Histologic Analysis of the Lymphatic Vessels Used for Supermicrosurgical Lymphatico-venous Anastomoses in Lymphedema

NCT03465930 | Unknown

• 1 other identifier: LVA2017
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

Lymphedema, primary or secondary, is a chronic disease that causes functional impairment and has an important impact on patient's quality of life. Lymphedema can be primary or secondary. Secondary lymphedema, which is more common, especially in industrialized countries, is often due to surgery and radiotherapy to treat cancer. There is no definite cure for lymphedema; conservative treatments such as elastic compression garments, bandages and manual lymphatic drainage help reducing the edema but do not resolve it. Many types of surgery have been used in the past, the most recent are lymphatic-venous anastomoses, a minimally invasive procedure that may be performed under local anesthesia. Briefly, after visualizing the lymphatic vessels with a fluorescent dye, one or more anastomosis are created between collecting lymphatic vessels and superficial veins in order to drain the lymph into the blood stream bypassing the obstacle. During this procedure, it is possible to take samples of the collecting lymphatic vessels that are to be anastomosed with veins and use them for histological and immunohistochemical studies, without causing any additional discomfort to the patient. These samples can be formalin fixed and paraffin embedded. The obtained sections will be stained with a lymphatic endothelium marker and a smooth muscle specific stain. A morphometric study will be conducted and, based on the results a statistical evaluation will be made. The analysis will be conducted on samples obtained from patients, affected by secondary or primary lymphedema willing to provide their free and informed consent. The aim of this study is to evaluate the histopathological characteristics of the collecting lymphatic vessels that have been anastomosed with adjacent veins during surgery, and relate the results with the obtained clinical response. The acquired knowledge will contribute to optimize the clinical approach to prevent and treat lymphedema, by helping to select the patients that will benefit more from the surgery, and to select vessels and anatomical sites that have better chances to provide efficient anastomoses.

Conditions

Lymphedema

Keywords

Lymphedema; Lymphatic collecting vessels; Supermicrosurgery; Lymphatic-venous anastomoses; Immunohistochemistry

Outcome Measures

Primary Outcomes (1)

• Expression of the lymphatic endothelial marker D2-40 in relation with the duration of lymphedema.

  On sections stained with D2-40, under light microscopy with the aid of the morphometric program NIS elements tracing the portions of the endothelium stained positively for this marker and comparing the sum of all positive segments of each vessel with the length of its inner profile. The duration of lymphedema in number of years can be obtained using previous medical records (e.g. lymphography or lymphoscintigraphy) when the patient comes to observation after the diagnosis has already been made or, when no previous medical record is available, through the anamnesis. The duration of lymphedema from clinical onset to the time of surgery is expressed in number of years.

  Collection of samples from different sites of at least 10 patients will require at least 6 months

Secondary Outcomes (5)

• Area of the vessel wall versus area of the lumen

  Collection of samples from different sites of at least 10 patients will require at least 6 months

• The relative proportion of smooth muscle cells and collagen fibers in the lymphatic vessel wall.

  Collection of samples from different sites of at least 10 patients will require at least 6 months

• Differences in the histology of lymphatics between primary and secondary lymphedema.

  Since primary lymphedema is rare, collection of an adequate number of cases of primary lymphedema (at least 10) to evaluate whether there are histologic differences with secondary lymphedema will require at least three years.

• Relation between the anatomic site of the anastomosis and histologic parameters.

  Collection of samples from different sites of at least 10 patients will require at least 6 months.

• Correlation between histologic modifications and morphologic appearance at lymphography and / or at MRL (Magnetic Resonance Lymphography).

  Collection of samples from different sites of at least 10 patients will require at least 6 months

Study Arms (1)

Patients with lymphedema

Patients affected by primary or secondary lymphedema. The intervention will consist in supermicrosurgical lymphatico-venous anastomoses (sLVA) to allow drainage of the lymph in the venous stream distal to the obstruction. sLVA is a minimally invasive procedure performed under local anesthesia. It requires an accurate visualization of the lymphatic vessels that are still functional.

