Assessment of BRCA1 and BRCA2 Germline Variant Data From Patients With Breast Cancer in a Real-World Data Registry.

PURPOSE: The emergence of large real-world clinical databases and tools to mine electronic medical records has allowed for an unprecedented look at large data sets with clinical and epidemiologic correlates. In clinical cancer genetics, real-world databases allow for the investigation of prevalence and effectiveness of prevention strategies and targeted treatments and for the identification of barriers to better outcomes. However, real-world data sets have inherent biases and problems (eg, selection bias, incomplete data, measurement error) that may hamper adequate analysis and affect statistical power. METHODS: Here, we leverage a real-world clinical data set from a large health network for patients with breast cancer tested for variants in BRCA1 and BRCA2 (N = 12,423). We conducted data cleaning and harmonization, cross-referenced with publicly available databases, performed variant reassessment and functional assays, and used functional data to inform a variant's clinical significance applying American College of Medical Geneticists and the Association of Molecular Pathology guidelines. RESULTS: In the cohort, White and Black patients were over-represented, whereas non-White Hispanic and Asian patients were under-represented. Incorrect or missing variant designations were the most significant contributor to data loss. While manual curation corrected many incorrect designations, a sizable fraction of patient carriers remained with incorrect or missing variant designations. Despite the large number of patients with clinical significance not reported, original reported clinical significance assessments were accurate. Reassessment of variants in which clinical significance was not reported led to a marked improvement in data quality. CONCLUSION: We identify the most common issues with BRCA1 and BRCA2 testing data entry and suggest approaches to minimize data loss and keep interpretation of clinical significance of variants up to date.

Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.

Variants of uncertain significance (VUSs) in BRCA2 are a common result of hereditary cancer genetic testing. While more than 4,000 unique VUSs, comprised of missense or intronic variants, have been identified in BRCA2, the few missense variants now classified clinically as pathogenic or likely pathogenic are predominantly located in the region encoding the C-terminal DNA binding domain (DBD). We report on functional evaluation of the influence of 462 BRCA2 missense variants affecting the DBD on DNA repair activity of BRCA2 using a homology-directed DNA double-strand break repair assay. Of these, 137 were functionally abnormal, 313 were functionally normal, and 12 demonstrated intermediate function. Comparisons with other functional studies of BRCA2 missense variants yielded strong correlations. Sequence-based in silico prediction models had high sensitivity, but limited specificity, relative to the homology-directed repair assay. Combining the functional results with clinical and genetic data in an American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP)-like variant classification framework from a clinical testing laboratory, after excluding known splicing variants and functionally intermediate variants, classified 431 of 442 (97.5%) missense variants (129 as pathogenic/likely pathogenic and 302 as benign/likely benign). Functionally abnormal variants classified as pathogenic by ACMG/AMP rules were associated with a slightly lower risk of breast cancer (odds ratio [OR] 5.15, 95% confidence interval [CI] 3.43-7.83) than BRCA2 DBD protein truncating variants (OR 8.56, 95% CI 6.03-12.36). Overall, functional studies of BRCA2 variants using validated assays substantially improved the variant classification yield from ACMG/AMP models and are expected to improve clinical management of many individuals found to harbor germline BRCA2 missense VUS.

Saturation genome editing-based functional evaluation and clinical classification of BRCA2 single nucleotide variants.

Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to breast, ovarian, prostate and pancreatic cancer. However, variants of uncertain significance (VUS) (n>4000) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all BRCA2 variants. Here we report on comprehensive saturation genome editing-based functional characterization of 97% of all possible single nucleotide variants (SNVs) in the BRCA2 DNA Binding Domain hotspot for pathogenic missense variants that is encoded by exons 15 to 26. The assay was based on deep sequence analysis of surviving endogenously targeted haploid cells. A total of 7013 SNVs were characterized as functionally abnormal (n=955), intermediate/uncertain, or functionally normal (n=5224) based on 95% agreement with ClinVar known pathogenic and benign standards. Results were validated relative to batches of nonsense and synonymous variants and variants evaluated using a homology directed repair (HDR) functional assay. Breast cancer case-control association studies showed that pooled SNVs encoding functionally abnormal missense variants were associated with increased risk of breast cancer (odds ratio (OR) 3.89, 95%CI: 2.77-5.51). In addition, 86% of tumors associated with abnormal missense SNVs displayed loss of heterozygosity (LOH), whereas 26% of tumors with normal variants had LOH. The functional data were added to other sources of information in a ClinGen/ACMG/AMP-like model and 700 functionally abnormal SNVs, including 220 missense SNVs, were classified as pathogenic or likely pathogenic, while 4862 functionally normal SNVs, including 3084 missense SNVs, were classified as benign or likely benign. These classified variants can now be used for risk assessment and clinical care of variant carriers and the remaining functional scores can be used directly for clinical classification and interpretation of many additional variants. Summary: Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to several types of cancer. However, variants of uncertain significance (VUS) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all BRCA2 variants to facilitate current and future clinical management of individuals with these variants. Here we show the results from a saturation genome editing (SGE) and functional analysis of all possible single nucleotide variants (SNVs) from exons 15 to 26 that encode the BRCA2 DNA Binding Domain hotspot for pathogenic missense variants. The assay was based on deep sequence analysis of surviving endogenously targeted human haploid HAP1 cells. The assay was calibrated relative to ClinVar known pathogenic and benign missense standards and 95% prevalence thresholds for functionally abnormal and normal variants were identified. Thresholds were validated based on nonsense and synonymous variants. SNVs encoding functionally abnormal missense variants were associated with increased risks of breast and ovarian cancer. The functional assay results were integrated into a ClinGen/ACMG/AMP-like model for clinical classification of the majority of BRCA2 SNVs as pathogenic/likely pathogenic or benign/likely benign. The classified variants can be used for improved clinical management of variant carriers.

Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer.

PURPOSE: To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS). EXPERIMENTAL DESIGN: A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes. RESULTS: One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE. CONCLUSIONS: Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the MHC I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.

Two distinct mechanisms underlie estrogen-receptor-negative breast cancer susceptibility at the 2p23.2 locus.

Genome wide-association studies (GWAS) have established over 400 breast cancer risk loci defined by common single nucleotide polymorphisms (SNPs), including several associated with estrogen-receptor (ER)-negative disease. Most of these loci have not been studied systematically and the mechanistic underpinnings of risk are largely unknown. Here we explored the landscape of genomic features at an ER-negative breast cancer susceptibility locus at chromosome 2p23.2 and assessed the functionality of 81 SNPs with strong evidence of association from previous fine mapping. Five candidate regulatory regions containing risk-associated SNPs were identified. Regulatory Region 1 in the first intron of WDR43 contains SNP rs4407214, which showed allele-specific interaction with the transcription factor USF1 in in vitro assays. CRISPR-mediated disruption of Regulatory Region 1 led to expression changes in the neighboring PLB1 gene, suggesting that the region acts as a distal enhancer. Regulatory Regions 2, 4, and 5 did not provide sufficient evidence for functionality in in silico and experimental analyses. Two SNPs (rs11680458 and rs1131880) in Regulatory Region 3, mapping to the seed region for miRNA-recognition sites in the 3' untranslated region of WDR43, showed allele-specific effects of ectopic expression of miR-376 on WDR43 expression levels. Taken together, our data suggest that risk of ER-negative breast cancer associated with the 2p23.2 locus is likely driven by a combinatorial effect on the regulation of WDR43 and PLB1.

Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance.

PURPOSE: BRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for thousands of variants to aid in variant classification. METHODS: We have collected, curated, and harmonized functional data for 2701 missense variants representing 24.5% of possible missense variants in BRCA1. Results were harmonized across studies by converting data into binary categorical variables (functional impact versus no functional impact). Using a panel of reference variants we identified a subset of assays with high sensitivity and specificity (≥80%) and apply the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to assign evidence criteria for classification. RESULTS: Integration of data from validated assays provided ACMG/AMP evidence criteria in favor of pathogenicity for 297 variants or against pathogenicity for 2058 representing 96.2% of current VUS functionally assessed. We also explore discordant results and identify limitations in the approach. CONCLUSION: High quality functional data are available for BRCA1 missense variants and provide evidence for classification of 2355 VUS according to their pathogenicity.

A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants.

