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We investigated the utility of serum S100 determined by means of immunoradiometric assay in a cohort of 438 patients affected by cutaneous melanoma (126 untreated and 312 previously treated). Using 0.2 microg/l cut-off value, determined in 134 healthy blood donors, the sensitivity was 4.2% in stage I patients (4/94), 5.3% in stage II patients (1/19), and 38.5% in stage III patients (5/13). Even though the sensitivity increased progressively from stage I to stage II and III, these differences were not statistically significant. The prognostic significance of S100 evaluation at diagnosis was investigated in terms of survival but no statistical correlation between S100 basal levels and survival was found. In the 312 previously treated patients serum S100 levels were correlated to disease extent, high levels of the marker were observed in 42.8% (9/21) of patients with local recurrence, in 32% (16/50) of patients with lymph node and/or in-transit metastases, in 77.3% (17/22) of patients with distant metastases, and in patients with NED, the specificity of the marker was 96.8% (212/219). The difference between these groups were statistically significant. In conclusion, S100 protein was abnormally high in patients with metastatic malignant melanoma. Serial S100 measurements in a follow-up study are necessary to test the importance of the protein in the management of patients with metastatic malignant melanoma.

Several arguments support the idea of a link between longevity and heredity, both in humans and in experimental animals. We have therefore investigated the possibility of an association between the human leukocyte antigens (HLA) and longevity in two groups of Italian subjects: 108 healthy subjects over 85 years old, and 749 healthy blood donors (controls). Only four antigens showed a higher frequency in the elder group: HLA-A31(19), B7, Cw7 and DQ1. These findings suggest an involvement of HLA antigens in human longevity, but the real biological meaning of these results is still unclear.

Sister chromatid exchanges (SCE) were analyzed in peripheral blood lymphocytes of 24 individuals, following diagnosis, and prior to surgical removal, of a sporadic dysplastic nevus (DN). Lower SCE values and variability were found in 23 sporadic DN individuals compared with controls (2.52 +/- 0.12 and 3.76 +/- 0.22 SCE/cell, respectively). These DN individuals, contrarily to healthy controls and some types of tumor patients whose cells are hypersensitive to mutagenic agents, did not show increased SCE rates as a consequence of cigarette smoking, alcohol consumption and diagnostic radiation treatments. These observations are in contrast with clinical evidence that similar lesions are both markers or risk and precursors of malignancy in individuals with multiple nevi, affected by the dysplastic nevus syndrome (DNS) or belonging to FMM (familial malignant melanoma) families. Three HLA class I alleles out of 72 tested were found more frequently in sporadic DN individuals compared with controls: B37 (p < 0.05), B52 (p < 0.01) and B70 (p < 0.01). Whether the greater chromosomal stability (as shown by the SCE analysis), and/or the altered frequency of some HLA alleles could influence the chance of developing cutaneous malignancy in DN individuals is yet to be evaluated.

The most common mutations in the familial breast and ovarian cancer susceptibility gene BRCA1 are frameshift and nonsense mutations, which lead to the synthesis of truncated proteins. On this ground, we have analysed BRCA1 exon 11, which includes about 61% of coding region, in germline DNA from 70 Italian breast and/or ovarian cancer patients, using the protein truncation test (PTT). BRCA1 mutations were identified in nine of 29 (approximately 31%) patients with a family history of cancer and in three of 41 (approximately 7%) women with early-onset breast carcinomas, and were subsequently characterized by sequence analysis. In addition, BRCA1 mutations were also detected in six affected relatives of two positive index cases. The observed frequencies of mutations were not significantly different from those expected on the basis of the phenotypic characteristics of patients and their families, indicating that PTT is a rapid and sensitive method that can be used for a first BRCA1 mutational screening. The histological findings in BRCA1 mutated cases showed that eight of nine (approximately 89%) breast carcinomas were of grade III and nine of 9 (100%) ovarian carcinomas were of the endometrioid type (eight of grade III and one of grade II). This suggests that specific histological characteristics may represent additional criteria for selection of cases eligible to BRCA1 mutational analysis.

