Clinical Practice Guidelines for Melanoma.
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Journal Article↗
Biomedical subjects
D Rapaport
Publications and source records attributed to D Rapaport.
Florida's undeclared epidemic: malignant melanoma.
Contrary to the trend of early diagnosis observed in other parts of the world, in Florida melanoma is still being discovered in the more advanced stages. This is characterized by thicker lesions at diagnosis, which are hallmarked by bleeding, itching, ulceration, and increased vertical growth. In a study of 1,626 cutaneous melanoma patients at the H. Lee Moffitt Cancer Center in Florida, three prognostic factors, tumor thickness, Clark level, and presence of ulceration in the primary tumor, have remained relatively constant over an eight-year period (1987-1994). Despite the lack of change in tumor thickness in the last four years, mortality rate is decreasing, possibly due to more effective treatments. Regardless of these apparent improvements in mortality rates, definite progress must be made in the early detection of malignant melanoma through the initiation of statewide programs of lay public and professional education. In addition, it is proposed that the establishment of statewide screening programs of the Caucasian population with skin phenotypes 1 and 2 will also facilitate the early diagnosis of melanoma in the future, improve the outlook for these patients, and begin to address a major public health problem in the state of Florida.
Adolescent↗
Investment in new technology research can save future health care dollars.
OBJECTIVE: To perform a cost analysis of the emerging technology of lymphatic mapping for patients with malignant melanoma. DESIGN: A retrospective, computer-aided chart and financial cost and charge review of consecutive patients with the diagnosis of melanoma registered at a cancer center from December, 1995 to March, 1996. PARTICIPANTS: 73 consecutive patients with the diagnosis of Stage 1 and 2 melanoma (cutaneous disease only) had nodal staging of their disease with either a sentinel node (SLN) biopsy or an elective complete node dissection (ELND). This was determined largely by patient choice and the protocol in operation at the time of the presentation of the patient to the clinic. OUTCOMES MEASURED: There were no deaths in the series. Patient morbidity endpoints included rates of infection, incidence of extremity lymphedema, development of a seroma in the regional nodal basin wound and wound healing. Clinical outcome was measured by the ability to obtain complete nodal staging information with the new lymphatic mapping technology, and recurrence rates in the nodal basin after a negative SLN biopsy. Total charges, direct costs and total costs were calculated from all hospital, OR, pathology and lab charges. Professional fees were included in the analysis. RESULTS: Group 1 patients (50) had melanomas greater than 0.76 mm in thickness treated with a wide local excision (WLE), lymphatic mapping and SLN biopsy under general anesthesia. Five patients (Group 2) had their procedure performed under a straight local anesthesia. Group 3 patients (18) had nodal staging performed with an elective node dissection. In Groups 1 and 2, if the SLN was positive for micrometastases, the patients were taken back to the OR for a complete node dissection. The total charges per patient were $13,835, $6,853 and $19,285, respectively. Significant dollar savings were achieved if the nodal staging could be accomplished with the lymphatic mapping technology (p = 0.001). Morbidity was significantly less in Groups 1 and 2 compared to Group 3. After a mean follow-up of three years, only one patient has recurred in a SLN negative basin. CONCLUSIONS: With 38,300 new cases of melanoma diagnosed each year in the United States, a projected savings of $172 million per year (general anesthesia) and $350 million per year (local anesthesia) could be realized if this new mapping technology could be incorporated into the care of the melanoma patient. Patient morbidity is minimized, nodal staging is complete and patients return to work sooner. Recently approved adjuvant therapy can be applied in a selective fashion, treating only those patients in which a documented benefit has been obtained, saving the health care system more dollars. Initial investment in defining the technology was minimal.
Anesthesia, General↗
Redefining cutaneous lymphatic flow: the necessity of preoperative lymphoscintigraphy in the management of malignant melanoma.