We sought to identify susceptibility genes for high-grade serous ovarian cancer (HGSOC) by performing a transcriptome-wide association study of gene expression and splice junction usage in HGSOC-relevant tissue types (N = 2,169) and the largest genome-wide association study available for HGSOC (N = 13,037 cases and 40,941 controls). We identified 25 transcriptome-wide association study significant genes, 7 at the junction level only, including LRRC46 at 19q21.32, (P = 1 × 10-9), CHMP4C at 8q21 (P = 2 × 10-11) and a PRC1 junction at 15q26 (P = 7 × 10-9). In vitro assays for CHMP4C showed that the associated variant induces allele-specific exon inclusion (P = 0.0024). Functional screens in HGSOC cell lines found evidence of essentiality for three of the new genes we identified: HAUS6, KANSL1 and PRC1, with the latter comparable to MYC. Our study implicates at least one target gene for 6 out of 13 distinct genome-wide association study regions, identifying 23 new candidate susceptibility genes for HGSOC.

Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus.

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. SIGNIFICANCE: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene.See related commentary by Choi and Brown, p. 439.

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Análise computacional do dano térmico no olho humano portador de um melanoma de coroide quando submetido à termoterapia transpupilar a laser / Computational analysis of thermal damage in the human eye carrying a choroidal melanoma when exposed to laser transpupillary thermotherapy treatment

Este trabalho apresenta um modelo bidimensional do olho humano para investigar a evolução da temperatura em estado transitório e o dano térmico associado nas camadas do olho e, principalmente, no melanoma de coroide. A modelagem e simulação computacional foram executadas para um paciente portador de um melanoma de coroide, submetido a um tratamento por irradiação com laser. Para determinar o campo de temperaturas, foi desenvolvido um modelo que utiliza a equação da biotransferência de calor de Pennes (BHTE - Bioheat Transfer Equation) que possui um termo de fonte/sumidouro que responde pelo calor transferido através da perfusão sanguínea. O modelo de Birngruber foi utilizado para determinar a função dano térmico durante a termoterapia transpupilar a laser (TTT). A análise foi efetuada a partir de uma imagem de ultrassom do paciente. Este tipo de exame forneceu as dimensões do olho e do tumor. O software comercial de CFD (Computational Fluid Dynamics) FLUENT, que emprega o Método dos Volumes Finitos (MVF), foi utilizado nas análises do modelo. Foram calculadas as temperaturas em estado estacionário para o olho não irradiado e estes resultados foram utilizados como condição inicial para a simulação de estado transitório para o olho irradiado, durante 60 segundos, com um laser de diodo (810 nm e potências de saída de 178, 222, 400 e 500 mW) cujos feixes apresentavam diâmetros de 2,0 e 3,0 mm e intensidades de 56.588 W/m² e 70.736 W/m² sobre a córnea. Para validar o modelo, os resultados das temperaturas, em estado estacionário para o olho não exposto à radiação do laser, foram comparados com outros mostrando uma boa concordância entre eles. Os resultados das temperaturas e do dano térmico, estado transitório, para o olho irradiado com o laser estão, qualitativamente, em acordo com a literatura disponível.

This paper presents a two-dimensional model of the human eye to investigate the evolution of temperature in transient state and the associated thermal damage in the layers of the eye and, especially in the choroidal melanoma. The computer modeling and simulation were performed for a patient with a choroidal melanoma, undergoing treatment by laser irradiation. To determine the temperature field, we developed a model that uses the Pennes Bioheat Transfer Equation (BHTE) that has a term of source/sink that responds to the heat transferred through the blood perfusion. The Birngruber model was used to determine the function of thermal damage during the laser transpupillary thermotherapy (TTT). The analysis was carried out from an ultrasound image of the patient. This type of examination provided the dimensions of the eye and the tumor. The CFD (Computational Fluid Dynamics) commercial software FLUENT&®, which uses the Finite Volume Method (FVM) was used in the analysis of the model. The temperatures, steady-state, were calculated for the normal eye, i.e, without laser irradiation and these results were used as initial condition for the simulation of transient state to the eye irradiated for 60 seconds with a diode laser (810 nm and output power of 178, 222, 400 and 500 mW) whose beam had a diameter of 2.0 to 3.0 mm and irradiance of 56,588 and 70,736 W/m² on the cornea. To validate the model, the results of temperatures, in steady state to the eye not exposed to laser radiation, were compared with others showing a good agreement between them. The results of thermal damage and transient state, for the eye irradiated by the laser, show that the values of damage depth are in agreement with the literature.

