Prolongation of skin homograft survival by local intralymphatic radioisotope injections.
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Animals↗
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Transport of viral-size particulate matter after intravenous versus intralymphatic entry.
OBJECTIVE: Investigation of the transport of viral-size particles after intravenous versus intralymphatic injection and the functional validity of lymphatico-venous communications. METHODS: In the canine model, [99mTc] sulfur colloid particles (100-200 nm) were injected into either the principal vein or into the main lymphatic channel exposed at the paw. Samples of blood and lymph were collected at the groin from the cannulated femoral vein and from a major lymphatic vessel. Parameters including particle arrival time, concentration, flux, and accumulation were determined for a 45-minute period using gamma counting. RESULTS: After intralymphatic injection, particles arrived in the venous blood in an average of 4 seconds. The mean arrival time of particles in the lymph after intravenous injection was 25.4 +/- 6.44 minutes. Intralymphatic injection increased lymph flow and enhanced particle transport. Concentration values in the venous blood after intralymphatic injection and in lymph after intravenous injection were comparable. Flux values depended primarily on flow conditions. Particle accumulation in the lymph after intravenous injection was delayed, but continued to increase throughout the experiment. CONCLUSIONS: There are functional lymphatico-venous communications at the very peripheral level under physiological conditions, which allow rapid transport of viral-size particulate matter between the two pathways and may contribute to the spread of viral infection.
Animals↗
Distribution and consequences of cell suspensions following intralymphatic infusion.
The fate and consequences of intralymphatic injections of cells was investigated in dogs. The distribution of intact radiolabeled cells was determined in vivo by whole body gamma scanning. Comparison of distributions resulting from intralymphatic, subcutaneous, intradermal and intravenous routes of administration showed that the distribution and duration of radiolabel in various organs varied with the route of administration. Following intralymphatic injection, radiolabel was concentrated in first echelon lymph nodes draining the site of injection and was retained in these nodes for over 4 weeks. Histologic studies showed intense cortical and paracortical lymphopoiesis to be associated with the retention of intralymphatically injected tumor cells by first echelon lymph nodes. Serial histologic examination of lymph nodes from intralymphatically injected inbred beagles revealed that the consequent lymphopoiesis persisted for 5 weeks. In vitro evaluation of peripheral blood and lymph node lymphocyte cytotoxicity to the injected cells indicated that retention and nodal lymphopoiesis was associated with the development of direct lymphocyte cytotoxicity. The effects of concommitant tumor burden, cytotoxic drugs and ionizing radiation were also investigated and suggest that the therapeutic potential for use of the intralymphatic route has not yet been realized.
Animals↗
A phase I study of active specific intralymphatic immunotherapy (ASILI).
Twenty-one patients with advanced malignancies who had exhausted or refused conventional modalities of treatment were entered in a Phase I toxicology trial of active specific intralymphatic immunotherapy (ASILI). The patients were immunized with 1 X 10(7) to 1.2 X 10(8) viable autochthonous or allogeneic irradiated tumor cells intralymphatically each month and received no other antineoplastic treatment. To date, 274 intralymphatic injections have been performed and except for one case of bacterial lymphangitis, no adverse side effects have been observed. ASILI did not significantly alter peripheral blood lymphocyte counts, absolute E-rosette forming cell levels, or EA-rosette forming cell levels. PHA reactivity of peripheral blood lymphocytes increased slightly in all but one patient tested. Seven out of nine patients who had not had delayed hypersensitivity to recall antigens developed positive reactions following ASILI. Sixteen out of twenty patients tested also developed reactivity to their immunizing cells after treatment. Objective regression (greater than 50% reduction of tumor mass) was observed in five out of nineteen evaluable patients. Six patient showed stabilization of tumor growth and eight patients continued to progress under treatment.
Adult↗
Endolymphatic isotope and BCG in the management of malignant melanoma.
