Adenoviral Vector Codifying for TNF as a Co-Adjuvant Therapy against Multi-Drug-Resistant Tuberculosis.

Mycobacterium tuberculosis is the main causal agent of pulmonary tuberculosis (TB); the treatment of this disease is long and involves a mix of at least four different antibiotics that frequently lead to abandonment, favoring the surge of drug-resistant mycobacteria (MDR-TB), whose treatment becomes more aggressive, being longer and more toxic. Thus, the search for novel strategies for treatment that improves time or efficiency is of relevance. In this work, we used a murine model of pulmonary TB produced by the MDR-TB strain to test the efficiency of gene therapy with adenoviral vectors codifying TNF (AdTNF), a pro-inflammatory cytokine that has protective functions in TB by inducing apoptosis, granuloma formation and expression of other Th1-like cytokines. When compared to the control group that received an adenoviral vector that codifies for the green fluorescent protein (AdGFP), a single dose of AdTNF at the chronic active stage of the disease produced total survival, decreasing bacterial load and tissue damage (pneumonia), which correlated with an increase in cells expressing IFN-γ, iNOS and TNF in pneumonic areas and larger granulomas that efficiently contain and eliminate mycobacteria. Second-line antibiotic treatment against MDR-TB plus AdTNF gene therapy reduced bacterial load faster within a week of treatment compared to empty vector plus antibiotics or antibiotics alone, suggesting that AdTNF is a new potential type of treatment against MDR-TB that can shorten second-line chemotherapy but which requires further experimentation in other animal models (non-human primates) that develop a more similar disease to human pulmonary TB.

Immune Regulatory Effect of Osteopontin Gene Therapy in a Murine Model of Multidrug Resistant Pulmonary Tuberculosis.

Tuberculosis (TB) has been for many years a major public health problem since treatment is long and sometimes ineffective favoring the increase of multidrug-resistant mycobacteria (MDR-TB). Gene therapy is a novel and effective tool to regulate immune responses. In this study we evaluated the therapeutic effect of an adenoviral vector codifying osteopontin (AdOPN), a molecule known for their roles to favor Th1 and Th17 type-cytokine expression which are crucial in TB containment. A single dose of AdOPN administration in BALB/c mice suffering late progressive pulmonary MDR-TB produced significant lower bacterial load and pneumonia, due to higher expression of IFN-γ, IL-12, and IL-17 in coexistence with increase of granulomas in number and size, resulting in higher survival, in contrast with mice treated with the control adenovirus that codify the green fluorescent protein (AdGFP). Combined therapy of AdOPN with a regimen of second line antibiotics produced a better control of bacterial load in lung during the first days of treatment, suggesting that AdOPN can shorten chemotherapy. Taken together, gene therapy with AdOPN leads to higher immune responses against TB infection, resulting in a new potential treatment against pulmonary TB that can co-adjuvant chemotherapy.

Immunotherapeutic effect of adenovirus encoding antimicrobial peptides in experimental pulmonary tuberculosis.

As components of the innate immune response, antimicrobial peptides (AMPs) efficiently contribute to infection control and maintenance of a latent state in pulmonary tuberculosis (TB). As a therapeutic strategy, the administration of recombinant AMPs could be limited by enzymatic degradation and high production costs. Likewise, strategies based on the induction of AMPs have generated controversial results. In this study, 2 recombinant type-5 adenoviruses (Ad) expressing the human ß-defensin 3 (HßD3) or cathelicidin (LL37) were assessed in a murine pulmonary TB model. Mice infected with either a high dose of a drug-sensitive (H37Rv) or a multidrug-resistant (MDR) strain of Mycobacterium tuberculosis (Mtb) were treated with a single administration of AdHßD3, AdLL37, AdGFP (control vector expressing a green fluorescent protein), or saline solution (SS). Lungs were obtained to determine the bacterial burden, histologic damage, and cytokine expression at different time points. Mice treated with AdHßD3 or AdLL37 showed significantly lower bacterial load and pneumonia, and higher proinflammatory cytokine expression than the control groups AdGFP and SS. A synergistic therapeutic effect could be observed when first- or second-line antibiotics (ABs) were administered with adenoviral therapy in animals infected with H37Rv or MDR strains, respectively. Adenovirus-delivered AMP's administration constitutes a promising adjuvant therapy for current anti-TB drugs by enhancing a protective immune response and potentially reducing current AB regimes' duration.

