIg (n = 12) for 52 weeks. The efficacy criteria involved seronegativity for HBsAg and undetectable HBsAg/ HBcAg in the liver. RESULTS: Twenty-one of 24 patients completed the study without hepatitis B virus (HBV) recurrence (11 on HBIg, ten on lamivudine), while three patients became HBsAg-positive. Amongst those without HBV recurrence HBV DNA was detectable only by polymerase chain reaction, intermittently in serum and lymphocytes, and in liver specimens from six of eight patients receiving HBIg and five of seven receiving lamivudine. YMDD variant was found in four cases with no viral antigen expression. Eight patients continued lamivudine after the study and during an additional 6-22 months remained HBsAg-negative with normal graft function. CONCLUSIONS: Substitution of HBIg with lamivudine is effective for prevention of HBV recurrence in low-risk liver transplant recipients and offers a convenient and cost-effective alternative for long-term HBV prophylaxis.

Adult↗
PubMed2000

Prognostic factors in metastatic melanoma: a pooled analysis of Eastern Cooperative Oncology Group trials.

PURPOSE: To identify factors that are prognostic for survival in patients with metastatic melanoma treated in eight Eastern Cooperative Oncology Group (ECOG) trials conducted over the past 25 years. METHODS: We identified common, significant patient characteristics collected at baseline on 1,362 eligible patients for inclusion in a pooled analysis. Proportional hazards models were used to examine simultaneously the effects of multiple covariates on survival. RESULTS: Median survival was 6.4 months (95% confidence interval, 6.1 to 6.9 months.) Factors conferring the greatest increased risk of death included number of metastatic sites (relative risk [RR] = 1.12), ECOG performance status of 1 or more (RR = 1.49), or metastatic disease in the gastrointestinal (GI) tract (RR = 1.49), liver (RR = 1.44), pleura (RR = 1.35), or lung (RR = 1.19). Prior immunotherapy (RR = 0.84) and female sex (RR = 0. 87) were associated with prolonged survival. Although only 12% of patients responded to protocol treatment, landmark analysis showed this to be a significant prognostic factor (RR = 0.57). A model based on three recent studies in which baseline values for alkaline phosphatase, lactate dehydrogenase (LDH), and platelets were available identified an increased number of sites of metastasis (RR = 1.30), abnormal LDH (RR = 1.89), abnormal alkaline phosphatase (RR = 1.76), abnormal platelets (RR = 1.63), and GI metastases (RR = 1. 66) as prognostic for poorer survival. Response to treatment, when examined by landmark analysis of studies with laboratory parameters, was associated with decreased risk of death (RR = 0.47). CONCLUSION: This study demonstrates the importance and utility of laboratory parameters as prognostic factors for survival and confirmed the deleterious effects of multiple metastatic sites. Prior immunotherapy and female sex were associated with improved prognosis. Prognostic factors identified in this analysis are consistent with the findings of prior published studies and argue for the adoption of laboratory findings in the staging systems that are used for entry and stratification of clinical trials in the future.

Adolescent↗
PubMed2000

Evolution of lamivudine-resistant hepatitis B virus and HIV-1 in co-infected individuals: an analysis of the CAESAR study. CAESAR co-ordinating committee.

OBJECTIVES: Lamivudine has potent activity against HIV-1 and hepatitis B virus (HBV). Co-infection with these two viruses is common, and this may therefore influence the choice of antiretroviral therapies. A cohort of co-infected patients treated with lamivudine were studied in order to evaluate the differential effects of lamivudine on the two viral populations within the same individual after 44-52 weeks of therapy. DESIGN AND METHODS: Retrospective virological analysis of an HIV-1/HBV co-infected lamivudine cohort derived from a randomized, placebo-controlled study of lamivudine in HIV infection, the CAESAR study. RESULTS: Five of thirteen patients with HBV viral load > 10,000 copies/ml after 44-52 weeks of lamivudine therapy had genotypic drug resistance. Four of these five had a rebound of viral replication over the period of study and in one case this was associated with an alanine transaminase serum elevation. Ten of the thirteen patients had a 44-52 week HIV viral load > 1000 copies/ml, all of whom also had HIV reverse transcriptase M184V or M184I mutations. CONCLUSIONS: Extrapolating these results to the population yields an estimated 1-year incidence of drug-resistant HBV of at least 14% in lamivudine-treated HIV-1/HBV co-infected patients. The clinical and virological benefit of HBV lamivudine monotherapy in co-infected patients should be balanced against the potential for emergence of drug resistance. Further, these data suggest that the determinants of HIV and HBV drug resistance are different and that parallel evolution, rather than co-evolution of HBV and HIV-1 in co-infected individuals occurs.

CD4 Lymphocyte Count↗
PubMed2000

Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study.

