Abstracts LymphForsch 1/2018

– full text in German –

New medication for lymphedema? A survey of clinical trials on lymphedema listed by the National Institutes of Health

J. Becker
LymphForsch 22 (1) 2018;6-8

Lymphedema is caused by various factors. Primary lymphedema is hereditary, i.e., genetically determined, while secondary lymphedema may occur after tumor manifestation or be caused by parasite infestation, surgical complications, or in association with other diseases. Research from the National Institutes of Health (NIH, USA) database for clinical trials on lymphedema shows that manual and physical methods are by far most common types of lymphedema treatment and are continuously improved by new materials and techniques. While the prospect of drugs and molecular approaches may offer more sustainable or even curative approaches, they are still in their infancy. Still, they appear to be promising therapy alternatives for the future. This article will provide a brief overview of these studies, as well as a more general perspective on clinical trials for the treatment of lymphedema.

Keywords: National Institutes of Health, lymphedema, clinical trials, metaanalysis
E-mail: juergen.becker@med.uni-goettingen.de

The lymphatic system and Starling‘s equilibrium

E. Brenner
LymphForsch 22 (1) 2018;9-13

In his pioneering work in 1896, Ernest Henry Starling determined “that an absorption of fluid by the blood vessels by a process of backward filtration is impossible in the connective tissues

of the limbs, in muscles and in all glandular structures (…).” Nevertheless, it has been – and still is – accepted and taught that continuous capillaries filter fluid on the arterial side and resorb most (about 90 %) of it on the venous side, with the remainder taken up by the initial lymphatic vessels as “lymphatic load”. This factoid is based on an assumed “fact” of bodily fluid physiology, namely, that most tissues maintain fluid balance by filtering the fluid in the arterial side of the capillary into the interstitial space, while the venous side of the capillary continuously captures most of the filtered fluid. In fact, filtration occurs that decreases along the microvascular axis but does not become negative. Thus, although capillaries may temporarily absorb fluid from the interstitial space when, for example, the blood pressure is lowered acutely, this is not the case in steady-state, which is consistent with the sum of the forces of Starling's equilibrium. The assumption of longitudinally decreasing but continuous filtration shifts the task of maintaining the tissue fluid balance to the lymphatic system alone, i.e. the interstitial space and the draining lymphatic vessels.

Keywords: Starling’s equilibrium, lymphatic load, filtration, capillaries
E-mail: Erich.Brenner@i-med.ac.at

Differential lymphangiogenic and hemangiogenic profiles of extraocular and intraocular melanomas

J. M. Mor , L. M. Heindl
LymphForsch 22 (1) 2018;14-19

Uveal and conjunctival melanomas are two of the most common ocular malignancies. Despite their shared melanocytic origin, there are fundamental differences between these entities. Apart from the significantly different tissue tropism of their metastases, there is a notably different pattern of hemangiogenesis and lymphangiogenesis in the tumors’ microenvironments. Multiple humoral and cellular factors regulate these processes. Clinically,

the degree of angiogenic alterations correlates with the patients’ prognosis. In this article we aim to elucidate the pathophysiology of tumoral hemangiogenesis and lymphangiogenesis in uveal and conjunctival melanoma. We also provide a literature review and present and discuss our own clinical and experimental data. In conjunctival melanoma, tumor-associated lymphangiogenesis was demonstrated in premalignant as well as later stages of the disease and was shown to correlate with tumor progression. In uveal melanoma, the advent of lymphangiogenesis cannot be expected before extraocular spread occurs. In both entities, the degree of lymphangiogenesis correlates with the risk of metastasis and overall prognosis. No significant differences in the expression of VEGF isoforms between uveal and conjunctival melanoma were found that would account for these different angiogenesis patterns. Other pathways of angiogenesis-related signaling have to be considered to fully understand   the regulation of the balance between hemangiogenesis and lymphangiogenesis. The analysis of tumoral lymphangiogenesis should be included in the routine pathology work-up of ocular melanomas. Before novel targeted antiangiogenic therapies for the treatment of ocular melanoma can be established, further preclinical studies need to be conducted.

Keywords: lymphangiogenesis, hemangiogenesis, melanoma, ocular tumor
E-mail: Ludwig.heindl@uk-koeln.de

The lymphatic system of the outer orbital region and its relation to lymphoid organs

J. Wilting, R. Pabst
LymphForsch 22 (1) 2018;21-25

The lymphatic system of the orbital region has rarely been described owing to the difficulty of performing immunohistological studies of bony structures. We decalcified heads of 14-day-old mice and performed immunohistology of serial paraffin sections with the lymphatic endothelial marker LYVE-1 and the pan-leukocyte marker CD45. Lymphatics are present in the limbus of the cornea, immediately next to the avascular cornea. The conjunctiva contains lymphatics, which are evidently connected to those of the upper and lower eyelids. Mice possess a nictitating membrane behind the upper eyelid that also contains lymphatics. The nasolacrimal duct (NLD) originates in the medial angle of the eye and is accompanied by a dense lymphatic network. When the NLD connects to the inferior turbinates, these lymphatics are continued by those accompanying the palate and pharynx into the deep lymphatics of the neck. Along the lymphatics of the outer orbital region there are evidently three immunological control stations. The first resides along the NLD and represents the lacrimal ductassociated lymphoid tissue (LDALT); the second is located above the palate in the inferior turbinates and represents the nose-associated lymphoid tissue (NALT); the third comprises the deep lymph nodes of the neck. Comparable conditions have been described in the human. This is apparently relevant for lymphedema developing, e.g., in the eyelids, as a consequence of lymphoma in the head region.

Keywords: LYVE-1, CD45, lymphatic endothelial cell, nasolacrimal duct, LDALT, NALT
E-mail: joerg.wilting@med.uni-goettingen.de

The influence of aqua cycling on the volume of edematous swelling in patients with lipedema/lipolymphedema compared to manual lymph drainage – A pilot study

J. Becker, B. Kleinschmidt, J. Kleinschmidt, M. Jung
LymphForsch 22 (1) 2018;29-37

Background: Aquatic therapy is a popular form of treatment for the prevention, rehabilitationand therapy of acute illnesses and chronic disorders. Evidence-based proof of effectiveness of aqua cycling for reducing edematous swelling is scarce, however.

The study aimed to evaluate the effectiveness of aqua cycling in addition to manual lymph drainage for treating lipedema/lipolymphedema in the legs of female patients. A significant difference in the mean values of the population would indicate a positive effect.

The clinically controlled pilot study was conducted for a ten-week period and compared the effects of aqua cycling to the conventional physical therapy inter ventions for reducing edema. Ten female patients with lipedema/lipolymphedema were divided into two study arms (intervention group n = 5, control group n = 5). Both groups underwent manual lymph drainage once or twice a week. The intervention group additionally engaged in aqua cycling once a week. To compare the effects of the therapy, circumferential measurements were taken, analyzed and evaluated following a pre-post-design to ascertain volume.

There was no significant overall reduction of volume during the therapy. However, direct comparison of the two study arms based on the mean values of each leg shows that the intervention group exhibited distinct volume-reduction effects of 266.37 cm3 (SD 435.60) in contrast to the control group, which showed a volume increase of 438.95 cm3 (SD 1246.90). 

Aqua cycling is a worthwhile addition to the gold standard of manual lymph drainage. A combination of both interventions yields a noticeable average volume-reducing effect.

Keywords: aqua cycling, lipedema/lipolymphedema, manual lymph drainage, physical therapy
E-mail: becker.jessica@stud.hs-fresenius.de