Campaigns against homophobia in Argentina, Brazil, Colombia and Mexico

[Executive Summary]. Homophobia is defined as prejudice, stigma or discrimi- nation against people who engage in sexual relations with others of the same sex. It may result in homosexual people hav- ing low self-esteem, difficulty practicing safer sex, and less social support. In some cases, the fear of stigma and discrimination discourages people from requesting HIV testing, counseling, and treatment. In other cases, homophobic behavior actu- ally prevents them from accessing these services. As part of the response to HIV and homophobia, four mass media campaigns were carried out between 2002 and 2005 in Argentina, Brazil, Colombia, and Mexico. This publication describes and analyzes these campaigns, which had a total budget of US$4.2 million. Unlike previous campaigns of a similar nature, these had the support of their respective governments. They presented homophobia as an interrelated problem of rights and public health. They presented non-heterosexual people in a non-dis- criminatory light, and took advantage of the controversy that the issue generated to promote a public dialogue, in some cases unprecedented, among different sec- tors of civil society. Although none of the campaigns were systematically evaluated, the organizers identified various elements that, from their perspective, should be regarded as evi- dence of success. According to the organizers, the campaigns served to create more tolerant environment for homosexual men in the four countries.

Modelagem computacional da biotransferência de calor no tratamento por hipertermia em tumores de duodeno através do método dos volumes finitos em malhas não estruturadas / Computational modeling of the bioheat transfer during the hypertermic treatment of duodenum tumors using an unstructured mesh finite volume method

Tumores de duodeno não-operáveis podem ser irradiados com fontes de laser por via endoscópica. Sua função é causar uma elevação de temperatura local a fim de destruir as células cancerígenas, sem, no entanto, causar dano térmico à região sadia circunvizinha. A exatidão do cálculo das temperaturas está ligada à utilização de métodos numéricos adequados. O presente trabalho apresenta a análise térmica de um procedimento terapêutico, onde um tumor de duodeno de 2 cm de diâmetro é aquecido por uma sonda de laser Nd:YAG, através da utilização do método dos volumes finitos (MVF) para solucionar a equação da biotransferência de calor em malhas bidimensionais triangulares não-estruturadas. É feita uma descrição detalhada do modelo físico-matemático pertinente e da função dano térmico. São apresentadas as propriedades termofísicas dos tecidos envolvidos, bem como a escolha dafonte de laser mais adequada à utilização no procedimento a ser simulado. Em seguida é descrita brevemente a formulação do método dos volumes finitos com estrutura de dados por arestas e apresentados os resultados obtidos da análise térmica dos tecidos.

Tumors that cannot be surgically removed could be irradiated using laser sources through endoscopic procedures. The idea is to increase the local temperature to kill the cancer cells without a thermal damage on the healthy tissues in the neighborhood. The accuracy of the estimated temperatures is directly related to the proper choice ofthe adopted numerical methods. In this work a computational tool using the finite volume method was developed, in order to obtain the approximate equations of the bioheat transfer equation using bidimensional unstructured triangular meshes. The analyzed problem consists of a duodenum tumor with 2 cm of diameter that is heated using a Nd:YAG laser probe. The following items will be described: the appropriate physical-mathematical model; the damage function; the thermo-physical properties of the tissues involved; as well as the choice of the best laser source to be used in the procedure to be simulated. Next, the edge based finite volume formulation is described and the results obtained from the tissue thermal analysis are presented.

Campañas contra la homofobia en Argentina, Brasil, Colombia y México

[Resumen ejecutivo]. La homofobia es el prejuicio, estigma o discriminación hacia las personas que mantienen relaciones sexuales con otras de su mismo sexo. Las personas homóficas pueden tener baja autoestima, experimentar mayores dificultades en adoptar prácticas sexuales seguras, y contar con un menor soporte social. En muchas oportunidades, el temor al estigma y a la discriminación les disuade de solicitar pruebas de detección del VIH, consejería y tratamiento. En otros casos es la misma práctica homofóbica la que les auto impide acceder a estos servicios. Con el propósito de luchar contra el VIH y la homofobia, entre los años 2002 y 2005 se realizaron cuatro campañas de comunicación masiva en los países de Argentina, Brasil, Colombia y México. El presente documento analiza dichas campañas, cuyo presupuesto ascendió a un total de US$ 4.2 millones. A diferencia de campañas previas, éstas contaron con el respaldo del respectivo gobierno; posicionaron la homofobia como un problema de derechos en relación con la salud pública; cuestionaron la homofobia a través de los medios de comunicación masiva y/o presentaron a personas/parejas no heterosexuales desde una visión no discriminatoria; y aprovecharon la controversia creada sobre el tema para generar un debate público, en algunos casos sin precedentes, entre la sociedad civil y el gobierno. Aunque infortunadamente ninguna de las campañas estuvo acompañada de una evaluación sistemática, sus organizadores identificaron algunos elementos que a su modo de ver deben ser considerados como indicios de éxito. Según ellos, las campañas sirvieron para promover el debate hacia una sociedad más inclusiva.

