Biomedical subjects
Publications and source records attributed to A E Chang.
This report, the first known published account, describes an unusual case of suspected pancreatic pseudocyst diagnosed by ultrasonography which at operation and subsequent arteriography was found to be a coronary vein aneurysm. Owing to the nonspecificity of ultrasonographic detection of vascular anomalies and neoplasms, arteriography is recommended when surgery is planned.
The in vivo administration of lymphokines is a new approach to immunotherapy with possible applications to the treatment of tumors and infectious processes. These lymphokines are produced in very small quantities and purification of these molecules has proven difficult. A rapid two step method was used to isolate different lymphokines from large quantities of conditioned media produced by the murine EL-4 cell line. Interleukin-2 (IL-2), colony stimulating factor (CSF) and macrophage activating factor (MAF) are lymphokines with distinct biologic activities and are secreted by the EL-4 cell line. Their isolation involved initial batch purification on trimethylsilyl-controlled pore glass beads followed by reversed phase high pressure liquid chromatography. Recovery of IL-2 activity was greater than 100% of initial activity. The specific activity of the purified IL-2 ranged from 2 X 10(6) to 3.6 X 10(7) U/mg protein. Colony stimulating factor (CSF) and macrophage activating factor (MAF) were also separated on the chromatographic columns. This technique is useful for the purification of large quantities of these lymphokines which have potential in vivo applications.
The recent availability of recombinant human interleukin-2 (RIL-2) has increased interest in the potential clinical use of this lymphokine. We have examined the biologic effects of intermittent bolus and continuous intravenous administration of RIL-2 in rats. The mean (+/- SEM) half-life after an intravenous bolus injection of RIL-2 was determined to be 2.9 +/- 0.5 min (n = 4). The administration of intermittent intravenous bolus injections of RIL-2 of doses up to 10(6) units/kg every other day for 2 weeks was well tolerated without toxicity as determined by organ histology and serum chemistries. The continuous intravenous infusion of RIL-2 through an indwelling external jugular vein catheter was tolerated for 2 weeks at doses less than or equal to 3,000 U/kg/h and was associated with no abnormal serum chemistries or organ pathology. By contrast, animals that received less than 10,000 U/kg/h demonstrated RIL-2 toxicity leading to death of treated rats. Serum chemistries revealed a fourfold increase in serum glutamate oxaloacetic transaminase and serum glutamate pyruvic transaminase. Liver histology revealed hepatocellular necrosis with mononuclear cell infiltration. The thymus was depleted of lymphocytes and lymphoid infiltrates were present in liver, spleen, and lung. This is the first documentation of toxicity secondary to RIL-2 administration and suggests that hepatopathy may be the dose-limiting toxicity accompanying the administration of RIL-2.
Pulmonary embolism in high-risk patients may be minimized by inferior vena caval interruption by ligation, plication, intraluminal filters, or intraluminal balloons. Vena caval filter implantation is the least traumatic of all surgical methods of preventing pulmonary embolism. These nonocclusive methods are preferred to minimize the possible sequelae of venous insufficiency. The prevention of septic emboli requires complete ligation of the inferior vena cava. The transvenous approach to caval interruption by intraluminal filters is particularly useful in severely ill patients. When major surgical procedures are performed for the purpose of caval interruption, the intra-abdominal approach has greater associated mortality and morbidity than does the retroperitoneal approach. The Mobin-Uddin and Kim-Ray Greenfield filters are at present the most frequently used modalities for prevention of fatal pulmonary embolism when intervention is required. In large series of patients where intraluminal caval filters have been utilized, there has been an operative mortality of under 1 per cent, with an incidence of recurrent emboli of under 2 per cent, and an incidence of venous stasis sequelae of approximately 20 per cent. Some clinicians prefer the Greenfield filter over the Mobin-Uddin umbrella because of greater ease and flexibility of placement. In general, however, both transvenous intraluminal filters have been used effectively with acceptable mortality and morbidity, and the device used might properly be determined by the experience of the surgeon.
