Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
1999-02-05
2002-09-03
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C424S009500, C600S458000
Reexamination Certificate
active
06444192
ABSTRACT:
FIELD OF THE INVENTION
In a broad aspect, the present invention is directed to methods of imaging lymphocytic structures. More particularly, the present invention advantageously uses contrast agents to identify and image lymphatic ducts, sentinel nodes and/or other lymph nodes by various means, including ultrasound and MRI.
BACKGROUND OF THE INVENTION
The lymphatic system is made of vessels or ducts that begin in tissues and are designed to carry lymph fluid to local lymph nodes where the fluid is filtered and processed and sent to the next lymph node down the line until the fluid reaches the thoracic duct where it enters the blood stream. Lymph vessels infiltrate all tissues and organs of the body. Lymph fluid is generated from capillaries which because of tissue motion and hydrostatic pressure, enters the lymph vessels carrying with it local and foreign substances and materials from the tissues. These local and foreign molecular, micromolecular and macromolecular substances include antigens, infectious agents, particles and cells. Lymph nodes, the lymph “filters”, consist of essentially two major compartments: the fluid spaces, or sinuses, and the cellular elements. There is one major sinus at the outer margin of the node that feeds a maze of sinuses that serve to percolate the fluid slowly towards the hilum of the node from where it is carried downstream. The sinuses are lined by macrophages that phagocytose materials carried by the fluid, particularly if the materials have certain surface charges or specific shapes. The remainder of the cellular elements in the lymph node performs the immunologic function of the node. In this regard, the lymph nodes process fluid by sieving and phagocytosis to remove particulate and cell materials delivered by the lymphatic vessels, thereby cleaning it before it is returned to the blood stream.
The local particulate materials carried to the node are typically proteins that either escaped the capillary beds or were produced by tissues or organs. Foreign particulates are micromolecular (less than 1 micrometer) or macromolecular (greater than one micrometer), and include viruses, bacteria, and injectable suspensions such as contrast media or radiopharmaceuticals. The particles enter the lymph vessel from the interstitium through gaps between lymphatic endothelial cells or by transcellular endo-exocytosis. The gaps change in caliber with physiologic or pathologic conditions. Entry of the particle into the gap is believed to be a hit-or-miss affair and should be weakly related to particle size at dimensions less than the size of the gap.
On average, smaller particles (10-50 nm) are more likely to enter than larger particles. As particles approach 1000 nm, their uptake into lymphatics is so poor that they become ineffective. Very large particles in the interstitial space must be carried away by phagocytes or reduced in size by local processes. In fact over 95% of particles larger than 400 nm were found to remain at the injection site (Oussoren et al., Pharm Res. (1997) 4(10):1479-1484 and Oussoren et al., Biochim Biophys Acta. (1997) 1328(2):261-272) whereas 74% of particles 10 times smaller (40 nm) were absorbed. Small particles (less than 5 nm) and particles without appropriate surface characteristics are not retained by the first lymph node and are carried to downstream lymph nodes or directly into the blood stream by the capillaries.
Several attempts have been made to improve retention of diagnostic agents in the lymph node. One is to administer a viscous substance such as ethiodol directly into the lymph vessel thereby plugging the sinuses and hindering the forward progress of the liquid. This technique, called direct lymphangiography, is performed to detect tumor deposits in lymph nodes but is limited to the few regions of the body where direct canulation of the lymph vessel is possible. Another technique is to administer particulate suspensions such as emulsions with specific size distributions that are phagocytosed by macrophages (Wolf et al., U.S. Pat. No. 5,496,536 and Bergquist, et al., Sem. Nucl. Med (1983) 13: 9-19). These agents, although phagocytosed, are not sufficiently retained in the lymph node to halt their progress and highlight several lymph nodes in the local chain. The third technique to promote retention is the placement of surface active substances that promote phagocytosis (Vera et al., J Nucl Med (1997) 38(4):530-5).
The cellular elements carried in lymph or that gain access to lymph nodes are typically the circulating white cells or phagocytes that are involved in the cellular defense mechanism. Although these cells are very large (several tens of micrometers in diameter) they gain access to the lymph space by their ability to deform and migrate through tiny openings. These cells patrol the extracellular space, phagocytose materials and carry such materials into the lymph and the lymph nodes for further action by the immune system. When cancer occurs in tissues or organs, its loose matrix allows the dislodging of cells that gain access to the lymph space. However, because they lack the functionality of white blood cells, they can become trapped in the lymph node and grow. In the early stages of cancer development in the node, the cancer remains limited to the node. However, in time, the nodal deposit can grow to totally replace the node or can spread downstream to the next node. The lymph nodes that drain the tissue or organ of interest (i.e., the cancerous tissue), called the regional nodes, and the first node that traps the cancer is called the sentinel node.
Unfortunately, although certain patterns in the spread of tumors are recognized, these patterns are complicated. Metastasis of neoplastic cells does not simply result in the spread of the neoplastic cells to the next physically nearest node. Nodes in close physical proximity to the primary tumor are more likely to contain the sentinel node, however, the sentinel node may be in a more distant nodal group. This can occur due to normal anatomic pathways that can bypass adjacent nodal clusters. Complex patterns can also arise because tumors, current or prior infections, injury or previous treatments can block the lymph vessels that directly drain the tissue or organ, promoting the development of collateral and aberrant pathways.
Lymphadenectomy is a common procedure that provides local control and staging of breast cancer patients as well as establish prognosis and method of treatment. The degree of involvement of axillary lymph nodes remains the most important prognostic indicator (Cancer 1993:71). These nodes are positive in as many as 40% of breast cancers including those cancers between 5-10 mm in size. Because of the associated morbidity with axillary dissection in as many as 20% of patients (Coburn M C and Bland K I,
Curr Opin Oncol
1995; 7:506; Petrek J A and Blackwood MM.
Curr Prob Surg
1995; 267), attempts at limiting dissection have led to the development of sentinel node resection. The concept of the sentinel node dissection was popularized by Morton DL (Arch Surg 1992; 127:392-99) for staging melanoma and Giuliano A E applied it to breast cancer (Ann Surg 1994; 220:391-401). They showed that limiting the dissection to the sentinel node can predict the status of the remainder of the nodal system. When the sentinel node was negative, the remainder of the nodes were negative in 126 out 127 cases. When the node was positive, it was the only positive node in over 60% of cases (Morton DL et al.,
Arch Surg
1992; 127:392) and contained five times more micrometastasis than nonsentinel nodes (Giuliano A E et al.,
Ann Surg
1995; 394). So, in addition to staging, sentinel node resection provides some therapeutic benefit, as all micrometastases would be removed in a majority of cases.
Sentinel lymphadenectomy begins with the injection of 3 to 5 mL of isosulfan blue in the breast mass and surrounding tissue (Giuliano A E et al.,
Ann Surg
1994; 220:391). Approximately 5 minutes later blunt dissection is made to locate a blue lymphatic channel or a blue nod
Gray Cary Ware & Freidenrich LLP
Hartley Michael G.
The Regents of the University of California
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