Evolución del melanoma maligno cutáneo en los últimos 19 años en un hospital terciario de la cuenca mediterránea / changes in incidence of malignant melanoma in the last years in a tertiary Hospital on the Mediterranean coast

Introducción. La incidencia del melanoma ha aumentado más que la de ninguna otra neoplasia maligna. Nuestro objetivo fue analizar la evolución del melanoma cutáneo en los últimos años en una población mediterránea. Material y métodos. Los pacientes con melanoma diagnosticados entre 1988-2006 fueron incluidos en el estudio. Se comparan los datos de la primera mitad con la segunda mitad del periodo analizado. Resultados. El número de melanomas in situ pasó de 36/302 casos (11,92 %) en la primera mitad del periodo a224/724 (30,94 %) en la segunda. Los melanomas mayores de 4 mm pasaron de 29/302 casos (9,60 %) a 62/724(8,56 %). La media de la profundidad máxima fue 1,91 mm y se mantuvo estable a lo largo del periodo. Conclusiones. El aumento de incidencia del melanoma en nuestra población se debe mayoritariamente al incremento de casos incipientes. Sin embargo, se mantiene estable la proporción de melanomas mayores de 4 mm, y en números absolutos se ha duplicado el número anual de melanomas con estas dimensiones. Consideramos que hay que seguir insistiendo en campañas de prevención y detección precoz, especialmente dirigidas a la población de mayor edad (AU)

Introduction. The incidence of melanoma has increased more than that of any other type of malignant tumor. Our aim was to analyze the changes in incidence of cutaneous melanoma in recent years in a Mediterranean population. Material and methods. Patients with melanoma diagnosed between 1988 and 2006 were included in the study. Data from the first half of this period were compared with data from the second half. Results. The number of in situ melanomas increased from 36/302 cases (11.92 %) in the first half of the period to 224/724 (30.94 %) in the second half. Melanomas measuring more than 4 mm increased from 29/302 cases (9.60 %) to 62/724 (8.56 %). The mean maximum thickness for the whole study period was 1.91 mm and was similar for both halves. Conclusions. The increase in incidence of melanoma in our population was due mainly to an increase in incipient cases. The proportion of melanomas larger than 4 mm remained constant, although, in absolute terms, twice as many such melanomas were detected per year. We believe that campaigns for prevention and early detection must continue, and should focus in particular on the older population (AU)

[Changes in incidence of malignant melanoma in the last 19 years in a tertiary hospital on the Mediterranean coast]. / Evolución del melanoma maligno cutáneo en los últimos 19 años en un hospital terciario de la cuenca mediterránea.

INTRODUCTION: The incidence of melanoma has increased more than that of any other type of malignant tumor. Our aim was to analyze the changes in incidence of cutaneous melanoma in recent years in a Mediterranean population. MATERIAL AND METHODS: Patients with melanoma diagnosed between 1988 and 2006 were included in the study. Data from the first half of this period were compared with data from the second half. RESULTS: The number of in situ melanomas increased from 36/302 cases (11.92 %) in the first half of the period to 224/724 (30.94 %) in the second half. Melanomas measuring more than 4 mm increased from 29/302 cases (9.60 %) to 62/724 (8.56 %). The mean maximum thickness for the whole study period was 1.91 mm and was similar for both halves. CONCLUSIONS: The increase in incidence of melanoma in our population was due mainly to an increase in incipient cases. The proportion of melanomas larger than 4 mm remained constant, although, in absolute terms, twice as many such melanomas were detected per year. We believe that campaigns for prevention and early detection must continue, and should focus in particular on the older population.

Prolactin, growth hormone, and epidermal growth factor activate Stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects.

