Influence of estrogen administration on tumor characteristics and survival in women with cutaneous melanoma.

A prospective study on 289 women with clinical stage I cutaneous melanoma was done to determine the relationship between estrogen administration, tumor characteristics, and survival. Eighty-two women took oral contraceptives (OC) and 44 took menopausal estrogens (MPE) prior to the diagnosis of melanoma. Users of OC presented with thinner primary tumors than nonusers of OC (P less than .01). A similar trend was observed in users of MPE. Women who used OC in the year prior to the diagnosis of melanoma had statistically thinner tumors than those who had discontinued use of OC more than 1 year prior to diagnosis (P less than .025). A statistically significant preponderance of truncal lesions was observed among users of OC (P less than .01). Other tumor characteristics were unaltered by estrogen administration. Duration of use and time in relation to diagnosis of melanoma did not affect survival. Women who took hormones had slightly better 5- and 9-year survival rates than nonusers. These results suggest that prior estrogen use and, particularly, use of OC in women developing melanoma have no deleterious effect.

Assessment of homology with the helical mimicry algorithm.

Homologies based on structural motifs characterize conserved structures and mechanisms of maintaining function. An algorithm was developed to quantitate homology among segments of two proteins based upon structural characteristics of an amphipathic alpha-helix. This helical mimicry algorithm scored homology among sequences of two proteins in terms of: (i) presence of Leu, Ile, Val, Phe, or Met in a longitudinal, hydrophobic strip-of-helix at positions n, n + 4, n + 7, n + 11, etc. in the primary sequence, (ii) identity or chemical similarity of amino acids at intervening positions and (iii) exchanges of amino acids from positions n to n - 1, n + 3, n + 4, n + 1, n - 3, n - 4 around n (on the surface of a putative helix). While such exchanges of amino acids on the surfaces of homologous helices may conserve function, they did not maintain specific interactions of those residues with apposing groups.

Prognosis of clinical stage I melanoma patients with positive elective regional node dissection.

We tested 12 clinical and histologic variables to see which ones best predicted death from melanoma in 66 patients with positive elective regional node dissections (clinical stage I, pathologic stage II [CSI, PSII]). Despite the presence of lymph node metastases, not all patients had poor prognoses. Patients with tumors less than or equal to 3.5 mm and a percentage of positive nodes less than or equal to 20% had a 7-year survival rate of 66%. Within this low-risk group the subset with primary lesions on the trunk or extremities (except hands and feet) had a 7-year survival rate of 76%. This compares with poor 7-year survivals of 29% and 30% observed in other defined high-risk groups. Our results confirm and extend earlier observations concerning the prognoses of CSI, PSII melanoma patients and are relevant to any ongoing and future studies concerning elective regional node dissection (ERND) or adjuvant therapy trials in melanoma.

Lentigo maligna melanoma has no better prognosis than other types of melanoma.

We studied 48 patients with lentigo maligna melanoma (LMM) and compared the clinical stage I patients with non-LMM melanoma patients (matched by site and thickness) to see if prognosis differed. There was no significant difference in mortality from melanoma between the two groups (P = .68) after a mean follow-up time of five years (67.5 months for LMM, 60.5 months for non-LMM). In addition, a Cox multivariate analysis of the entire matched group showed that only thickness was significantly associated with death from melanoma (P = .0007) while histology (LMM v non-LMM) did not make a significant contribution (P = .61). Our data suggest that after accounting for primary tumor thickness and site, LMM and non-LMM have the same prognosis and biologic behavior, in contrast to the widely held belief that LMM has a better prognosis than other forms of melanoma.

Comparison of three related methods to select T cell-presented sequences of protein antigens.

