Influence of schedule of interleukin 2 administration on therapy with interleukin 2 and lymphokine activated killer cells.

The purpose of this study was to compare the toxicity, immunomodulatory changes, and antitumor efficacy of interleukin 2 (IL-2) and lymphokine activated killer (LAK) cell therapy with two durations of IL-2 infusion. Patients with progressive melanoma, non-Hodgkin's lymphoma, renal carcinoma, or colon carcinoma received IL-2 at 3 X 10(6) units/m2/day on days 1-5 and 13-17, either by bolus injection every 8 h (q8h) or by continuous i.v. (CIV) administration. Peripheral blood mononuclear cells were harvested by leukapheresis on days 8, 9, and 10, were incubated in vitro for 5 days for generation of LAK cells, and were infused on days 13, 14, and 15. The first 11 patients were treated with IL-2 q8h, and the subsequent 13 patients were treated by CIV infusion. Toxicity consisted primarily of fever, chills, emesis, diarrhea, weight gain, and edema but did not require intensive care unit support and did not differ significantly between treatment groups. IL-2-induced lymphocytosis on day 8 was higher with CIV than with q8h administration with a mean lymphocyte count/microliter of 5610 +/- 700 (SE) versus 3300 +/- 500. Immunomodulatory changes observed on days 8 and 20 were also greater with CIV IL-2 and included an increase in peripheral blood mononuclear cell IL-2 receptor expression as well as a marked rise in the number of Leu-11+ and Leu-19+ peripheral blood mononuclear cells. The total leukapheresis yield per patient and total number of LAK cells infused per patient were higher with CIV than q8h administration, with 49.8 +/- 4.9 X 10(9) versus 39.4 +/- 5.4 X 10(9) and 42.6 +/- 5.0 X 10(9) versus 34.0 +/- 5.4 X 10(9), respectively. The cells infused displayed phenotypic evidence of activation and exhibited marked lytic reactivity to Daudi, Raji, and HT-144 targets. One complete and one minimal response were observed in 2 of 8 patients with metastatic renal cell carcinoma who received CIV IL-2 and LAK cells. The results show that IL-2 is more biologically active by CIV than q8h administration, as demonstrated by greater rebound lymphocytosis, LAK cell yield, and in vivo immunostimulation.

Association of elevated fasting C-peptide level and increased intra-abdominal fat distribution with development of NIDDM in Japanese-American men.

The Japanese-American population of King County, Washington, is known to have a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM). As part of a community-based study, we reexamined 146 second-generation Japanese-American men who had been initially classified as nondiabetic. At a mean follow-up period of 30 mo, 15 men had developed NIDDM, and 131 remained nondiabetic. The variables measured at the initial visit that distinguished the 15 diabetic men from the 131 nondiabetic men were older age, higher serum glucose level at 2 h after 75 g oral glucose, higher fasting plasma C-peptide level, and increased cross-sectional intra-abdominal fat area as determined by computed tomography. Both older age and higher 2-h glucose levels are variables that have been associated with the development of NIDDM, but the association of higher fasting C-peptide level and greater intra-abdominal fat area with subsequent development of NIDDM were new observations. The elevated fasting C-peptide level persisted after adjustment for fasting serum glucose. The elevated C-peptide level represents hypersecretion of insulin and was interpreted to reflect a compensatory response to an underlying insulin-resistant state that antedates the development of NIDDM. The fasting C-peptide level was correlated with the intra-abdominal fat area, suggesting that the intra-abdominal fat area may be associated with insulin resistance. Thus, in individuals who develop NIDDM, insulin resistance, increased insulin secretion, and increased intra-abdominal fat are present before diabetic glucose tolerance can be demonstrated.

Prevalence of diabetes mellitus and impaired glucose tolerance among second-generation Japanese-American men.

