Activity of trabectedin in germline BRCA1/2-mutated metastatic breast cancer: results of an international first-in-class phase II study.

BACKGROUND: Breast cancer is a heterogeneous disease defined by both germline and somatic abnormalities. In preclinical models, tumors carrying homologous recombination defects are highly sensitive to trabectedin. This phase II trial evaluated the efficacy and safety of trabectedin in BRCA1/2 germline mutation carriers with pretreated metastatic breast cancer (MBC). PATIENTS AND METHODS: Trabectedin 1.3 mg/m(2) as a 3-h i.v. infusion was administered every 3 weeks until progression or intolerance. The primary efficacy end point was the objective response rate (ORR) as per RECIST. Secondary efficacy end points comprised time-to-event end points, and changes in tumor volume and expression of tumor marker CA15.3. Safety was evaluated using the NCI-CTCAE. RESULTS: Forty BRCA1/2 germline mutation carriers with MBC were included. Confirmed partial response (PR) occurred in 6 of 35 assessable patients [ORR = 17%; 95% confidence interval (CI) 7% to 34%] and lasted 1.4-6.8 months. Median PFS was 3.9 months (95% CI 1.6-5.5 months). Eight patients (21%) showed changes in tumor volume, and 14 (40%) a clinical benefit. Trabectedin-related adverse events were generally mild/moderate, the most common being fatigue, nausea, constipation and anorexia. Severe laboratory abnormalities (neutropenia, transaminase increases) were mostly transient and noncumulative, and were managed by dose adjustments. CONCLUSIONS: With the caveat of the limited patient number, trabectedin monotherapy showed activity and was well tolerated in heavily pretreated MBC patients selected for germline BRCA mutation. These results prompt further evaluation of trabectedin alone or combined with other specific drugs in this indication. CLINICALTRIALSGOV: NCT00580112.

Multicenter phase II study of trabectedin in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: This multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Two schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m(2) for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m(2) (Cohort B1, n = 5) and 1.2 mg/m(2) (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP). RESULTS: Trabectedin resulted in PSA declines ≥ 50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1-8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m(2) (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m(2) q3wk and 0.58 mg/m(2) weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase. CONCLUSIONS: Two different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.

Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma.

BACKGROUND: To evaluate neoadjuvant trabectedin (1.5 mg/m(2) 24-h i.v. infusion every 3 weeks; three to six cycles) in patients with locally advanced myoxid liposarcoma (ML) previously untreated with chemotherapy or radiation. PATIENTS AND METHODS: Primary efficacy end point was pathological complete response (pCR) or tumoral regression rate. Objective response according to RECIST (v.1.0) was a secondary end point. RESULTS: Three of 23 assessable patients had pCR [13%; 95% confidence interval (CI), 3% to 34%]. Furthermore, very good and moderate histological responses were observed in another 2 and 10 patients, respectively. Histological decrement in the cellular and vascular tumor component and maturation of tumor cells to lipoblasts were observed in both myoxid and myoxid/round cell variants. Seven patients had partial response according to RECIST (objective response rate of 24%; 95% CI, 10% to 44%). No disease progression was reported. Neoadjuvant trabectedin was usually well tolerated, with a safety profile similar to that described in patients with soft tissue sarcoma or other tumor types. CONCLUSION: Trabectedin 1.5 mg/m(2) given as a 24-h i.v. infusion every 3 weeks is a therapeutic option in the neoadjuvant setting of ML.

Analysis of the ligand-binding domain of human retinoic acid receptor alpha by site-directed mutagenesis.

Three subtypes of retinoic acid receptors (RAR), termed RAR alpha, RAR beta, and RAR gamma, have been described. They are composed of different structural domains, including distinct domains for DNA and ligand binding. RARs specifically bind all-trans-retinoic acid (RA), 9-cis-RA, and retinoid analogs. In this study, we examined the functional role of cysteine and arginine residues in the ligand-binding domain of hRAR alpha (hRAR alpha-LBD, amino acids 154 to 462). All conserved cysteine and arginine residues in this domain were mutated by site-directed mutagenesis, and the mutant proteins were characterized by blocking reactions, ligand-binding experiments, transactivation assays, and protease mapping. Changes of any cysteine residue of the hRAR alpha-LBD had no significant influence on the binding of all-trans RA or 9-cis RA. Interestingly, residue C-235 is specifically important in antagonist binding. With respect to arginine residues, only the two single mutations of R-276 and R-394 to alanine showed a dramatic decrease of agonist and antagonist binding whereas the R272A mutation showed only a slight effect. For all other arginine mutations, no differences in affinity were detectable. The two mutations R217A and R294A caused an increased binding efficiency for antagonists but no change in agonist binding. From these results, we can conclude that electrostatic interactions of retinoids with the RAR alpha-LBD play a significant role in ligand binding. In addition, antagonists show distinctly different requirements for efficient binding, which may contribute to their interference in the ligand-inducible transactivation function of RAR alpha.