We analysed the effect of HLA loci on the secondary sex ratio, and investigated whether allele sharing between parents and between mother and child, or child homozygosity, affected the viability of male embryos, which are generally less resistant to unfavourable conditions during pregnancy. The sharing conditions at the B and DR loci showed significantly differing effects: HLA-B seemed to favour female births, while, in pregnancies subsequent to the first, HLA-DR seemed to favour male births. Both HLA-B and DR loci seemed to work through immunological mechanisms.

We have evaluated the frequency of HLA class I and II antigens in 205 Italian patients with hepatocellular carcinoma (HCC) and 749 blood donors (controls). Moreover, we have looked for correlations between HLA antigen frequencies and HBV and/or HCV infections in HCC patients. We found great differences in HLA antigen frequencies considering only two groups: HCC patients and controls. The polymorphism is smaller when we consider the different groups of HCC patients in regard to the previous viral infections (HBV and/or HCV). The most interesting finding is the higher frequency of Cw7, B8 and DR3 in almost all groups of HCC patients. It is well known, that the HLA A1, Cw7, B8, DR3 antigen haplotype is associated with a rapid decline of CD4 cells, and HLA B8, DR3 positive subjects may display some changes in immune parameters and are prone to develop several immunological diseases. Thus HCC might be the result of a lower sensitivity (genetically given) to mitogenic stimuli of HBV and HCV.

The activity of pidotimod ((R)-3-[(S)-(5-oxo2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) on immunological parameters was evaluated in a double-blind trial, involving two Research Centres. 16 patients with a primary or metastatic neoplasm, 16 elderly patients under immunodeficiency conditions and 11 healthy volunteers were enrolled in the present study. The patients, randomized within each centre, were assigned to one of the following treatments lasting 15 days: one vial i.m. of pidotimod 50 mg, 100 mg, 200 mg twice a day, respectively; one vial i.m. of physiological saline twice a day. The lymphocyte PHA-stimulation test evidenced a significant variability due to the different treatment groups (p = 0.004). The analysis of the stimulation index (SI), computed from the mean c.p.m. before and after PHA-stimulation, showed a significant difference, dose-independent, between saline and active treatment (p = 0.002). The SI analysis, on the basis of the data of the allogenic stimulation test (mixed lymphocyte culture), confirmed the difference between saline and active treatment (p = 0.05) with a significant linear component in the time-effect curve (p = 0.001) but not in the dose-effect curve. A 12% increase in CD 3 lymphocytes compartment was observed with pidotimod 400 mg/day. The drug was well tolerated by all the patients included in the study.

The aim of this study was to evaluate the activity of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) on 52 patients affected with chronic obstructive pulmonary disease (COPD). The study was carried out in a randomized, parallel, double-blind trial, followed by incomplete blocks design. Pidotimod 800 mg was administered orally twice a day for 30 days. The follow-up period was 5 weeks. Our results show that in patients with COPD pidotimod potentiates T-cell activity. The effects on T-cells appear after 15 days of treatment and last for 5 weeks after the end of therapy. Since other studies demonstrated that pidotimod displays an immunopotentiating activity also on macrophages and granulocytes, the drug is useful to increase the immune defense during infections. The drug has a good compliance and is well tolerated also during long-term treatment.

Two human melanoma lines were transduced by a retroviral vector with the gene of the human interleukin-2 (IL-2) and characterized for their immunological properties in comparison with the parental lines. Transduction resulted in the production of biologically active IL-2 in the average amounts of 2,282 and 2,336 pg/ml per 10(5) cells per 24 hr over 3 and 2 months by the Me14932/IL-2 and the Me1B6/IL-2 lines, respectively. Melanoma-transduced cells lost their tumorigenicity in nude mice. No major changes in the phenotype were observed in IL-2 gene-transduced lines. In fact, more than 90% of cells expressed class I and II(DR) HLA, adhesion molecules, integrins, and melanoma-associated antigens. Irradiation with 100-400 Gy, while inhibiting tumor cell growth in vitro, allowed the release of IL-2 by the transduced cells for at least 5 weeks. The two melanoma lines also maintained susceptibility to lysis by lymphokine-activated killer (LAK) cells and by a HLA-A2-restricted melanoma-specific cytotoxic T lymphocyte (CTL) clone recognizing the melanoma antigen (Melan-A). In a limiting dilution assay, transduced, but not parental melanoma lines unless added with an amount of IL-2 comparable to that released by the transduced cells, were able to expand both nonspecific and melanoma-specific CTL precursors from autologous peripheral blood lymphocytes (PBL). In mixed lymphocytes-tumor cultures, IL-2 gene-transduced melanoma cells stimulated the expansion of major histocompatibility complex (MHC)-unrestricted effectors from autologous PBL, and of CD3+ CD8+ MHC-restricted CTL from tumor-invaded lymph nodes. These results indicate that IL-2 gene transduction does not alter significantly the expression of the immunologically relevant molecules of human melanoma lines while increasing their ability to stimulate both specific and nonspecific lymphocyte responses. These lines will be of value in the vaccination of melanoma patients.

