Biomedical subjects
M Atkins
Publications and source records attributed to M Atkins.
Reservist fitness evaluations.
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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.
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.
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.
Preventing osteoporosis: an independent study (continuing education credit).
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Breath-holding time in normal subjects, snorers, and sleep apnea patients.
BACKGROUND: The onset of irregular inspiratory muscle activity has been observed toward the breakpoint of the breath-holding maneuver. We wondered if this was similar to the increased respiratory effort with paradoxical breathing seen during the resolution of an apnea in obstructive sleep apnea syndrome (OSAS). STUDY OBJECTIVE: To compare the breakpoint of breath holding in normal subjects, OSAS patients, and snorers. METHODS: Thirty normal subjects, 30 patients with OSAS, and 16 snorers performed serial breath-holding maneuvers at functional residual capacity (FRC) under standardized pretest conditions using the rebreathing method of Read. RESULTS: Intergroup comparisons were carried out by analysis of variance with post hoc Tukey's Highest Significant Difference tests. Basal end-tidal carbon dioxide (EtCO2) was significantly higher in OSAS than in normal subjects and snorers. Basal breath-holding time (BHT) was shorter in OSAS as compared with that in normal subjects and snorers (p < 0.05). The maximal EtCO2 level attained was higher in OSAS as compared with normal subjects (p < 0.05) and snorers (p = 0.052). The maximal BHT in OSAS was shorter than in normal subjects (p < 0.05) but not in snorers. The slope of BHT/EtCO2 differed significantly in OSAS compared with normal subjects and snorers (p < 0.05). No significant correlation was found between slope BHT/EtCO2 and age or body mass index using multiple regression analysis. The FRC of OSAS patients and snorers were similar (p = 0.792). CONCLUSION: We conclude that BHT and slope of BHT/EtCO2 are different in OSAS subjects as opposed to those in normal subjects and snorers.
Parvovirus B19 outbreak on an adult ward.
In November and December 1992, an outbreak of parvovirus B19 infection occurred among patients and staff on an adult mixed surgical ward at a large hospital in London. Three patients and 15 staff members were serologically confirmed as acute cases. The attack rate among susceptible members of staff was 47%. In those infected, arthralgia (80%) and rash (67%) were the most common symptoms. Of six susceptible in-patients on the ward, three became infected. One of the in-patients who had carcinoma of the mouth was viraemic for more than 10 days with marrow suppression resulting in the postponement of chemotherapy until intravenous immunoglobulin was given and he was no longer viraemic. Control measures taken included closure of the ward to new admissions, transfer of only immune staff to the ward, and restriction of the ward nursing staff to working only on that ward. Although no specific exposure was conclusively identified as a risk factor, there was a suggestion of an increased risk of acquiring parvovirus B19 infection among those staff who did not adopt strict hand washing procedures after each physical contact with a patient (RR = 2.33; P = 0.07). Knowledge of parvovirus B19 among interviewed health care workers was poor: only 42% reported knowing about parvovirus B19 and only 38% could name a patient category at risk of a severe outcome following infection. This is the first report of a nosocomial outbreak affecting an adult ward and of possible transmission of parvovirus B19 infection from staff to in-patients. Hospital control of infection teams should include parvovirus B19 in their outbreak containment plans.
Nasal resistance in obstructive sleep apnea.
BACKGROUND: Acute increases in nasal resistance are known to induce upper airway occlusion in predisposed subjects. With the limited efficacy of nasal surgery alone in the treatment of obstructive sleep apnea (OSA), the relevance of chronically increased nasal resistance in the pathophysiologic features of OSA remains undetermined. METHODS: Seventy-one patients with OSA (apnea+hypopnea index > 15 [AHI]) and 70 antisocial snorers (ASS [AHI < 15]) referred for routine assessment of sleep-disordered breathing had concomitant measurement of combined (CNR) and highest unilateral (HUNR) nasal resistance by anterior rhinomanometry. RESULTS: Nine individuals (five of 71 in the OSA group and 4 of 70 in the ASS group, 0.5 < p < 0.75) had an abnormally elevated CNR. The HUNR was increased in 21 individuals (11 of 70 in the ASS group and 10 of 71 in the OSA group, 0.25 < p < 0.5). There was no significant difference between CNR in OSA (1.5[0.5]) (mean [SE]) and ASS (1.6 [0.2]) groups. No correlation was found between CNR and the AHI in OSA or in ASS. The Mean HUNR in the OSA group was 5.5 (0.9) (mean [SE]) and in ASS was 5.3(0.6), which were not significantly different (p = 0.89). The HUNR also did not correlate with the AHI in either OSA or ASS. CONCLUSION: Chronic changes in nasal resistance are not a significant risk factor for the development or severity of OSA.
Hepatitis A virus infection. Should susceptible homosexual men be offered immunization.
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Cytomegalovirus mononucleosis: risk for fathers of young children.
A case of pyrexia of unknown origin in a 35-year-old man, who had become a father nine months earlier, is presented. A diagnosis of cytomegalovirus mononucleosis was achieved only after extensive investigations. It is suggested that cytomegalovirus mononucleosis should be added to the differential diagnosis when investigating pyrexia of unknown origin in fathers of young children.
Pathophysiology of upper airway closures during sleep.
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Environmental contamination during tracheal suction. A comparison of disposable conventional catheters with a multiple-use closed system device.