Procedure: Supermicrosurgical lymphatico-venous anastomoses

Interventions

Supermicrosurgical lymphatico-venous anastomoses PROCEDURE

Supermicrosurgical lymphatico-venous anastomoses (sLVA) require an accurate visualization of the lymphatic vessels that are still functional. Lymphatic vessels are visualized with lymphography using a fluorescent dye, indocyanine green. Adjacent superficial veins mapping is obtained with Accuvein device.

Patients with lymphedema

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

All the patients affected by lymphedema that come to us to undergo s-LVA surgery, that match the eligibility criteria and give their free and informed consent. There is no restriction of sex, gender, race, ethnics, country, region, town, etc.

You may qualify if:

• age over 18 years old;
• patients affected by primary or secondary lymphedema;
• patients willing to give their free and informed consent.

You may not qualify if:

• patients currently undergoing radiotherapy;
• patients currently undergoing chemotherapy.

Sponsors & Collaborators

• Paolo Gennaro: lead
• Elisabetta Weber, MD: collaborator

Study Sites (1)

Dept. of Maxillofacial Surgery, Azienda Ospedaliera Universitaria Senese

Siena, 53100, Italy

RECRUITING

Related Publications (12)

• Koshima I, Inagawa K, Urushibara K, Moriguchi T. Supermicrosurgical lymphaticovenular anastomosis for the treatment of lymphedema in the upper extremities. J Reconstr Microsurg. 2000 Aug;16(6):437-42. doi: 10.1055/s-2006-947150.

  PMID: 10993089 BACKGROUND

• Yamamoto T, Narushima M, Yoshimatsu H, Seki Y, Yamamoto N, Oka A, Hara H, Koshima I. Minimally invasive lymphatic supermicrosurgery (MILS): indocyanine green lymphography-guided simultaneous multisite lymphaticovenular anastomoses via millimeter skin incisions. Ann Plast Surg. 2014 Jan;72(1):67-70. doi: 10.1097/SAP.0b013e3182605580.

  PMID: 23241778 BACKGROUND

• Mihara M, Hara H, Hayashi Y, Narushima M, Yamamoto T, Todokoro T, Iida T, Sawamoto N, Araki J, Kikuchi K, Murai N, Okitsu T, Kisu I, Koshima I. Pathological steps of cancer-related lymphedema: histological changes in the collecting lymphatic vessels after lymphadenectomy. PLoS One. 2012;7(7):e41126. doi: 10.1371/journal.pone.0041126. Epub 2012 Jul 24.

  PMID: 22911751 BACKGROUND

• Mihara M, Murai N, Hayashi Y, Hara H, Iida T, Narushima M, Todokoro T, Uchida G, Yamamoto T, Koshima I. Using indocyanine green fluorescent lymphography and lymphatic-venous anastomosis for cancer-related lymphedema. Ann Vasc Surg. 2012 Feb;26(2):278.e1-6. doi: 10.1016/j.avsg.2011.08.007. Epub 2011 Nov 12.

  PMID: 22079465 BACKGROUND

• Liu NF, Lu Q, Liu PA, Wu XF, Wang BS. Comparison of radionuclide lymphoscintigraphy and dynamic magnetic resonance lymphangiography for investigating extremity lymphoedema. Br J Surg. 2010 Mar;97(3):359-65. doi: 10.1002/bjs.6893.

  PMID: 20101589 BACKGROUND

• Yamamoto T, Yamamoto N, Yamashita M, Furuya M, Hayashi A, Koshima I. Efferent Lymphatic Vessel Anastomosis: Supermicrosurgical Efferent Lymphatic Vessel-to-Venous Anastomosis for the Prophylactic Treatment of Subclinical Lymphedema. Ann Plast Surg. 2016 Apr;76(4):424-7. doi: 10.1097/SAP.0000000000000381.

  PMID: 25389716 BACKGROUND

• Kahn HJ, Marks A. A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors. Lab Invest. 2002 Sep;82(9):1255-7. doi: 10.1097/01.lab.0000028824.03032.ab. No abstract available.