We conducted a randomized trial comparing expectant management versus immunotherapy with paternal leukocytes to improve obstetric outcome in women with unexplained recurrent abortion. Eligible for the study were women with unexplained recurrent abortion (three or more miscarriages and no live birth), negative findings of immunological screening and no inhibition of the mixed lymphocyte culture. These women were seen for the first time between October 1988 and March 1991 in a network of obstetric departments in Northern Italy. Subjects positive for HLA DR3 or with a partner positive for hepatitis virus B antigen were not eligible. A total of 44 women entered the study. Patients were randomly allocated to immunotherapy (22 women) or expectant management (22 women). Women allocated to immunotherapy were given 200 x 10(6) purified paternal lymphocytes before pregnancy. Median follow-up was 24 months (range 10-39) in the immunotherapy group and 25 months (range 11-38) in the expectant management group. Out of the 22 women randomized to immunotherapy, 16 became pregnant and the corresponding value was 14 in the expectant management group. Spontaneous abortion occurred in six out of the 16 pregnancies observed in the treated women. Among the 14 pregnancies observed in the expectant management group, two aborted and one late fetal death occurred. The cumulative proportions of women who became pregnant over 4 years were 37 and 45% in the immunotherapy and expectant management groups respectively; this difference was not significant. No adverse effect was observed in treated women.

The survival of stage I melanoma patients was evaluated and compared with the detectable expression of HLA antigens. Of 904 patients who were surgically treated, 219 were HLA typed on peripheral blood lymphocytes. Four consecutive HLA typings were considered necessary. Median follow-up was 8 years. Two main groups of patients were considered: (a) patients with consistent detectable expression of antigens; and (b) patients with inconsistent detectable expression of antigens. Patients with consistent HLA antigens detection had an 8-year survival rate of 87.7% compared with 49.2% of patients with an inconsistent rate (P10(-7). Multivariate analysis of survival of the 182 HLA-typed patients who survived at least 24 months from surgery showed that two of the criteria had an independent impact on survival: tumour thickness (P 0.02) and HLA typing (P 2 x 10(-5). Inconsistent detection of HLA antigens on peripheral blood lymphocytes during the first 24 months after surgery is an indicator of poor prognosis in stage I melanoma patients.

The possible correlation between HLA system and liver cirrhosis secondary to HBV infection has been studied in 102 hospitalized elderly patients affected by liver cirrhosis (histologically proven) and 749 elderly health controls. Increased frequencies of HLA-A2, Cw4, Cw5, DR4, DR5 and DR7 have been observed in patients with liver cirrhosis and previous HBV infection, while a lower frequency of HLA-A2 and higher frequencies of HLA-A3, B35, Cw4, DR3 have been observed in patients without previous HBV infection when compared with controls.