OBJECTIVE: The purpose of this study is to emphasize the instrumental role of preoperative lymphoscintigraphy in the surgical treatment of patients with malignant melanoma. SUMMARY BACKGROUND DATA: The efficacy of lymphoscintigraphy is reflected in its ability to reveal cutaneous lymphatic drainage to regional nodal basins that are at risk for melanoma metastases but not necessarily discernable to be at risk through standard historical anatomical guidelines or clinical experience. This preoperative lymphatic mapping technique has contributed greatly to the accuracy and efficiency of staging procedures including sentinel node biopsy and elective lymph node dissection. PATIENTS AND METHODS: After informed consent, a selected series of four patients with primary melanomas located in watershed areas of the body (left neck, right mid-abdomen, right scapula, left back) and two patients with extremity melanomas (right distal forearm and left ankle) underwent pre-operative lymphoscintigraphy to identify all basins for metastases. RESULTS: In all of the cases, lymphatic drainage occurred in an unusual and unexpected basin that could not have been predicted clinically and in three of the cases the resected basins contained positive sentinel nodes. If not for the preoperative lymphoscintigraphy, these nodal basins would not have been resected and metastatic disease would have been left behind. In addition, the staging of the melanoma patient would have been inaccurate. CONCLUSION: If the sentinel node biopsy of elective lymph node dissection (ELND) were based on clinical predictions only, nodes equally at risk for metastatic disease would not have been resected and in some cases, nodal basins not at risk for metastases would have been resected unnecessarily. Without lymphoscintigraphy, the validity and efficacy of the ELND or the sentinel node biopsy for nodal staging is greatly compromised. These six case studies illustrate the difficulty of predicating lymphatic drainage from primary sites located on the head and neck, truck and even the extremities and demonstrate the indispensability of preoperative lymphoscintigraphy in the management of malignant melanoma.
Abdomen↗
Lymphatic mapping and sentinel node biopsy in patients with malignant melanoma.
Intra-operative sentinel lymph node (SLN) mapping and biopsy is a procedure that accurately stages the regional lymph node basin. Defined patterns of lymphatic drainage allow intra-operative determination of the first (sentinel) lymph node in the regional basin, and the absence of metastatic disease in the SLN accurately reflects the absence of melanoma in the remaining regional nodes. The use of a radiocolloid and a handheld gamma probe together with a vital blue dye provides optimal results, and allows for the successful identification of the SLN(s) in over 98 percent of the procedures. Close collaboration between surgeons, nuclear radiologists and pathologists is required to ensure optimal results. Surgical excision of the SLN allows for a more thorough and focused pathological examination of one or two nodes. Examination of serially sectioned SLNs by H&E staining, immunohistochemical staining and perhaps RT-PCR should reduce the number of patients with missed microscopic melanoma in the regional lymph nodes. Recently reported survival data from the Intergroup Melanoma Trial suggest that patients may benefit from identification and removal of regional lymph nodes that contain metastatic melanoma. Furthermore, the survival benefit recently reported in patients with melanoma metastatic to regional nodes prospectively randomized to receive high dose Interferon alfa-2b signals that the surgeons should aggressively examine patients for the presence of occult regional melanoma metastases. Intra-operative SLN mapping and SLN biopsy is a cost-effective procedure that allows accurate identification of regional lymph nodes that contain metastatic melanoma.
Antineoplastic Agents↗
Lymphatic mapping and sentinel node biopsy in the patient with breast cancer.
OBJECTIVES: To identify the sentinel lymph node(s) (SLN[s]) (the first node[s] draining the primary tumor in the regional lymphatic basin) in patients with invasive breast cancer and to test the hypothesis that the histologic characteristics of the SLN predict the histologic characteristics of the remaining lymph nodes in the axilla. DESIGN: A prospective trial. PARTICIPANTS: Sixty-two patients with newly diagnosed invasive breast cancers. INTERVENTION: Patients underwent intraoperative lymphatic mapping using a combination of a vital blue dye and filtered technetium-labeled sulfur colloid. The SLN was identified and removed, followed by a definitive cancer operation, including a complete axillary node dissection. MAIN OUTCOME MEASURE: The metastatic distribution in the axilla was determined in patients with occult nodal disease. RESULTS: The SLN was successfully identified in 57 (92%) of 62 patients using the 2 lymphatic mapping procedures. After localization, 18 patients (32%) were found to have metastatic disease, and the SLN tested positive in all 18 patients. There were no "skip" metastases, defined as an SLN that tested negative with higher nodes that tested positive. In 12 (67%) of 18 patients with metastatic disease, the SLN was the only site of disease. The metastatic distribution significantly favored SLN involvement. Among subjects with discordant nodal involvement, the probability of observing the distribution of SLN involvement by chance is very small (P<.001). CONCLUSIONS: This study confirms that lymphatic mapping is technically possible in the patient with breast cancer and that the histologic characteristics of the SLN probably reflect the histologic characteristics of the rest of the axillary lymph nodes. The procedure also allows the pathologist to focus the histologic examination on 1 or 2 nodes, potentially increasing the yield of positive dissections and the accuracy of staging.