A comparison of three methods to predict T cell-presented sequences within antigenic proteins led to the view that recurrent hydrophobic residues might nucleate excised peptides as alpha-helices against hydrophobic surfaces. Such helices could be protease-protected structures on their way to desetope binding. The compared methods were: the amphipathicity algorithm of DeLisi and Berzofsky [Proc. natn. Acad. Sci. U.S.A. 82, 7048-7052. (1985)] as modified by Margalit et al. [J. Immun. 138, 2213-2229. (1987)] the strip of-helix hydrophobicity algorithm (SOHHA) of Stille et al. [Molec. Immun. 24, 1021-1027. (1987)] and the motifs algorithm of Rothbard and Taylor [EMBO J. 7, 93-100. (1988)]. Correct prediction was defined at two levels of stringency: (1) the predicted sequence overlapped the experimentally reported sequence when the ratio of the intersection of both to the union of both greater than or equal to 0.5 or (2) the sequences touched when there was a non-empty intersection of both sequences. We determined the sensitivity (correct predictions/number of reported T cell-presented sequences) and efficiency (correct predictions/number of predictions) at each level of stringency. In terms of overlap, the SOHHA was more sensitive (0.43) than the amphipathicity (0.29) (not significant) and motifs (0.0, 0.0) (p less than 0.05) predictions and more efficient (0.35) than the amphipathicity (0.14) and motifs (0.0, 0.0) predictions. At the less stringent criterion touching, the amphipathicity method (0.71) was as sensitive as motif Rothbard-4 (0.79) and more sensitive than SOHHA (0.57) and motif Rothbard-5 (0.43). At that criterion, the SOHHA was more efficient (0.47) than the amphipathicity (0.36) and motifs (0.25, 0.40) methods. We hypothesize that the comparability of these approaches reflected the common, predominant influence of recurrent hydrophobicity in their predictions.

Common principles in protein folding and antigen presentation.

The regular recurrence of hydrophobic amino acid residues along a peptide sequence determines the formation of a longitudinal hydrophobic strip when the peptide forms an alpha-helix. An understanding of the ways this may affect both folding of nascent proteins and antigen presentation should facilitate vaccine and therapeutics design.

Case-control study of melanoma and dietary vitamin D: implications for advocacy of sun protection and sunscreen use.

The rapid increase in melanoma incidence and mortality has given rise to nationwide and international campaigns that encourage the public to protect themselves from solar radiation with clothing, sunscreens, and other measures. The basis of these campaigns has been challenged by proponents of the theory that vitamin D, which is generated in the skin by ultraviolet B radiation, inhibits the development of melanoma. The present investigation tests this theory by examining the relation between dietary vitamin D and melanoma risk in a case-control study. Vitamin D intake was assessed by a food-frequency questionnaire in 165 melanoma patients and 209 controls. After controlling for age, hair color, and family history of melanoma, there was no association of melanoma risk with total vitamin D intake, calorie-adjusted vitamin D intake, vitamin D intake from foods, or consumption of milk or vitamin D supplements. We find no evidence to suggest that vitamin D protects against melanoma, and therefore continue to support the ongoing public health campaigns aimed at reducing sun exposure for the prevention of melanoma.

Early death from clinical stage I melanoma.

We studied 13 prognostic factors in 582 patients with clinical stage I melanoma to determine which factor or combination of factors was associated with death from melanoma within the first 24 months following diagnosis. Thirty-six patients died during this period. Only 2 deaths occurred in patients with primary tumors thinner than 1.70 mm, and only 2 patients of 189 died with tumors located on the non-BANS extremities, excluding the hands and feet. Individual factors associated with high risk for death within 2 years included level V tumors, acral location, thickness greater than or equal to 3.65 mm, histologic ulceration greater than 3 mm, nodular type, presence of microscopic satellites, greater than 6 mitoses/mm2, positive elective node dissection, absence of lymphocyte response at the tumor base, and absence of an associated nevus histologically. Many of the preceding individual factors are highly correlated. By the use of logistic regression analysis, only one very high risk group was found: 71 percent of patients with level V tumors greater than 1.70 mm thick with histologic ulceration width greater than 3 mm located in an area other than the extremities (excluding hands and feet) had died within 2 years of diagnosis. The ability to select high-risk groups should be useful to investigators involved with the design and evaluation of adjuvant therapy studies.

Factors associated with death from melanoma from 2 to 5 years following diagnosis in clinical stage I patients.

We studied 14 prognostic factors in 428 patients with clinical stage I melanoma to determine which factor or combination of factors was associated with death from melanoma from 24 to 60 months following diagnosis. Forty-eight patients (11 percent) died during this period. All 17 patients who had visceral metastases present at 24 months died during this period. All surviving patients were followed for at least 60 months. Individual high risk factors included ulceration width (as determined by histology), level IV or V tumor, recurrence other than visceral, 6 or more mitoses per square millimeter, presence of involved nodes on elective dissection, absent or slight lymphocyte response, tumor type other than superficial spreading, location other than extremities (excluding hands and feet), microscopic satellites, thickness, sex, and wide local excision. The presence of sex as a risk factor for patients dying from 2 to 5 years following diagnosis is noteworthy because no sex difference was noted in the early death (less than 24 months) group. Age, presence of a nevus, and histologic regression were not significant factors. A logistic regression analysis selected a combination of the following independent factors: (1) location on extremities excluding hands and feet (favorable), (2) thickness, (3) recurrence other than visceral, (4) positive elective nodal dissection, (5) 6 or more mitoses per square millimeter, and (6) moderate to marked lymphocyte response (favorable). Twenty-five percent of patients with level IV lesions died between 24 and 60 months compared with only a 6 percent death rate within the first 24 months.