Lymphocytic lymphoma of intermediate differentiation: morphologic, immunophenotypic, and prognostic factors.

Diffuse intermediately differentiated lymphocytic lymphoma (IDL) is a rare (approximately 2.5%) histologic subtype of malignant lymphoma. We have reviewed the morphologic, immunophenotypic, and clinical features of this disease in 23 patients treated at the National Cancer Institute in the 25-year period between 1963 and 1988. These tumors are uniformly of B-cell origin, but most of them express the T-cell antigen CD5; lambda light chain was expressed nearly twice as frequently as kappa. Median age at diagnosis was 58 years; all patients presented with stage III or IV disease, and the natural history of disease in these patients was heterogeneous. Median survival of patients was more than 5 years, but those with liver involvement documented by biopsy had a significantly shorter survival. No other prognostic factor or combination of prognostic factors significantly affected survival in this small series; however, patients with high expression of the proliferation-associated nuclear antigen Ki-67, absence of cell-surface antigens CD9 and CD10, and blastic morphology appeared to have poorer survival. Treatment was heterogeneous, but patients who achieved a complete response to combination chemotherapy survived longer than patients who failed to achieve a complete response. Only two patients had complete responses lasting longer than 2 years. Unlike patients with follicular lymphoma, those with relapsed IDL did not undergo histologic progression of the disease to an aggressive lymphoma. However, as with patients with follicular lymphoma, it was possible to observe patients with IDL without therapy for periods up to 5 years. Although a significant minority of patients may have very aggressive disease, it appears that, in most patients, IDL behaves similarly to other lymphomas with indolent histology, and thus, an optimal therapeutic approach has not yet been defined.

Lymphocytic lymphoma of intermediate differentiation. Morphologic and immunophenotypic spectrum and clinical correlations.

All cases of lymphocytic lymphoma of intermediate differentiation (IDL) referred to the National Cancer Institute were reviewed in order to define the histopathologic spectrum of the disease and to investigate morphologic and immunophenotypic features with potential prognostic relevance. Thirty-three cases were classified as IDL according to histologic criteria. Immunophenotypic analysis was performed in 27 cases, and clinical records were available for 22 patients. The median age was 58 years, and the male-to-female ratio, 3.4:1. All patients presented with stage III or IV disease, and five had extranodal presentations. Median survival was 56.3 months, with only three patients having a prolonged relapse-free survival (greater than 2 years). Morphologically, 14 cases were diffuse or only vaguely nodular; 18 cases showed a mantle zone pattern with naked germinal centers. There was a trend toward prolonged median survival for patients with the mantle zone (77.4 months, p = 0.098). The neoplastic population was composed of irregular or cleaved small lymphoid cells with a mitotic rate ranging from 5 to 62 per 20 high-power fields (hpf). A histologically distinctive variant with blastic cytologic features was identified (seven cases). The blastic variant was associated with a higher mitotic index (51.3 versus 19.0) and shortened survival (24.9 months). In contrast to the histologic progression often observed in follicular lymphomas, in no case was transformation to a large-cell or small noncleaved lymphoma observed. All cases had a mature B-cell phenotype demonstrating monoclonal Ig and B-cell surface antigens. Seventy-eight percent were CD5 positive; three of six CD5-negative cases presented in mucosal-associated extranodal sites. CD10 and CD25 were expressed in 52% and 44%, respectively, but did not show clinical correlations. The proliferative rate measured by Ki-67 positivity correlated with the mitotic index, but neither of these parameters had a statistically significant influence on survival.

Ketoconazole therapy: hormonal and clinical effects in non-tumoral hyperandrogenism.