Axilla↗
Evaluation of new putative tumor markers for melanoma.
BACKGROUND: The early diagnosis of recurrent melanoma can contribute to better outcome if the disease can be surgically resected or if the metastases are responsive to systemic therapies. Lipid-associated sialic acid (LASA-P) and the S-100 protein (S-100) were evaluated as tumor markers for melanoma with the goal of early detection of recurrence. METHODS: Sixty-seven patients were identified who had levels of S-100 and LASA-P drawn during their clinical course. A multivariate regression analysis was performed to determine the significance of the serum markers in relation to other prognostic factors for melanoma. RESULTS: After a median follow-up of 30 months, 58 patients had recurrences, and 49 patients died of disease. LASA-P elevation was not associated with the time to recurrence (p = 0.2176) or survival (p = 0.2507). S-100 positivity was a significant predictor of recurrence (p < 0.0001) and survival (p = 0.0059). The median time to recurrence for S-100-positive and S-100-negative patients was 7.6 and 33.8 months, respectively. The median survival time was 59.2 months for S-100-negative patients and 29.6 months for patients positive for S-100. CONCLUSIONS: Serum S-100 shows significant correlations to both time to recurrence and survival and could be useful in the clinical detection of malignant melanoma.
Adult↗
Reversible surface aggregation in pore formation by pardaxin.
The mechanism of leakage induced by surface active peptides is not yet fully understood. To gain insight into the molecular events underlying this process, the leakage induced by the peptide pardaxin from phosphatidylcholine/ phosphatidylserine/cholesterol large unilamellar vesicles was studied by monitoring the rate and extent of dye release and by theoretical modeling. The leakage occurred by an all-or-none mechanism: vesicles either leaked or retained all of their contents. We further developed a mathematical model that includes the assumption that certain peptides become incorporated into the vesicle bilayer and aggregate to form a pore. The current experimental results can be explained by the model only if the surface aggregation of the peptide is reversible. Considering this reversibility, the model can explain the final extents of calcein leakage for lipid/peptide ratios of > 2000:1 to 25:1 by assuming that only a fraction of the bound peptide forms pores consisting of M = 6 +/- 3 peptides. Interestingly, less leakage occurred at 43 degrees C, than at 30 degrees C, although peptide partitioning into the bilayer was enhanced upon elevation of the temperature. We deduced that the increased leakage at 30 degrees C was due to an increase in the extent of reversible surface aggregation at the lower temperature. Experiments employing fluorescein-labeled pardaxin demonstrated reversible aggregation of the peptide in suspension and within the membrane, and exchange of the peptide between liposomes. In summary, our experimental and theoretical results support reversible surface aggregation as the mechanism of pore formation by pardaxin.
Amino Acid Sequence↗
Intraoperative radio-lympho-scintigraphy improves sentinel lymph node identification for patients with melanoma.