The production of recombinant human interleukin-2 (RIL-2) in large amounts has made possible studies of the in vivo effects of this lymphokine in the normal murine host. We have studied a variety of routes of administration of RIL-2 in mice to maximize the bioavailability of this lymphokine. The serum half-life after intravenous administration was 1.6 +/- 0.3 min (mean +/- SEM, n = 3). Intraperitoneal and subcutaneous administration resulted in RIL-2 serum levels greater than or equal to 10 units/ml for 3-5 h, and was prolonged by gelatin for 7-11 h. Continuous infusion of RIL-2 was accomplished with osmotic pumps placed intraperitoneally or subcutaneously, and resulted in RIL-2 serum levels greater than or equal to 8 units/ml for greater than 4 days. RIL-2 given intraperitoneally three times daily for 3 days enhanced natural killer activity of splenocytes as measured by lysis of YAC cells. Specific augmentation of C57BL/6 splenocyte cytotoxicity to a secondary challenge of irradiated allogeneic P815 was found in mice receiving RIL-2 intraperitoneally three times daily for 3 days. The continuous administration of RIL-2 over a 4-day period resulted in the in vivo generation of lymphokine-activated killer cells in the spleen and peritoneal exudate. The exogenous administration of RIL-2 in the normal murine host enhances three different cell-mediated cytotoxic mechanisms and has potential applications in the treatment of tumors and immunodeficient conditions.
We have employed bifunctional T cell hybridomas, which can be stimulated to secrete lymphokine(s) and lyse specific target cells, to analyze the effect of Cyclosporin A (CsA) on T cell helper and effector functions. We report here the effects of CsA on antigen- and lectin-induced lymphokine secretion. We have found that a pharmacologic level of CsA (10 ng/ml) blocks antigen- and lectin-driven interleukin 2 (IL 2) secretion without affecting cell proliferation. In addition, one monoclonal hybridoma that is induced by concanavalin A to secrete colony stimulating factors (CSF) as well as IL 2 is concomitantly blocked by CsA for production of IL 2 and CSF. Because the hybridomas grow constitutively and are devoid of functional IL 2 receptors, they permit analysis of the kinetics of the inhibitory response. We have shown that CsA blocks not only stimulation of lymphokine secretion but also ongoing IL 2 production, probably by interfering with the effective interaction of receptor and antigen. Thus, blocking of IL 2 secretion from preactivated cells by CsA occurs by 1 to 2 hr, the time required to stop IL 2 production by removal of Ag/Lectin stimulator. The results are consistent with a mechanism of action of CsA on T cells that involves a direct interference of CsA with binding of Ag to Ag-receptor and results in blocking of induction and active secretion of multiple lymphokines.
Significant serum titers of interleukin 2 (IL 2) can be maintained in mice for 12 h after i.p. injection in a 15% gelatin solution. We have tested the ability of IL 2 administered systemically in this fashion to enhance the therapeutic effect of adoptively transferred specifically sensitized lymphoid cells that were expanded in IL 2. Mice with established local and disseminated FBL-3 lymphoma, induced by intrafootpad injection of 10(7) cells after 500 rad total body irradiation, were treated with a combination of i.v. injected murine splenocytes and either murine supernatants containing IL 2 or pure human IL 2 in gelatin. Splenocytes from immune mice were resensitized to irradiated tumor in vitro and were expanded for 7 days in lectin-free IL 2 supernatants. Treatment with these murine splenocytes administered with murine IL 2 supernatants prolonged mean survival to 33.6 days compared with mean survival times of 16.9 days (p less than 0.001) and 23.4 days (p = 0.007) for mice treated with IL 2 alone or splenocytes alone. Human IL 2, purified to homogeneity from the Jurkat cell line, was also capable of improving the therapeutic efficacy of transferred cells in mice. Mean survival was significantly prolonged to 32.1 days when cells and purified human IL 2 were administered, whereas mean survival times of 18.1 days (p = less than 0.001) and 21.5 (p = less than 0.001) were seen for mice treated with IL 2 alone or expanded immune cells alone. Cure rates in this model were also significantly enhanced with the combined treatment of IL 2 and expanded immune cells. Combined immunotherapy utilizing IL 2 and immune cells was thus significantly better than either component used alone. The systemic administration of IL 2 in conjunction with sensitized expanded lymphoid cells may be a useful approach to the immunotherapy of other murine and human tumors.
