Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-06-30
2004-11-09
Saucer, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S040500
Reexamination Certificate
active
06815170
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of surgery, cancer and histopathology. More particularly, it concerns a method for identification of lymph nodes and the presence or absence of lymph node metastases as an important prognostic factor in early stage cancers of all types. In particular aspects, the present invention relates to carbon particle dye compositions for sentinel lymph node identification in cancers such as melanoma. In other aspects, the present invention relates to carbon particle dye compositions for use in determining the histopathologic status of sentinel lymph nodes.
2. Description of Related Art
Routine lymphadenectomy for patients with clinical stage I melanoma remains controversial. Since the first description of a technique for intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) (Morton et al., 1990; Morton et al., 1992), the histologic status of the sentinel node has become a widely accepted criterion upon which to base a decision for complete lymph node dissection in melanoma (Morton, 1997; Thompson et al., 1995).
A large number of studies using the mature technique of LM/SL to identify sentinel nodes with blue dye and radiocolloid support the concept that the histopathologic status of the sentinel nodes is representative of the histopathologic status of all the lymph nodes present in the same basin (Morton et al., 1993; Reintgen et al., 1994; Thompson et al., 1995; Krag et al., 1995; Pijpers et al., 1995; Albertini et al., 1996; Joseph et al., 1997; Bostick et al., 1999; Leong et al., 1997; Loggie et al., 1997; Lingam et al., 1997; Thompson et al., 1997; van der Veen et al., 1994). Unfortunately, a low but definite recurrence risk exists in the same basin after LM/SL is performed as the solitary procedure for tumor-free sentinel nodes (Essner et al., 1999; Gershenwald et al., 1998; Miliotes et al., 1996).
Recurrence in the operated basin that may be due to three reasons. First, in-transit lymphatic metastasis in evolution at the time of LM/SL may subsequently seed the basin. Unfortunately, surgeons presently have no control over this biologic phenomenon.
Second, LM/SL is fallible because a false-negative rate exists due to a failure of surgery, lymphoscintigraphy or histopathology (Morton and Chan, 1999; Morton and Bostick, 1999). Isosulfan Blue and Patent Blue V dyes are the most commonly used agents to identify the sentinel lymph node(s). Surgeons experienced in sentinel node mapping for melanoma have reported successful identification of the sentinel node using blue dye alone in up to 96% of cases (Morton et al., 1992; Morton et al., 1993; Kelley et al., 1998), and the technique is being applied to breast cancer and other solid neoplasms (Giuliano et al., 1997; Morton et al., 1998; Bilchik et al., 1998).
However, isosulfan blue dye-directed mapping is subject to error. The relatively rapid washout of dye from the sentinel node to successive nodes in the basin can lead to intraoperative misidentification of the sentinel node (Bostick et al., 1997; Bostick et al., 1999). This problem led to the use of radionucleotide tracers to assist in identification of the sentinel node. The tracer, usually a technetium-labeled sulfur or albumin colloid, passes through lymphatics into lymph nodes. The sentinel or “hot” node is then identified by use of a gamma counter. Unfortunately, there is still no clear definition of a sentinel node when using radionucleotide tracer technology (Morton et al., 1998). In patients with breast cancer, Krag et al. (1993) defined a sentinel node as having greater than 25 counts per 10 seconds. Veronesi et al. (1997) defined a sentinel node as having between 10 and 2000 counts per second. Others have defined the sentinel node as a lymph node having ten times as many counts as an adjacent, nonsentinel node (Albertini et al., 1996). As should be evident, these arbitrary standards can lead to confusion and misjudgement.
All blue nodes and/or all radioactive sentinel nodes may not be removed at LM/SL. Time-dependent drainage of radiotracer into multiple nodes has been reported (Glass et al., 1998). This allows non-sentinel nodes to become radioactive, which may mislead the surgeon to remove non-sentinel nodes but inadvertently leave behind the true sentinel nodes (Glass et al., 1998; Morton and Bostick, 1999). Thus, lymph nodes that are declared to be sentinel nodes by the surgeon may not be the true sentinel nodes; however, precise examination of these supposedly sentinel nodes may find them truly histopathologically negative. Additionally, an inherent difficulty with pathologic evaluation of sentinel nodes is that nodes identified and declared by the surgeon as sentinel nodes cannot be histopathologically confirmed, unless metastases are present.
Third, histopathologic evaluation of sentinel nodes may erroneously label sentinel nodes as tumor-negative when micrometastases are actually present. Neither isosulfan blue or radiocolloid is retained in sentinel nodes after processing, and so these agents cannot be identified by light microscopy. This histopathologic shortcoming of LM/SL could be mitigated if the sentinel nodes were stained with a mapping agent that remains in the tissue after histopathologic processing. Upon re-evaluation of sentinel nodes by sectioning and immunohistochemical staining of additional levels in patients with recurrent nodal melanoma after LM/SL, it is often the case that micrometastases were unappreciated at the initial examination (Miliotes et al., 1996). Therefore, any measure which can decrease the false negative rate or the histopathological error rate would potentially decrease the same basin recurrence after removal of tumor-free sentinel nodes.
Thus, there exists a need for improved methods for sentinel lymph node mapping. These improved methods should not exhibit the rapid washout of dyes or the time-dependent drainage of radiotracers. In addition, improved methods of histopathological confirmation of sentinel nodes and identification of tumor cell micrometastases in the sentinel node following lymphadenectomy is needed to promote better survival among this subset of patients.
SUMMARY OF THE INVENTION
The present invention describes materials and methods for the identification of sentinel lymph nodes by the surgeon and the pathologist and the presence or absence of lymph node metastases as an important prognostic factor in early stage cancers of all types. The present invention further defines a region of the sentinel lymph node that is identifiable by the surgeon and pathologist and is most likely to contain metastases.
The invention first provides a method of identifying a disease-associated lymph node in an excised tissue sample, comprising, administrating to a subject at least one fluid composition comprising of from about 0.1% carbon particles to about 6.0% carbon particles, excising at least one tissue sample suspected of comprising at least one lymph node, identifying a lymph node by the accumulation of said carbon particles, and; identifying, diagnosing, staging or predicting the presence of neoplastic tissue in said lymph node. As used herein certain embodiments, “fluid” means a liquid composition, such as a solution, a suspension, an emulsion and the like. However, in particular aspects, a suspension of carbon particles is preferred. In certain embodiments, the concentration of the carbon particles may vary. In specific aspects, the carbon particle concentration may be about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, about 1.00%, about 1.10%, about 1.20%, about 1.30%, about 1.40%, about 1.50%, about 1.60%, about 1.70%, about 1.80%, about 1.90%, about 2.00%, about 2.10%, about 2.20%, about 2.30%, about 2.40%, about 2.50%, about 2.60%, about 2.70%, about 2.80%, about 2.90%, about 3.00%, about 3.10%, about 3.20%, about 3.30%, ab
Fulbright & Jaworski LLP
John Wayne Cancer Institute
Saucer Sandra E.
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