BACKGROUND: The sentinel lymph node (SLN), the first node draining the primary tumor site, has been shown to reflect the histologic features of the remainder of the lymphatic basin in patients with melanoma. Intraoperative localization of the SLN, first proposed by Morton and colleagues, has been accomplished with the use of a vital blue dye mapping technique. Technical difficulties resulting in unsuccessful explorations have occurred in up to 20% of the dissections. OBJECTIVES: The authors aimed to define the SLN using gamma detection probe mapping and to determine whether intraoperative radiolymphoscintigraphy using technetium sulfur colloid and a hand-held gamma-detecting probe could be used to improve detection of all SLNs for patients with melanoma. METHODS: To ensure that all initial nodes draining the primary site were removed at the time of selective lymphadenectomy, the authors used intraoperative radiolymphoscintigraphy to confirm the location of the SLN, which was determined initially with the preoperative lymphoscintigram and the intraoperative vital blue dye injection. PATIENT POPULATION: The patient population consisted of 106 consecutive patients who presented with cutaneous melanomas larger than 0.75 mm in all primary site locations. RESULTS: The preoperative lymphoscintigram revealed that 22 patients had more than one lymphatic basin sampled. Two hundred SLNs and 142 neighboring non-SLNs were harvested from 129 basins in 106 patients. After the skin incision was made, the mean ratio of hot spot to background activity was 8.5:1. The mean ratio of ex vivo SLN-to-non-SLN activity for 72 patients who had SLNs harvested was 135.6:1. When correlated with the vital blue dye mapping, 139 of 200 (69.5%) SLNs demonstrated blue dye staining, whereas 167 of 200 (83.5%) SLNs were hot according to radioisotope localization. With the use of both intraoperative mapping techniques, identification of the SLN was possible for 124 of the 129 (96%) basins sampled. Micrometastases were identified in SLNs of 16 of the 106 (15%) patients by routine histologic analysis. CONCLUSION: The use of intraoperative radiolymphoscintigraphy can improve the identification of all SLNs during selective lymphadenectomy.
Adolescent↗
The use of intraoperative radiolymphoscintigraphy for sentinel node biopsy in patients with malignant melanoma.
BACKGROUND: Selective lymphadenectomy or "sentinel node" biopsy has been introduced recently by Morton and colleagues (Arch Surg 1992;127:392-9) to stage patients with intermediate and thick malignant melanomas. It has proven to be an effective way to identify nodal basins at risk for metastasis without the morbidity of a complete lymph node dissection. The majority of biopsies can be performed under local anesthesia with small incisions, but technical difficulties occasionally result in unsuccessful explorations. Identification of the sentinel node can be enhanced by a intraoperative radiolymphoscintigraphy, a technique introduced Alex and Krag (Surg Oncol 1993;137-43) that uses radiolabeled sulfur colloid and a hand-held gamma probe. OBJECTIVE: We used intraoperative radiolymphoscintigraphy in conjunction with 1% lymphazurin blue dye to define the sentinel node(s) in 148 patients with greater than 0.76 mm in thickness or Clark level IV melanomas. Sentinel lymph nodes were isolated, harvested, and examined using conventional histopathology, and immunohistochemistry for S-100 and HMB-45 antibodies. RESULTS: The overall success rate of sentinel lymph node localization was 97% using a combination of the two techniques. Twenty-one (14%) patients had micrometastasis, and 17 of these subsequently underwent complete lymph node dissection. A total of 220 of 275 (80%) sentinel nodes harvested were radioactive or "hot" compared with 165 of 275 (60%) with the blue dye alone. Four of the patients with micrometastasis had sentinel nodes positive by gamma probe, but negative by blue dye mapping techniques. CONCLUSION: Our results suggest that intraoperative radiolymphoscintigraphy using a hand-held gamma detecting probe improves the identification of sentinel lymph nodes during selective lymphadenectomy. This may reduce the number of "unsuccessful explorations" using the vital blue dye technique for lymphatic mapping, and appeal to a greater variety of surgeons, including dermatologic surgeons.
Biopsy↗
The tumor biology of melanoma nodal metastases.
Approximately 20 per cent of melanomas greater than 0.76 mm in thickness will metastasize to the regional lymph nodes if treated with wide local excision alone (WLE). Elective lymph node dissection (ELND) is associated with significant morbidity, which includes lymphedema, wound complications, and paresthesias of the extremity. An alternative operative approach uses selective lymphadenectomy with the identification of the sentinel node, defined as the first node in the lymphatic basin that drains the primary cutaneous site. This study consisted of 132 patients with melanomas greater than 0.76 mm. One hundred nine patients (83%) had histologic negative sentinel nodes, and 23 patients (17%) had one or more sentinel nodes positive for disease. In patients with metastatic disease, 30/35 (86%) sentinel nodes were positive, and 25/357 (7%) nonsentinel nodes were positive (P < 0.001). In 18 patients (78%) of the 23 patients with metastatic disease, the sentinel node was the only node positive, strongly suggesting that there is an orderly progression of metastases. Two patients developed metastatic nodal disease after removal of a negative sentinel node (false negative rate = 1.5). The mean follow-up was 1 year. Sentinel node histology reflects the histology of the remainder of the nodes in the lymphatic basin and "skip" metastases, defined as a negative sentinel node but positive nodes higher in the regional chain positive for metastases or an axillary recurrence after a negative sentinel node biopsy, are rare for malignant melanoma. Harvesting the sentinel node in patients with intermediate or greater thickness melanoma will, therefore, identify a subset of patients with metastatic disease who have the most to benefit from a complete node dissection. This surgical approach allows for complete pathological staging and therapeutic management of patients while significantly reducing expense and overall morbidity.
