Consistency of dominance rank order: a comparison of David's Scores with I&SI and Bayesian methods in macaques.

In nonhuman primate social groups, dominance ranks are usually assigned to individuals based on outcomes of dyadic agonistic encounters. Multiple approaches have been used, but currently there is no consensus. One approach, David's Scores (DS), offers dual advantages of yielding cardinal scores that may in turn be used to compute hierarchical steepness. Here we correlate rank orders yielded by DS with those yielded by both the traditionally used I&SI approach and the recently proposed parametric Bayesian approach. We use six datasets for female macaques (three despotic and three tolerant groups), and 90 artificially generated datasets modeling macaque groups. We also use the artificial datasets to determine the impact of three characteristics (group size, interaction frequency, and directional asymmetry of aggression) on the magnitude of correlation coefficients, and assess the relative utility of two indices used to compute DS: Dij versus Pij. DS-based rank orders were strongly positively correlated with those yielded by the other two approaches for five out of the six macaque datasets, and for the majority of artificial datasets. Magnitudes of correlation coefficients were unrelated to group size or interaction frequency, but increased with directional asymmetry, suggesting methodological inconsistencies were more likely when dyads had more frequent reversals in directions of aggression. Finally, rank orders calculated using the Dij and Pij indices were similarly consistent with orders from other methods. We conclude that DS offers consistent estimates of rank orders, except perhaps in groups with very low levels of aggression asymmetry. In such "tolerant" groups, we suggest that the relatively greater methodological variability in rank orders may reflect behavioral characteristics of tolerant groups rather than computational inconsistencies between methods. We hypothesize that this quality may be quantified using posterior probability scores of Bayesian rank orders and may also index macaque social styles.

Using biological markets principles to examine patterns of grooming exchange in Macaca thibetana.

Biological markets principles offer testable hypotheses to explain variation in grooming exchange patterns among nonhuman primates. They predict that when within-group contest competition (WGC) is high and dominance hierarchies steep, grooming interchange with other "commodity" behaviors (such as agonistic support) should prevail. In contrast, when WGC is low and gradients shallow, market theory predicts that grooming reciprocity should prevail. We tested these predictions in a wild, provisioned Tibetan macaque (Macaca thibetana) group across six time periods during which the group had been subjected to varying degrees of range restriction. Data on female-female aggression, grooming, and support were collected using all-occurrences and focal animal sampling techniques, and analyzed using ANCOVA methods and correlation analyses. We found that hierarchical steepness varied significantly across periods, but did not correlate with two indirect indicators of WGC (group size and range restriction) in predicted directions. Contrary to expectations, we found a negative correlation between steepness and group size, perhaps because the responses of group members to external risks (i.e. prolonged and unavoidable exposure to humans) may have overshadowed the effects of WGC. As predicted, grooming reciprocity was significant in each period and negatively correlated with steepness, even after we controlled group size, kinship, rank differences, and proximity. In contrast, there was no evidence for grooming interchange with agonistic support or for a positive relationship between interchange and steepness. We hypothesize that stressful conditions and/or the presence of stable hierarchies during each period may have led to a greater market demand for grooming than support. We suggest that future studies testing these predictions consider more direct measures of WGC and commodities in addition to support, such as feeding tolerance and access to infants.

A platelet alpha granule membrane protein that is associated with the plasma membrane after activation. Characterization and subcellular localization of platelet activation-dependent granule-external membrane protein.

We have identified and purified a platelet integral membrane protein (140,000 mol wt), using the KC4 monoclonal antibody specific for activated platelets, that is internal in resting platelets but exposed on activated platelets (Hsu-Lin S.-C., C.L. Berman, B.C. Furie, D. August, and B. Furie, 1984, J. Biol. Chem. 259: 9121-9126.). The expression of the protein on the platelet surface is secretion-dependent. This protein has been named platelet activation-dependent granule-external membrane (PADGEM) protein. PADGEM protein is distinct from the surface glycoproteins of resting platelets, but identical to the S12 antigen, GMP-140. Using immunofluorescent staining, resting platelets failed to stain for PADGEM protein with the KC4 antibody, but after permeabilization showed a punctate staining of the cell interior. Thrombin-stimulated intact platelets stained with a peripheral rim pattern thus demonstrating the translocation of PADGEM protein from an internal location to the cell surface. PADGEM protein expression on the platelet surface at varying thrombin concentrations correlated with alpha granule release, as measured by the secretion of platelet factor 4. Further evidence for an alpha granule localization of PADGEM protein was provided by nitrogen cavitation of resting platelets followed by metrizamide density gradient centrifugation; PADGEM protein codistributed with platelet factor 4. Using immunoelectron microscopy, the protein was localized to the alpha granule in frozen ultrathin sections of resting platelets labeled using rabbit anti-PADGEM protein antibodies, whereas in thrombin-activated platelets, the plasma membrane was labeled. These studies indicate that PADGEM protein is a component of the alpha granule membrane of resting platelets and is incorporated into the plasma membrane upon activation and secretion.