Endolymphatic isotope therapy had such promising early clinical results that the M.R.C. (Medical Research Council) U.K. set up a clinical trial in 1966. This was to compare the effect of endolymphatic isotope therapy with the results of standard methods in the treatment of lower limb malignant melanoma. The interim report had three groups for analysis: Standard Methods (S); Endolymphatic Satisfactory (ES); and Endolymphatic Unsatisfactory (EU). This third group was a subdivision, as a significant number of patients did not have the correct endolymphatic treatment. The five-year survival figures expressed as actuarial percentages were ES=78.8%; S=82.3%; and EU=57.3%. Lymph node recurrence showed a significant difference: ES=2.3%; EU=12%; and S=19%. The conclusions were that endolymphatic isotope therapy was justified in specialized centres where good results could be obtained. Further animal experiments using the VX2 tumour in rabbits indicated that BCG given intracutaneously or intravenously had no therapeutic effect, whereas when applied by intralymphatic injection BCG was successful in treating lymph node metastases. Nineteen patients with poor-prognosis malignant melanoma have received endolymphatic BCG. The clinical results are recorded in this paper and are sufficiently encouraging to warrant its continued use.
Animals↗
Vitiligo-like depigmentation and morpheas after specific intralymphatic immunotherapy for malignant melanoma.
We report the case of a patient with stage 2 malignant melanoma (MM), who received a specific immunotherapy consisting of intralymphatic injections of irradiated MM cells. She developed subsequently vitiligo-like leukoderma and several plaques of localized scleroderma. Simultaneously an increase in the patient's cytotoxic activity against MM cells was detected in vitro. The responsibility of immune phenomena and specific immunotherapy for the appearance of depigmentation and morpheas is discussed.
Aged↗
Patent blue V encapsulation in liposomes: potential applicability to endolympatic therapy and preoperative chromolymphography.
The water soluble dark blue stain Patent Blue V was incorporated into liposomes to increase its depot properties. Experiments with intraperitoneal and intramuscular application in rats and with intralymphatic injections in rabbits showed a substantial difference between the pharmacokinetics of aqueous and liposomal solutions. Independent of the route of administration, the dye-stain remained much longer in the tissues using liposomes. Most notably, retroperitoneal lymph nodes in rabbits remained dark blue up to 28 days after hindlimb endolymphatic instillation of liposomal patent blue. This vastly superior depot effect may be clinically adaptable for endolymphatic therapy with cytostatic drugs to enhance nodal drug retention and concentration or for preoperative chromolymphography to facilitate nodal visualization at laparotomy.
Animals↗
Accelerated cytodifferentiation of antibody-secreting cells in guinea-pig lymph nodes stimulated by sheep erythrocytes and lymphokines.
Lymphokines, produced in response to structurally unrelated antigens, altered the course of a primary anti-sheep erythrocyte plaque-forming cell response within the regional lymph nodes of normal guinea-pigs. Intralymphatic injection of a small dose of lymphokines (0-5-8 mug) 1 day after antigen priming accelerated the rate of indirect plaque-forming cell cytodifferentiation between the 5th and the 9th days of the response. This effect was not related to changes in the level of antigen trapping by lymph node macrophages, but the lymphocyte mitogenic activity may have been important for the response since there was a significant increase in [3H]thymidine incorporation within the lymphokine-treated nodes on the 3rd day following immunization.
Animals↗
Vestibular effects of antibiotics introduced in the inner ear. Behavioral and electrophysiological studies in the frog.
The aim of this study was to find a rapid and suitable method for testing the toxicity of drugs upon the vestibular end organs. The experiments were performed in the frog and the action of two antibiotics, streptomycin sulphate and penicillin G, was studied by carefully observing the equilibrium behaviour of the animals and recording the spontaneous activity of the nerve of the horizontal semicircular canal. The results obtained show that: 1) injection of streptomycin sulphate (20 microgram) directly into the labyrinthic cavity elicited disorders of the equilibrium and reduced the spontaneous activity of the horizontal canal nerve; 2) these disorders were reversible or not depending on the animal; 3) there is a good correlation between behavioral observations and electrophysiological data (i.e. the activity of the ampullary nerve was low in frogs whose behaviour was impaired at the time of sacrifice; the activity did not differ from controls when the normal behaviour was completely restored); 4) injection of penicillin G or 0.7% NaCl into the labyrinthic cavity had no effect on the equilibrium of the frogs or on the activity of the ampullary nerve; 5) intramuscular or intralymphatic injections of streptomycin sulphate produced a neuromuscular block but did not alter the activity of the ampullary nerve. In conclusion, the question of ototoxicity is discussed.