Adolescent↗
A synthetic peptide corresponding to a conserved heptad repeat domain is a potent inhibitor of Sendai virus-cell fusion: an emerging similarity with functional domains of other viruses.
A series of peptides derived from three domains within the fusion protein of Sendai virus was synthesized and examined for their potential to inhibit the fusion of the virus with human red blood cells. These domains include the 'fusion peptide' and two heptad repeats, one adjacent to the fusion peptide (SV-163) and the other to the transmembrane domain (SV-473). Of all the peptides tested, only SV-473 was highly inhibitive. Using fluorescently-labelled peptides, the mechanism through which the SV-473 peptide inhibits the haemolytic activity of the virus was investigated. The results suggest that interactions of the active peptide with virion elements and lipid membranes are involved. Since it has recently been found that synthetic peptides corresponding to putative coiled-coil domains of the human immunodeficiency virus (HIV) type 1 transmembrane protein gp41 are potent inhibitors of HIV, we discuss the general property of virus-derived coiled-coil peptides as inhibitors of viral infection.
Amino Acid Sequence↗
Accurate Nodal Staging of Malignant Melanoma.
The incidence of malignant melanoma is increasing at a faster pace than that of any other cancer in the United States. It is estimated that people born in the year 2000 will have a 1:75 risk of developing melanoma sometime during his or her lifetime. Stimulated by novel lymphatic mapping techniques, the surgical care of the melanoma patient is evolving toward more conservative resections that can provide the same staging information but without the added morbidity of more radical surgeries. This approach promises to yield positive results in the age of health care reform, outcome measurements, and cost:benefit considerations.
Journal Article↗
The identification and mapping of melanoma regional nodal metastases: minimally invasive surgery for the diagnosis of nodal metastases.
The most controversial part of melanoma surgical care involves the role of elective lymph node dissection (ELND). Whereas proponents cite retrospective studies demonstrating the ability to control regional metastases and more accurate staging, opponents cite the unnecessary morbidity of a complete node dissection for the majority of patients. The technology of sentinel node mapping and selective lymphadenectomy, defined as the identification and removal of the first node into which the primary melanoma drains, may revolutionize melanoma care. If the sentinel node is negative, then theoretically the remainder of the nodes should also be negative (no "skip" metastases), and a complete lymphadenectomy would not be required to control occult nodal disease. The location of the sentinel node may be variable in the lymphatic basin. Ideally, the surgeon needs a map of the position of the sentinel node in reference to the other nodes in the basin in order to do the procedure under local anesthesia with small incisions. In this way, patients are subjected to minimal morbidity and the procedure can be performed as an out-patient. Twenty-nine patients with clinically negative nodes and melanomas greater than 0.76 mm in thickness were judged to be candidates for ELND. Preoperative lymphoscintigraphy in two planes was used to mark the sentinel node, and the patients were taken to the operating room for intraoperative lymphatic mapping and sentinel node biopsy followed by complete dissection.(ABSTRACT TRUNCATED AT 250 WORDS)
Humans↗
Capacities of pardaxin analogues to induce fusion and leakage of negatively charged phospholipid vesicles are not necessarily correlated.