Prolactin (Prl)-induced phosphorylation of Stat (signal transducer and activator of transcription) 5 is considered a key event in functional mammary development and differentiation. We now demonstrate that not only Prl, but also growth hormone (GH) and epidermal growth factor (EGF), can activate Stat5 in mammary tissue. We investigated the roles of these hormones in mammary development using mice in which the respective receptors had been inactivated. Although Prl receptor (PrlR)-null mice are infertile, we were able to maintain pregnancies in a few mice by treatment with progesterone. Mammary tissue in these mice was severely underdeveloped and exhibited limited differentiation as assessed by the phosphorylation status of Stat5 and the expression of milk protein genes. PrlR +/- mice showed impaired mammary development and alveolar differentiation during pregnancy, which corresponded with reduced phosphorylation levels of Stat5a and 5b, and impaired expression of milk protein genes. Development of the glands in these mice was arrested at around day 13 of pregnancy. While Prl activated Stat5 only in the epithelium, GH and EGF activated Stat5 preferentially in the stroma. To assess the relevance of the GH receptor (GHR) in the mammary gland, we transplanted GHR-null epithelium into cleared fat pads of wild-type mice. These experiments demonstrated that the GHR in the epithelium is not required for functional mammary development. Similarly, the EGFR in the epithelium is not required for alveolar development. In contrast, epithelial PrlR is required for mammary development and milk protein gene expression during pregnancy. Although GH is not required for alveolar development, we were able to demonstrate its lactogenic function in cultured mammary epithelium from PrlR-null mice. However, ductal development in GHR-null mice was impaired, supporting the notion that GH signals through the stromal compartment. Our findings demonstrate that GH, Prl, and EGF activate Stat5 in separate compartments, which in turn reflects their specific roles in ductal and alveolar development and differentiation.

Functional rescue of Stat5a-null mammary tissue through the activation of compensating signals including Stat5b.

Prolactin induces mammopoiesis and lactogenesis through the Janus kinase-signal transducers and activators of transcription pathway, with Stat5a being a principal and obligate cytoplasmic and nuclear signaling molecule. Mice from which the Stat5a gene has been deleted fail to develop functional mammary tissue during their first pregnancy. Lobuloalveolar outgrowth is curtailed, and epithelial cells fail to progress to functional differentiation. Here, we investigate whether the effect of Stat5a deficiency is restricted to the epithelium and whether the gland has the capacity to activate alternative signaling pathways that could restore development and function. Mammary gland transplant experiments showed that Stat5a-deficient epithelium does not differentiate in wild-type stroma, thus demonstrating a cell-autonomous role for Stat5a. The capacity of Stat5a-deficient mammary tissue to develop and secrete milk was measured after consecutive pregnancies and with postpartum suckling. Neither of these regimens could independently restore lactation. However, the combination of several pregnancies and suckling stimuli resulted in a partial establishment of lactation and an increase of Stat5b activity. These experiments demonstrate that the mammary gland has inherent plasticity that allows it to use different signals to achieve its ultimate purpose, the production of milk to nurture newborn offspring.

Recurrent integration of papillomavirus DNA within the human 12q14-15 uterine breakpoint region in genital carcinomas.

Genital carcinomas are associated with human papillomaviruses, and the viral DNA is frequently integrated in the host cell genome. Recurrent chromosomal alterations are genetic markers for specific tumor phenotypes. To demonstrate that papillomavirus DNA integration is indeed a recurrent chromosomal aberration, we mapped two independent papillomavirus integration sites in the human 12q14-15 region, one containing HPV16 DNA and the other HPV18 DNA. The two HPV integration sites map approximately 10 kbp from each other within the cosmid LLNL12NCO1-196E1 clone. The integration site corresponding to HPV16 DNA in SK-v cells is proximal to the 5' end of a DNA segment known to be rearranged by integration of HPV18 DNA in another cervical carcinoma cell line, SW756. Both integrations are located in the PAL2 locus within the uterine leiomyoma cluster region of translocation.

The production of MLR-blocking factors after lymphocyte immunotherapy for RSA does not predict the outcome of pregnancy.