Early death from clinical stage I melanoma.

We studied 13 prognostic factors in 582 patients with clinical stage I melanoma to determine which factor or combination of factors was associated with death from melanoma within the first 24 months following diagnosis. Thirty-six patients died during this period. Only 2 deaths occurred in patients with primary tumors thinner than 1.70 mm, and only 2 patients of 189 died with tumors located on the non-BANS extremities, excluding the hands and feet. Individual factors associated with high risk for death within 2 years included level V tumors, acral location, thickness greater than or equal to 3.65 mm, histologic ulceration greater than 3 mm, nodular type, presence of microscopic satellites, greater than 6 mitoses/mm(2), positive elective node dissection, absence of lymphocyte response at the tumor base, and absence of an associated nevus histologically. Many of the preceding individual factors are highly correlated. By the use of logistic regression analysis, only one very high risk group was found: 71 percent of patients with level V tumors greater than 1.70 mm thick with histologic ulceration width greater than 3 mm located in an area other than the extremities (excluding hands and feet) had died within 2 years of diagnosis. The ability to select high-risk groups should be useful to investigators involved with the design and evaluation of adjuvant therapy studies.

Factors associated with death from melanoma from 2 to 5 years following diagnosis in clinical stage I patients.

We studied 14 prognostic factors in 428 patients with clinical stage I melanoma to determine which factor or combination of factors was associated with death from melanoma from 24 to 60 months following diagnosis. Forty-eight patients (11 percent) died during this period. All 17 patients who had visceral metastases present at 24 months died during this period. All surviving patients were followed for at least 60 months. Individual high risk factors included ulceration width (as determined by histology), level IV or V tumor, recurrence other than visceral, 6 or more mitoses per square millimeter, presence of involved nodes on elective dissection, absent or slight lymphocyte response, tumor type other than superficial spreading, location other than extremities (excluding hands and feet), microscopic satellites, thickness, sex, and wide local excision. The presence of sex as a risk factor for patients dying from 2 to 5 years following diagnosis is noteworthy because no sex difference was noted in the early death (<24 months) group. Age, presence of a nevus, and histologic regression were not significant factors. A logistic regression analysis selected a combination of the following independent factors: (1) location on extremities excluding hands and feet (favorable), (2) thickness, (3) recurrence other than visceral, (4) positive elective nodal dissection, (5) 6 or more mitoses per square millimeter, and (6) moderate to marked lymphocyte response (favorable). Twenty-five percent of patients with level IV lesions died between 24 and 60 months compared with only a 6 percent death rate within the first 24 months.

Distribution and characterization of peptidylglycine alpha-amidating monooxygenase activity in the ovine brain and hypothalamo-pituitary axis.

The production of alpha-amidated peptide hormones from their glycine-extended precursors is catalyzed by the specific enzyme peptidylglycine alpha-amidating monooxygenase (PAM). In the present study, the distribution and subcellular localization of PAM activity in the sheep brain was examined and compared with known sites of amidated peptide synthesis and release. Of the brain regions assayed, the preoptic anterior and medial basal areas of the hypothalamus contained the greatest concentration of amidating activity. Lower concentrations (greater than 3-fold less) were found in the anterior and neurointermediate pituitary, median eminence, cerebral cortex, hippocampus, pons-medulla, and brainstem. Very low amounts of activity were present in the cerebellum and pineal gland. In most tissues tested, PAM activity was 40-75% higher in the membrane-associated fraction than in the soluble fraction. In the hypothalamus, affinity constants were identical for both membrane-associated and soluble fractions, and ranged from 12.3-13.3 microM. Maximal velocity was higher in the membrane fraction (4.7-4.8 pmol/microgram.h) than in the soluble fraction (2.6-2.9 pmol/microgram/h). Levels of amidating activity in hypophysial-portal and jugular plasma were similar and were 20- to 25-fold lower than in hypothalamic extracts. Insulin-induced hypoglycemia did not significantly alter PAM levels in portal or peripheral plasma, suggesting that amidating activity is not released during this stress. These results indicate that the hypothalamus is the richest source of amidating activity in the sheep brain, and suggest that amidation of neurohypophysial and hypothalamic releasing peptides may occur before axonal transport, given the much lower levels in median eminence, neurointermediate pituitary, and portal plasma.

The prognosis in Alzheimer's disease. 'How far' rather than 'how fast' best predicts the course.