A case of primary malignant duodenocolic fistula is presented. Colonic carcinoma is the most common etiology of this entity. clinical features include diarrhea, weight loss, anemia, and feculent vomiting. Review of the literature indicates that the treatment of choice is a right hemicolectomy with a pancreaticoduodenectomy or segmental duodenectomy if the disease is localized. Forty-six percent of patients undergoing this procedure have been reported to be alive more than 2.5 years later. If the disease is disseminated, the best palliative procedure appears to be a right hemicolectomy with a partial duodenectomy. The early morbidity and mortality associated with this latter procedure have been attributed most often to dehiscense of the duodenal closure.
A randomized, double-blind, placebo-controlled trial of oral and smoked delta-9-tetrahydrocannabinol (THC) was performed in eight patients with resected soft tissue sarcomas who received adjuvant Adriamycin and Cytoxan chemotherapy. Each patient served as his own control. Delta-9-tetrahydrocannabinol, in comparison with a placebo, did not significantly reduce the number of vomiting and retching episodes, volume of emesis, degree of nausea, or duration of nausea. In contrast to a previous report where significant antiemetic effects of THC were observed in patients receiving high-dose methotrexate, THC did not effectively reduce emesis induced by Adriamycin and Cytoxan. These findings suggest that the antiemetic properties of THC are effective only against specific chemotherapeutic drugs.
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Utilizing a dual isotope assay, the effect of passively transferred enhancing alloantibody on the specific accumulation of cytotoxic T cells in murine skin allografts were examined. (C57BL/6 x A/J)F1 (B6AF1) mice hyperimmunized with weekly injections of B10.D2 and B10.BR lymphoid cells served as a source of anti-B10.D2 and anti-B10.BR alloantibody. Intraperitoneal injections of alloantibody in B6AF1 hosts on days 0,2, and 4 significantly prolonged skin allograft survival. Dually skin allografted B6AF1 mice with or without the administration of enhancing alloantibody received differentially labeled (3H/14C) cytotoxic T cells on day 5. On day 7, a "homing index" derived from the comparison of 3H to 14C ratios was calculated for the skin allografts and draining axillary lymph nodes of each mouse. In unenhanced, normal mice significant preferential homing of cytotoxic T cells to skin allografts was demonstrated. However, enhanced mice receiving cytotoxic T cells had significantly dimished homing to skin allografts. Preferential localization of effector cells to the draining axillary lymph nodes was not present in either unenhanced or enhanced mice. These data demonstrate that enhancing alloantibody interferes with the specific accumulation of cytotoxic T cells in skin allografts and may be an important previously undescribed mechanism of immunological enhancement.
The adoptive transfer of cytotoxic effector cells to induce accelerated skin allograft rejection in the normal murine host was used as an assay of lymphocyte function in vivo. Splenocytes sensitized in vivo caused specific accelerated skin allograft rejection when administered i.v. at a dose of 5 X 10(7) cells 1 day after grafting. Graft rejection was specific for the immunizing alloantigen and could not be transferred with freeze-thawed or irradiated cytotoxic cells. In this assay the i.v. and local routes of administering cytotoxic cells were effective whereas the i.p. and s.c. routes were not. T cells were necessary in that pretreatment of the cells with anti-Thy-1.2 plus rabbit complement abrogated this phenomenon. Immune cells from spleens of mice sensitized but no longer actively cytotoxic did not demonstrate in vivo activity. If hyperimmunized mice were challenged by i/p. allogeneic tumor, their spleen cells were highly cytotoxic by in vitro assay but acted as suppressor cells in vivo by prolonging skin graft survival. Adoptively transferred in vivo sensitized cells subsequently expanded in number by T cell growth factor did not demonstrate in vivo activity. This skin allograft assay may be used to demonstrate T cell activity in vivo by inducing accelerated allograft rejection, and immune suppression by prolonging graft survival. Also a comparison of in vivo and in vitro effects was possible.
