Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic.

Background: Treatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required. Materials and methods: In this review, we outline the evolution of TMB as a biomarker in oncology, delineate how TMB can be applied in the clinic, discuss current limitations as a diagnostic test, and highlight mechanistic insights unveiled by the study of TMB. We review available data to date studying TMB as a biomarker for response to ICB by tumor type, focusing on studies proposing a threshold for TMB as a predictive biomarker for ICB activity. Results: High TMB consistently selects for benefit with ICB therapy. In lung, bladder and head and neck cancers, the current predictive TMB thresholds proposed approximate 200 non-synonymous somatic mutations by whole exome sequencing (WES). PD-L1 expression influences response to ICB in high TMB tumors with single agent PD-(L)1 antibodies; however, response may not be dependent on PD-L1 expression in the setting of anti-CTLA4 or anti-PD-1/CTLA-4 combination therapy. Disease-specific TMB thresholds for effective prediction of response in various other malignancies are not well established. Conclusions: TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed before broader use in different tumor types.

Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution.

The apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer.

Differential binding affinity of mutated peptides for MHC class I is a predictor of survival in advanced lung cancer and melanoma.

Background: Cancer mutations generate novel (neo-)peptides recognised by T cells, but the determinants of recognition are not well characterised. The difference in predicted class I major histocompatibility complex (MHC-I) binding affinity between wild-type and corresponding mutant peptides (differential agretopicity index; DAI) may reflect clinically relevant cancer peptide immunogenicity. Our aim was to explore the relationship between DAI, measures of immune infiltration and patient outcomes in advanced cancer. Patients and methods: Cohorts of patients with advanced non-small-cell lung cancer (NSCLC; LUAD, n = 66) and melanoma (SKCM, n = 72) were obtained from The Cancer Genome Atlas. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n = 131) and NSCLC (n = 31) were analysed. Neopeptides and their clonal status were defined using genomic data. MHC-I binding affinity was predicted for each neopeptide and DAI values summarised as the sample mean DAI. Correlations between mean DAI and markers of immune activity were evaluated using measures of lymphocyte infiltration and immune gene expression. Results: In univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. In SKCM, the association between mean DAI and survival bordered significance (P = 0.068), reaching significance in an immunotherapy-treated melanoma cohort (P = 0.003). Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P = 0.027) and LUAD (P = 0.024). Conclusions: The association between mean DAI, survival and measures of immune activity support the hypothesis that DAI is a determinant of cancer peptide immunogenicity. Investigation of DAI as a marker of immunologically relevant peptides in further datasets and future clinical studies of neoantigen based immunotherapies is warranted.

Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters.

BACKGROUND: Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. PATIENTS AND METHODS: Forty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy. Seventy-nine tumour regions from 25 patients with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification. RESULTS: We demonstrated extensive somatic nucleotide variation and somatic copy number alteration heterogeneity in high-risk PC. Overall, the mutational burden was low (0.93/Megabase), but two patients had hypermutation, with loss of mismatch repair (MMR) proteins, MSH2 and MSH6. Somatic copy number alteration burden was higher in patients with metastatic hormone-naive PC (mHNPC) than in those with high-risk localised PC (hrlPC), independent of Gleason grade. Mutations were rarely ubiquitous and mutational frequencies were similar for mHNPC and hrlPC patients. Enrichment of focal 3q26.2 and 3q21.3, regions containing putative metastasis drivers, was seen in mHNPC patients. We found evidence of parallel evolution with three separate clones containing activating mutations of ß-catenin in a single patient. We demonstrated extensive intratumoural and intertumoural T-cell heterogeneity and high inflammatory infiltrate in the MMR-deficient (MMRD) patients and the patient with parallel evolution of ß-catenin. Analysis of all patients with activating Wnt/ß-catenin mutations demonstrated a low CD8+/FOXP3+ ratio, a potential surrogate marker of immune evasion. CONCLUSIONS: The PROGENY (PROstate cancer GENomic heterogeneitY) study provides a diagnostic platform suitable for studying tumour ITH. Genetic aberrations in clinically high-risk PC are associated with altered patterns of immune infiltrate in tumours. Activating mutations of Wnt/ß-catenin signalling pathway or MMRD could be considered as potential biomarkers for immunomodulation therapies. CLINICAL TRIALS.GOV IDENTIFIER: NCT02022371.