Understanding and responding to HIV/AIDS-related stigma and discrimination in the health sector

This review aims to contribute to deeper understanding of HIV/AIDS-related stigma and discrimination in the health services. It does so firstly through an analysis of the components of the phenomenon, how they relate and where gaps in knowledge exist; secondly by comparing studies of stigma and discrimination and projects designes to reduce their incidence and impact; and thirdly by outlining strategies for a comprehensive response. The perspective is global, but this publication makes extensive references to Latin America and the Caribbean.

Comprensión y respuesta al estigma y a la discriminación por el VIH/SIDA en el sector salud

El presente análisis procura profundizar la comprensión del estigma y la discriminación en relación con el VIH/SIDA en los servicios de salud. Con este fin, primero se examinan los componentes del fenómeno, su interrelación y las lagunas en los conocimientos actuales. En segundo lugar, se comparan estudios sobre el estigma y la discriminación y proyectos destinados a reducir su incidencia y repercusiones. Por último, se esbozan las estrategias para una respuesta integral. La perspectiva es mundial; no obstante, las referencias a América Latina y el Caribe son abundantes.

Tratamento farmacologico da hiperplasia benigna da prostata / Pharmacological treatment of benign prostatic hyperplasia

A hiperplasia benigna da prostata e uma patologia bastante prevalente na populacao masculina de idade avancada. Com o aumento da expectativa media de vida, decorrente dos avancos cientifico-tecnologicos das ultimas decadas, este problema tem despertado um interesse ainda maior ao nivel da saude publica. Recentemente tem sido investigadas varias opcoes de tratamento farmacologico do paciente prostatico, tais como os alfa-bloqueadores e agentes que promovem supressao androgenica. Os autores abordam as principais modalidades de tratamento farmacologico da hiperplasia benigna da prostata existentes atualmente, enfatizando aspectos relacionados a farmacodinamica, efeitos colaterais, indicacoes e resultados obtidos com o uso destes farmacos na literatura. Concluem que os alfabloqueadores e os tratamentos hormonais de bloqueio androgenico podem ser uteis em pacientes selecionados, porem a real aplicabilidade destas terapias so sera conhecida atraves de ensaios clinicos mais bem delineados, de maior poder estatistico, e com um melhor conhecimento da historia natural da hiperplasia prostatica

Valor de determinaçäo dos níveis de PSA nas neoplasias prostáticas / Determination of PSA in prostatic neoplasms

A avaliaçäo do paciente prostático é de fundamental importância e interesse da classe médica em geral, tendo em vista a frequencia das neoplasias de próstata. Neste aspecto, a determinaçäo do antígeno prostático específico passa a ser decisiva. sabe-se que a determinaçäo do antígeno na avaliaçäo do prostatismo aumenta a taxa de detecçäo do câncer prostático, quando associada ao toque retal. Os autores revisam aspectos relacionados ao antígeno, como método de dosagem, importância na detecçäo precoce do carcinoma da próstata e alguns conceitos atuais sobre este marcador. Concluem da utilidade do mesmo como parâmetro de atividade da doença cancerosa prostática, de resposta ao tratamento instituido e de prognóstico desta patologia

Fasciite necrosante / Necrozing fasciitis

A fasciite necrosante deve-se a uma infecçäo polibacteriana incomum e é de prognóstico reservado. Neste trabalho, os autores apresentam dois casos ocorridos no Hospital Universitário de Santa Maria - Santa Maria - RS, no ano de 1988. Discutem a fisiopatologia e o tratamento mais adequado para a patologia. Ambas as infecçöes foram polimicrobianas. O tratamento insituído foi: medidas gerais para o choque séptico, antibioticoterapia de amplo espectro e debridamento cirúrgico radical. Houve sucesso terapêutico em um dos casos, com cura da infecçäo e reconstituiçäo da área debridada com enxertos. A outra paciente foi ao óbito no sétimo dia pós-operatório