We describe the initial findings from a multidisciplinary, epidemiologic study of diabetes mellitus conducted in a population of second-generation Japanese-American (Nisei) men born between 1910 and 1939 who reside in King County, Washington (n = 1746). From this study population, 487 volunteered, and 229 were enrolled to comprise the study sample. A random sample of Nisei men was also drawn from the population to develop a reference sample of 189 men. All subjects participated in a 75-g oral glucose tolerance test; the National Diabetes Data Group (NDDG) and World Health Organization (WHO) diagnostic criteria as well as a modification of the WHO criteria were used to classify individuals with normal glucose tolerance, impaired glucose tolerance (IGT), or diabetes. Within the study sample, 79 men were found to have normal glucose tolerance, 72 had IGT, and 78 had type II diabetes. The mean age of the study sample was 61.4 yr. Based on comparison of the study sample to the reference sample, the study sample was ascertained to be representative of Nisei men in King County. Extrapolating from our observations in the reference sample and in the study sample, we have estimated that approximately 56% of Nisei men in the study population have abnormal glucose tolerance. Much of this is undiagnosed because only approximately 13% of the reference sample of Nisei men reported a prior diagnosis of diabetes. Of the men who enrolled in the study as nondiabetic subjects, 11.1% had diabetes and 39.2% had IGT; i.e., 50.3% had previously unknown abnormalities in glucose tolerance. We estimate that approximately 20% of Nisei men have diabetes (both previously diagnosed and undiagnosed) and approximately 36% have IGT.

Prevalence of complications among second-generation Japanese-American men with diabetes, impaired glucose tolerance, or normal glucose tolerance.

In a study sample of 229 second-generation Japanese-American (Nisei) men, 79 with normal glucose tolerance, 72 with impaired glucose tolerance (IGT), and 78 with non-insulin-dependent diabetes, we have determined prevalence rates for certain conditions (ischemic heart disease, peripheral vascular disease, hypertension, retinopathy, neuropathy, and nephropathy) associated with diabetes. All subjects participated in a 75-g oral glucose tolerance test. World Health Organization (WHO) diagnostic criteria and information from the subject's medical history and personal physician were used to classify the subjects. Retinopathy was observed only in diabetic men in the study sample (11.5% of diabetic men). Furthermore, it was observed only in men who were receiving drug treatment for diabetes--40.0% of insulin-treated and 17.2% of sulfonylurea-treated men. Electrophysiologic evidence of peripheral neuropathy was observed in 46.2% of diabetic men and in 4.0% of nondiabetic (normal and IGT) men. For diabetic men with fasting serum glucose greater than or equal to 140 mg/dl, 63.8% had peripheral neuropathy and 19.1% had retinopathy, whereas for diabetic men with fasting serum glucose less than 140 mg/dl, 19.4% had neuropathy and none had retinopathy. For diabetic men with a diabetes duration of greater than or equal to 10 yr, 72.7% had neuropathy and 31.8% had retinopathy; with a diabetes duration of 5-9 yr, 70.6% had neuropathy and 11.8% had retinopathy; and with a diabetes duration of less than 5 yr, 20.5% had neuropathy and none had retinopathy. Nephropathy was distinctly uncommon, and among the measurements of kidney function, only proteinuria was clearly abnormal with diabetes. Prevalence rates of hypertension, peripheral vascular disease, and ischemic heart disease were highest in Nisei men with diabetes, lowest in men with normal glucose tolerance, and intermediate in men with IGT.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatness, fat distribution, and glucose tolerance in second-generation Japanese-American (Nisei) men.

The association between amount and distribution of fat and glucose tolerance was examined in 229 second-generation Japanese-American men. According to the results of a 75-g oral glucose tolerance test and by World Health Organization (WHO) diagnostic criteria, 79 men were normal, 72 had impaired glucose tolerance (IGT), and 78 had noninsulin-dependent diabetes mellitus. Diagnostic groups were compared by using 10 measures of fatness derived from body mass indices, skinfold thicknesses, and fat areas, which were determined by computed tomography. IGT men were fatter than normal men on five measures; diabetic men were fatter on four and group differences were marginally significant (p greater than or equal to 0.03). Diabetic subjects had the largest deposits of subscapular (p = 0.01) and more biceps fat than normal men (p = 0.01); IGT men had more midthigh fat than diabetic men (p = 0.01). The diabetes and IGT groups possessed more intraabdominal fat (p = 0.003). For serum glucose levels there was an interaction between body mass index and subscapular fat.

Cigarette smoking, adiposity, non-insulin-dependent diabetes, and coronary heart disease in Japanese-American men.