Consensus on precision medicine for metastatic cancers: a report from the MAP conference.

Recent advances in biotechnologies have led to the development of multiplex genomic and proteomic analyses for clinical use. Nevertheless, guidelines are currently lacking to determine which molecular assays should be implemented in metastatic cancers. The first MAP conference was dedicated to exploring the use of genomics to better select therapies in the treatment of metastatic cancers. Sixteen consensus items were covered. There was a consensus that new technologies like next-generation sequencing of tumors and ddPCR on circulating free DNA have convincing analytical validity. Further work needs to be undertaken to establish the clinical utility of liquid biopsies and the added clinical value of expanding from individual gene tests into large gene panels. Experts agreed that standardized bioinformatics methods for biological interpretation of genomic data are needed and that precision medicine trials should be stratified based on the level of evidence available for the genomic alterations identified.

[Monitoring indicators of the program "Chile Grows with You" 2008-2011]. / Monitoreo de los indicadores del Programa "Chile Crece Contigo" 2008-2011.

OBJECTIVE: To monitor coverage and outcomes associated with the activities of the integrated protection system for early childhood Chile Grows with You (CHCC), which includes the comprehensive psychosocial development of children between 18 months and 3 years old, in each of the 29 Health Services of the country, as well as the changes observed after 4 years. MATERIAL AND METHOD: Database analysis of all local public networks in the country between 2008 and 2011 was performed. The application of the test regarding psychomotor development, prevalence of development delay and risk, participation of mothers in educational workshops, home visits and recovery rate of deficient children by age were studied. Median and observed changes of each indicator were analyzed developing a ranking based on the results observed. RESULTS: Approximately 75% of children were evaluated, with a prevalence of delay or risk of about 5% and a rate of recovery close to 50%. The participation of mothers in educational workshops increased from 7.6 to 11.0% (p<0.001) and home visits to developmentally delayed children increased 6 times between 2009 and 2011 (p<0.001). Most changes were positive, although the prevalence of developmentally delayed children under 2 years slightly increased (0.6%), and the recovery of 3 year olds decreased (-14.4%). A great variability was observed among the Health Services. CONCLUSIONS: There are some positive results in relation to psychomotor development, with significant regional differences. A lower than expected deficit rate regarding psychomotor development was observed, which implies the need to further analyze the instrument used or the conditions of application.

Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer.

The past few years have witnessed something of a renaissance in the field of cancer immunotherapy, relating largely to the clinical advances that have been associated with the development of monoclonal antibodies targeting the immune inhibitory co-receptors CTLA-4 and PD-1 and to the pursuit of genetically modified antigen-redirected adoptive T-cell therapies. These advances are based on a more substantial understanding of the factors restricting effective immune therapies that has been derived from the study of pre-clinical models of tumour growth in immune competent mice. Just as the recognition of the importance of positive co-stimulatory signaling has been instrumental to recent advances in the development of genetically modified antigen-specific adoptive cellular therapies, an increasing awareness of the ability of tumours to subvert multiple immune inhibitory pathways, effectively blunting the development or expansion of any anti-tumour immunity, is fostering the development of novel therapies that appear active as monotherapies but may achieve their greatest impact in combinatorial regimens. This mini-review will focus on attempts to target co-inhibitory members of the immunoglobulin superfamily.

Prediction of early and late pre-eclampsia from maternal characteristics, uterine artery Doppler and markers of vasculogenesis during first trimester of pregnancy.

