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Grading system of lymphatic invasion according to D2-40 immunostaining is useful for the prediction of nodal metastasis in squamous cell carcinoma of the uterine cervix.

AIMS: To determine the relationship between lymphatic invasion detected by D2-40 immunostaining and nodal metastasis in squamous cell carcinoma (SCC) of the cervix. METHODS AND RESULTS: Seventy-five cases of FIGO stage IB to IIB SCC of the cervix, treated by radical hysterectomy and lymph node dissection, were examined. Immunohistochemistry for D2-40 was performed. Overestimation of lymphatic invasion on conventional histological examination was demonstrated by assessment of D2-40 immunoreactivity in 22 cases. A significant difference in lymphatic invasion detected by D2-40 immunostaining was found between the metastatic group (30 cases) and the non-metastatic group (45 cases) (P < 0.001). A grading system (grade 0-2) of lymphatic invasion according to D2-40 immunostaining was devised. Subsequently, the frequency of nodal metastasis significantly increased in accordance with the grade of lymphatic invasion (P < 0.001) and in eight cases with grade 2, seven cases (87.5%) had nodal metastasis. CONCLUSIONS: In cervical SCC, a grading system for lymphatic invasion according to D2-40 immunostaining is useful for the prediction of nodal metastasis and grade 2 lymphatic invasion is a strong predictor of nodal metastasis.

Adult↗

The balance between lymphatic and systemic absorption determines the outcome of sensitization for anaphylaxis in rats.

Rats were sensitized to chicken ovalbumin or human gamma-globulin by inoculation without adjuvants into the peritoneal cavity in the healing phase of a chemical peritonitis. This phase is associated with striking enhancement of lymphatic absorption. Small doses of antigen sensitized the rats for subsequent induction of anaphylaxis, but large doses were almost completely ineffective (inverse dose-response relation). When certain adjuvants were added to the antigen, both high and low doses of antigen were effective sensitizers for anaphylaxis. Neither high nor low doses of antigen sensitized if injected without adjuvants into the unprepared peritoneal cavity or by any other route. The effects of sensitization with low or high doses of antigen and the results of inoculation by effective and ineffective routes were interpreted in terms of the balance between absorption into the lymphatics and into the systemic blood circulation. Supplemental antigen inoculated into the systemic circulation was able to tip the balance against sensitization even when sensitization was done with potent adjuvants and by a favorable route. Splenectomy had little or no effect on suppression by supplemental antigen.

Absorption↗

Micro-magnetic resonance lymphangiography in mice using a novel dendrimer-based magnetic resonance imaging contrast agent.

Major advances in cancer biology and immunology have been gained using mouse models. However, very few methods are currently available to visualize the deep lymphatic system. A new micro-magnetic resonance lymphangiography (MRL) method in mice, which uses dendrimer-based magnetic resonance imaging contrast agents, was developed. Micro-MRL imaging clearly visualized most of the mouse lymphatic system, including both lymphatics and lymph nodes. This method could detect and distinguish among dilation of lymphatic vessels in a lymphangitis model, proliferative or neoplastic lymph node swellings in a lymphoproliferative model, and inflammatory lymph node swellings in an infection/inflammation model. Changes in the lymphoid system of transgenic mice overexpressing interleukin-15 could be visualized. Abnormal enlarged lymph nodes identified by micro-MRL were selectively removed and analyzed to demonstrate their cell type, receptor expression, and clonality in individual mice. We conclude that the enhanced resolution of this noninvasive micro-MRL can detect and classify lymphatic and lymph node abnormalities in mice, which should have wide applicability to the study of immunology and cancer in both experimental animals and clinical medicine.

Animals↗

Occult persistence and lymphotropism of hepadnaviral infection: insights from the woodchuck viral hepatitis model.