Clinical features at the initial examination of 42 patients with probable Alzheimer's disease were tested for prognostic value at subsequent follow-up of 54 +/- 25 months. These potential prognostic features were of three types: degree of severity features (eg, IQ scores); variable clinical features (eg, extrapyramidal signs); and individual distinguishing features (eg, gender, education, and age). The power of these potential prognostic features to predict prognosis was assessed using the Kaplan-Meier life-tables method and the Cox proportional hazards model. Three clinical end points were considered: total dependence in activities of daily living; incontinence; and institutionalization at follow-up. Degree of severity features (subtests of the Wechsler Adult Intelligence Scale-Revised and the Wechsler Memory Scale, and the Clinical Severity Score) predicted subsequent dependence in activities of daily living, incontinence, and institutionalization. Historical disease duration, age, gender, family history of dementia, retrospective rate of progression, anxiety, psychosis, depression, and extrapyramidal signs did not influence prognosis. These results suggest that initial degree of severity ("how far") rather than variation in the rate of progression ("how fast") best predicts prognosis in the early to intermediate stages of Alzheimer's disease. The relationship of disease severity to prognosis should be taken into account before concluding that there are subtypes of Alzheimer's disease that have different rates of progression.

The role of EC 3.4.24.15 in the post-secretory regulation of peptide signals.

In the present studies, we characterized the degradation of gonadotropin-releasing hormone (GnRH) by tissues of the ovine hypothalamo-pituitary axis. Membrane and soluble fractions of the medial basal hypothalamus, the pre-optic area, the median eminence and the anterior pituitary demonstrated greater GnRH-degrading activity than either hypophysial-portal or jugular plasma. The primary stable product of the membrane fractions was GnRH1-3, while the major product of the soluble fractions was GnRH1-5, both fragments were generated by plasma. Of all tissue fractions, the highest specific activity was observed in the soluble median eminence. Partial purification and characterization of soluble hypothalamic peptidase activity suggested that GnRH degradation by this tissue occurs via a two-step mechanism involving both post-proline cleaving enzyme and the metalloendopeptidase 3.4.24.15.

Prediction of alpha helices and T cell-presented sequences in proteins with algorithms based on strip-of-helix hydrophobicity index.

Recurrent aliphatic hydrophobic amino acids which occur in the sequence of a protein or a peptide at positions which form an axial, hydrophobic strip when the sequence is coiled as an alpha helix might stabilize coiling against hydrophobic surfaces. That effect can lead to helix formation against hydrophobic cores of nascent proteins or excised T cell-presented peptides and to protease protection and scavenging for presentation by MHC molecules. Such consensus sequences of recurrent hydrophobicity creating a scavenger "S" site might overlap to varying degrees the T cell-presented "T" epitope which actually sits in the antigen-binding site of a MHC molecules, as long as a cleavage "C" site does not fall between them when they are relatively separated. Cooperatively among the residues in an axial, hydrophobic strip to stabilize helix formation is reflected in the SOHHI, which is the mean hydrophobicity of residues in such potential strips. Algorithms based on the SOHHI, with additional considerations related to length and caps, lead to sensitive and efficient predictions of structural helices and of T cell-presented epitopes. In experimental tests of these ideas, the SOHHI was found to correlate to helical coiling of amphiphilic peptides in the presence of lipid vesicles. These principles lead to hypotheses to alter the potency and range of MHC restriction of peptide vaccines or to decrease the immunogenicity of therapeutic proteins.

Morbidity and mortality in children associated with the use of tobacco products by other people.

OBJECTIVE: To evaluate the impact of adult tobacco use on the health of children. DESIGN: A literature review identified relevant research reports. Meta-analysis was used to compute a pooled risk ratio for each condition studied. The risk ratios were combined with data on exposure rates to produce estimates of the population-attributable risk. RESULTS: Each year, among American children, tobacco is associated with an estimated 284 to 360 deaths from lower respiratory tract illnesses and fires initiated by smoking materials, more than 300 fire-related injuries, 354,000 to 2.2 million episodes of otitis media, 5200 to 165,000 tympanostomies, 14,000 to 21,000 tonsillectomies and/or adenoidectomies, 529,000 physician visits for asthma, 1.3 to 2 million visits for coughs, and in children younger than 5 years of age, 260,000 to 436,000 episodes of bronchitis and 115,000 to 190,000 episodes of pneumonia. CONCLUSIONS: The use of tobacco products by adults has an enormous adverse impact on the health of children. Although more research is needed in several areas, action to reduce the morbidity and mortality among children should not be delayed. New laws and policies are needed to grant children protection from bodily injury and death attributable to use of tobacco products by others.