OBJECTIVE: To develop a predictive model for pre-eclampsia using clinical, biochemical and ultrasound markers during the first trimester of pregnancy. METHODS: This was a nested case-control study within a pre-eclampsia screening project that involved 5367 asymptomatic pregnant women undergoing routine transvaginal uterine artery (UtA) Doppler at 11 + 0 to 13 + 6 weeks. Following exclusions, there were 70 pregnant women who later developed pre-eclampsia and 289 control patients enrolled during the first trimester who had serum or plasma samples taken at enrolment available for the purposes of this study. Of these, 17 pregnancies were diagnosed with early-onset (delivery < 34 weeks) pre-eclampsia and 53 with late-onset (delivery ≥ 34 weeks) pre-eclampsia. The lowest, highest and mean of left and right UtA pulsatility indices (PI) were calculated. Blood samples were stored at -84 °C until biochemical analysis for markers of vasculogenesis was performed. The distributions of the lowest UtA-PI and the biochemical markers were adjusted for maternal characteristics, expressed as multiples of the median (MoM), and compared between groups. Logistic regression analysis was used to evaluate if any variable was significantly associated with pre-eclampsia. RESULTS: Pregnancies that later developed pre-eclampsia were associated with higher maternal prepregnancy body mass index. An increased lowest UtA-PI was significantly associated with both early- and late-onset disease. Placental growth factor (PlGF) MoM was significantly reduced in women who later developed early- or late-onset pre-eclampsia compared with controls (median (interquartile range), 0.69 (0.33-1.46) and 1.10 (0.39-1.56), respectively, vs 1.19 (0.65-1.84), P < 0.05). Different combined models were generated by logistic regression analysis, and the detection rate with a fixed 10% false-positive rate was 47% and 29% for early- and late-onset pre-eclampsia, respectively. CONCLUSION: Pregnancies that later developed early or late pre-eclampsia were characterized by impaired placentation and an anti-angiogenic state during the first trimester of pregnancy. Regression models which include maternal characteristics, UtA Doppler and PlGF can apparently predict approximately half of pregnancies that will be complicated by early-onset pre-eclampsia. We believe more research in several areas is needed to aid in the creation of a better and more population-specific screening test for pre-eclampsia during the first trimester of pregnancy.

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

Cancer immunotherapy: co-stimulatory agonists and co-inhibitory antagonists.

The generation and maintenance of immune responses are controlled by both co-stimulatory and co-inhibitory signalling through T cell co-receptors, many of which belong to the immunoglobulin-like superfamily or the tumour necrosis factor receptor superfamily. Agonistic or antagonistic monoclonal antibodies targeting these co-receptors have the potential to enhance immunity. Furthermore, their activity on the immunosuppressive regulatory T cell populations which are prevalent within many tumours provides an additional rationale for their use as anti-cancer therapies. This review summarizes the interactions between cancer and the immune system, highlighting the ways in which these new classes of immunostimulatory antibodies might enhance anti-tumour immunity and summarizing early clinical experience with their use.

α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFß antibody to promote durable rejection and immunity in squamous cell carcinomas.

BACKGROUND: Checkpoint blockade immunotherapy has improved metastatic cancer patient survival, but response rates remain low. There is an unmet need to identify mechanisms and tools to circumvent resistance. In human patients, responses to checkpoint blockade therapy correlate with tumor mutation load, and intrinsic resistance associates with pre-treatment signatures of epithelial mesenchymal transition (EMT), immunosuppression, macrophage chemotaxis and TGFß signaling. METHODS: To facilitate studies on mechanisms of squamous cell carcinoma (SCC) evasion of checkpoint blockade immunotherapy, we sought to develop a novel panel of murine syngeneic SCC lines reflecting the heterogeneity of human cancer and its responses to immunotherapy. We characterized six Kras-driven cutaneous SCC lines with a range of mutation loads. Following implantation into syngeneic FVB mice, we examined multiple tumor responses to α-PD-1, α-TGFß or combinatorial therapy, including tumor growth rate and regression, tumor immune cell composition, acquired tumor immunity, and the role of cytotoxic T cells and Tregs in immunotherapy responses. RESULTS: We show that α-PD-1 therapy is ineffective in establishing complete regression (CR) of tumors in all six SCC lines, but causes partial tumor growth inhibition of two lines with the highest mutations loads, CCK168 and CCK169. α-TGFß monotherapy results in 20% CR and 10% CR of established CCK168 and CCK169 tumors respectively, together with acquisition of long-term anti-tumor immunity. α-PD-1 synergizes with α-TGFß, increasing CR rates to 60% (CCK168) and 20% (CCK169). α-PD-1 therapy enhances CD4 + Treg/CD4 + Th ratios and increases tumor cell pSmad3 expression in CCK168 SCCs, whereas α-TGFß antibody administration attenuates these effects. We show that α-TGFß acts in part through suppressing immunosuppressive Tregs induced by α-PD-1, that limit the anti-tumor activity of α-PD-1 monotherapy. Additionally, in vitro and in vivo, α-TGFß acts directly on the tumor cell to attenuate EMT, to activate a program of gene expression that stimulates immuno-surveillance, including up regulation of genes encoding the tumor cell antigen presentation machinery. CONCLUSIONS: We show that α-PD-1 not only initiates a tumor rejection program, but can induce a competing TGFß-driven immuno-suppressive program. We identify new opportunities for α-PD-1/α-TGFß combinatorial treatment of SCCs especially those with a high mutation load, high CD4+ T cell content and pSmad3 signaling. Our data form the basis for clinical trial of α-TGFß/α-PD-1 combination therapy (NCT02947165).