The effects of finasteride (Proscar) on hair growth, hair cycle stage, and serum testosterone and dihydrotestosterone in adult male and female stumptail macaques (Macaca arctoides).

Finasteride, a 5 alpha-reductase inhibitor, was administered orally (1 mg/kg.day) for 6 months to six male and five female stumptail macaques. Vehicle was given to five male and five female animals over the same period of time. Hair weights in a defined 1-in.2 area of frontal scalp were measured periodically every 1-2 months, and serum was collected for measurement of testosterone and dihydrotestosterone. In addition, scalp biopsies were taken before and 6 months after treatment to evaluate the micromorphometry of hair follicles. Results showed that both male and female serum dihydrotestosterone levels were significantly reduced (60-70%) by finasteride treatment. Both males and females showed statistically significant increases in mean hair weight over the treatment period compared to controls (P = 0.034). In addition, there was a statistically significant increase in mean follicle length (measured histologically in scalp biopsies) compared to baseline in the finasteride-treated animals (P = 0.028). These data show that an inhibition of 5 alpha-reductase in the stumptail macaque can reverse the balding seen with age in both the male and female animals.

Screening Childhood Cancer Survivors for Breast Cancer.

The development of second primary solid tumors, especially breast neoplasms, is increased among patients who have survived childhood or adolescent malignancies. With the increased long-term survival of patients with pediatric cancer, questions regarding breast cancer screening in this group have been raised. At this time, there are no established guidelines for breast cancer surveillance in this high-risk population. The objective of this review is to summarize the incidence, list additional risk factors for the development of breast cancer, and discuss the benefits of early detection of second primary breast cancers in pediatric cancer survivors. We have devised an algorithm for breast cancer screening in survivors of childhood malignancy. Implications of treatment with radiation and chemotherapy and the influence on prognosis of genetic abnormalities such as p53 mutations are debated.

Pathologic examination of the sentinel lymph node in malignant melanoma.

Sentinel lymphadenectomy is gaining increasing popularity in the staging and treatment of patients with melanoma at risk for metastases. As a result, pathologists are encountering these specimens more frequently in their daily practice. The pathologic status of the sentinel lymph node is pivotal to the patient's care because it provides staging information that dictates the need for further therapy, and therefore detailed pathologic assessment is warranted. A standard pathology protocol to handle these nodes has been developed at our institution and involves complete submission of all tissue with routine use of immunohistochemical staining for S-100 protein. By using this protocol, 838 sentinel lymph nodes from 357 patients have been examined, and metastases were found in 16% of patients. Although the metastasis was clearly seen on sections stained with hematoxylin and eosin in 55% of the positive patients, the immunostain showed metastatic disease not appreciable on initial hematoxylin and eosin screening in an additional 28 lymph nodes (45% of node-positive patients). Intraoperative touch preparation cytology may be used as an adjunct technique in sentinel lymph nodes grossly suspicious for metastatic disease. This technique has been performed on 23 sentinel lymph nodes, with no false positives and an overall sensitivity of 62%. The thorough pathologic evaluation of sentinel lymph nodes in patients with malignant melanoma requires complete submission of all tissue, routine use of immunohistochemistry, and touch preparation cytology in selected cases.

Azasteroids as inhibitors of rat prostatic 5 alpha-reductase.