The aim of this study was to assess the usefulness of ketoconazole as a therapeutic alternative to polycystic ovary syndrome. The study group comprised 37 women with signs of hyperandrogenism (hirsutism, acne) and oligomenorrhea. A low dose (400 mg/day) of ketoconazole was tested in a 9-month prospective clinical study. Clinical response (Ferriman & Gallway score, acne) and modifications in hormone pattern (luteinizing hormone, follicle-stimulating hormone, estradiol, testosterone, prolactin, 17-hydroxy-progesterone, androstenedione, steroid hormone-binding globulin, dehydroepiandrosterone sulfate, cortisol, adrenocorticotropin (ACTH) and free testesterone index) were measured, and ACTH stimulation tests were performed. Tolerance and side-effect also were assessed. After 9 months of ketoconazole treatment, the patients' Ferriman & Gallway scores (18.26 +/- 4.6 vs 12.4 +/- 4.1; p < 0.001) and acne had improved markedly. Hormone patterns also became more favorable, with decreases in androgenic steroids (testosterone, androstenedione, free testosterone index and dehydroepiandrosterone sulfate; p < 0.01) and increases in estradiol (p < 0.01). Basal cortisol levels and cortisol after ACTH stimulation were not changed significantly, remaining within the reference range. Increases in ACTH were observed only in the 3rd month (p < 0.01). Initial levels of androgenic steroids were correlated inversely with their percentage decrease in successive samplings. Decreases in adrenal androgenic steroids were associated with an increase in steroid hormone-binding globulin. The side-effects of treatment, although not severe, caused some discomfort and led to a high drop-out rate (30%).(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant lymphoma involving a Warthin's tumor: a case with immunophenotypic and gene rearrangement analysis.

We describe a Warthin's tumor which was involved by malignant lymphoma. The lymphoma was classified in the Working Formulation as follicular and diffuse, mixed small cleaved and large cell type. Frozen section immunohistochemical studies revealed an abnormal immunophenotype: immunoglobulin-negative and B-lineage. Gene rearrangement analysis confirmed the diagnosis by demonstrating rearrangements of both the immunoglobulin heavy and kappa light chain genes. The bcl-2 gene was also rearranged, consistent with the presence of the t(14;18) (q32;q21) translocation which is typically seen in follicular lymphomas. The T-cell receptor beta chain gene retained the germline configuration. The results in this case highlight an advantage of molecular techniques as compared with immunophenotypic analysis: gene expression is not required to demonstrate clonality.

Determination of lineage and clonality in diffuse lymphomas using the polymerase chain reaction technique.

Malignant lymphomas of the diffuse mixed or diffuse large cell subtype are immunologically heterogeneous and morphologic features do not allow prediction of lineage. Applications of immunophenotypic and gene rearrangement techniques has greatly improved our ability to determine clonality and lineage. Nevertheless, some diffuse lymphomas are composed of numerous reactive cells accompanying a small clonal population, thereby making determination of clonality difficult, even with gene rearrangement techniques. In this study, we report two malignant lymphomas in which immunophenotypic and genotypic studies failed to elucidate evidence of clonality. In both cases, the polymerase chain reaction amplified segments of DNA containing the bcl-2/JH sequence, providing evidence of clonality and suggesting B-cell lineage. We conclude that the polymerase chain reaction technique may be useful in the diagnosis of some diffuse mixed and large cell lymphomas.

Intravenous administration among heroin users having treatment in Spain.

BACKGROUND: Of critical importance to AIDS control in Spain is the analysis of geographical variation and trend over time in the prevalence of intravenous administration in heroin users, as well as the factors associated with the use of this route. METHODS: We carried out a cross-sectional study of 27,655 people admitted to outpatient treatment for heroin dependence in 15 of the 17 Autonomous Communities of Spain during 1991, using data provided by the State Information System on Drug Abuse (SEIT). To assess the association of some factors with use of the intravenous route crude and logistic analysis was performed. RESULTS: The prevalence of intravenous administration in this population was 64.4% with regional differences ranging between 33% and 90%. Crude and logistic analysis demonstrated a strong association with two factors in addition to geography: the year of first use and the age at first use (the earlier the first use, the greater the strength of the association). CONCLUSIONS: These findings are of paramount importance for the control of the HIV epidemic in Spain and further study in this area could help to guide policy development.

Geographical variations in the prevalence of HIV infection among drug users receiving ambulatory treatment in Spain.