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1-4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3-5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5-8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-alpha2B (9 MIU/mZ) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10-25). The median response duration was 8 months (range, 3-51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1-53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4-week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts are directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment versus treatment with outpatient s.c. injection of IL-2 plus IFN.

Adult↗
PubMed1999

Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B. Asian Hepatitis Lamivudine Trial Group.

In the reported Asian lamivudine trial, the rate of hepatitis B e antigen (HBeAg) seroconversion, defined as HBeAg/hepatitis B virus (HBV) DNA seroclearance and development of anti-HBe, during 52 weeks of treatment was only 13% to 16%. To evaluate whether any factors influenced HBeAg seroconversion, data from 345 patients in that trial were reanalyzed to correlate HBeAg seroconversion with variables including treatment, age, gender, body build, histology, baseline HBV-DNA levels, and alanine transaminase (ALT) levels. Exploratory analysis using stepwise modeling revealed that HBeAg seroconversion correlated highly with pretherapy ALT (P <.001) followed by lamivudine therapy (P =.013), but only marginally with baseline HBV-DNA (P =.071) and cirrhosis (P =.066) for lamivudine 100 mg and placebo comparison. Among these four variables, only pretherapy ALT still had a highly significant (P <.001) correlation and lamivudine therapy had a borderline association (P =.066) for lamivudine 25 mg and placebo comparison. Categorical analysis revealed that HBeAg seroconversion occurred earlier and the cumulative rate was significantly higher in patients with pretherapy ALT values over 2 times the upper limit of normal (ULN) as compared with treated patients with lower ALT levels or untreated control patients with the same ALT levels (P <.001, respectively). The highest HBeAg seroconversion rate was observed in 100 mg lamivudine-treated patients with ALT levels greater than 5 times the ULN (64%) compared with patients with ALT 2 to 5 times the ULN (26%, P =.03); and ALT less than 2 times the ULN, (5%, P <.001). These results suggest that pretherapy ALT is the strongest determinant for HBeAg seroconversion during lamivudine therapy, and should be considered in selecting patients for treatment.

Alanine Transaminase↗
PubMed1999

Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B virus-coinfected persons in a randomized, controlled study (CAESAR). The CAESAR Coordinating Committee.

The efficacy and safety of lamivudine in persons coinfected with human immunodeficiency virus (HIV) type 1 and hepatitis B virus (HBV) were examined in the CAESAR study, a randomized placebo-controlled trial assessing the addition of lamivudine (150 mg 2x/day) or lamivudine (150 mg 2x/day) plus loviride (100 mg 3x/day) to zidovudine-containing background antiretroviral treatment. Baseline hepatitis B surface antigen (HBsAg) results were available for 1790 study subjects, of whom 122 (6.8%) tested positive. Retrospective analyses for serial HBV DNA, HBsAg, and hepatitis B e antigen (HBeAg) were performed on stored sera from 118 HBsAg-positive subjects. HBV DNA and HBeAg were present in 83% and 63%, respectively. At weeks 12 and 52, median log10 HBV DNA change was -2.0 and -2.7, respectively, in the lamivudine arms, compared with no reduction among placebo recipients (P<.001). A trend to lower alanine transferase level, and delayed progression of HIV-1 disease (relative hazard, 0.26; 95% confidence interval, 0.08-0.80) were also seen in the lamivudine arms, compared with the placebo group.

Acetamides↗
PubMed1998

Quantitative differences in the distribution of zidovudine resistance mutations in multiple post-mortem tissues from AIDS patients.

Replication of HIV introduces errors into the genome which are responsible for conferring a growth advantage over wildtype virus when drugs such as zidovudine (ZDV) exert a selective pressure. The molecular basis for HIV-1 resistance to ZDV has been mapped to codons 41, 67, 70, 215 and 219 of the reverse transcriptase gene both in vitro and in clinical samples of blood. This study has investigated the relationship between the quantitative prevalence of ZDV resistance in multiple organs of the same individual. Proviral HIV-1 load was measured by quantitative-competitive PCR in 90 samples from organs of 11 patients dying with AIDS. Nine of these patients had been prescribed zidovudine. The distribution of wildtype and mutant sequences at the positions 41, 67, 70, 215 and 219 of the reverse transcriptase was assessed using a point mutation assay. The results showed that the highest proviral loads were predominately found in lymph node, spleen and lung and there was a significant association between viral load and resistance to ZDV (P=0.008). Inter-organ distribution of wildtype and mutant sequences at codons 41, 67, 70, 215 and 219 was frequently not uniform and in some patients differed markedly between the lymphoreticular system and other organs. These results demonstrate that treatment of HIV-1 infection with zidovudine does not exert uniform selective pressures in multiple organs. These findings have implications for the interpretation of resistance data and design of treatment strategies for HIV, arguing in particular that alterations in therapeutic regimens should consider the likelihood of different resistance patterns being present in multiple sites within the same individual.