PURPOSE: Coronary heart disease has been described to be increased with both glucose intolerance and cigarette smoking. All three of these have also been reported to be associated with central adiposity (disproportionate deposition of fat on the trunk compared to the extremities). The purpose of this analysis was to determine the relationship of cigarette smoking to glucose intolerance and coronary heart disease, the relationship of cigarette smoking to risk factors such as adiposity, body fat distribution, and plasma lipoprotein and insulin levels, the relationship of cigarette smoking to these risk factors independent of disease status, and whether these risk factors could account for any of the relationship between cigarette smoking and disease status. PATIENTS AND METHODS: The study design was cross-sectional. The study sample contained 219 middle-aged and elderly Japanese-American men: 77 with normal and 74 with impaired glucose tolerance and 68 with type II diabetes. There were 54 men with coronary heart disease. A detailed smoking history was obtained. Glucose tolerance status was established by medical history and a 75-g oral glucose tolerance test. Coronary heart disease was determined by medical history and a resting electrocardiogram. Adiposity and fat distribution measurements were body mass index (kg/m2), skinfold thicknesses, body circumferences, and cross-sectional fat areas by computed tomography. Levels of insulin, C-peptide, cholesterol (total, low-density lipoprotein [LDL], high-density lipoprotein [HDL], HDL2, HDL3, very-low-density lipoprotein [VLDL]), and triglyceride (total, VLDL) were measured in fasting blood specimens. RESULTS: A central pattern of body fat was associated with both non-insulin-dependent diabetes mellitus and coronary heart disease. Smoking history was related to both adiposity and body fat distribution, and was strongly related to coronary heart disease but not to diabetes. Past smokers who had smoked up to a month ago were the heaviest while present smokers who were currently smoking or had smoked within the past month were the leanest. However, although present smokers had reduced amounts of fat, this was attributable to those present smokers without heart disease. Present smokers with heart disease were not as lean and had increased amounts of intra-abdominal fat. Past smokers had the greatest amount of central fat and this was attributable to those with heart disease. By two-way (smoking history and coronary heart disease status) analysis of covariance, smoking history was significantly related only to subcutaneous fat disposition on the chest and abdomen independent of coronary heart disease, while coronary heart disease status was strongly related to plasma levels of insulin C-peptide, VLDL, HDL, HDL2, and HDL3 cholesterol, and total and VLDL triglyceride, independent of smoking history. Further analysis showed that none of the body fat variables could account for the risk of coronary heart disease associated with smoking history. Higher fasting plasma C-peptide levels in past smokers accounted statistically for part of the risk of coronary heart disease associated with cigarette smoking. However, this effect was not mediated by any of the body fat measurements. CONCLUSIONS: Disproportionately increased intra-abdominal fat is related to coronary heart disease but not to smoking history. Smoking history is related to coronary heart disease but not to diabetes. Weight gain is associated with smoking cessation and appears to be concentrated in the central subcutaneous regions, especially for those who have coronary heart disease. Weight gain associated with cessation of smoking appears to be unrelated to atherogenic changes in lipids, lipoproteins, or insulin. Other pathogenic processes must be considered in the association between smoking and coronary heart disease.

LOCATE: an application of computed tomography in radiation therapy treatment planning with emphasis on tumor localization.

Computed tomography can provide precise information for radiation therapy treatment planning. However, inaccuracies in radiation field design may occur when the radiation oncologist attempts to transfer information about tumor location from the transverse plane of the CT scan to the longitudinal plane of the simulation film. This report describes a new computer program, LOCATE, which addresses this problem. The program uses operator generated information from the cross sectional CT images to draw an outline of tumor on AP and lateral longitudinal scanned projection radiographs. The resultant images are useful because they are in the same plane as radiographs obtained on a therapy simulator. The impact of LOCATE on radiation treatment planning for 26 patients is discussed along with several cases in which LOCATE was particularly helpful.

The role of computed tomography scanning in the initial assessment and the follow-up of malignant pleural mesothelioma.