  PMID: 12218087 BACKGROUND

• Nagase T, Gonda K, Inoue K, Higashino T, Fukuda N, Gorai K, Mihara M, Nakanishi M, Koshima I. Treatment of lymphedema with lymphaticovenular anastomoses. Int J Clin Oncol. 2005 Oct;10(5):304-10. doi: 10.1007/s10147-005-0518-5.

  PMID: 16247656 BACKGROUND

• Gennaro P, Borghini A, Chisci G, Mazzei FG, Weber E, Tedone Clemente E, Guerrini S, Gentili F, Gabriele G, Ungari C, Mazzei MA. Could MRI visualize the invisible? An Italian single center study comparing magnetic resonance lymphography (MRL), super microsurgery and histology in the identification of lymphatic vessels. Eur Rev Med Pharmacol Sci. 2017 Feb;21(4):687-694.

  PMID: 28272715 RESULT

• Mihara M, Hara H, Kikuchi K, Yamamoto T, Iida T, Narushima M, Araki J, Murai N, Mitsui K, Gennaro P, Gabriele G, Koshima I. Scarless lymphatic venous anastomosis for latent and early-stage lymphoedema using indocyanine green lymphography and non-invasive instruments for visualising subcutaneous vein. J Plast Reconstr Aesthet Surg. 2012 Nov;65(11):1551-8. doi: 10.1016/j.bjps.2012.05.026. Epub 2012 Jul 19.

  PMID: 22817883 RESULT

• Mihara M, Hara H, Furniss D, Narushima M, Iida T, Kikuchi K, Ohtsu H, Gennaro P, Gabriele G, Murai N. Lymphaticovenular anastomosis to prevent cellulitis associated with lymphoedema. Br J Surg. 2014 Oct;101(11):1391-6. doi: 10.1002/bjs.9588. Epub 2014 Aug 13.

  PMID: 25116167 RESULT

• Gennaro P, Gabriele G, Mihara M, Kikuchi K, Salini C, Aboh I, Cascino F, Chisci G, Ungari C. Supramicrosurgical lymphatico-venular anastomosis (LVA) in treating lymphoedema: 36-months preliminary report. Eur Rev Med Pharmacol Sci. 2016 Nov;20(22):4642-4653.

  PMID: 27906440 RESULT

Biospecimen

Retention: SAMPLES WITHOUT DNA

Biospecimens to be retained are tissue, more precisely they are segments of the lymphatic vessels which are to be anastomosed with the veins, they are therefore very small structures (maximum 0.4mm diameter, 2-5mm in length) that are removed for technical reasons in a variable number between 1 and 3 for each patient during surgery. This doesn't affect in any way the success of the surgery itself. These samples instead of being destroyed, will be formalin fixed and transported to the laboratory of Prof. Elisabetta Weber where they will be paraffin embedded. Histologic sections will be obtained and adequate staining will be made.

MeSH Terms

Conditions

Lymphedema

Condition Hierarchy (Ancestors)

Lymphatic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Paolo Gennaro, MD, PhD

  Department of Biotechnology, University of Siena; Department of Maxillofacial Surgery, Azienda Ospedaliera Universitaria Senese

  STUDY DIRECTOR

• Elisabetta Weber, MD

  University of Siena, Dept. of Molecular and Developmental Medicine.

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Paolo Gennaro, MD, PhD

CONTACT

+390577585447; info@supramicrosurgery.com

Elisabetta Weber, MD

CONTACT

+390577234083; elisabetta.weber@unisi.it

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, PhD. Associate Professor of Maxillofacial Surgery, University of Siena

Study Record Dates

• First Submitted: December 7, 2017
• First Posted: March 15, 2018
• Study Start: June 1, 2017
• Primary Completion: December 31, 2018
• Study Completion: December 31, 2023
• Last Updated: March 15, 2018

Record last verified: 2018-03

Locations

IT (1)