Genetic Interactions and Tissue Specificity Modulate the Association of Mutations with Drug Response.

In oncology, biomarkers are widely used to predict subgroups of patients that respond to a given drug. Although clinical decisions often rely on single gene biomarkers, machine learning approaches tend to generate complex multi-gene biomarkers that are hard to interpret. Models predicting drug response based on multiple altered genes often assume that the effects of single alterations are independent. We asked whether the association of cancer driver mutations with drug response is modulated by other driver mutations or the tissue of origin. We developed an analytic framework based on linear regression to study interactions in pharmacogenomic data from two large cancer cell line panels. Starting from a model with only covariates, we included additional variables only if they significantly improved simpler models. This allows to systematically assess interactions in small, easily interpretable models. Our results show that including mutation-mutation interactions in drug response prediction models tends to improve model performance and robustness. For example, we found that TP53 mutations decrease sensitivity to BRAF inhibitors in BRAF-mutated cell lines and patient tumors, suggesting a therapeutic benefit of combining inhibition of oncogenic BRAF with reactivation of the tumor suppressor TP53. Moreover, we identified tissue-specific mutation-drug associations and synthetic lethal triplets where the simultaneous mutation of two genes sensitizes cells to a drug. In summary, our interaction-based approach contributes to a holistic view on the determining factors of drug response.

Immunotherapeutic effects of recombinant adenovirus encoding interleukin 12 in experimental pulmonary tuberculosis.

High dose of Mycobacterium tuberculosis (Mtb) strain H37Rv administered by intratracheal injection in BALB/c mice induce progressive tuberculosis (TB). In this model, during the first month there is a temporal control of bacillary growth, in coexistence with macrophage activation, granuloma formation and Th-1 response. Then, bacterial proliferation recommences, accompanied by progressive pneumonia and decreasing expression of protective cytokines (IFN-γ and TNF-α). In this model, we studied the IL-12 gene expression kinetics and cellular source. There is a rapid and progressive IL-12 expression peaking at day 14, when granulomas start their formation and numerous macrophages show strong IL-12 immunostaining, while during progressive TB there is a significant decrease of IL-12 expression and occasional macrophages showed IL-12 immunolabeling. In the second part of this study, we determined the immunotherapeutic effect of recombinant adenoviruses that codify IL-12 (AdIL-12). Intratracheal administration of only one dose of AdIL-12 one day before Mtb infection produced significant decrease of bacterial loads, lesser pneumonia and higher expression of TNF-α, IFN-γ and iNOS. When only one dose of AdIL-12 was given in healthy mice cohoused with infected mice with highly virulent and transmissible Mtb, total prevention of infection was conferred. Moreover, when AdIL-12 was administered by intranasal route in animals suffering late active TB after 2 months of infection, a very low pulmonary bacilli burdens was detected. These experimental data confirm that IL-12 is a significant cytokine in the immune protection against Mtb, and gene therapy based in adenoviruses coding this cytokine increased protective immunity and prevent Mtb transmission.

Detecting drug-resistant tuberculosis in chest radiographs.

PURPOSE: Tuberculosis is a major global health threat claiming millions of lives each year. While the total number of tuberculosis cases has been decreasing over the last years, the rise of drug-resistant tuberculosis has reduced the chance of controlling the disease. The purpose is to implement a timely diagnosis of drug-resistant tuberculosis, which is essential to administering adequate treatment regimens and stopping the further transmission of drug-resistant tuberculosis. METHODS: A main tool for diagnosing tuberculosis is the conventional chest X-ray. We are investigating the possibility of discriminating automatically between drug-resistant and drug-sensitive tuberculosis in chest X-rays by means of image analysis and machine learning methods. RESULTS: For discriminating between drug-sensitive and drug-resistant tuberculosis, we achieve an area under the receiver operating characteristic curve (AUC) of up to 66%, using an artificial neural network in combination with a set of shape and texture features. We did not observe any significant difference in the results when including follow-up X-rays for each patient. CONCLUSION: Our results suggest that a chest X-ray contains information about the likelihood of a drug-resistant tuberculosis infection, which can be exploited computationally. We therefore suggest to repeat the experiments of our pilot study on a larger set of chest X-rays.