Action Potentials↗
Lymphatic metastasis; lymphangiochemotherapy of mammary cancer: ascitic form of rat mammary adenocarcinoma 13762.
When 5 million cells of the ascitic form of the RMT 13762 are injected into syngeneic F344 rat footpads there is consistent metastasis to the popliteal node more rapidly than when the solid form is used. A greater number of tumor cells escapes from the footpad to the draining node via the afferent lymph than with the solid tumor. Local intralymphatic injection of 5FU produces cure or retardation of nodal metastasis in a significant number of animals (p less than 0.002).
Adenocarcinoma↗
A pilot study of intralymphatic interleukin-2. I. Cytotoxic and surface marker changes of peripheral blood lymphocytes.
Patients with metastatic solid tumors were treated with six escalating doses of weekly intralymphatically injected recombinant interleukin 2 (i.l. IL-2). Nine patients completed the treatment and were evaluated for immunologic features of their peripheral blood lymphocytes (PBLs). The patients' PBL counts increased 4 days after the first i.l. IL-2 injection. The cell counts remained higher than baseline in week 6 prior to the last i.l. IL-2 injection. However, the PBL number decreased below baseline 1 day after the sixth injection, and recovered to normal levels after 3 days more. Natural killer (NK) activity showed similar changes when calculated as total activity per ml of blood. In vitro 1 h treatment of PBLs with IL-2 greatly enhanced NK cytotoxicity. The enhancement was only slight in the first week of i.l. IL-2 treatment, but was significantly greater on day 35 (7 days after dose 5) and day 39 (4 days after dose 6). In contrast, the increase was similar to the baseline on day 36, the day after the sixth injection. No lymphokine-activated killer activity was detected in the patients' PBLs with or without short-term in vitro IL-2 treatment. Besides the NK cytotoxic function, lymphoid subpopulations were evaluated numerically for total T cells (CD3/OKT3), T-cell subsets (CD4/OKT4 and CD8/OKT8), B cells (OKB7), NK cells (CD56/NKH1/Leu19, CD16/Leu11), and monocytes/NK cells (CD11b/OKM1). The activation markers (HLA-DR, CD25/Tac, and CD38/OKT10/Leu17) were also included. Intralymphatic IL-2 treatment had no effect on the PBL surface marker expression in the first week of treatment. However, by week 6, the percentages of cell populations expressing the NK-associated antigens CD56, CD16, and CD11b were significantly increased. In contrast, the percentage of CD3-positive T cells showed no change or a marginal decrease. Prior to and after i.l. IL-2 treatment, the CD56-positive cells in the PBLs were predominantly CD16 positive and CD3 negative. The i.l. IL-2 treatment did not induce PBL proliferation, or changes in the expression of CD25 (Tac), HLA-DR, CD38, CD4, CD8, CD57, or OKB7 in the patients' PBL. These results indicate that i.l. IL-2 treatment does affect the total number of PBLs, the cells expressing NK activity, and NK-associated surface markers.
Antigens, Differentiation↗
Inhibition of needlestick-induced simulated viremia by local measures.