Hepatitis B virus (HBV) is a major human pathogen that causes chronic infection and life-threatening liver diseases in millions of individuals. While pathological and epidemiological consequences of clinically evident HBV infections are well recognized, there is no similar knowledge on an asymptomatic, silently progressing virus persistence. Contrary to previous opinion, current evidence indicates that a serologically undetectable (occult) HBV carriage is a common outcome of recovery from symptomatic illness and that scanty amounts of the virus are carried by apparently healthy individuals for years after resolution of hepatitis B despite the presence of presumably protective antiviral antibodies. Recent studies on this silent form of hepadnavirus carriage in an experimental woodchuck hepatitis virus (WHV) infection, which is considered to be the closest natural model of HBV disease, revealed that the life-long occult persistence of traces of pathogenic virus is an invariable consequence of recovery after hepadnaviral invasion and that this state always co-exists with a steady low-rate virus replication in both the liver and the lymphatic system. Importantly, this serologically concealed infection can be accompanied by development of hepatocellular carcinoma in convalescent animals and is transmittable from mothers to offspring as an asymptomatic, indefinitely long infection which involves the lymphatic system but not always the liver. This review focuses on the features of hepadnavirus occult persistence and its lymphotropism, and on what is currently understood about the contribution of the lymphatic system in maintaining hepadnavirus carriage based on insights provided by analysis of the woodchuck-WHV experimental system.

Animals↗

Primary lymphatic dysplasia in children: chylothorax, chylous ascites, and generalized lymphatic dysplasia.

Primary lymphatic "dysplasia", a congenital maldevelopment, interferes with function of the lymphatic system and causes effusion of chyle or lymph into the limbs and pleural or peritoneal cavity. Between 1955 and 1982, 38 Mayo Clinic patients were found to have a chylous effusion or dysplasia of the lymphatic system. In 22, the condition was secondary to surgery or other medical problems and in 16 it was primary. These cases were separated into three categories: chylothorax, chylous ascites, and generalized lymphatic dysplasia. Conservative therapy, such as a restricted fat diet or total parenteral nutrition with repeated thoracentesis or paracentesis, was effective in the children with isolated abnormalities of the lymphatic system (75% resolution rate, no deaths). All five children with documented generalized dysplasia reported in the literature had died; of the three reported here, one has died and two have become progressively worse.

Adolescent↗

[The clinico-physiological validation of the use of the endolymphatic route for antibiotic administration for preventing the translocation of intestinal microflora during the treatment of sepsis patients].

One of the main mechanisms of generalization of infection in purulent-inflammatory processes of the abdominal cavity, retroperitoneal space and pelvis minor is translocation of the pathogenic microflora of the intestine in the lymphatic system via regional lymphatic nodes with subsequent rupture into the systemic circulation. Endolymphatic administration of antibacterial agents into the peripheral lymphatic vessel favours saturation of the reticuloendothelial structures of the lymph nodes by the antibiotic agent that increases their barrier function and, thus, prevents generalization of the infection and development of polyorganic insufficiency.

Abdomen↗

Regulation of lymphangiogenesis--from cell fate determination to vessel remodeling.

Lymphatic vessels are important for the maintenance of normal tissue fluid balance, immune surveillance and adsorption of digested fats. During the past decade, the identification of lymphatic-specific markers and growth factors has enabled detailed studies of the lymphatic system, and gain- and loss-of-function experiments have greatly increased our understanding of the mechanisms of normal lymphatic development. Understanding the basic biology has provided novel insights into the pathologic conditions of the lymphatic system that contribute to lymphedema, inflammation or lymphatic metastasis, and opened possibilities for the development of better therapeutic strategies. Here we review the current knowledge about the molecular mechanisms regulating the development of the lymphatic vasculature; of the differentiation of lymphatic endothelial cells, of the regulation of the growth of lymphatic vessels, and of remodeling of the vasculature into a network consisting of lymphatic capillaries and collecting lymphatic vessels. Furthermore, we will discuss the molecular mechanisms involved in the pathological conditions of the lymphatic vessels.

Angiopoietins↗

[Pulmonary lymphangiomatosis associated with renal angiomyolipoma. Presentation of a case and review of the literature].

The case concerned is one of lymphangiomyomatosis (LAM) in a woman aged 39, that after a episode of spontaneous pneumothorax was subject to medical research for progressive dyspnea of medium efforts and bloodstained sputum. High resolution CT showed numerous thin-walled cystic airspaces of varying sizes distributed diffusely throughout the lungs. The abdominal CT and ultrasound developed multiple right renal angiomyolipomas. The histopathological study of the sample obtained by open lung biopsy was conclusive of LAM. The main feature of this rare disease, which occurs almost exclusively in women of reproductive age, is the abnormal proliferation of immature smooth muscle at the level of the distal airway, small blood vessels and lung lymphatic system, including sometimes the mediastinal and retroperitoneal lymphatic system. The clinical, functional, radiological and differential diagnostic aspects with entities histopathologically similarities are discussed and the therapeutic possibilities are reviewed.