Gene therapy based in antimicrobial peptides and proinflammatory cytokine prevents reactivation of experimental latent tuberculosis.

Mycobacterium tuberculosis (Mtb) latent infection can lead to reactivation. The design of new strategies to prevent it is an important subject. B6D2F1 mice were infected intratracheally with a low dose of Mtb H37Rv to induce chronic infection. After 7 months, mice were treated with one dose of recombinant adenoviruses encoding TNFα, ß defensin-3 and LL37. Immunosupression was induced 1 month later with corticosterone. In comparison with the control group, mice treated with adenoviruses showed significantly less bacterial load and pneumonia, the adenoviruses encoding TNFα and LL37 being the most efficient. Gene therapy based in a proinflammatory cytokine or antimicrobial peptides is a potentially useful system to prevent reactivation of latent tuberculosis.

Efficacy of gene-therapy based on adenovirus encoding granulocyte-macrophage colony-stimulating factor in drug-sensitive and drug-resistant experimental pulmonary tuberculosis.

Tuberculosis (TB), although a curable disease, remains a major cause of morbidity and mortality worldwide. It is necessary to develop a short-term therapy with reduced drug toxicity in order to improve adherence rate and control disease burden. Granulocyte-macrophage colony-stimulating factor (GM-CSF) may be a key cytokine in the treatment of pulmonary TB since it primes the activation and differentiation of myeloid and non-myeloid precursor cells, inducing the release of protective Th1 cytokines. In this work, we administrated by intratracheal route recombinant adenoviruses encoding GM-CSF (AdGM-CSF). This treatment produced significant bacterial elimination when administered in a single dose at 60 days of infection with drug sensitive or drug resistant Mtb strains in a murine model of progressive disease. Moreover, AdGM-CSF combined with primary antibiotics produced more rapid elimination of pulmonary bacterial burdens than conventional chemotherapy suggesting that this form of treatment could shorten the conventional treatment.

CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma.

Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.

The implication of pro-inflammatory cytokines in the impaired production of gonadal androgens by patients with pulmonary tuberculosis.

BACKGROUND: The chronic nature of tuberculosis and the protracted immuno-inflammatory reactions are implied in a series of metabolic and immune-endocrine changes accompanying the disease. We explored components from the hypothalamous-pituitary-gonadal axis and their relationship with cytokines involved in disease immunopathology, in male TB patients. METHODS: Plasma samples from 36 active untreated pulmonary TB male patients were used to determine TNF-α, IFN-γ, TGF-ß, IL-6, cortisol, dehydroepiandrosterone, testosterone, progesterone, estradiol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by ELISA. Healthy controls corresponded to 21 volunteers without contact with TB patients and similar age (40 ± 16,8 years). Testicular histological samples from necropsies of patients dying from TB were immune-stained for IL-1ß, TNF-α, IL-6 and IFN-γ. The TM3 mouse Leydig cell line was incubated with recombinants TNF-α, IFN-γ and TGF-ß, supernatants were collected and used to measure testosterone by ELISA. RESULTS: Patients showed decreased levels of testosterone in presence of high amounts of LH, together with augmented IFN-γ, IL-6 and TGF-ß levels. Testicular histological sections showed abundant presence of IL-1ß, TNF-α, IL-6 and IFN-γ in interstitial macrophages, Sertoli cells and some spermatogonia. In vitro treatment of Leydig cells with these cytokines led to a remarkable reduction of testosterone production.

Deriving a mutation index of carcinogenicity using protein structure and protein interfaces.

With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/.

Granulocyte-macrophage colony-stimulating factor: not just another haematopoietic growth factor.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is often used to treat leucopenia. Other haematopoietins may increase the number of circulating leucocytes with higher efficiency, but GM-CSF has additional effects that may be far more relevant than its haematopoietic activity. GM-CSF induces differentiation, proliferation and activation of macrophages and dendritic cells which are necessary for the subsequent T helper cell type 1 and cytotoxic T lymphocyte activation. GM-CSF haematopoietic and non-haematopoietic functions have pro-inflammatory and immune regulatory potential to treat a variety of autoimmune diseases and tumours. On the other hand, GM-CSF deficiency leads to various immune dysfunctions and the current utilization of GM-CSF as haematopoietic factor might be an accurate but very incomplete indication for a cytokine with vast clinical potential.