HLA-A, B, C, DR and DQ typing was performed in 381 Italian insulin-dependent diabetic patients and in 905 normal Italian subjects. The diabetic patients had significantly higher frequencies of HLA-Cw7, B8, B18, DR3, DR4, DQw2 and DQw3 and significantly lower frequencies of HLA-B17, Bw51, DR2, DR7 and DRw11. The frequency of heterozygosity for HLA-DR3/DR4 was significantly higher in patients who developed the disease in the first 2 years of life and DR3+/DR4-, DQw2 and DQw3 alleles were higher in those aged less than 14 years at onset. The HLA-DR4 allele was associated with onset of diabetes in autumn and HLA-B18 with onset in Autumn-winter. Diabetic children who were breast fed had a later onset of insulin-dependent diabetes mellitus than those who were bottle fed but these differences were independent of HLA typing (11.8 +/- 0.72 years vs 9.23 +/- 0.42 years; mean +/- SEM). We conclude that: (1) in general, HLA distribution in Italian insulin-dependent diabetic patients reflects previous data reported in other European and North American populations; (2) HLA-DR3 and DR4 are strongly associated with insulin-dependent diabetes in Italy as well, and these alleles seem to predispose to an earlier onset of the disease; and (3) breast feeding may delay the onset of the disease.

Sister chromatid exchange (SCE) analysis was carried out on peripheral blood lymphocytes of 20 familial malignant melanoma (FMM) and 39 sporadic malignant melanoma (SMM) untreated patients, belonging to 10 and 39 families, respectively. The study was extended to 39 unaffected close relatives of FMM patients, to 187 unaffected close relatives of SMM patients, and to 20 unaffected unrelated individuals (control group), all examined under the same conditions. The mean SCE rates/cell were significantly higher in MM families than in the control group, and in melanoma patients than in their close relatives. The mean SCE levels of FMM and SMM patients, (8.4 +/- 0.8 and 8.0 +/- 0.3, respectively) were similar, and so were the distributions of individuals in classes of increasing SCE values (with a modal value at 7-8 SCEs/cell). The mean SCE levels of close relatives of FMM and SMM patients were also similar (5.4 +/- 0.2 and 5.4 +/- 0.1, respectively, with a modal value at 4-5 SCEs/cell), and slightly higher than in the control group (4.7 +/- 0.2 SCEs/cell). More than 7 SCEs/cell were observed in the majority (41 of 59) of FMM or SMM patients, in a smaller fraction (25 of 227) unaffected relatives, and in none of 20 unrelated unaffected individuals. These observations favor the hypothesis that higher SCE levels may be an expression of constitutional lesions predisposing to this neoplastic disease.

IgA and IgG antigliadin antibodies were measured in 498 patients with insulin dependent diabetes mellitus and no history of intestinal malabsorption. Thirty patients had abnormal concentrations of antigliadin antibodies; 22 of these had an intestinal biopsy carried out and 16 of the 22 had subtotal villous atrophy suggestive of coeliac disease (prevalence 3.2%). There were no significant differences between patients with coeliac disease and diabetes and diabetic patients with normal IgA antigliadin antibodies in any of the nutritional variables measured, duration of diabetes, and mean insulin requirement. The mean age of onset of diabetes and attainment of expected height for age were both significantly lower in the patients with both diseases. Typing HLA classes I and II was done in 242 patients. The incidence of HLA-B8, DR3, and DQW2, which are commonly associated with both the diseases, is increased when both are present.

We analyzed HLA-A, -C, -B, -DR and -DQ specificities in 104 Italian multiple sclerosis patients and in 905 healthy controls. The frequencies of HLA-A23, A26, Cw4, DR3 and, especially DR5 antigens were significantly higher in multiple sclerosis patients than in controls. Patients with progressive course were characterized by high frequencies of B7, B8 and DR3 antigens: Cw1 and DRw11 shows a negative correlation with the extent of intrathecal IgG production. These data confirm that the HLA system may influence the clinical expression and the immune responses to the disease.

21 Italian families with at least two members who had had febrile convulsions (FC) were HLA-typed for class I antigens. A total of 49 subjects and 43 close relatives (parents or sibs) were examined. No single antigen or haplotype was statistically more frequent among pooled FC subjects. The study, however, is not conclusive regarding a relationship between FC and HLA region because of the possible genetic heterogeneity of proneness to FC. In a significant proportion of cases two FC affected sibs had unaffected parents: besides the models of inheritance so far proposed for this pathology, the involvement of two complementary dominant factors was also considered. The report includes uncommon cases: a family where one FC affected parent transmitted the same HLA haplotype to all three affected sibs; two more families, with both parents and progeny affected by FC. The HLA typing of all members of these unusual families, although not furnishing relevant information at present, may be of value to other investigators.