Behavior and Inactivation of Enterotoxin-Positive Clostridium perfringens in Pork Picadillo and Tamales Filled with Pork Picadillo under Different Cooking, Storage, and Reheating Conditions.

This study analyzed the behavior of Clostridium perfringens in individual ingredients and tamales containing different pathogen concentrations upon exposure to different temperatures and methods of cooking, storage, and reheating. In ground pork, C. perfringens cells were inactivated when exposed to 95°C for 30 min. Three lots of picadillo inoculated with 0, 3, and 5 log CFU/g C. perfringens cells, respectively, were exposed to different storage temperatures. At 20°C, cell counts increased 1 log in all lots, whereas at 8°C, counts decreased by 2 log. Four lots of tamales prepared with picadillo inoculated with 0, 2, 3, and 7 log CFU/g prior to the final cooking step exhibited no surviving cells (91°C for 90, 45, or 35 min). Four lots of tamales were inoculated after cooking with concentrations of 0, 0.6, 4, and 6 log CFU/g of the pathogen and then stored at different temperatures. In these preparations, after 24 h at 20°C, the count increased by 1.4, 1.7, and 1.8 log in the tamales inoculated with 0.6, 4, and 6 log inoculum, respectively. When they were stored at 8°C for 24 h, enumerations decreased to <1, 2.5, and 1.9 log in the tamales inoculated with 0.6, 4, and 6 log of C. perfringens cells, respectively. However, when the lots were exposed to 20°C and then 8°C, 0.8, 1.8, and 2.4 log changes were observed for the tamales inoculated with 0.6, 4, and 6 log, respectively. Microwaving, steaming, and frying to reheat tamales inoculated with 6 log CFU/g C. perfringens cells showed that the pathogen was inactivated after 2 min of exposure in the microwave and after 5 min of exposure to steam. In contrast, no inactivation was observed after 5 min of frying. The tamales inoculated with spores (7 log most probable number [MPN]/g) showed a decrease of 2 log after steaming or frying, and no survival was observed after microwaving. Tamales inoculated with spores (7 log MPN/g) after cooking were susceptible to microwaves, but 2.4 and 255 MPN/g remained after frying and steaming, respectively.

Massive myeloid sarcoma affecting the central nervous system, mediastinum, retroperitoneum, liver, and rectum associated with acute myeloblastic leukaemia: a case report.

Myeloid sarcomas are extramedullary tumours with granulocytic precursors. When associated with acute myelogenous leukaemia (AML), these tumours usually affect no more than two different extramedullary regions. This report describes a myeloid sarcoma associated with AML with tumour formation at five anatomical sites. The patient was a 37 year old man admitted in September 1999 with a two month history of weight loss, symptoms of anaemia, rectal bleeding, and left facial nerve palsy. The anatomical sites affected were: the rectum, the right lobe of the liver, the mediastinum, the retroperitoneum, and the central nervous system. A bone marrow smear was compatible with AML M2. Flow cytometry showed that the peripheral blood was positive for CD4, CD11, CD13, CD14, CD33, CD45, and HLA-DR. A karyotypic study of the bone marrow revealed an 8;21 translocation. The presence of multiple solid tumours in AML is a rare event. Enhanced expression of cell adhesion molecules may be the reason why some patients develop myeloid sarcomas.