A series of A-ring heterocyclic steroids has been prepared and tested for inhibition of rat prostatic steroid 5 alpha-reductase in vitro. Strikingly high inhibitory activity was found with a group of 17 beta-substituted 4-methyl-4-aza-5 alpha-androstan-3-ones. These compounds were prepared from 3-keto-delta 4-precursors by oxidative (O3 or NaIO4-KMnO4) A-ring cleavage followed, in turn, by ring closure with an amine and hydrogenation over platinum catalyst. Other A-ring azasteroids were made by Beckmann rearrangement of oximes of 2-oxo-A-nor, 3-oxo- and 4-oxo-5 alpha-androstanes. An A-nor-2-oxo-3-azasteroid was prepared by oxidative decarbonylation of a precursor 2,3-dioxo-4-azasteroid with m-chloroperbenzoic acid. A-ring modifications of the 4-azasteroids included delta 1-unsaturation, 2- and 4-substituents, and 3-carbonyl replacements. Side chains at the 17-position were varied with an emphasis on carboxylate derivatives (salts, esters, and amides).

Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding.

A series of steroids, primarily 4-azasteroids, were prepared and tested in vitro as inhibitors of human and rat prostatic 5 alpha-reductase and of binding of dihydrotestosterone to the rat androgen receptor. The primary structural modifications were changes of the A ring and of moieties attached at the C-17 position of the steroid nucleus. New A-ring modifications included the 4-cyano-3-oxo-delta 4 system in the carbocyclic series and 1 alpha-CN, 1 alpha-CH3, 1 alpha,2 alpha-CH2, 2 beta-F, 2-aza, 2-oxa, and A-homo changes in the 3-oxo-4-aza series. In addition, 4-azasteroids with a D-homo ring or methyl substitution at C-7 (alpha and beta) or C-16 (alpha and beta) were prepared. The majority of the C-17 substituents were prepared from reactive intermediates derived from the 17 beta-COOH. Enhanced 5 alpha-reductase inhibition in both the human and rat enzyme assays is seen with 4-CN substitution on 3-oxo-delta 4 steroids and with a C-17 side chain incorporating a lipophilically substituted semipolar group on the 4-aza-3-oxo-5 alpha-androstane nucleus. Fewer highly active compounds were found in the human enzyme assay than in the rat assay. Structural requirements for inhibition of the rat androgen receptor are much different from those for inhibition of the enzyme. The 17 beta-OH moiety enhances potency more than any other feature while introduction of double bonds at C-1 or C-5 in the azasteroid gives a small improvement. Azasteroids unsubstituted at the 4-position show greatly diminished receptor activity.

Melanoma lymphoscintigraphy and lymphatic mapping.

Lymphoscintigraphy in melanoma has proven to be a reliable method to identify regional lymph nodes at risk for metastases. The first lymph node to drain a cutaneous lesion, the sentinel lymph node (SLN), is predictive of the metastatic status of the regional lymph node group. Lymphatic mapping allows for the identification of the SLN and for selective lymph node sampling. Selective lymph node sampling is less invasive and because only a small quantity of high-risk tissue is submitted for pathological examination, it allows for a more complete and comprehensive pathological examination, which identifies melanoma with up to 100 times the sensitivity of conventional examinations.

A paternally derived inverted duplication of 7q with evidence of a telomeric deletion.

We report on a de novo constitutional rearrangement involving the long arm of chromosome 7 in a second trimester fetus with the karyotype of 46,XX, inv dup del (7)(pter-q36::q36-q21.2:) pat. Both a large duplication (q21.2-q36) and a small deletion (within q36) were confirmed by FISH studies. DNA analysis on the family showed that the abnormal chromosome was derived from a single paternal homolog. A mechanism is proposed in light of this finding. The phenotype at autopsy was consistent with reported cases of similar duplications in chromosome 7 in that hydrocephalus, a depressed nasal bridge, low set ears, microretrognathia and a short neck were present.

Panic disorder and depression in female alcoholics.

Eight (32%) of 25 alcoholic women on an inpatient detoxification unit met modified DSM-III criteria for panic disorder, 2 (8%) of 25 met criteria for depressive illness, and 7 (28%) of 25 met criteria for both disorders. These findings replicate the findings of other recent studies and lend preliminary support to the self-medication model of alcoholism.

Characteristics of the sentinel lymph node in breast cancer predict further involvement of higher-echelon nodes in the axilla: a study to evaluate the need for complete axillary lymph node dissection.