Between October 1983 and April 1987, 20 patients with malignant mesothelioma underwent computed tomography scans of the chest and upper abdomen to evaluate the extent of disease before treatment. Twelve of these 20 patients deemed to have some potential for long-term survival had scans performed every 3 months after operation to help detect recurrent disease. Anatomic correlation of computed tomography scan findings was available in all 20 patients. The limitations of computed tomography in initial evaluation were its difficulties in assessing (1) chest wall involvement (nine patients), (2) mediastinal lymph nodes (four patients), (3) transdiaphragmatic extension of tumor (four patients), and (4) peritoneal studding and solid organ metastases less than 2 mm in size (one patient). Computed tomography was helpful in detecting recurrent disease in the 12 patients having long-term follow-up. In six of eight cases with histologically proved recurrence, computed tomography detected tumors from 1 to 8 months before the onset of signs or symptoms. Although computed tomography is known to provide far more information about the extent of disease than plain radiographs, it remains an imperfect tool for the staging of disease in patients with malignant mesothelioma. Despite its limitations, computed tomography is probably the most accurate way to provide follow-up for patients during treatment.

Cross-sectional imaging method. A system to compare ultrasound, computed tomography, and magnetic resonance with histologic findings.

Studies comparing imaging modalities require a precise knowledge of the type and location of tissue structures. When comparing cross-sectional techniques such as ultrasound, computed tomography, and magnetic resonance imaging, the images must be obtained through the same tissue section that is examined histologically. An experimental system that permits comparison of these modalities with histologic sections of precisely corresponding tissue is described. Application in 30 gastrointestinal tissue specimens shows a high degree of correspondence between cross-sectional images and histologic sections. This method should be useful in tissue imaging research for anatomic correlation and for comparisons between imaging modalities.

Abnormal body fat distribution detected by computed tomography in diabetic men.

Previous studies of body fat using tape measurement of body circumference and hand-held caliper skinfold measurements have suggested abnormal fat distribution in patients with diabetes mellitus. These methods, however, have high interobserver variability and cannot assess intra-abdominal fat independent of subcutaneous fat. We used computed tomography to evaluate body fat distribution in a group of 53 Japanese-American men of similar age and body mass index (weight divided by height squared). As determined by a 75-g oral glucose tolerance test, 29 subjects had type II diabetes and 24 were normal. Computed tomography cuts were obtained at three body levels to measure thorax, abdomen, and thigh subcutaneous fat area as well as intra-abdominal fat area. We found greater intra-abdominal fat in men with diabetes than in those without (123.74 vs. 95.54 cm2, P = 0.034) and a greater ratio of thorax to thigh subcutaneous fat (2.55 vs. 1.88, P = 0.016). These findings support the hypothesis that fat in different areas of the body differs metabolically. Computed tomography can be a useful tool for investigating whether abnormal body fat distribution is associated with the pathogenesis of abnormal glucose tolerance.

Effect of intensive endurance training on lipoprotein profiles in young and older men.

Although there are considerable data concerning the effects of endurance exercise training (ET) on plasma lipoproteins, the results have been quite inconsistent. The observed variability of response may be related to the age, sex, adiposity, or diet of the subjects tested, or to the type and intensity of the exercise intervention. Furthermore, there is relatively little such data in older individuals. Therefore, in the present study, we investigated the effects of intensive ET on lipoprotein profiles in healthy young (n = 12; 28.2 +/- 2.4 years) and older (n = 15; 67.5 +/- 5.8 years) men. Unlike subjects in most similar studies, our subjects were weight-stabilized on a constant-composition diet for 21 days prior to determination of the lipoprotein profile before and after the ET program. At baseline, the two groups were not significantly different with respect to any individual component of their lipoprotein profiles, relative weight, or percent body fat, but the older men had a more central distribution of fat by both waist to hip ratio (WHR) and computed tomography (CT). Maximal aerobic power, expressed per kilogram of body weight (VO2 max), was 33% lower (P less than .001) in the older men at baseline. Following the 6-month, walk/jog/bike ET program (5 d/wk), both the young (+18%, P less than .001) and the older (+22%, P less than .001) men increased their VO2 max. This was associated with small, but significant, decrements in weight, percent body fat, and WHR only in the older men.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of intensive endurance exercise training on body fat distribution in young and older men.