HLA antigens of locus A, C, B, DR and DQ were typed in 104 Italian multiple sclerosis patients and in 905 healthy controls; the results have been compared with those published in the Italian literature. The Italian studies have been reviewed regarding the ethnic origin of the typed population and the corresponding prevalence of the disease. The data suggest a lack of association between A3 and B7 antigens and Italian multiple sclerosis and a relevance of other DR locus antigens (mainly DR4 and DR5), in addition to DR2, in the susceptibility to the disease.

Molar tissue expresses HLA antigens evidenced in the father. These antigens are present on the trophoblastic extravillous tissue, not on the syncytium and cytotrophoblast. These antigens show some characteristics of Qa murine antigens mapped in the HLA system linked to class I antigens. Antibodies anti HLA against the partner antigens and lymphocytotoxic antibodies have been evidenced in the serum of patients with vesicular mole. In vesicular mole the production of antibodies should be determined by the immunogenicity of cells that infiltrate the decidua, expressing paternal HLA antigens. It has been demonstrated that the recognition of "not self" antigens in the mother should stimulate a cellular immune response. We do not know why the tumor grows. Maybe the woman is not able to produce anti HLA antibodies although recognizes them as "not self", or the patients is not antigenically stimulated because there is immunocompatibility between the two partners. The literature shows that the development and progression of the disease are stimulated by histocompatibility, although this factors does not seem fundamental. If the two partners are histocompatible the tumor can be less immunogenic, so the mother shows a lower response and the growth of the tumor appears to be favoured.

In order to study the immunogenetics of myasthenia gravis (MG), we analysed the TCR and HLA-class II genes from Italian and Californian myasthenic patients. We investigated polymorphisms of the TCR using the full length cDNA probes pGA5 and the pT10 for the alpha and beta chains, respectively. The 6.3 kb and 2.0 kb polymorphic markers, revealed by the PssI enzyme and the alpha chain probe, were shown to be significantly associated with MG. Italian MG patients were HLA typed, and allele frequencies showed a significant association of DR3 and DQw2 with MG. The relative risk calculated for DR3 was 7.4. T-cell proliferative responses to peptides of the AchR alpha chain were also studied and no associations with TCR RFLP analysis or HLA-class II typing were observed.

Two groups of malignant melanoma (MM) patients were considered: the group of 140 patients previously published and a new one of 58, both typed for HLA-A, -B and -C antigens at the Istituto Nazionale Tumori of Milan. The control group consisted of healthy blood donors not related to the patients. Only the HLA-Bw35 antigen frequency was significantly decreased in both groups of patients. To investigate the HLA-A and -B blanks, 62 MM patients and 90 healthy controls, who showed non-homozygotic blanks when they were firstly HLA typed, volunteered to repeat the HLA typing three or more times in a 2-year period. A significant increase in both HLA-A and -B blanks in the patients as compared to controls was noticed (p = 3 X 10(-4) and 3 X 10(-5), respectively). In the future, attempts should be made to correlate the HLA antigen and blank frequencies with the evolution of the disease and, also, to verify the hypothesis that the HLA-Bw35 antigen may be an associated resistance factor against the tumor.

One hundred and forty melanoma patients, divided in 2 groups, i.e., patients with clinical evidence of melanoma and patients with no clinical evidence of melanoma, were typed for HLA-A, -B and -C antigens and compared with 340 to 905 (according to each HLA antigen examined) healthy adult blood donors. Overall, a highly significant increase in HLA-B40 antigen (p = 5.6 x 10(-7)) and a decrease in HLA-BW35 (p = 1.6 x 10(-4)) was observed. No relevant difference was found between the 2 groups. Moreover, an unexpected excess of HLA blanks was observed at both A and B loci in the first group (p = 1.3 x 10(-2) and p = 3.3 x 10(-6), respectively) and only at the B locus in the second (p = 1.2 x 10(-2)), when the patients were compared to 288 healthy individuals HLA typed at the same time and with the same HLA antisera as the patients. The increase in HLA blanks in melanoma patients deserves further investigation to ascertain whether it may be due to the tumor not yet surgically removed or may be referred to technical pitfalls.