PROBLEM: The questions of whether production of mixed lymphocyte reaction-blocking factors (MLR-BFs) after immunotherapy with lymphocytes for recurrent spontaneous abortion (RSA) has prognostic value and whether cytotoxic antibodies are also involved were tested. METHOD OF STUDY: A prospective study with 33 patients who had a history of two or more abortions, lacking MLR-BFs, was carried out. The patients received immunizations with lymphocytes and 6 weeks or later were tested for seroconversion of MLR-BFs. Seventeen of these thirty-three patients were evaluated for antipaternal cytotoxic antibodies. The results were correlated with the outcome of the next pregnancy after treatment. RESULTS: Eighty percent of the 33 patients had a live child. Of those patients having success, only 50% produced MLR-BFs. Of those patients having a new loss, five did and two did not produce MLR-BF (P > 0.05). Regarding the 17 patients tested for cytotoxic antibodies, 4 of the 5 patients who tested positive had a new abortion, whereas only 1 of 12 whose tests remained negative did not have gestational success (P < 0.01). CONCLUSION: The presence of MLR-BFs is not a prognostic criterium for the outcome of pregnancy after alloimmunotherapy, and, consequently, it is not a good diagnostic tool for RSA of alloimmune cause.

Complex genomic rearrangement within the 12q15 multiple aberration region induced by integrated human papillomavirus 18 in a cervical carcinoma cell line.

Human papillomavirus (HPV) DNA is integrated into the host genome in cervical cancer. The cervical carcinoma cell line SW756 has integrated HPV-18 DNA in chromosome region 12q15, in the papillomavirus-associated locus-2 (PAL2). By polymerase chain reaction and hybridization of an arrayed cosmid library with oligonucleotides from the rearranged allele, we determined the pre-integration germline structure of the region. PAL2 was located approximately 10 kb from sequence-tagged site marker U27131, which was the marker most proximal to the 3' flank of the integrated viral DNA. HPV-18 DNA integration induced a complex genomic rearrangement resulting in inversion and deletion of cellular sequences. PAL2 is within the multiple aberration region, which has been shown to be affected in several types of benign tumors of mesenchymal origin. The integrated viral DNA was located 50 kb from a CpG island and 150 kb upstream of the high-mobility group I-C (HMGI-C) gene. The HMGI-C gene and the integrated HPV-18 DNA had opposite transcriptional orientations. No overexpression or altered message of the HMGI-C gene was detected in three cervical carcinoma cell lines. The integrated viral DNA did not affect any other known gene in the region and may be a marker for an unknown gene associated with malignant tumor phenotypes.

Deletion in human chromosome region 12q13-15 by integration of human papillomavirus DNA in a cervical carcinoma cell line.

In human cervical carcinomas papillomavirus DNA is frequently integrated in the cell genome. We have cloned the integration site of human papillomavirus-18 DNA in human chromosome region 12q13-15 present in the SW756 cervical carcinoma cell line. Viral DNA is broken from nucleotides 2643 to 3418 in the E1 and E2 open reading frames, resulting in a deletion of 775 bases of viral DNA. Cloning and sequence analysis of the rearranged and germline alleles shows that there is no homology between the target cellular and viral DNA, suggesting it is a nonhomologous recombination. The target cellular region is called papillomavirus associated locus 2 (PAL2). The 5'- and 3'-flanking probes derived from the hybrid viral-cellular clone detect completely different germline restriction fragments in DNA from cells with normal chromosome 12. There is no overlap between the restriction maps of the target germline clones obtained with 5'- and 3'-flanking probes. Probes from these germline clones beyond the breakpoint position do not detect any DNA rearrangement in SW756 cells DNA. These data prove that there is a deletion of cellular DNA as consequence of the integration, with an estimated minimum size of 14 kilobases. Both cellular flanking probes are outside the amplicon of this chromosome region identified in the OSA and RMS13 sarcoma cell lines, comprising SAS-CHOP-CDK4-MDM2 genes and where translocation breakpoints are located in liposarcomas. The integration at 12q13-15 might have been selected by its contribution to the tumor phenotype.