Peptide-induced vesicle fusion is frequently accompanied by leakage of vesicle contents. To determine the correlation between these two processes, we studied the interaction of the amphiphilic peptide pardaxin and two of its analogues with large unilamellar vesicles composed of phosphatidylserine. A pardaxin analogue with a positive charge at both its C- and N-termini induced significantly more fusion but less leakage than the parent peptide. Fusion and leakage were studied with large unilamellar vesicles of two sizes. Aggregation of vesicles was found to be the rate-limiting step in the overall fusion process induced by the peptides. The rates and extents of fusion, determined by membrane mixing, increase in vesicle size, and mixing of aqueous contents, were significantly enhanced in the presence of 2.5-5 mM Mg2+ which promoted vesicle aggregation. Model calculations showed that increasing the peptide to lipid ratio resulted in a parallel increase in the fusion rate constants. As the average vesicle diameter was increased, the extent of leakage was enhanced, as more peptide molecules were bound to each vesicle. The mode of leakage induced by the peptides was also investigated. Our results suggest that the potency of a peptide to induce vesicle fusion is not necessarily associated with its capacity to induce leakage, and we further elucidate how these capacities depend on the structures of the peptides.
Amino Acid Sequence↗
Interaction of fluorescently labeled analogues of the amino-terminal fusion peptide of Sendai virus with phospholipid membranes.
A peptide representing the NH2-terminal (33 amino acid residues) of the fusion protein (F) of Sendai virus, as well as its Gly12-->Ala12 mutant, were synthesized, fluorescently labeled, and spectroscopically and functionally characterized. Peptide-induced vesicle fusion was demonstrated by a combination of increased visible absorbance, lipid mixing assay, and electron microscopy. Both peptides, with the mutant peptide being significantly more potent, were shown to induce membrane fusion and bilayer perturbation of negatively charged phospholipid vesicles. These results are consistent with a previous study that showed that a similar mutation in the homologous NH2-terminal segment of simian virus 5 greatly enhanced syncytium formation (Horvath, C. M., and Lamb, R. A. (1992) J. Virol. 66, 2443-2455). Circular dichroism spectroscopy revealed similar high alpha-helical contents of both peptides in methanol and in trifluoroethanol. Using fluorescently labeled peptide analogues we found that (i) the peptides' membrane partition coefficients are in the range of 10(5) M-1; (ii) the NH2 terminus of the wild-type peptide is located within the lipid bilayer, whereas that of the variant peptide lies on the surface; and (iii) both peptides tend to self-associate in their membrane-bound state. The results support a model in which an alpha-helical secondary structure and self-aggregation of peptides are necessary conditions for membrane fusion. The observed differences in the peptides' fusogenic abilities are hypothesized to result from differences in the peptides' degree of penetration into the membrane, induction of membrane destabilization, and ability to cause vesicles to aggregate. The data support Sendai virus-cell fusion models in which the fusion peptide plays a crucial role in fusion induction by destabilizing the bilayer and by triggering the association of viral fusion protein molecules.
Amino Acid Sequence↗
Dp71, the nonmuscle product of the Duchenne muscular dystrophy gene is associated with the cell membrane.
The 70.8 kDa protein, Dp71, is the major Duchenne muscular dystrophy (DMD) gene product in many nonmuscle tissues including the brain. Dp71 shares most of the C-terminal and cysteine-rich domains with the dystrophins but lacks the entire large rod shaped domain of spectrin-like repeats, and the N-terminal actin-binding domain. The function of Dp71 is unknown. Using subcellular fractionation and immunostaining we show that Dp71 is associated with the plasma membrane. Dp71 is also associated with the plasma membrane in mdx myogenic cells transfected with a vector expressing Dp71.
Animals↗
Somatosensory cortical plasticity in adult humans revealed by magnetoencephalography.
Microelectrode recordings in adult mammals have clearly demonstrated that somatosensory cortical maps reorganize following peripheral nerve injuries and functional modifications; however, such reorganization has never been directly demonstrated in humans. Using magnetoencephalography, we have been able to demonstrate the somatotopic organization of the hand area in normal humans with high spatial precision. Somatosensory cortical plasticity was detected in two adults who were studied before and after surgical separation of webbed fingers (syndactyly). The presurgical maps displayed shrunken and nonsomatotopic hand representations. Within weeks following surgery, cortical reorganization occurring over distances of 3-9 mm was evident, correlating with the new functional status of their separated digits. In contrast, no modification of the somatosensory map was observed months following transfer of a neurovascular skin island flap for sensory reconstruction of the thumb in two subjects in whom sensory transfer failed to occur.
Adult↗