We have analysed the DNA of peripheral blood leukocytes (PBL) from 55 melanoma patients and 53 healthy individuals and failed to find any significant association between melanoma and rare HRAS1 alleles defined by MspI/HpaII digestion. However, the analysis of the same DNAs for a different polymorphism based on the presence of additional TaqI sites in the variable tandem repeat region of HRAS1 showed that the total frequency of a group of allelic variants, named Tp, was significantly higher in melanoma patients than in normal donors.

Close correlation between HLA antigens and haplotypes and familial polyposis coli, an infrequent inherited condition which results in an early onset of colonic adenomas and carcinoma is reported. Similarity between the patients' group and their healthy relatives is recorded, both groups differing from a healthy control group (HLA B35, DR5). This haplotype cannot be considered as a marker of the disease but provides a statistical indication of a high risk of adenomas in each family affected by FPC.

Sixty five patients affected by ovarian carcinoma, 40 controls with benign ovarian disease were typed for HLA A, B and C antigens and compared with 132 adult female blood donors. A highly significant increase in HLA B7 antigen (p = 0,0083) and a decrease in HLA A11, A28, B12 (p = 0,04; p = 0.03 respectively) in patients vs controls has been noticed. The comparison among the ovarian benign disease patients, and those with ovarian carcinoma and the healthy controls showed a decrease in the HLA A1 antigen frequency. Besides, the patients presented an increased and a decreased frequency of the A and O blood phenotypes respectively. These data confirm those of other Authors, and we can conclude that the neoplastic disease does not show a strong association with histocompatibility antigens.

Six families with familial malignant melanoma (FMM) were HLA-A, -B, and -C typed to ascertain whether or not FMM would segregate with the HLA complex. The HLA-B12 antigen was present in five of the six families. In three families the HLA-FMM linkage could be analyzed: linkage was possible in two but not in the third. These findings suggested that two types of FMM may exist: a more frequent type (five cases) that apparently segregates with the HLA complex and another (one case) that does not segregate with the HLA complex. Moreover, a factor included in the HLA region or another factor linked to it may have played an important role, in five of the six families, in FMM pathogenesis, whereas in the sixth family its role may have been performed by some other factor. These findings are consistent with the hypothesis of two complementary factors (one of which was included in the HLA complex) for the promotion of FMM with dominant inheritance and high penetrance.

The frequency of secondary failure to oral hypoglycaemic agents (OHA) in patients with non-insulin dependent diabetes (NIDDM) is still unknown, despite more than 30 years of use of OHA. The term secondary failure should be limited to patients who, despite maximal dosages of OHA and despite full compliance with diet and therapy, are no longer controlled and require insulin to obtain an acceptable glucose metabolism. We evaluated 248 out-patients, either on OHA, or on insulin because of poor metabolic control with OHA, in order to assess duration of treatment with OHA since diagnosis, by means of actuarial curves (Mantel-Cox test). Patients with low relative body weight (RBW less than or equal to 100) experienced secondary failure earlier and more often than obese patients (RBW greater than 120) or overweight (RBW 101-120) patients. In 66 of the above out-patients, 33 OHA-treated and 33 insulin-treated, matched for age at onset and duration of disease, islet-cell-antibodies (ICA) and C-peptide release at fasting, 6 min after i.v. glucagon and post prandially were evaluated. Only among lean and overweight patients, was C-peptide release significantly lower in insulin-treated than in OHA-treated patients; differences disappeared in obese patients. ICA were found in only 7 patients (10.6%). HLA phenotype was different from that of healthy blood donors for the loci HLA B5, B13, CW4, with no differences between OHA-treated and insulin-treated patients. These data indicate that secondary failure is more frequent in lean patients with NIDDM, and is related to reduced insulin release.

Sister chromatid exchange (SCE) was analyzed in stimulated lymphocytes and skin fibroblasts in members of three families with cutaneous malignant melanoma (CMM). Two of these families were characterized by familial CMM; the other family had one patient affected by CMM and two others with other cutaneous melanocytic lesions. All the patients had undergone surgery but no chemotherapy. Higher and differing SCE rates were found in lymphocytes and in fibroblasts of all patients. A wide range of SCE distribution was found in patients with high SCE rate. A few healthy close relatives also showed relatively high SCE rates and wide range distributions. These subjects may be regarded as a subset of family members at high risk for developing cancer. The variability of SCE rates and distribution may reflect genetic heterogeneity of CMM.