The human zinc-finger protein-7 gene is located 90 kb 3' of MYC and is not expressed in Burkitt lymphoma cell lines.

The zinc-finger gene-7 (ZNF7) was located 90 kb 3' of MYC on human chromosome 8 band q24 by pulsed-field gel electrophoresis (PFGE). This position lies between the MLV14 and BVR1 loci, 2 variant translocation breakpoints in Burkitt lymphomas. The structure of the ZNF7 gene was not altered by translocations in Burkitt-lymphoma cell lines as shown by its germline-restriction map configuration. The chromosomal region surrounding the ZNF7 gene was extensively methylated. The ZNF7 gene was not expressed in 19 BL cell lines. Expression was detected only in the BL41 and BL47 cell lines and in the SW756 cervical-carcinoma cell line. The RNA in each was of a different size. We postulate that the lack of ZNF7 expression in Burkitt lymphomas might contribute to the tumor phenotype.

Integration site of human papillomavirus type-18 DNA in chromosome band 8q22.1 of C4-I cervical carcinoma: DNase I hypersensitivity and methylation of cellular flanking sequences.

The C4-I cell line derived from a non-keratinizing squamous cell carcinoma of the uterine cervix contains integrated human papillomavirus-18 DNA. Fluorescence in situ hybridization of C4-I cells demonstrated a single viral integration site at 8q22.1 on a derivative chromosome originating from an 8q;12q translocation. 8q22 is a site of chromosome fragility and is also recombinogenic in several human malignancies. DNase I hypersensitivity of the integration site was studied with a cellular flanking probe. A hypersensitive site was detected within 3 kb from viral DNA. The integration sites are undermethylated in C4-I and HeLa cells and fully methylated in tumor cell lines of other origin, such as lymphoid cells.

Variant translocations in two Burkitt's lymphoma cell lines are located in the MLV14 locus.

The human MLV14 locus, located 20 kilobases 3' of MYC, is rearranged in two Burkitt's lymphoma cell lines with either a t(2;8)(p12;q24) or t(8;22)(q24;q11). Alterations of MLV14 may have prognostic significance in some types of B-cell malignancies.

Genetic alterations by human papillomaviruses in oncogenesis.

The integration sites in the cellular genome of human papillomavirus are located in chromosomal regions always associated with oncogenes or other known tumor phenotypes. Two regions, 8q24 and 12q13, are common to several cases of cervical carcinoma and can have integrated more than one type of papillomavirus DNA. These two chromosomal regions contain several genes implicated in oncogenesis. These observations strongly imply that viral integration sites of DNA tumor viruses can be used as the access point to chromosomal regions where genes implicated in the tumor phenotype are located, a situation similar to that of non-transforming retroviruses.

Prevalence of parasite eggs and cysts in faeces from dairy cows in Colombia.

When 1,711 bovine faecal samples from 113 farms in eight dairy areas of Colombia were examined for the presence of helminth eggs Fasciola hepatica eggs were found in the faeces from 60% of the farms and samples from animals kept above 2,000 m. Strongyle eggs were found in faeces from 82% of the farms and in 18% of the samples.

Levels of some reproductive diseases in the dairy cattle of Colombia.

Of 4,144 serum samples collected from cows on 113 farms from eight areas of Colombia 3.3% had positive and 8.8% inconclusive titres to Brucella abortus, 21.7, 6.3, 1.6, 0.6 and 0.7% of cows had positive titres to Leptospira serovars hardjo, pomona, canicola, icterohaemorrhagiae and grippotyphosa respectively. Questionnaires completed on 110 farms revealed that 6, 2.5 and 4.6% of cows had had metritis, aborted or retained their placentas respectively in the previous 12 months. Trichomonas foetus and Campylobacter fetus were isolated from 13.7% and 15% of the bulls sampled on 103 farms. Six and two bulls had inconclusive and positive titres to Brucella abortus. Eight and 23 bulls had positive titres to pomona and hardjo. The results were discussed and remedies for control suggested.