[EXPERIMENTAL STUDY OF THE ACUTE TOXICITY OF VARIOUS OILY SUBSTANCES INJECTED BY INTRAVENOUS OR LYMPHATIC ROUTE].
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Administration, Intravenous↗
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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↗
Regional cancer chemotherapy.
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Antineoplastic Agents↗
Immunotherapy of metastatic kidney cancer.
From April 1986 to September 2000, 122 MRCC patients were treated by monthly intralymphatic injections (containing a mean of 573 IL-2 U and 26 x 10(6) LAK cells) and i.m. administration of IFN and TF; 71 patients also received a 3-day cycle of monthly IL-2 inhalations with a mean of 998 daily U. MRCC cases not treated by immunotherapy (n = 89) represent our historical controls. Adverse clinical side effects related to treatment were negligible. CR (n = 11) and PR (n = 13) were noticed in 24/122 patients. Of 24 responding patients, 17 resumed progression, whereas 7 remain in remission 11-69 months later. The overall median survival of treated patients (28 months) was 3.5-fold higher than the median survival of historical controls (7.5 months), and a Kaplan-Meier curve showed 25% survival 11 years after the beginning of immunotherapy. Apparently, the addition of IL-2 by inhalation improved survival. The present immunotherapy protocol appears to be efficacious, safe, devoid of adverse side effects, far less costly than others and able to offer a good quality of life to MRCC patients; if confirmed in a multicenter trial, it could set the basis for developing low-dose immunomodulatory treatments.
Adolescent↗
Rationale for superficial injection techniques in lymphatic mapping in breast cancer patients.
One of the most avidly debated issues in lymphatic mapping is where the tracers are best deposited in patients with breast cancer. The four superficial approaches are easy to perform and have several other distinct advantages. They are based on the hypothesis that the entire breast parenchyma and the overlying skin drain to a common node in the axilla because of their common embryological origin. Evidence is presented that casts doubt upon the correctness of this assumption. Tracer administration close to the tumor site appears to be the safest approach for the time being. Excellent results can be obtained with this latter approach, despite the fact that it is technically more demanding.
Axilla↗
[Influencing of lung function using lymphography with oily contrast medium].
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Animals↗
Comparative metabolism of histamine in two Amphibia anura.
The metabolism of histamine has been compared in Rana ridibunda and Discoglossus pictus, both Amphibia anura. An intralymphatic injection of 14C-histamine (5 microCi) was administered to the animals and the total radioactivity excreted in the urine was measured 24, 48, and 72 hours later. The metabolites excreted in the urine at 24 hours were analyzed by thin-layer chromatography and subsequent autoradiography. In both species approximately 60--70% of the injected dose was found in the urine by 72 hours. In Rana ridibunda two histamine metabolites were found: imidazoleacetic and methylimidazoleacetic acid. The present results suggest that the catabolism of histamine differs in the two species.
Amphibians↗
Responses of afferent and efferent neurons to visual inputs in the vestibular nerve of the frog.
In the frog immobilized by intralymphatic injection of D-tubocurarine, stimulation of the visual apparatus with either electrical shocks applied to the optic chiasma or light pulses elicited, in many cases, an increase and a decrease of firing of efferent and afferent vestibular neurons, respectively, recorded from the horizontal semicircular canal nerve. Optokinetic stimulation was completely inefficient in modulating the efferent and afferent discharge. These results show that stimulation of the visual system can modify vestibular apparatus fuctioning at the most peripheral level. However, it is likely that the effects observed were due to an arousal phenomenon or/and to a motor corollary discharge.
Action Potentials↗
Separate pools for endogenous and exogenous cholesterol in rat intestines.
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Animals↗
Percutaneous inoculation of lymph nodes.
Injections into rat lymph nodes are easily performed percutaneously, without the need for a skin incision, if the nodes are enlarged in advance. The requisite enlargement of the popliteal lymph node can be obtained in 2 or 3 weeks by a single injection of tin powder or other particulate material into the foot. This method may be especially useful when multiple intranodal inoculations are contemplated.
Animals↗