Acquired Immunodeficiency Syndrome↗
PubMed1998

A contextually relevant assessment of the impact of child maltreatment on the social competencies of low-income urban children.

OBJECTIVE: A developmental-ecological model was used to explore the psychological adjustment and peer social competencies of maltreated preschool children. METHOD: Enhanced research methods were used that included verification of maltreatment status, multiple-variable matching of comparison children, and contextually relevant assessment. One hundred eight Head Start children, of whom 54 were maltreated, participated. Assessment of social functioning included measurement of peer play interactions, global social skills, peer sociometrics, and teacher and parent ratings of behavior problems. RESULTS: Findings indicated that maltreated children were significantly less interactive in peer play and overall exhibited less self-control and interpersonal skill in social interactions than nonmaltreated children. In addition, maltreated children were more likely than their nonmaltreated peers to receive low sociometric ratings and were found by both teachers and parents to display more internalizing behavior problems than comparison children. CONCLUSIONS: These findings indicate the importance of using developmentally sensitive research methods to inform contextually relevant interventions.

Case-Control Studies↗
PubMed1997

Progression of HIV disease is associated with increased expression of Fc gammaRI and CR1 on alveolar macrophages.

The expression of receptors for complement and the Fc region of immunoglobulin by alveolar macrophages (AM) constitutes a valuable aid to effector function of these cells. However, during HIV infection such expression may also act to increase binding of immune complexes, thus facilitating viral infection of these cells. This study was designed to determine whether changes in the expression of these receptors occurs in situ during HIV infection. Lung macrophages were isolated by bronchoalveolar lavage in groups of HIV+ subjects segregated on the basis of peripheral CD4 count. A group of normal subjects was also investigated. Expression of CR1 and Fc gammaRI was quantified by measuring the optical density of reaction product following controlled immunoperoxidase staining with MoAbs CD35 and CD64. Both CR1 and Fc gammaRI were increased over normal in all HIV+ subjects. This increase was progressive with advancing disease as determined by correlation with declining peripheral CD4 count. Comparison of asymptomatic and symptomatic subjects with HIV infection showed no difference in CR1 expression but a rise in Fc gammaRI expression in the latter group. An overall inverse correlation was also found between peripheral CD4 count and Fc gammaRI expression, but not CR1 expression. These data demonstrate a significant increase in the expression of these receptors on AM from HIV+ subjects, and show that this increase may occur before any symptoms in these patients.

Adult↗
PubMed1997

Domestic violence and children: prevalence and risk in five major U.S. cities.

OBJECTIVE: Children witnessing domestic violence is a major national concern. The present study provided data on the prevalence of children's exposure to substantiated cases of adult female assaults in five U.S. cities. METHOD: Data for this study were drawn from the Spouse Assault Replication Program (SARP) database, collected from police officers and female victims of misdemeanor domestic violence. In addition, household demographic data and data on involvement of children in the violent incidents were collected. Data from the SARP households were compared with census data from each city. RESULTS: Results indicated that children were disproportionately present in households with domestic violence and that young children were disproportionately represented among these children. Moreover, these children were exposed to excessive levels of additional developmental risk factors and they were involved in the incidents to varying degrees. CONCLUSIONS: These findings underscore the importance of establishing a more rigorous interdisciplinary, scientific research agenda to inform assessment and treatment efforts for a very vulnerable group of children who witness domestic violence, children aged 0 through 5 years.

Adolescent↗
PubMed1997

War pensions.

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Humans↗
PubMed1997

Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997.

PURPOSE: This article reviews long-term follow-up data from three phase II studies conducted by the Cytokine Working Group from 1989 to 1995 that evaluated various recombinant interleukin-2 (rIL-2) -based regimens in patients with metastatic renal cell cancer. Response rates, long-term response duration, and toxicity are compared. PATIENTS AND METHODS: The Cytokine Working Group studies reviewed here investigated the safety and efficacy of two high-dose intravenous rIL-2-based regimens and two moderate-dose outpatient subcutaneous rIL-2-based regimens in patients with progressive metastatic renal cell cancer. A randomized phase II study, initiated in 1989, investigated the safety and efficacy of high-dose intravenous rIL-2 alone and high-dose intravenous rIL-2 plus recombinant interferon-alpha (rIFN-alpha). A second phase II study, initiated in 1992, tested the safety and efficacy of moderate-dose subcutaneous rIL-2 plus subcutaneous rIFN-alpha in the outpatient setting. The third trial, initiated in 1995, investigated a regimen consisting of the previous subcutaneous rIL-2 plus rIFN-alpha regimen alternating with intravenous bolus 5-fluorouracil (5-FU) plus subcutaneous rIFN-alpha. Median follow-up for these studies is 72 months, 48 months, and 24 months, respectively. RESULTS: The overall response rates observed with each of these regimens were similar (17% with high-dose rIL-2 alone, 11% with high-dose rIL-2/rIFN-alpha, 17% with outpatient subcutaneous rIL-2/rIFN-alpha, and 16% with outpatient rIL-2/rIFN-alpha, plus 5-FU/rIFN-alpha). However, the high-dose rIL-2 regimen produced a 7% complete response rate, compared with 0%, 4%, and 4%, respectively, with each of the other regimens. Median response duration was also much longer with high-dose intravenous rIL-2 alone (53 months), compared with 7 months, 12 months, and 9 months, respectively, with each of the other regimens. CONCLUSION: Complete response rate and response duration appear to favor the high-dose intravenous rIL-2 regimen. This will require verification in a randomized study comparing the best high-dose arm (rIL-2 alone) with the best outpatient regimen (rIL-2/IFN-alpha). The Cytokine Working Group is currently conducting such a study.

