Roger Aamodt

Phase I study of the adoptive immunotherapy of human cancer with lectin activated autologous mononuclear cells

In previous in vitro studies, the authors showed that phytohemagglutinin (PHA) stimulated peripheral blood lymphocytes (PBL) from cancer patients to generate cells that were lytic for fresh autologous tumor but not for lymphocytes or lymphoblasts. Thus, after IRB approval, a phase I clinical protocol was instituted in cancer patients who had failed all other therapy to determine the toxicity and effects, in vivo, of the infusion of large numbers of such PHA activated autologous PBL. Ten patients were treated on the protocol, six with sarcoma, one with melanoma, and three with colorectal cancer. Up to a total of 1.7 × 1011 PBL were obtained from 7 to 15 successive leukaphereses, the cells from each leukapheresis being incubated in vitro in medium containing PHA and human AB serum for 2 days and then reinfused following the next leukapheresis 2 days later. Toxicity encountered included fever and chills in 10/10 patients, headaches in 5/10, nausea and vomiting in 3/10, and requirement for erythrocyte transfusion in 8/10. No evidence for autoimmune disease, abnormal serum chemical or coagulation studies, or pulmonary emboli was found. 111Indium trafficking studies showed distribution of infused cells mainly to the spleen and liver, with some accumulation in the lungs and tumor especially after repeated infusions. In 9/10 patients, activated PBL were detected in the peripheral circulation by the sixth leukapheresis. Evidence for this was found by assaying the incorporation of tritiated thymidine (3H‐Tdr) into, and lysis of fresh tumor cells by, unstimulated PBL from successive leukaphereses. No tumor regression was seen in these patients with bulk disease. These studies demonstrated that large numbers of PHA‐activated PBL can be safely obtained and infused into humans, achieving an increase in the number of circulating activated cells with evidence of migration of cells to tumor, lungs, liver and spleen. Further studies of the use of activated lymphocyte infusion in conjunction with chemotherapy in humans are in progress.

Effects of oral zinc loading on zinc metabolism in humans II: In vivo kinetics

The effects of oral zinc loading on zinc metabolism were studied in 10 patients with taste and smell dysfunction following oral administration of Zn-65 (physical t1/2 = 245 d) and subsequent administration of oral stable zinc. Patients took an ad libitum dietary zinc intake of 8-13 mg daily for 290-440 days (mean, 336) following Zn-65 administration, followed by an intake of an additional 100 mg/day of zinc ion (as ZnSO4) over the next 112-440 days (mean, 307). A previously developed compartmental model, based on five day studies of patients with taste and smell dysfunction, was extended in such a way that it was consistent with both short term and long term kinetics. In this extended model, the turnover of 90% of total body zinc, previously unaccounted for by the kinetics in the short term studies could be explained by a single compartment, as postulated in the short term studies. Using the model, it was found that changes in the rate constants for gastrointestinal absorption and renal excretion of zinc were both necessary and sufficient to explain the changes seen in the kinetic curves following oral zinc loading. Michaelis-Menten type saturation mechanisms were adequate to explain the observed parameter changes. These changes also accounted for the observed mean plasma zinc mass increase of only 37% above pre-load levels in face of an 11-fold increase in zinc intake.

A multidisciplinary approach to honest broker services for tissue banks and clinical data: a pragmatic and practical model.

Honest broker services are essential for tissue‐ and data‐based research. The honest broker provides a firewall between clinical and research activities. Clinical information is stripped of Health Insurance Portability and Accountability Act‐denoted personal health identifiers. Research material may have linkage codes, precluding the identification of patients to researchers. The honest broker provides data derived from clinical and research sources. These data are for research use only, and there are rules in place that prohibit reidentification. Very rarely, the institutional review board (IRB) may allow recontact and develop a recontact plan with the honest broker. Certain databases are structured to serve a clinical and research function and incorporate ‘real‐time’ updating of information. This complex process needs resolution of a variety of issues regarding the precise role of the HB and their interaction with data. There also is an obvious need for software solutions to make the task of deidentification easier.