Little is known about the effects of exercise interventions on the distribution of central and/or intra-abdominal (IA) fat, and until now there were no studies in the elderly. Therefore, in this study we investigated the effects of an intensive 6-month endurance training program on overall body composition (hydrostatic weighing), fat distribution (body circumferences), and specific fat depots (computed tomography [CT]), in healthy young (n = 13; age, 28.2 +/- 2.4 years) and older (n = 15; age, 67.5 +/- 5.8 years) men. At baseline, overall body composition was similar in the two groups, except for a 9% smaller fat free mass in the older men (P less than .05). The thigh and arm circumferences were smaller (P = .001 and P less than .05, respectively), while the waist to hip ratio (WHR) was slightly greater in the older men (0.92 +/- 0.04 v 0.97 +/- 0.04, P less than .01). Compared with the relatively small baseline differences in body composition and circumferences, CT showed the older men to have a twofold greater IA fat depot (P less than .001), 48% less thigh subcutaneous (SC) fat (P less than .01), and 21% less thigh muscle mass (P less than .001). Following endurance (jog/bike) training, both the young (+18%, P less than .001) and the older men (+22%, P less than .001) significantly increased their maximal aerobic power (VO2max). This was associated with small but significant decrements in weight, percent body fat, and fat mass (all P less than .001) only in the older men.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnostic imaging in the initial staging of mycosis fungoides and Sézary syndrome.

Four imaging examinations-gallium citrate Ga 67 scintigraphy, liver-spleen scans, lymphangiography, and computed tomography-were used in the initial staging of mycosis fungoides and Sézary syndrome in 62 patients (85% with stage I or II disease). None of the imaging modalities added significantly to the information already available from physical examinations and routinely performed lymph node biopsies. The results of this investigation did not support routine performance of imaging studies in patients with early stages of cutaneous T-cell lymphoma.

Soft-tissue changes after head and neck radiation: CT findings.

To identify possible soft-tissue changes of the head and neck after radiation therapy, 102 CT scans from 78 patients with head and neck tumors were reviewed to assess (1) skin thickening, (2) epiglottic thickening, (3) stranding of subcutaneous fat, and (4) stranding of deep cervical fat. Scans were obtained after radiation therapy alone (10 cases), after radiation and surgery (27 cases), after surgery alone (24 cases), or before either surgery or radiation (41 cases). Skin thickening, epiglottic thickening, and stranding of subcutaneous fat were seen more frequently after radiation therapy than before such treatment. However, skin thickening and stranding of subcutaneous fat were sometimes also associated with tumor involvement and/or previous surgery, while epiglottic thickening was only occasionally associated with tumor involvement. Stranding of deep cervical fat was noted with increased frequency after radiation or surgery, but postradiation effects could not be reliably distinguished from postsurgical or tumor effects. We conclude that soft-tissue changes of the head and neck on CT may commonly be associated with previous radiation therapy, but these postradiation effects are not always distinguishable from postsurgical effects or tumor.

Intraoperative neurosonography: application and technique.

Intraoperative neurosonography was performed in 44 patients with contact transdural or transgyral scanning technique. Localization of intracranial pathology included primary brain tumors (24), metastatic tumors (11), aneurysms (two), abscesses (two), arteriovenous malformation (one), thrombosed arteriovenous malformations (two), and plasmacytoma (one). Sonographic guidance was used in transdural decompression of three cystic lesions, therapeutic and diagnostic aspiration of two abscesses, and biopsy of three solid lesions. The expertise of the physician-sonographer with sonographic equipment facilitates accurate and expedient intraoperative neurosurgical localization of pathology.

Intraoperative ultrasound detection of metastatic tumors in the central cortex.

Real-time sector ultrasonography precisely located metastatic tumors of the central motor cortex during craniotomy in two patients. In these two cases, the only surface abnormality was swelling of several overlying gyri. Intraoperative ultrasonography precisely located the 1.5- and 2.5-cm-diameter tumors to a position below a specific gyrus, enabling the surgeon to excise the tumors through small, accurately placed cortical windows. The precise location minimized exploratory probing and the size of the cortical incision required to identify and remove the tumors. This technique will have general application in similar situations when the cortical surface gives no indication of underlying tumor location. By charting the best trajectory for the surgical approach, this technique may replace a variety of stereotactic and computed tomography-guided techniques for biopsy of deep brain tumors.