To identify the factors responsible for the regional differences in HIV-positive serostatus among drug users in Spain receiving outpatient treatment, the 17 autonomous regions into which Spain is divided were classified as high (mean 52%) or low prevalence groups (mean 34%) depending on the prevalence of seropositivity. In regions where the prevalence of positive serostatus was high, unemployment was more markedly associated with HIV infection than in low prevalence regions, while other potential risk factors yielded the same strength of association. Even so, adjustment for all the factors only accounted for 13% of the total difference in HIV+ prevalence between regions. The current distribution of risk factors among the two groups of autonomous regions does not explain these differences.

PIP: The objective was to identify the factors responsible for the regional differences in HIV-positive serostatus among outpatient drug users (OPDU) in the 17 autonomous regions (AR) of Spain who were receiving ambulatory treatment for opiate or cocaine abuse between April and September 1989. In 83 participating outpatient treatment centers, 1233 patients were recruited. HIV serostatus was obtained for 809 OPDU (65.6%), 18 (2.2%) declined to know their results. A questionnaire collected basic demographic information, data on drug consumption practices, sexual habits, knowledge of HIV and its transmission, desired treatment, and changes in risk behaviors after treatment for drug dependency or after learning of their HIV-positive serostatus. Significant differences were found for sharing injecting equipment, use of condoms, and years of prior drug use. The low-prevalence group (LPG), where mean prevalence was 0.34 (or a mean of 34% among the OPDU), comprised Andalusia, Aragon, Asturias, Balearic Islands, Canary Islands, Cantabria, Valencia, Castilla-La Mancha, Castilla Leon, Extremadura, Murcia, and Navarre. The HIV high prevalence of 0.52 (or a mean of 52% among the OPDU) comprised the regions of Catalonia, Madrid, Basque Country, Galicia, and La Rioja. In the LPG, duration in years of prior drug use, use of non-sterile syringe, and frequency of condom use were significantly associated with the prevalence of HIV infections, while low educational level almost achieved a significant adjusted prevalence odds ratio. In the HPG, only employment status (unemployment) and 3 years of prior drug use were significantly related to seropositivity. In the LPG, the predominant age group was 20-24 years, while in the HPG, it was 25-29 years. The crude association of HPG with seropositivity gave a crude prevalence odds ratio of 2.08. Adjustment for all the factors accounted for only 13% of the total difference in HIV prevalence between regions.

Genotypic analysis of diffuse, mixed cell lymphomas. Comparison with morphologic and immunophenotypic findings.

Malignant lymphoma, diffuse, mixed small and large cell type, as defined in the Working Formulation, is heterogeneous both morphologically and immunophenotypically and, in some cases, clonality may be difficult to determine. Because gene rearrangement analysis has been shown to be a sensitive method for determining clonality, the authors genotyped 20 cases and compared the results with histologic and immunophenotypic findings. Immunophenotypic studies demonstrated that all lesions were composed predominantly of T cells. In addition, in eight cases either a monoclonal B-cell population (five lesions) or an aberrant immunophenotype (two T, one B) was detected, supporting a malignant diagnosis. In seven of these eight lymphomas, genotypic analysis confirmed the presence of a population of clonal cells. One case with an abnormal T-cell phenotype was germline. In 12 cases the immunophenotypic results were uncertain (i.e., no clonal population or abnormal immunophenotype was identified). Genotypic analysis provided evidence of clonality in eight. In four cases with uncertain immunophenotypic results, a clonal population also could not be identified with the use of Southern blot analysis. Thus, the authors conclude that gene rearrangement analysis is a valuable tool in the study of diffuse mixed cell lymphomas and is complementary to immunophenotypic studies. In addition, the authors analyzed the major breakpoint region of the bcl-2 protooncogene on chromosome 18, either by Southern blot analysis and/or with the polymerase chain reaction. The authors identified the t(14;18)(q32;q21) translocation in seven B-cell lymphomas, five of which were not considered to be of follicular center cell type on the basis of morphologic findings. These results suggest that the histologic spectrum of follicular center cell lymphomas is greater than is appreciated in the literature.

Mn2(+)-activated aspartate aminopeptidase activity, subcellular localization in young and adult rat brain.

The levels of soluble and membrane-bound aminopeptidase activities were assayed in subcellular fractions from young (4 weeks old) and adult (20 weeks old) rat brains, using Asp-2-naphthylamide as substrate. The young rats showed the highest soluble and membrane-bound levels of activity in the microsomal fraction but no differences among fractions were found at 20 weeks of age. The membrane-bound activity was significantly higher than the soluble one in all subcellular fractions of young rats. Soluble activity of the homogenate and the mitochondrial fraction was significantly increased in adult animals when compared to that of younger ones.