The significance of augmented radiocolloid uptake by the spleen in patients with malignant melanoma.

Increase in splenic uptake of Tc-99m sulfur colloid was noted in 47 of 147 (32%) patients with cutaneous malignant melanoma early in the coure of disease. Patients with disseminated disease and/or clinical or laboratory evidence of hapatic dysfunction were excluded from study. Recurrence rate of 2 yr was higher for those patients with splenic scans demonstrating augmented uptake compared with patients having normal scans, 36% against 16% (p less than 0.02). These differences resulted from a much more favorable prognosis in women with normal scans contrasted with women with increased uptake, 6% against 26% (p less than 0.05). Women with increased splenic uptake, and all men regardless of scan status, seemed to have a higher rate of recurrence than women with normal spleen scans. Scan status may be an adjunctive prognostic marker in women.

Prognosis in Stage 1 malignant melanoma: seven-year follow-up study of splenic radiocolloid uptake as predictor of death.

In an earlier study we found that patients with clinical Stage 1 and 2 cutaneous malignant melanoma and increased splenic radiocolloid uptake had more frequent recurrence at 24 mo, compared with melanoma patients having normal liver-spleen scintigrams. This report, an 80-mo follow-up study, gives further information on 119 clinical Stage 1 patients. Fifteen of 35 patients with increased splenic uptake (42.9%) died from melanoma as opposed to only 16 of 84 (19.1%) with normal liver-spleen images (p less than 0.01). Multivariate analysis showed that augmented splenic uptake of technetium-99m sulfur colloid is a marker for adverse prognosis in patients with malignant melanoma but does not appear to be an independent variable in predicting death. In clinical Stage 1 patients, increased splenic uptake correlated significantly with pathologic stage (positive elective node biopsy) as well as thickness and mitotic rate in patients with thicker lesions. It may be that patients with thicker, pathologically aggressive tumors have an increased splenic blood flow and/or enhanced immune and reticuloendothelial response (as manifested by abnormal liver-spleen scintigram). If so, the enhanced immune response does not appear to contribute to overall survival.

Role of bradykinin receptors in the renal effects of inhibition of angiotensin converting enzyme and endopeptidases 24.11 and 24.15 in conscious rabbits.

1. We tested the effects on systemic haemodynamics and renal function, of inhibition of endopeptidase (EP) 24.15 (E.C. 3.4.24.15), in conscious uninephrectomized rabbits in which the activities of angiotensin converting enzyme (ACE, E.C. 3.4.15.1) and neutral endopeptidase (EP 24.11, E.C. 3.4.24.11) were already inhibited. To test the role of bradykinin B2-receptors in mediating the effects following inhibition of these enzymes, the antagonist Hoe 140 was used. 2. Hoe 140 (0.1 mg kg-1, i.v.) did not affect resting mean arterial pressure or heart rate, but antagonized the depressor effect of right atrial administration of bradykinin. The dose-response curve for bradykinin was shifted more than 1000 fold to the right for more than 4 h. Hoe 140 approximately doubled resting urine flow and increased fractional Na+ excretion from 4.2 to 6.0%; consistent with the hypothesis that it exerts a partial agonist effect on the kidney. 3. Combined inhibition of ACE (captopril; 0.25 mg kg-1 plus 0.2 mg kg-1h-1) and EP 24.11 (SCH 39370; 3 mg kg-1 plus 3 mg kg-1h-1) was followed by a sustained reduction in arterial pressure (-6 +/- 2 mmHg) and increase in heart rate (35 +/- 7 beats min-1). There was a small increase in renal blood flow (by 6.5 +/- 3.2% relative to vehicle-treatment) without a change in glomerular filtration rate, and about a 150% increase in Na+ excretion. Hoe 140 (0.1 mg kg-1, i.v.) pretreatment did not influence the renal effects of captopril and SCH 39370, although it did appear to blunt their hypotensive and tachycardic effects. 4. When EP 24.15 was inhibited with N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB; 5 mg kg-1 plus 3 mg kg-1h-1, i.v.) in rabbits pretreated with captopril and SCH 39370, no changes in systemic haemodynamics or renal function were observed. 5. We concluded that in conscious uninephrectomized rabbits, EP 24.15 does not play a major role in modulating renal function, at least under conditions where ACE and EP 24.11 are already inhibited. In contrast, ACE and/or EP 24.11 do modulate renal function in this model, but their influences are mediated chiefly through metabolism of peptides other than bradykinin.