One hundred and twenty-four subjects belonging to 25 families, 51 with familial malignant melanoma (FMM), and 186 subjects belonging to 41 families, 41 with sporadic malignant melanoma, were typed for the HLA A, B, C and DR loci of the HLA system. There was the same statistically significant difference in the frequency of the haplotype A9, B35, Cw4 between each group of patients and the respective healthy relatives (p = 0.01, p = 0.01 and p = 4 x 10(-3), respectively). Moreover, the higher frequency of the haplotype A9, B35, Cw4 in the healthy members of the FMM families (42.46%) compared with the healthy members of the SMM families (23.44%) indicates that in the latter group other individuals are at risk for the disease. Furthermore, the different frequency of haplotypes B5, DR5 and B5, Cw1 suggest that differences exist between the two groups of healthy relatives. These observations confirm that the HLA region is involved in the etiology of malignant melanoma.

To study human leukocyte antigens (HLA) and sister chromatid exchanges (SCE) in multiple adenomatosis coli (MAC), eight families were evaluated. Twenty-five subjects (14 affected members and 11 healthy relatives) were studied with HLA A, B, and C typing of peripheral lymphocytes and SCE count in cells that had replicated twice. The results of the present immunogenetic study, although limited to a small number of cases, suggest a correlation between HLA, SCE, and MAC. When the results of further investigations on larger series confirmed by clinical follow-up of these subjects are available, these methods might give useful information in predicting the risk of each family member to become affected by MAC and consequently develop a colorectal carcinoma.

There is some evidence that genes at loci on the lower end of chromosome 14, encoding for the immunoglobulin heavy chains allotypes (Gm), may influence susceptibility to human tumors. We examined the Gm and Km (IgK light chain) allotype distribution in a sample of 41 patients with familial malignant melanoma and in 79 healthy relatives. An increased frequency of the haplotype carrying the Gm (2) allotype, namely Gm (1, 2, 17;..;21), seemed to be peculiar to patients, since it was almost twice as frequent in them than in the healthy population and four times as frequent with respect to the healthy relatives. Our findings are in keeping with previous suggestions that in Caucasian melanoma patients genes of the immunoglobulin heavy chain constant region, or Gm-linked genes, may enhance susceptibility to malignant melanoma.

In order to study the HL-A antigen turnover in vivo, the HL-A reactivities of the lymphocytes of eight blood donors were tested every week for six weeks with antisera HL-A1, 2, 3, 5, 7, 8 and 11. The analysis of variance showed that the "time" effect and the "time times donors" interaction were statistically significant for the HL-2, 3, 5 and 11 specificities. This supports the hypothesis that phenotypic expression of such antigens on the lymphocyte membrane of some of the blood donors examined varied with time. From a practical point of view, the HL-A antigenic fluctuation with time should be taken into consideration when lymphocyte typing is required for tissue transplantation.

Sister chromatid exchange (SCE) and the proliferative pattern of phytohemagglutinin-stimulated lymphocytes were examined in 36 nonfamilial cutaneous malignant melanoma (CMM) patients. One close relative of each of 27 CMM patients was also examined. All the patients had undergone surgical treatment for the neoplasm, but had received no chemotherapy or radiotherapy. The SCE rates were found to be higher and more variable in a significant fraction of CMM patients, and in relatively fewer unaffected relatives, which is in contrast to findings in unrelated subjects taken as controls. Also, variable and higher proportions of cells in metaphase of the first cell cycle (M1), after 72-hr culture in the presence of bromodeoxyuridine, were more often found among the CMM patients than in the controls; however, no effect of clinical progression of the neoplastic disease on SCE rates or on the lymphoproliferative pattern was observed. The present study indicates heterogeneity among subjects who develop CMM and suggests that the peculiarities of SCE rates and of the lymphoproliferative patterns observed in some of the CMM patients and in a few of their close relatives may be connected with the mechanism of onset of the neoplasm.