Association of CD28 IVS3 +17T/C polymorphism with soluble CD28 in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology in which inflammatory pathology involves T cell activation and the CD28 costimulatory molecule involved in T cell presentation. The gene includes the CD28 IVS3 +17T/C polymorphism that could be associated with susceptibility to RA whereas the soluble concentrations of CD28 (sCD28) could be related to clinical activity. METHODS: We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients. RESULTS: RA patients had significantly higher frequencies of the CD28 T allele compared to HS (p = 0.032 OR = 1.59, C.I. 1.02-2.49). In addition, the IVS3 +17 T/T genotype frequency was also increased in RA vs. HS (p = 0.026). The RA patients showed higher sCD28 serum levels than HS (p = 0.001). Carriers of the T/T genotype in RA patients showed higher sCD28 levels than C/C carriers (p =0.047). In addition, a correlation between sCD28 and Spanish HAQ-DI (correlation, 0.272; p =0.016), was found. CONCLUSION: The T allele in CD28 IVS3 +17T/C polymorphism is associated with a susceptibility to RA in Western Mexico. In addition, increased sCD28 levels are related to T/T genotype in RA patients.

Tratamiento laparoscópico de la obstrucción intestinal por bridas / Laparoscopic treatment of adhesive small bowel obstruction

Background: Treatment options for adhesive small bowel obstruction (ASBO) involve conservative and surgical management, traditionally through open adhesiolysis. Laparoscopic approach has been performed in recent years; however, limited data exist on its safety and results vary considerably. Our aim is to report our experience of laparoscopic treatment for ASBO. Methods: Retrospective study including patients admitted with the diagnosis of adhesive small bowel obstruction and that were submitted to laparoscopic exploration, between June 2003 and April 2013. We analyzed demographic, surgical variables and outcomes in terms of conversion rate, operative time, re-feeding time and length of stay. Non-parametric tests were used for statistical analysis. Results: Series of 38 patients submitted to laparoscopic exploration, mean age: 51 +/- 16 years, 47 percent male. 53 percent had prior intra-abdominal surgeries. Laparoscopic resolution of bowel obstruction was possible in 31 patients (82 percent), with 7 conversions to open surgery. Median operative time was 60 (25-180) minutes, median re-feeding time was 24 (24-192) hours and median length of stay was 4 (2-52) days. Two patients required re-intervention during their hospital stay, one due to persistent bowel obstruction and one due to ischemic colitis. There were no other complications or mortality. Conclusions: Laparoscopy in adhesive small bowel obstruction was a feasible approach in this series, with good results when laparoscopic resolution is achieved. Patients with no prior surgeries seem to be good candidates for this approach.

Introducción: El tratamiento de la Obstrucción Intestinal por Bridas (OIB) incluye alternativas conservadoras y quirúrgicas, esta última tradicionalmente a través de cirugía abierta. El abordaje laparoscópico ha sido incorporado recientemente, sin embargo, existe información limitada sobre su seguridad y sus resultados varían considerablemente. Nuestro objetivo es presentar la experiencia de nuestro centro en el tratamiento laparoscópico de la OIB. Material y Métodos: Estudio retrospectivo incluyendo pacientes con el diagnóstico de OIB que fueron sometidos a cirugía laparoscópica en nuestro centro, entre junio de 2003 y abril de 2013. Análisis de variables demográficas, quirúrgicas y resultados obtenidos en términos de tasa de conversión, tiempo operatorio, tiempo de realimentación y estadía hospitalaria. Análisis estadístico con pruebas no paramétricas. Resultados: Serie de 38 pacientes, edad promedio: 51 +/- 16 años, 47 por ciento sexo masculino. 53 por ciento con antecedente de cirugía abdominal previa. Resolución completa por laparoscopía fue posible en 31 pacientes (82 por ciento), con 7 conversiones a cirugía abierta. La mediana de tiempo operatorio fue de 60 m (25-180), la mediana de tiempo a la realimentación fue de 24 h (24-192) y la mediana de estadía hospitalaria de 4 (2-52) días. Dos pacientes requirieron reoperaciones durante su hospitalización; uno debido a obstrucción intestinal persistente y otro debido a colitis isquémica. No se presentaron otras complicaciones ni mortalidad en esta serie. Conclusiones: El abordaje laparoscópico en OIB es factible de realizar en pacientes seleccionados, logrando buenos resultados en caso de resolución completa por laparoscopía. Pacientes sin cirugías abdominales previas son buenos candidatos para un abordaje laparoscópico inicial.