Adult↗

[Lymph circulation dynamics and protein-cellular responses of central lymph during the early postresuscitation period].

Lymph circulation, the biochemical and cytologic composition of thoracic duct lymph were studied in experiments on dogs in the early postresuscitation period. In the course of rehabilitation of vital functions, the experimental animals manifested a considerable increase in the lymph flow rate in the thoracic ducts. Concurrently there was a significant rise, seen immediately after the postresuscitation period, in the absolute amount of protein and lymphoid cells transported by the lymphatic system into the general protein circulation. A conclusion is made that the lymphatic system plays an important role in the compensation of deranged homeostasis in the maintenance of optimal conditions for the metabolic processes in the intertissue space as well as in the mobilization and redistribution of body lymphoid cells in the postresuscitation period.

Animals↗

Alymphoplasia (aly)-type nuclear factor kappaB-inducing kinase (NIK) causes defects in secondary lymphoid tissue chemokine receptor signaling and homing of peritoneal cells to the gut-associated lymphatic tissue system.

Alymphoplasia (aly) mice, which carry a point mutation in the nuclear factor kappaB-inducing kinase (NIK) gene, are characterized by the systemic absence of lymph nodes and Peyer's patches, disorganized splenic and thymic architectures, and immunodeficiency. Another unique feature of aly/aly mice is that their peritoneal cavity contains more B1 cells than normal and aly/+ mice. Transfer experiments of peritoneal lymphocytes from aly/aly mice into recombination activating gene (RAG)-2(-/-) mice revealed that B and T cells fail to migrate to other lymphoid tissues, particularly to the gut-associated lymphatic tissue system. In vivo homing defects of aly/aly peritoneal cells correlated with reduction of their in vitro chemotactic responses to secondary lymphoid tissue chemokine (SLC) and B lymphocyte chemoattractant (BLC). The migration defect of aly/aly lymphocytes was not due to a lack of expression of chemokines and their receptors, but rather to impaired signal transduction downstream of the receptors for SLC, indicating that NIK is involved in the chemokine signaling pathway known to couple only with G proteins. The results showed that the reduced serum levels of immunoglobulins (Igs) and the absence of class switch to IgA in aly/aly mice are due, at least in part, to a migration defect of lymphocytes to the proper microenvironment where B cells proliferate and differentiate into Ig-producing cells.

Animals↗

Submucosal territory of the direct lymphatic drainage system to the thoracic duct in the human esophagus.

OBJECTIVE: To investigate how large submucosal drainage territory extends in lymphatic drainage vessels of the esophagus with and without nodal delay and which morphologies are shown when passing through the muscularis propria. METHODS: Submucosal territories of the 22 highly selected direct drainage vessels of 17 esophagi were histologically examined using transverse or sagittal serial sections. Afferent vessels from the esophagus to the subcarinal (6 esophagi) and para-esophageal (5 esophagi) nodes were also examined to identify their courses and drainage territories. RESULTS: We found the direct drainage vessel from the esophagus in 17 of 75 cadavers macroscopically (22.7%). A single submucosal drainage unit gave off 1-3 thick drainage vessels passing through a complete muscle gap of the 2 muscular layers. The unit extended longitudinally for >40 mm but was restricted to the right and/or dorsal quadrants of the esophagus. In contrast, drainage routes with a nodal relay originated from the intermuscular area, except 1 case when the adjacent or concomitant esophageal artery and vein provided the complete muscle gap. CONCLUSIONS: Due to the extended longitudinal but restricted transverse territory of the direct drainage system without a nodal relay and because of the suggested much more frequent occurrence in patients than in cadavers, when superficial carcinoma is found in the dorsal and/or right quadrants of the esophagus, we recommend detailed presurgical investigations of cervical nodes. In contrast, afferents from the esophagus to the first regional node usually seemed to be less responsible for early nodal metastasis than the direct drainage route because of their intermuscular origins.

Esophagus↗

[Contribution of a combination of alpha and beta benzopyrones, flavonoids and natural terpenes in the treatment of lymphedema of the lower limbs at the 2d stage of the surgical classification].