Acute Coronary Occlusion: Prolonged Increase in Collateral Flow Following Brief Administration of Nitroglycerin and Methoxamine

Regional coronary blood flow was determined with the radioactive microsphere technique 10 an 70 minutes and 2 1/2 and 5 hours after abrupt occlusion of the left anterior descending coronary artery in 12 closed chest sedated dogs. In six dogs, nitroglycerin, 200 to 400 microng/min, was infused intravenously 10 to 70 minutes after occlusion. Methoxamine was administered to return blood pressure and heart rate to prenitroglycerin levels. Ten minutes after occlusion (before treatment) collateral flow values and ischemic zone endocardial/epicardial flow ratios were equivalent in untreated (0.11+/-0.03 ml/min per g; 0.31+/-0.05) and treated dogs (0.14+/-0.02 ml/min per g; 0.29+/-0.03). In untreated dogs, collateral flow did not change over 5 hours; the endocardial/epicardial flow ratio was decreased at 5 hours (0.21+/-0.05, P less than 0.05). In contrast, in treated dogs, collateral flow and the endocardial/epicardial flow ratio were increased at 70 minutes (0.27+/-0.04 ml/min per g, P less than 0.05; 0.53+/-0.10, P less than 0.05). Most importantly, collateral flow remained elevated 5 hours after occlusion (0.26+/-0.03 ml/min per g, P less than 0.05) although treatment was discontinued 70 minutes after occlusion. Hence, collateral flow was unchanged over 5 hours of occlusion in untreated dogs, but short-term treatment with nitroglycerin and methoxamine resulted in a sustained increase in collateral flow. These findings may be a result of stimulation by nitroglycerin and methoxamine of the spontaneous rate at which intrinsic collateral function increases after ischemia. Alternatively, nitroglycerin and methoxamine may maintain cell viability until collateral vessels develop spontaneously.

The cooperative human tissue network. An update

Background. During the past decade, the National Cancer Institute became aware of a lack of availability of human tissues for research, especially in the fields of molecular biology, genetics, and immunology.

Zinc metabolism in adrenal cortical insufficiency: effects of carbohydrate-active steroids.

Detailed studies of zinc kinetics were performed in two patients with adrenal cortical insufficiency to investigate the effects of carbohydrate-active steroids (CAS) on zinc metabolism. Zinc- 69m was administered intravenously to each patient under two conditions: (1) treated with CAS replacement therapy and (2) untreated, ie, without hormone treatment for five to six days. Radioactivity was measured in blood plasma, red blood cells, urine, and stool and by means of external probes placed over liver and thigh. Data were analyzed using a previously developed multicompartmental model, which describes the early phase of zinc metabolism. The results of these studies suggest that CAS promotes the internalization of zinc into red blood cells and liver cells. These results are consistent with previous in vitro and in vivo studies in which CAS was shown to induce the synthesis of metallothionein in liver cells.

Effects of oral zinc loading on zinc metabolism in humans—I: Experimental studies

The effects of oral zinc on distribution, retention and excretion of orally administered 65Zn were studied in 50 patients with taste and smell dysfunction. The study was conducted in three phases. In the first phase all patients were studied for 21 days after receiving 3-18 microCi of 65Zn as ZnCl2 orally after an overnight fast. In the second phase, started after 21 days and continued for 290 to 440 (mean 336) days, all 50 patients received placebo for ZnSO4. In the third phase 14 patients continued on placebo while 36 received ZnSO4 (100 mg/day Zn++) for 112 to 440 (mean 307) days. Phases two and three were a controlled clinical trial of the effects of zinc on retention of 65Zn tracer. Total body retention and activity in plasma and red cells were measured for all patients throughout the study. Ten of the 36 patients treated with ZnSO4 had additional measurements of 65Zn activity in liver and thigh made using external detectors. Total body retention during the second phase placebo period was not significantly different (p greater than 0.25) for the 36 subjects subsequently treated with ZnSO4 (biological half-time (Tb) 378 +/- 12 days) (mean +/- SEM) and the 14 who were continued on placebo through the third phase of the study (Tb = 384 +/- 8 days). During the third phase patients receiving ZnSO4 showed an accelerated loss of total body 65Zn (Tb = 235 +/- 8 days) which was significantly different (p greater than 0.001) from half-time values during placebo treatment. Accelerated loss of 65Zn from the thigh was apparent immediately while that from the liver began after a mean delay of 107 days. There was no apparent effect of zinc on loss of mean 65Zn activity from red blood cells.