BACKGROUND: The possibility of confinement of simulated retrovirus to the inoculation site after needlestick injuries to enhance chances of local intervention and function of lymphaticovenous communications was investigated. METHODS: Using the canine model, technetium-99 m sulfur colloid particles were injected subcutaneously and into the vein and lymphatics. Blood and lymph were collected at a higher level from the femoral vein and the major lymphatic. Flow rates, particle arrival times, concentrations, and other variables were evaluated for 45 minutes by gamma counting. A tourniquet was used to slow dissemination after subcutaneous injection. RESULTS: After subcutaneous inoculation, particles arrived in the blood at 2.81 +/- 0.54 minutes and in the lymph at 6.0 +/- 1.47 minutes. Application of a tourniquet delayed appearance in the blood to 7.11 +/- 1.5 minutes and in the lymph to 40.0 +/- 5.1 minutes. Concentration of particles in lymph was 1,000 times higher than in the blood. Flux values were comparable in both pathways, but accumulation patterns were different. After intravenous injection, particles arrived in lymph at 25.4 +/- 6.44 minutes. After intralymphatic injection particles arrived in the blood within 4 seconds. CONCLUSIONS: There are functional lymphaticovenous communications at the peripheral level. The period between virus inoculation and blood and lymph invasion may be extended by application of a tourniquet; therefore, time could be gained for local intervention.
Animals↗
The effects of silica on lymph nodes and vessels--a possible mechanism in the pathogenesis of non-filarial endemic elephantiasis.
Non-filarial tropical elephantiasis, which occurs in certain volcanic areas of the world, has been postulated to be an obstructive lymphopathy due to the fibrogenic effects of silica absorbed through the plantar skin of bare-footed people. Animal experiments involving the direct intralymphatic injection of fine silica particles have been carried out in order to assess the extent to which this substance can engender lymphatic obstruction and to determine its main site of action. Intralymphatic silica provoked an immediate and intense macrophage reaction with later fibrosis both within lymph vessels and to a lesser extent within lymph nodes. Lymphography indicated that the consequent obstruction resulted more from the effects of silica on vessels than on nodes.
Animals↗
Locoregional treatment of low-grade B-cell lymphoma with CD3xCD19 bispecific antibodies and CD28 costimulation. II. Assessment of cellular immune responses.
Ten patients with advanced B-cell lymphoma were treated with a single locoregional injection of CD3xCD19 bispecific and costimulating CD28 monospecific antibodies to activate tumor-infiltrating T-lymphocytes. Antibodies were administered at 4 different dose levels (30 microg, 270 microg, 810 microg, 1,600 microg of each antibody) either by intratumoral or intralymphatic injection. Most patients developed responses within different compartments of the immune systems (T cells, NK cells) subsequent to the antibody application. Comparative studies in 2 patients of which treated as well as untreated lymph nodes were available revealed the up-regulation of T-cell activation markers induced by the antibody injection. Additionally, in 1 patient the induction of apoptosis of lymphoma B cells in the antibody-treated lymph node was observed. Specificity analyses of peripheral blood T cells by means of IFN-gamma ELISpot measurement indicated the recruitment of idiotype-specific T cells, as in 1 out of 3 investigated patients an increased T-cell response toward autologous idiotype peptides could be demonstrated. We conclude that a single injection of CD3xCD19 bispecific antibodies is capable to induce an activation of autologous T lymphocytes if simultaneous costimulatory signaling by CD28 antibodies is provided. Furthermore, our data suggest that at least in some patients lymphoma-specific T cells can be recruited by this immunotherapeutic approach toward B-cell lymphoma.
Aged↗
Retention of nociceptor responses during deep barbiturate anesthesia in frogs.