HYPOTHESIS: To create a phlebolymphologic therapy in order: to activate venous system; to activate lymphatic system; to activate macrophagic system; to reduce the proteic lymphatic load. EXPERIMENTAL: A study was performed on the use of an ideal phlebolymphological association (Tonka Beans, Gingko Biloba, Melilotus Officinalis) as a practical standpoint in the treatment of lymphedema of lower limbs in order to create an efficacious dose of Coumarin, Benzopyrones and Ginkolidi. CLINICAL: We investigated a population of 76 patients treated in an open-label study for six-eight months with a dosage of Coumarin 60 mg/daily + Gingko Biloba 40 mg/daily + Melilotus 40 mg/daily. CONCLUSION: This trilogy induced a very significant improvement in lymphedema (centimeter-aspect) both in functional symptoms (pain heaviness in affected limbs) and physical signs (edema, episodes of infection). Tolerance of long term treatment was good and the improvement was observed from the third month of treatment.

Adolescent↗

Proteomic technologies to study diseases of the lymphatic vascular system.

Now that the human genome has been mapped, a new challenge has emerged: deciphering the various products of individual genes. Consequently, new proteomic technologies are being developed to monitor and identify protein function and interactions responsible for the total activities of the cell. The application of these new proteomic technologies to study cellular activities, will lead to a faster sample throughput and increased sensitivity for the detection of individual proteins, thus providing major opportunities for the discovery of new biomarkers for the early detection of protein alterations associated with the progression of the disease state.

Animals↗

Visualization of the lymphatics of the heart and the mediastinal drainage pathways in the living cynomolgous (Macaca mulatta) monkey.

Our interest in the effects of impaired cardiac lymph drainage on coronary atherosclerosis led us to study the cardiac lymphatic anatomy in the monkey, generally considered the ideal experimental animal for examining coronary artery disorders. Short-term and long-term studies to visualize the cardiac lymphatic system and its mediastinal drainage pathways in 14 living monkeys confirmed that the epicardial collecting lymphatic anatomy is comparable to that of man, dog, and pig. These lymphatics, and particular lymphatic drainage to the cardiac lymph node in the right mediastinum, are difficult to visualize, in good part, because lymph uptake of such tracers as India Ink and T1824 blue dye is extremely slow. By modifying our techniques and taking cognizance of the slow lymphatic uptake of the tracers, we have been more successful in visualizing the mediastinal cardiac lymph node. Though our studies confirm that the lymphatic drainage of the monkey heart is similar to that in other mammals, we conclude that the "monkey model" has several drawbacks to study the effects of impaired cardiac lymph flow because of the laborious requirements to visualize successfully the cardiac lymph node. Perhaps the development of new markers would make this lymphatic system more approachable for experimental investigation.

Animals↗

Bacterial translocation from the biliary tract to blood and lymph in rats with obstructive jaundice.

BACKGROUND: The disruption of the hepatocyte tight junctions observed in biliary obstruction suggests altered permeability of the blood-bile barrier. In this study the role of biliary obstruction and increased biliary pressure on the translocation of bacteria from biliary tract to bloodstream and lymphatic system were evaluated. MATERIALS AND METHODS: Rats underwent distal bile duct ligation (BDL, n = 33) for two weeks or a sham celiotomy (n = 21). Seventeen of the 33 BDL rats underwent subsequent biliary decompression by a choledochojejunostomy (CJ). Two weeks after the final operation, a laparotomy was performed again and the CBD, the thoracic duct, and the caval vein were canulated. Next, a suspension containing 10(8) Escherichia coli/ml was retrogradely infused in the CBD for 5 min at 5 or 20 cm H2O above the secretory biliary pressure. RESULTS: A higher biliary infusion pressure resulted in a significant increase of cfu E.coli per milliliter of blood in all the three groups (Sham, BDL, CJ). BDL rats showed significantly more bacterial translocation to the bloodstream than the shams. After biliary decompression, translocation normalized to the control levels. At 5 cm H2O infusion pressure only one lymph culture was positive (CJ group). At 20 cm H2O overpressure, nine lymph cultures were E.coli positive (P = 0.03). These were found mainly in groups with a nonobstructed bile duct (Sham and CJ 40% vs BDL 10%). CONCLUSION: Translocation of bacteria from biliary tract to bloodstream increased at higher intrabiliary pressures. Longstanding bile duct obstruction was an independent determinant for cholangiovenous reflux. Bacterial translocation to the lymphatic system did not parallel translocation to the bloodstream, although in the nonobstructed biliary tract, increased bacterial translocation to the lymphatic system was pressure related.

Animals↗