Polymorphism of the beta3-adrenergic receptor and lipid profile in patients with rheumatoid arthritis and systemic lupus erythematosus treated with chloroquine.

We investigated the effect of beta 3-adrenergic receptor (beta(3)AR) polymorphism on lipid profiles in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) treated with chloroquine. One hundred sixty-eight subjects were classified into three groups: 61 RA patients, 57 SLE patients, and 50 healthy subjects. All patients fulfilled the 1987 and 1982 classification criteria for RA and SLE, respectively, of the American College of Rheumatology. Demographic data and clinical characteristics of the patients were registered. Fasting lipid profile determination and leukocyte genomic DNA isolation from peripheral blood was performed in all the participants. Screening of the beta(3)-AR gene polymorphic region (exon 1) was done by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Quantitative and qualitative variables were analyzed using analysis of variance (ANOVA) with the LSD and chi(2) tests, respectively. An association between the arg64/arg64 beta(3)-AR genotype and high levels of triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-c) was found in three RA patients ( P=0.01), two of them taking chloroquine. Arg64/arg64 beta(3)-AR polymorphism may contribute to increased TG and VLDL-c in RA patients, independently of chloroquine treatment.

Micetoma por Actinomadura madurae en el pie: reporte de un caso en Chile / Actinomadura madurae mycetoma of the foot: report of one case

Mycetoma is a chronic infection that affects skin, subcutaneous tissue and bone. Its etiology can be mycotic or bacterial. It affects mainly the lower extremities ofmiddie age men livingin tropical climates. We repon a 44 year-old male ¡ivingin a template zone, consulting for swelling and pain in the left foot, lasting for 10 years. Physical examination showed a swollen left foot with hyperpigmented skin and a few crustedpapules. Radiology showed an extensive bone involvement of the midfoot with several oval and radiolucid images. Magnetic resonance showed son and bone tissue involvement, with múltiple oval and low intensity images in TI and T2. The biopsy was compatible with an unspecific chronic osteomyelitis. A bacterial identification by polymerase chain reaction and sequencing in the biopsy determined the presence of an Actinomadura madurae. Treatment with cotrimoxazol was started).

Nefrectomía parcial laparoscópica: nuestra experiencia inicial / Laparoscopic partial nephrectomy: initial experience

La nefrectomía parcial por laparoscopia es una de las opciones de tratamiento conservador de nefronasutilizada en urología. Es una técnica quirúrgica compleja, que se asocia a mayores riesgos de complicacionesen omparación a otras de las técnicas urológicas. Nuestro objetivo fue revisar la serie, la técnica, las complicaciones operatorias y los resultados oncológicos en nuestra experiencia inicial denefrectomía parcial laparoscópica.Se consignan características epidemiológicas de los pacientes, detalles de la técnica quirúrgica,características de los tumores y resultados anátomo-patológicos de las 26 intervenciones realizadas.No hubo conversión de la técnica en esta revisión y 4 pacientes presentaron complicaciones post operatorias. La biopsia intraoperatoria resultó con bordes negativos en todos los pacientes.Palabras claves: Tumor renal, cirugía renal conservadora, laparoscopia.

Laparoscopic partial nephrectomy is an option of nephron sparing surgery used in urology. It is a complex surgical procedure, which is associated with increased risk of complications compared to other techniques urological. Our objective was to review the series, the technique, the operative complications and oncologic results in our initial experience of laparoscopic partial nephrectomy. We analyzed the epidemiological characteristics of patients, details of surgical technique, characteristics of the tumors and surgical pathology results of 26 surgeries. There was no conversion, but 4 patients had post-operative complications. Intraoperative biopsy was negative in all patients.