The relationship between oxygen pressure measured in a tissue bath (PBO2) and the contractile tension produced by an agonist (contractile responsiveness) was studied in a series of experiments using helical strips cut from thoracic aortas, femoral and deep femoral arteries, and small arteries taken from red and white skeletal muscle of the rabbit. The wall thicknesses of these samples ranged from 200 micron for aortas down to approximately 20 micron for the smallest skeletal muscle arteries. Contractile responsiveness of all samples became progressively depressed when PBO2 was reduced stepwise. The depression produced in the large thick-walled samples occurred at higher PBO2 levels than that produced in the small thin-walled samples. Responsiveness of all of the artery samples was depressed by hypoxia more at low than at high levels of stimulation. In a second series of experiments PO2 at the surface of artery samples (PSO2) was measured using an oxygen-sensitive microelectrode. These measurements in conjunction with calculations of the PO2 within the arterial wall (PWO2) indicated that contractile responsiveness of both large and small artery samples became depressed when PWO2 fell below a lowest-value estimate of 50 Torr. From these findings it is concluded that 1) the sensitivity of vascular smooth muscle cells to hypoxia is similar for large and small arteries; 2) this sensitivity occurs in a range of PO2 that is physiologic for resistance vessels in situ; and 3) this sensitivity to hypoxia cannot be explained by an anoxic core hypothesis and may or may not involve restricted energy metabolism.
Conventional linear x-ray tomography is often used to search for pulmonary metastases but tends to underestimate extent of disease when compared with operative findings. In a prospective study, operative findings were correlated with computed axial tomography and conventional linear tomography performed on 25 patients with a history of extrathoracic malignancy and pulmonary nodules. Computed tomography detected 69 nodules of which 31 proved to be metastases. Conventional linear tomography detected 38 nodules of which 25 were metastases. Of the 54 resected nodules measuring greater than 3 mm, computed tomography detected 42; whereas conventional tomography detected 32. Only six of the 31 additional nodules (20%) detected by computed tomography and not by conventional tomography proved to be metastases. These results suggest that computed tomography is more sensitive than conventional tomography in detecting small pulmonary nodules; however, there is diminished specificity in identifying metastatic nodules.
A technique for suturing ear skin on the lateral thoracic area of recipient mice is described. Using this technique the graft was visible from the day of grafting until rejection was complete and mice were not burdened by circumferential body dressings. Consistent mean survival times were observed in a donor-recipient combination over 1 year's time and technical failures could be recognized. This technique was useful to accurately assess accelerated rejection responses in normal mice that occur 4-8 days after grafting as a result of passively transferred effector cells.
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An assay which uses two differentially labeled cell populations was used to characterize the preferential localization of passively transferred syngeneic cells immunized to specific alloantigens. Splenocytes cytotoxic to B10.D2 and B10.BR alloantigens were harvested from (C57BL/6 X A/J)F1 (B6AF1) donors bearing acutely rejected skin allografts. One population was labeled in vitro with 3H-thymidine and the other with 14C-thymidine. The labeled cells were pooled and then transferred i.v. into B6AF1 hosts bearing 5-day-old skin grafts from B10.D2 and B10.BR donors. After 48 hr the mice were killed, and the relative amount of cells present in the skin grafts and draining axillary lymph nodes was derived by comparing the 3H:14C ratios of the harvested tissues. The results of these studies indicated that cytotoxic splenocytes harvested from donors bearing acutely rejected skin allografts preferentially localize to the relevant skin allograft after passive systemic transfer. The homing behavior of these splenocytes was augmented by T cell enrichment and significantly diminished by pretreatment with anti-Thy-1.2 serum plus rabbit complement. There was no evidence of preferential homing within the draining axillary lymph nodes. It can be concluded that a T cell population derived from in vivo sensitized splenocytes exhibits preferential homing to relevant skin allografts upon passive transfer.
Fifteen patients with osteogenic sarcoma receiving high-dose methotrexate chemotherapy were studied in a randomized, double-blind, placebo-controlled trial of oral and smoked delta-9-tetrahydrocannabinol (THC) as an antiemetic. Each patient served as his or her own control. Fourteen of 15 patients had a reduction in nausea and vomiting on THC as compared to placebo. Delta-9-tetrahydrocannabinol was significantly more effective than placebo in reducing the number of vomiting and retching episodes, degree of nausea, duration of nausea, and volume of emesis (P less than 0.001). There was a 72% incidence of nausea and vomiting on placebo. When plasma THC concentrations measured less than 5.0 ng/mL, 5.0 to 10.0 ng/mL, and greater than 10.0 ng/mL, the incidences of nausea and vomiting were 44%, 21%, and 6%, respectively. Delta-9-tetrahydrocannabinol appears to have significant antiemetic properties when compared with placebo in patients receiving high-dose methotrexate.