The extent of airborne environmental bacterial contamination which occurs following tracheal suction has been investigated in patients undergoing intermittent positive pressure ventilation in the intensive therapy unit. Two methods of performing suction, one using a conventional open technique and one using a closed system (Stericath), have been compared. Significantly lower levels of environmental contamination were observed when the closed system was used.
Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group study.
In a pilot clinical trial, treatment of patients with advanced colorectal carcinoma with the combination of fluorouracil (5FU) and recombinant interferon alfa-2a (IFN) resulted in objective tumor regression in 62% of patients. To confirm these findings in a multiinstitutional setting, a phase II clinical trial was initiated by the Eastern Cooperative Oncology Group (ECOG) in 1989. The treatment regimen was identical to that used in the earlier study: 5FU 750 mg/m2/d for 5 days as a continuous infusion followed by weekly outpatient bolus therapy and IFN 9MU subcutaneously beginning day 1 and administered three times per week. Doses were modified for gastrointestinal, hematologic, and neurologic toxicity and for fatigue, similarly to those used in the previous pilot trial. Thirty-eight patients were registered; 36 are evaluable for response (one lost to follow-up and one with nonmeasurable disease). All patients had metastatic or locally recurrent disease beyond the scope of resection; 31 of 38 had liver metastases, and 20 of 38 had two or more sites of involvement. Eight patients had grade 4 toxicities, including sepsis (nonneutropenic) (one), watery diarrhea (two), and granulocytopenia (six). Grade 3 neurologic toxicities were observed in two (5%) patients and included slurred speech and gait disturbance. Objective response was 42% (95% confidence interval [Cl], 27% to 58%), including one clinical complete responder and 14 partial responders. Among the responding patients, the median time to treatment failure was 8 months. Two patients remain on treatment at 10+ and 16+ months: median survival has not been reached. The results of this multiinstitutional trial suggest that the addition of IFN to 5FU enhances the objective response rates achieved in patients with advanced colorectal carcinoma and that the toxicities of this regimen are acceptable.
An outbreak of hepatitis A among cancer patients treated with interleukin-2 and lymphokine-activated killer cells.
An outbreak of hepatitis A virus (HAV) infection occurred among cancer patients treated with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells between July and September 1986 at six different clinical centers. Among 85 patients tested serologically for recent HAV infection, 22 (39%) of 56 susceptible patients developed acute HAV infection. Only exposure to LAK cells cultured in medium containing human serum from two specific manufactured pools was associated with HAV infection. Attack rates were 85% among patients exposed to pool X, 62% in patients exposed to pool Y, and 50% in those exposed to both pools, compared with none among the 24 susceptible persons exposed to other serum pools (P less than .001). The serum used in production of LAK cell medium was obtained from multiple paid donors. Twenty persons donated plasma to both serum pools X and Y. Although none of 12 donors tested had evidence of recent HAV infection, it is likely that an asymptomatic plasma donor viremic for HAV contaminated both serum pools and the LAK cell medium made from it.
Melanotropin receptors demonstrated in situ in human melanoma.
Although some cultured human melanoma cell lines are responsive to melanotropins (melanocyte-stimulating hormones [MSH]), the prevalence and tissue distribution of MSH receptors in melanoma are unknown. We report here the use of an in situ binding technique to demonstrate specific MSH receptors in surgical specimens of human melanoma. The distribution and binding properties of specific MSH binding sites were determined by autoradiography and image analysis after incubation of frozen tumor tissue sections with a biologically active, radiolabeled analogue of alpha-MSH, [125I]iodo-Nle4, D-Phe7-alpha-MSH ([125I]NDP-MSH). In melanoma specimens from 11 patients, 3 showed high levels of specific binding, 5 showed low levels, and in 3 patients specific binding of [125I]NDP-MSH was not detectable. Specific MSH binding sites were present in melanoma cells, but not in adjacent connective or inflammatory tissues. Melanotropins, including alpha-MSH, NDP-MSH, and ACTH, inhibited [125I]NDP-MSH binding in a concentration-dependent manner, whereas unrelated peptides (somatostatin and substance P) did not. The apparent affinity of alpha-MSH for this binding site was in the nanomolar range (EC50 = 2 X 10(-9) M for inhibition of [125I]NDP-MSH binding in situ), similar to that recently described for the murine melanoma receptor. In one patient, analysis of multiple intratumor samples and tumors excised on three separate occasions revealed high levels of specific MSH binding in all samples. These results suggest that endogenous melanotropins may modulate the activities of human melanoma cells in vivo.
Invasive Haemophilus influenzae infections in adults: a patient with prosthetic valve endocarditis.
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Soft neurological signs and impulsivity in children.
To evaluate the relationship between soft neurological signs and various proposed dimensions of impulsivity (behavioral and cognitive), 31 boys (6-13 years, mean +/- SD 10.1 +/- 1.8) with disruptive behavior disorders, and 45 age-matched boys without DSM-III-R pathology, were independently assessed on clinical ratings of impulsivity, a battery of cognitive tests intended to score impulsive responding, and a neurological examination for soft signs. After being corrected for age, neurological soft signs correlated positively with impulsive responding on the Matching Familiar Figures Test (inpatients and normals) and the Continuous Performance Test (in normals), but not with IQ or clinical impulsivity rating scores. These findings suggest a relationship between neurological dysfunction/immaturity and performance on specific tasks requiring response inhibition, thus adding value to the cognitive assessment of impulsivity.