Diabetes and diabetes risk factors in second- and third-generation Japanese Americans in Seattle, Washington.

In Seattle, Washington, the prevalence of diabetes was 20% in second-generation (Nisei) Japanese-American men and 16% in Nisei women 45-74 years old, while the prevalence of impaired glucose tolerance (IGT) was 36% in Nisei men and 40% in Nisei women. Hyperglycemia was less and duration of diabetes shorter in women. Related to diabetes and IGT in Nisei were higher fasting plasma insulin levels and central (visceral) adiposity. Prevalence of diabetes was low among the younger (34-53 years old) third-generation (Sansei) men and women. Among self-reported non-diabetic Sansei, however, prevalence of IGT was 19% in men and 29% in women, and IGT was associated with both increased fasting plasma insulin levels and more visceral fat, suggesting that many Sansei are at risk of future diabetes. An important lifestyle factor in the development of NIDD in Japanese Americans appeared to be dietary saturated (animal) fat. Another factor may be physical inactivity. In Japanese-American women, menopause also appeared to be an important risk factor. These risk factors may be related to fostering the accumulation of visceral fat and the development of insulin resistance. Five-year follow-up examinations performed in non-diabetic Nisei men and women have yielded additional information concerning the prognosis of IGT. Of those women who were IGT at baseline, 34% were diabetic at follow-up while 17% returned to normal. In men who had been IGT at baseline, 18% were diabetic at follow-up while 36% returned to normal. Over the 5-yr follow-up interval, proportionally more women progressed from normal to IGT (54%) then went from IGT to normal (17%). For men, roughly equal proportions went from normal to IGT (37%) as from IGT to normal (36%). It would therefore appear that greater proportions of Nisei women are progressing to IGT and to NIDD than are Nisei men. This observation may be related to the increased risk of developing central obesity and insulin resistance following menopause. Prevalence of cardiovascular disease (hypertension, peripheral vascular disease, and/or coronary heart disease) was increased in Japanese Americans with IGT and NIDD. Neuropathy and retinopathy were associated only with NIDD.

Neutron radiotherapy for malignant gliomas.

Neutron radiotherapy has been used for patients with malignant gliomas for over a decade; a substantial number of patients have been treated to date. Pathologic analysis of surgical specimens posttreatment and autopsy specimens have documented an increased antitumor effect of neutrons against malignant gliomas, compared with photon irradiation. However, results of neutron trials to date have not shown a survival advantage over conventional radiotherapy for these patients. This article reviews current surgical, radiotherapeutic, and chemotherapeutic approaches to these tumors, the rationale for neutron treatment, and the results of trials of neutron radiotherapy conducted to date for patients with malignant gliomas.

Computed tomographic pelvimetry.

Pelvimetry can be performed on a computed tomographic (CT) scanner using anteroposterior and lateral scanned projection radiographs (Scout View) plus a single CT slice through the low pelvis. This technique yields accurate measurements of the maternal pelvis that do not need compensation for magnification. The fetal lie and presentation can be easily assessed, along with the fetal neck for hyperextension. In addition, the total radiation dose to both mother and fetus is significantly lower than with routine plain film pelvimetry. Since the procedure is quick, easy to perform and competitive in cost, CT pelvimetry should be the procedure of choice in those rare instances in which pelvimetry is indicated.

CT manifestation of neutron radiotherapy-induced changes in lung.

Sixty-nine chest CT studies of 36 patients with lung cancer were obtained at various times (21 to 649 days) following completion of fast neutron radiotherapy. Multiple scans (2 to 7) were available in 16 cases. Fractionated neutron radiotherapy was delivered over four to seven weeks to a total dose of 60 to 67 Gy photon equivalent. Parenchymal change within the lung was noted in 43% by 12 weeks, in 91% between 12 and 24 weeks, and in 100% after 24 weeks. Three different patterns of lung parenchymal change were evident. Ectatic air-filled bronchi were observed in more than 50% after 24 weeks. Mediastinal shift and thoracic shrinkage were demonstrated in six and three cases, respectively. Serial CT scans revealed that lung parenchymal changes usually became stable or shrunk after 36 weeks. The possible effect of chemotherapy (mitomycin-C, vinblastin and cis-platinum), in 19 of these patients is also discussed.