Adult↗
PubMed1997

Prospective randomized trial of lisofylline for the prevention of toxicities of high-dose interleukin 2 therapy in advanced renal cancer and malignant melanoma.

The therapeutic application of high-dose interleukin (IL) 2 in human malignancy is limited by severe multiorgan toxicities that are mediated, in part, by tumor necrosis factor (TNF) and IL-1. CT1501R (lisofylline; LSF) is one of several methyl xanthine congeners that inhibit the effects of TNF by the interruption of specific signal transduction pathways. This randomized, placebo-controlled trial was designed to assess the activity of LSF in reducing the toxicities of high-dose IL-2 therapy. Fifty-three patients with metastatic renal cancer or malignant melanoma were treated with i.v. bolus IL-2, 600, 000 IU/kg every 8 h for 5 days (14 doses), followed by 9 days of rest and another 5-day course of IL-2. Patients were randomly assigned to LSF, 1.5 mg/kg i.v. bolus, or placebo every 6 h during IL-2 therapy. All patients were to be treated to individual maximum tolerance of IL-2 at the intensive care unit level of support. The end points for statistical analysis were the number of IL-2 doses administered during the first cycle of treatment (maximum, 28) and the toxicities experienced by each group after the first 8 planned IL-2 doses. There was no difference between the LSF and placebo groups in the mean number of IL-2 doses tolerated in the entire first cycle of therapy (19.6 +/- 5.4 versus 19.5 +/- 5.8, P = 0.86) or in the first or second 5-day course of IL-2. The only significant difference in toxicities occurring through the eighth dose of IL-2 was in the maximum elevation of serum creatinine (mean, 1.7 +/- 0.8 for placebo versus 1.5 +/- 0.6 mg/dl for LSF, P = 0.013). A Monte Carlo analysis of major toxicities over the first 14-dose course of therapy showed a statistically significant difference favoring the LSF-treated group (P = 0.025). LSF was well tolerated, associated only with mildly increased nausea (P = 0.006 after eight IL-2 doses, but not significant for the entire first cycle). The antitumor activity was comparable in both groups (objective responses, 2 of 28 with LSF versus 4 of 24 with placebo). The mean peak plasma concentrations of LSF on days 1, 5, and 19 were 6.24, 3.83, and 5.04 micromol/liter, respectively. In conclusion, with this dose and schedule, LSF did not alter the toxicities of high-dose i.v. IL-2 sufficiently to impact the overall dose intensity of IL-2. Successful IL-2 toxicity modulation may require the use of higher doses of LSF, the development of agents with more potent anti-TNF activity, and/or combined modulating agents that function via distinct mechanisms to interrupt cytokine-mediated signaling.

Adult↗
PubMed1996

Community-based resilient peer treatment of withdrawn maltreated preschool children.

The purpose of the present study was to evaluate differences in the social play of maltreated and nonmaltreated preschool children and the effectiveness of a resilient peer treatment (RPT) for socially withdrawn victims of physical abuse and neglect. RPT is a peer-mediated classroom intervention based on a developmental-ecological model. It involves pairing withdrawn children with resilient peers in the natural classroom under the supervision of a parent assistant. Forty-six Head Start children, of whom 22 were maltreated, were randomly assigned to RPT and control conditions. Outcome variables were observational categories of social play and standardized teacher ratings. Before treatment, maltreated children were significantly more isolated and less interactive in peer play than nonmaltreated children. RPT resulted in a significant increase in positive interactive peer play and a decrease in solitary play for maltreated and nonmaltreated, socially withdrawn children. Moreover, treatment gains in social interactions were validated 2 months following treatment. Findings are discussed in terms of a developmental-ecological model.

Child Abuse↗