BACKGROUND: Sentinel lymph node (SLN) biopsy techniques provide accurate nodal staging for breast cancer. In the past, complete lymph node dissection (CLND) (levels 1 and 2) was performed for breast cancer staging, although the therapeutic benefit of this more extensive procedure has remained controversial. HYPOTHESIS: It has been demonstrated that if the axillary SLN has no evidence of micrometastases, the nonsentinel lymph nodes (NSLNs) are unlikely to have metastases. OBJECTIVE: To determine which variables predict the probability of NSLN involvement in patients with primary breast carcinoma and SLN metastases. METHODS: An analysis of 101 women with SLN metastases and subsequent CLND was performed. Variables included size of the primary tumor, tumor volume in the SLN, staining techniques used to initially identify the micrometastases (cytokeratin immunohistochemical vs hematoxylin-eosin), number of SLNs harvested, and number of NSLNs involved with the metastases. Tumor size was determined by the invasive component of the primary tumor. Patients with ductal carcinoma in situ who were upstaged with cytokeratin staining were considered to have stage T1a tumors. RESULTS: Sentinel lymph node micrometastases (<2 mm) detected initially by cytokeratin staining were associated with a 7.6% (2/26) incidence of positive CLND compared with a 25% (5/20) incidence when micrometastases were detected initially by routine hematoxylin-eosin staining. Sentinel lymph node micrometastases, regardless of identification technique, inferred a risk of 15.2% (7/46) for NSLN involvement. As the volume of tumor in the SLN increased (ie, <2 mm, >2 mm, grossly visible tumor), so did the risk of NSLN metastases (P<.001). CONCLUSIONS: Our study demonstrated that patients with micrometastases detected initially by cytokeratin staining had low-volume disease in the SLN with a small chance of having metastases in higher-echelon nodes in the regional basin other than the SLN. Characteristics of the SLN can provide information to determine the need for a complete axillary CLND. Complete lymph node dissection may not be necessary in patients with micrometastases detected initially by cytokeratin staining since the disease is confined to the SLN 92.4% of the time. However, the therapeutic value of CLND in breast cancer remains to be determined by further investigation.

Lymphatic mapping in breast cancer.

The most accurate predictor of survival in breast cancer is the presence or absence of lymph node metastases. Lymphatic mapping with sentinel node biopsy is a new technique that provides more accurate nodal staging compared with routine histology for women with breast cancer, but without the morbidity of a complete lymph node dissection. Sentinel lymph node (SLN) biopsy is a more conservative approach to the axilla that requires close collaboration from the surgical team, nuclear medicine, and pathology. National trials are investigating the clinical relevance of the upstaging that occurs with a more intense examination of the SLN. As is the case with breast preservation as a viable alternative to mastectomy for the definitive treatment of the primary node, selective lymphadenectomy has the ability to decrease morbidity without compromising patient care.

The role of sentinel lymph node biopsy in breast cancer.

BACKGROUND: Lymphatic mapping and sentinel lymph node (SLN) biopsy are new techniques that accurately provide crucial staging information while inflicting far less morbidity than complete axillary dissection. As these techniques continue to gain acceptance, issues such as adequacy of training, certification, and outcomes measures become increasingly important. The purpose of this paper is to report the initial lymphatic mapping experience at the H Lee Moffitt Cancer Center and Research Institute and to provide a detailed description of the technical aspects of lymphatic mapping. STUDY DESIGN: From April 1994 to April 1998, 700 patients with newly diagnosed breast cancers underwent an IRB-approved prospective trial of lymphatic mapping using a combination of Lymphazurin (USSC, Norwalk, CT) blue dye and filtered technetium 99m-labeled sulfur-colloid. Failure of the procedure was defined as the inability to detect an SLN by either radiocolloid uptake within a lymph node by the gamma probe or the inability to visualize blue staining of a lymph node. Learning curves were then generated as the failure rate versus serial number of patients for each of the 5 surgeons involved in this study. RESULTS: The SLN was identified in 665 of 700 patients (95.0%). A total of 1,348 SLNs were successfully removed, of which 238 (17.7%) were positive for metastatic disease in 176 of 665 patients (26.5%). In patients who underwent a complete axillary dissection after SLN biopsy, SLNs were identified in 173 of 186 patients (93.0%). Of the 173 patients, 53 patients (30.6%) had positive SLNs and 120 patients (69.4%) had negative SLNs. In the 120 patients with negative SLNs, one patient was found to have disease on complete dissection, for a false-negative rate of 0.83% (95% CI: 0.02%, 4.6%). A learning curve representing the mean of the 5 surgeons' experience indicates that on average 23 patients are required by an individual surgeon to achieve a 90% +/- 4.5% success rate and 53 patients are required to achieve a 95% +/- 2.3% success rate (p = 0.05). CONCLUSIONS: These data validate lymphatic mapping and SLN biopsy as indispensable tools in the surgical treatment of breast cancer. With adequate multidisciplinary training, these techniques can be readily implemented at institutions treating breast cancer.