Detection of anti-interferon-gamma autoantibodies in subjects infected by Mycobacterium tuberculosis.

SETTING: Among the cytokines involved in defensive mechanisms against Mycobacterium tuberculosis infection, special attention has been given to interferon-gamma (IFN-gamma); a local synthesis of this cytokine as well as IL-2 (type 1 cytokines) at the site of disease in patients with tuberculous pleuritis has been demonstrated. Moreover, high levels of IgG autoantibodies against IFN-gamma have been shown in several clinical situations. It has been suggested that these antibodies could serve to limit the intensity or duration of the immune response or be able to interfere with the pathophysiological effects of IFN-gamma. OBJECTIVE: To investigate the potential role of anti-IFN-gamma antibodies in the course of M. tuberculosis infection. DESIGN: Investigation of the presence of these antibodies in sera from healthy and ill subjects infected with M. tuberculosis in relation to the extent of the disease and the presence of IFN-gamma in sera by enzyme-linked-immunosorbent assay (ELISA). In order to investigate the presence of these antibodies at the site of infection we included 12 pleural fluids from tuberculosis patients and 9 pleural fluids from other origins. RESULTS: In the course of M. tuberculosis infection the production of anti-IFN-gamma IgG antibodies is induced, being particularly higher in healthy skin test converters. Among tuberculosis patients, the presence of anti-IFN-gamma autoantibodies is significantly associated with detectable levels of the cytokine in sera. Levels of anti-IFN-gamma antibodies in moderately advanced and far advanced tuberculosis patients are significantly greater than in healthy individuals. These antibodies increase at the site of infection. CONCLUSION: Anti-IFN-gamma antibodies must be considered as a new element in the immune response to M. tuberculosis. It would be of great interest to investigate this point especially at the site of infection.

Validity of self reported utilisation of primary health care services in an urban population in Spain.

STUDY OBJECTIVE: To assess the validity and factors related with the validity of self reported numbers of visits to a primary health care centre, in comparison with the recorded number. DESIGN: Cross sectional study. SETTING: The urban area served by the Zaidín-Sur Primary Health Care Centre (Granada, Spain). PARTICIPANTS: Two population samples (236 high users and 420 normal users) who were seen at the centre from 1985 to 1991 were interviewed in 1993. MAIN RESULTS: A net tendency to overreport the actual number of visits was observed. Absolute concordance between self reported and recorded utilisation decreased as time interval lengthened, although this mainly reflected the increase in maximum variability both with time interval length and with the number of recorded visits. Corrected Spearman rho coefficients obtained between the number of self reported and recorded visits ranged from 0.602 for the two weeks before the interview to 0.678 for the year before. Regression slopes of self reported utilisation upon recorded utilisation did not change between periods. In multiple regression analyses the actual number of visits was the main factor associated with both underreporting and overreporting. Older age was also significantly associated with underreporting. Poor health status and high satisfaction with health care were significantly associated with overreporting. CONCLUSIONS: There was a substantial degree of inaccuracy in self reported utilisation, with a net tendency to overreport the number of visits. In relative terms, however, accuracy of self reports did not seem to decrease appreciably as the recall time lengthened. To compare the accuracy of different measures, it is important to take into account the maximum variability of each one. Otherwise, contradictory results may be obtained.

Influence of socioeconomic and health care development on infant and perinatal mortality in Spain 1975-86.

STUDY OBJECTIVE: This study aimed to analyse the influence of social, economic, and health development on infant and perinatal mortality in Spain between 1975 and 1986, and to identify possible changes in these relationships over time. DESIGN: Study of the association between mortality and a range of variables. SETTING: 50 Spanish provinces. MEASUREMENTS AND MAIN RESULTS: Mean infant and perinatal mortality were estimated for two periods--1975-8 and 1983-6. Social, economic, and health care indicators were collected as independent variables for these two periods. The rates of variation between periods were estimated for each variable. Multiple linear regression models were used to define the association between infant and perinatal mortality and their respective rate of variation with the former indicators. Mean familial income was the main predictive factor for infant and perinatal mortality in the first period but in the second period health care indicators were more relevant. CONCLUSIONS: The reduction in Spanish infant and perinatal mortality over the period can be attributed mainly to the improvement in prenatal and neonatal health care in Spain in recent years, while economic factors seem less important.