Timing of Consent for the Research Use of Surgically Removed Tissue Is Postoperative Consenting Acceptable

Consent by patients to perform surgery (‘surgical consent’) and consent for the research use of residual tissue (‘research consent’) is desirable to respect individual autonomy and human dignity. The need to obtain this research consent lies at the heart of ethical research involving human tissues, but it should be noted that in some jurisdictions and under certain circumstances, it is possible for researchers to obtain a ‘‘waiver of research consent.’’ This may occur if an Institutional Ethics Review Board (IRB) determines that the research use is of minimal risk and it is impractical to obtain the research consent. In the past, documentation of these consents has been conveniently obtained before surgery by the same person using the same form. More recently, however, ethical concerns have forced a separation between the 2 consents so that they are now often obtained by different people using different forms. This raises the possibility of obtaining the research consent postoperatively. Unfortunately, there have been uncertainties regarding this relatively new practice, and this has slowed down its widespread implementation. The current study seeks to clarify the issues and explain why a postoperative informed consent process has distinct advantages in certain circumstances. The points presented herein are based on a listserv discussion among members of the International Society for Biological and Environmental Repositories (ISBER).

The solid angle subtended by a solid, right, circular cylinder as seen from a point in space

Abstract A Monte-Carlo technique was utilized to calculate the solid angle subtended by a solid, right, circular cylinder as seen from a point in space for two height-to-radius ratios of the cylinder, two-to-one and one-to-one. The calculation was made for source-point distances out to twelve cylinder radii from the cylinder center and for angular displacements of the source point up to ninety degrees from the cylinder axis.

Impaired collateral blood flow reserve early after nontransmural myocardial infarction in conscious dogs

The purpose of this study was to determine the adequacy of collateral blood flow reserve of surviving myocardium 3 to 4 days after coronary occlusion in dogs. The proximal circumflex coronary artery was occluded in 9 conscious dogs, and in 7 of these the mid-left anterior descending coronary artery was also occluded. Three to 4 days after myocardial infarction, studies were performed under control conditions and during right ventricular pacing at the maximal heart rate that did not decrease aortic pressure. Pacing increased the heart rate from 110 to 222 beats/min, caused no change in mean aortic pressure (112 to 118 mm Hg), and increased left atrial pressure marginally (13.5 to 16.0 mm Hg) (0.05 <p <0.10). The ischemic zone mass that was dependent on collateral flow because of coronary occlusion was 56% (range 29 to 69) of the mass of the left ventricle, and the mass of the infarct occupied 21 % (range 4 to 41) of the mass of the left ventricle. Subendocardial and mid-myocardial ischemic zone samples contained infarcted tissue and had low control values of coronary vascular conductance (flow/100 mm Hg mean aortic pressure) which tended to decrease during pacing: subendocardium, 0.18 to 0.02 ml · min−1 · g−1/100 mm Hg (0.05 <p <0.11), and mid-myocardium, 0.38 to 0.11 (p <0.05). Coronary vascular conductance in normal zone subepicardium increased 35% from control conditions to pacing (1.24 to 1.69 ml · min−1 · g−1/100 mm Hg; p <0.03). In contrast, coronary vascular conductance in surviving myocardium located in the subepicardial layer of the ischemic zone did not change during pacing (1.17 to 1.21 ml · min−1 · g−1/100 mm Hg). It is concluded that collateral blood flow in surviving myocardium within the initial zone of ischemia returns to normal under control conditions by 3 to 4 days after coronary occlusion, but there is no reserve capacity to increase collateral conductance. Impaired collateral reserve in this unique canine model is probably related to multivessel occlusion and to the short period of time collateral vessels had to develop (3 to 4 days after coronary occlusion). If these findings are clinically applicable, they suggest that severe stress after acute myocardial infarction has the potential to provoke ischemia and its consequences in the surviving tissue supplied by occluded coronary arteries.