The effects of postinjection massage on the sensitivity of lymphatic mapping in breast cancer.

BACKGROUND: The technique of lymphatic mapping and sentinel lymph node (SLN) biopsy is rapidly becoming the preferred method of staging the axilla of the breast cancer patient. This report describes the impact of postinjection massage on the sensitivity of this surgical technique. STUDY DESIGN: Lymphatic mapping at the H Lee Moffitt Cancer Center is performed using a combination of isosulfan blue dye and Tc99m labeled sulfur colloid. Data describing the rate of SLN identification and the node characteristics from 594 consecutive patients were calculated. Patients who received a 5-minute massage after injection of blue dye and radiocolloid were compared with a control group in which the patients did not receive a postinjection massage. RESULTS: When compared with controls, the proportion of patients who had their SLN identified using blue dye after massage increased from 73.0% to 88.3%, and the proportion of patients who had their SLN identified using radiocolloid after massage increased from 81.7% to 91.3%. The overall rate of SLN identification increased from 93.5% to 97.8%. The proportion of nodes that were stained blue among those removed increased from 73.4% to 79.7% after massage. CONCLUSIONS: As experience increases with this new procedure, the surgical technique of lymphatic mapping continues to evolve. The addition of a postinjection massage significantly improves the uptake of blue dye by SLNs and may also aid in the accumulation of radioactivity in the SLNs, further increasing the sensitivity of this procedure.

Lymphatic Mapping for Melanoma: Long-term Results of Regional Nodal Sampling With Radioguided Surgery.

BACKGROUND: Lymphatic mapping and sentinel lymph node (SLN) biopsy are new techniques used in the surgical treatment of patients with malignant melanoma. These procedures have the potential to change the surgical treatment of the disease to provide a more rational approach to adjuvant therapy. METHODS: A prospective database of melanoma patients undergoing lymphatic mapping and SLN biopsy was reviewed to identify prognostic factors for overall and disease-free survival in this patient population. RESULTS: Five-year overall and disease-free survival was 92.3% and 79.0%, with a median follow-up of 17 months. The number of histologically positive SLNs was the most powerful predictor of overall and disease-free survival. Patients with no histologically positive SLNs had a five-year overall and disease-free survival of 97.9% and 93.3%, respectively. Tumor ulceration and Clark level greater than or equal to III were the significant prognostic factors for survival. CONCLUSIONS: The use of lymphatic mapping and SLN biopsy effectively stages patients with primary cutaneous melanoma. Additionally, the presence of histologically positive SLNs is the most powerful indicator of overall and disease-free survival for these patients.

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.

The Role of Selective Lymphadenectomy in Breast Cancer.

BACKGROUND: Axillary node dissection is considered a standard staging procedure in patients with breast cancer. The procedure is associated with significant morbidity and provides pathologists with many lymph nodes to evaluate. METHODS: A total of 174 women participated in a trial that included preoperative lymphoscintigraphy and intraoperative lymphatic mapping using a combination of a vital blue dye and radiocolloid mapping. RESULTS: The intraoperative lymphatic mapping correctly identified a sentinel lymph node (SLN) in 160 (92%) of 174 patients. One skip metastasis (0.7%) occurred in 136 women who had a subsequent complete node dissection. CONCLUSIONS: Lymphatic mapping and SLN biopsy using a combination of mapping techniques provide accurate nodal staging for women with breast cancer. With this technique, approximately 70% to 80% of women with no axillary metastases could be spared the morbidity of a complete node dissection.