IV drug users: changes in risk behaviour according to HIV status in a national survey in Spain.

STUDY OBJECTIVE: To determine whether HIV positive intravenous drug users (IVDUs) who were receiving outpatient treatment for opiate and cocaine abuse or dependence used practices aimed at reducing the spread of HIV. DESIGN: Cross sectional study of behaviour and HIV serostatus in IVDUs. SETTING: A nationwide sample, from 83 health centres for outpatient treatment, stratified by autonomous regions. PARTICIPANTS: Altogether 1074 IVDUs were recruited. HIV serostatus could be verified in 738 (68.7%) of these. MEASUREMENTS AND MAIN RESULTS: Crude and adjusted odds ratios and their 95% confidence intervals were estimated to assess the association between HIV serostatus and behavioural changes. In their daily interactions with other members of the same household, seropositive subjects more frequently used preventive methods aimed at avoiding transmission than seronegative patients. Treatment for abuse or dependency before the current regimen had a greater impact in HIV positive than HIV negative subjects in terms of abstaining from risk behaviours. There was a significant trend toward lower drug consumption in HIV positive subjects, and the number of seropositive and seronegative IVDUs who stopped injecting their drugs was significantly higher among the former. Seropositive subjects were also more likely to stop sharing drug injecting equipment and to change their sexual habits; they reported an increased consistent use of condoms. CONCLUSIONS: HIV positive IVDUs were more likely to change their risk behaviours than their HIV negative counterparts.

HIV-transmission knowledge in drug users from outpatient facilities in Spain. A national survey.

Knowledge of AIDS and its transmission was studied in patients undergoing drug-dependence treatment for opiates and/or cocaine. The study area included all of Spain and was carried out via a questionnaire assessing information about risk practices, HIV serostatus, etc, and 13 true or false questions concerning HIV-transmission knowledge. The main purpose of the present study was to analyse the relationship between the level of information found in patients and factors potentially related to it, including the practice of high-risk activities for HIV transmission, the sources of information and behaviour modification. Findings indicate that poor information was associated with the use of non-sterile needles, anal-penis sexual relations, non-use of condoms, lack of preventive measures in daily cohabitation, and lack of previous drug-dependence treatment. Determining factors of being well-informed were a high level of education, a longer duration of intravenous drug use, and contact with the Health Service as a source of information. These findings partially support the need to implement programs aimed at improving knowledge about HIV in the population of drug users.

Infant, neonatal, postneonatal and perinatal mortality in Spain, 1975-1984. Interregional and interannual differences.

The national infant, neonatal, postneonatal and perinatal mortality in Spain does not reflect the differences which exist among regions. The aim of the present study is to demonstrate and to quantify these differences, as well as their annual trends. We have also attempted to define groups of regions presenting similar rates. The results of the study confirmed a decrease in all mortality rates during the analyzed period. Regions were grouped according to their rates. Differences between the top and the bottom groups (with the lowest and the highest rates, respectively) resulted in statistical significance. However, the differences between these and the middle groups were not sharply defined. In addition, a clear geographic aggregation was evidenced in both top and bottom groups. These differences are mainly due to economic and sanitary factors.

Presence of cytomegalovirus genome and leucocyte subsets in renal transplant biopsies. Relationship with prognosis.

The influence of immunosuppressant therapy and of the presence of CMV genome on the distribution of lymphoid subpopulations of the inflammatory infiltrate in renal graft rejection was analyzed, as was the role of both factors in the evolution and survival of the graft. The study included 22 patients treated with Cyclosporin A (CsA) and 22 patients treated with Azathioprine (AZA). Inflammatory infiltrate was studied by immunostaining with a panel of monoclonal antibodies, and CMV DNA was detected by in situ hybridization on tissue sections. In patients treated with CsA, increased cellularity was found at both glomerular and interstitial levels, consisting mainly of macrophages and T-cells, which was consistent with the higher rate of glomerulointerstitial rejection found in this group. In contrast, the vascular type of rejection predominated in AZA treated patients. However, the presence of CMV DNA did not influence the phenotype of the inflammatory infiltrate, and was not associated with any specific lesion. Furthermore, the final outcome of the renal graft was independent of the detection of CMV. Therefore, this study provides no evidence of any active role of the CMV genome in renal graft rejection, and suggests that therapy should be adapted to the type of rejection as defined on morphologic and immunophenotypic grounds.