Bullfrogs (Rana catesbeiana) anesthetized with a large dose of thiopental (42.8 mg/kg) retained movement responses to nociceptor stimuli despite an average plasma drug level of 51 mg/l, of which 63% was bound to plasma proteins. This concentration, when corrected to include only unbound and uncharged drug, was 2-fold greater than those reported to abolish nociceptor response (NR) during surgical anesthesia in man. The median anesthetic dose (AD50) for loss of the righting reflex was 11.2 mg/kg by s.c. injection into the abdominal lymph sac; however, at 54.0 mg/kg, all frogs retained NRs, although otherwise deeply anesthetized. The ratio of NR-blocking dose to light AD was thus > 4.8, as compared to < 2 in mammalian studies. Whole body levels of thiopental determined at 3 h after intralymphatic injection showed that about half the injected drug had been eliminated by this time and that termination of anesthesia was chiefly due to drug elimination. Even though the pharmacokinetics of thiopental appears to differ markedly in frogs and men, the poor analgesia seen in the present study frequently has been reported during clinical barbiturate anesthesia. Since this deficiency is much more pronounced in the bullfrog than in man, its neurophysiological basis might profitably be studied using the bullfrog as a model; however, the high mortality associated with deep thiopental anesthesia in the frog should preclude its use as a practical anesthetic in amphibia.
Anesthetics↗
Lymphatic metastasis.
Lymphatic metastasis is an important mechanism in the spread of human cancer. During its course, tumor cells first penetrate the basement of membrane of the epithelium, in which they arise, and then the underlying connective tissue, carried partly by hydrostatic pressure. They enter the lymphatic partly by active movement, pass up the lymphatic trunk; they then settle and proliferate in the subcapsular sinus, penetrate its endothelium and proliferate and destroy the node. There are varied forms of immune response in the node and in human nodes often a complex fibrous and vascular response. The degree of lymphocytic response may be important for prognosis. The nodal reaction may be stimulated by release of antigens from the tumor. One of the most studied animal models of lymphatic metastasis is that which occurs in the politeal node after injection of tumor into the footpad. This model has been used to show that tumor cells enter lymphatics through gaps in endothelium, probably between endothelial cells, and that lymph nodes can destroy small numbers of tumor cells. Local immunotherapy and chemotherapy can sterilize a lymph node of tumor cells; the modes of treatment used have included intralymphatic injection and encapsulation of chemotherapeutic agents in liposomes. Prior radiotherapy may accelerate metastasis possibly by making tumor cells shed into lymphatic vessels. Lymph nodes are rather poor barriers to tumor cells. The prognostic significance of lymph node metastasis varies within tumor type; if hematogenous metastasis is early, then the presence of lymph node metastasis is of lesser prognostic significance. Lymph nodes can probably destroy only small numbers of tumor cells. Tumor cell heterogeneity is of importance in many aspects of metastasis; while clonal variation may be of importance in determining lymph node metastasis, it is not yet clear how important this is, nor whether specific clones metastasize specifically to lymph nodes. Lymphography is well established in diagnosis of lymphatic metastasis. A recent interesting development has been to inject antibodies labeled with a radioactive label, and image the label in lymph nodes with a gamma-camera. If anti-tumor antibodies are used in this way it may be possible to detect lymph node metastasis. Within the expanding field of tumor metastasis, lymphatic metastasis needs much more attention, particularly in relation to the diagnosis and treatment of the lymphatic spread of human cancer.
Animals↗
Lymph drainage from the vulva and the foot as demonstrated by 198Au.
From the central part of the labium majus the lymphatic transport of 198Au is invariably bilateral to inguinal and pelvic lymph nodes. Thus, bilateral inguinal and low pelvic lymph-adenectomy is logical in the treatment of carcinoma of the vulva. 198Au injected subcutaneously and Lipiodol injected intralymphatically in the dorsum of the foot were transported exclusively to ipsilateral inguinal and pelvic lymph nodes. Thus, there is no need for contralateral lymphadenectomy in malignancies on the dorsum of the foot.
Female↗
Lymph transport before and after regional lymphadenectomy as demonstrated with 99Tcm. Preliminary experiences.
The lymphatic transport of a radioactive tracer injected intralymphatically on the dorsum of the foot was determined before and after surgery in 3 patients with vulvar carcinoma. The centrally recorded activity curves showed different time courses before and after inguinal lymphadenectomy, suggesting that the lymphatic transport is short-circuited via lymphovenous anastomoses after lymphadenectomy. Thus, non-radical surgery for primary carcinoma combined with lymphadenectomy will increase the risk of haematogenous spread.
Female↗