[Incidence, diagnosis and treatment of colovesical fistula]. / Incidencia, diagnóstico y tratamiento de la fístula colovesical.

BACKGROUND: Enterovesical fistula, also known as vesicoenteric fistula, is an abnormal communication of the vesical bladder with a segment of the digestive tract. We undertook this study to describe diagnostic and therapeutic methods to treat colovesical fistula (CVF) in patients who attended the Coloproctology Unit of the Gastroenterology Service of the General Hospital in Mexico City. METHODS: This is a descriptive study in CVF patients carried out from January 2001 to June 2006; descriptive statistics were used for analysis of information. RESULTS: Eleven patients were identified (10 males and 1 female). Average age was 54.72 years (range: 39-73 years). Time from onset of symptoms to diagnosis was on average 11.9 months. The most frequent signs and symptoms were fecaluria, pneumaturia, dysuria, hematuria and chronic abdominal pain in hypogastric and left iliac regions. Nine patients were submitted to sigmoidectomy and primary colorectal anastomosis. Hartmann procedure was carried out in one patient with restoration of intestinal transit 6 weeks later. In one patient, a loop colostomy was built as a first operation, with sigmoidectomy with fistula resection as a second operation, and restoration of intestinal transit as the third. CONCLUSIONS: Surgery is the only treatment that assures cure and avoids relapses. Sigmoidectomy and primary anastomosis must be considered as the treatment of choice. Mortality, although low, continues being a negative factor when surgery is indicated in these patients.

Hidradenitis suppurativa / Hidradenitis suppurativa

Introducción: la hidradenitis supurativa es una enfermedad inflamatoria, crónica, recurrente, originada en las glándulas apocrinas; se puede localizar en axila, ingle, periné, región anoperineal y cuero cabelludo. Objetivo: conocer la frecuencia y el manejo terapéutico. Material y métodos: se trató de un estudio retrospectivo, transversal y descriptivo, Se incluyeron los pacientes portadores de hidradenitis supurativa atendidos en la Unidad de Coloproctología del Servicio de Gastroenterología, Hospital General de México, de enero de 1995 a diciembre de 2004. Resultados: se revisaron 12,689 expedientes clínicos y se identificaron 15 pacientes (0.12 %), de los cuales nueve cumplieron los criterios de inclusión. Conclusiones: la hidradenitis supurativa es una enfermedad compleja que constituye un reto diagnóstico y terapéutico.

BACKGROUND: Hidradenitis suppurativa is an inflammatory, chronic and recurrent disease of appocrine glands, located in inguinal, axillar, perineal, perianal areas and scalp. OBJECTIVE: To determine the frequency and therapeutic management. METHODS: A retrospective, transverse, and descriptive study was carried out. All patients with hidradenitis suppurativa, and who were managed by the Coloproctology Unit from the Gastroenterology Service of the General Hospital of Mexico City from January 1995 to December 2004, were included. RESULTS: We reviewed 12,689 files and identified 15 patients (0.12%) with hidradenitis suppurativa; nine fulfilled inclusion criteria. CONCLUSIONS: This is a complex disease with a diagnostic and therapeutic challenge.

[Management of the rectovaginal fistula. A review of five years at the Colon and Rectal Unit of the General Hospital of Mexico City]. / Manejo de la fístula rectovaginal. Revisión de cinco años en la unidad de coloproctología del Hospital General de México.

BACKGROUND: Rectovaginal fistula, although infrequent, produces considerable discomfort to the patients and disables them in their social life. OBJECTIVES: To review and report the experience in the management of rectovaginal fistula in the Colon and Rectal Unit of the General Hospital of Mexico City, from January 1997 to December 2001. MATERIAL AND METHODS: A retrospective, observational and descriptive study was designed including all patients diagnosed with rectovaginal fistula, who had not been previously operated for this condition in the Colon and Rectal Unit of the General Hospital of Mexico City from January 1977 to December 2001. RESULTS: Thirty-eight patients were included, aged between 17 and 70 years with a mean age of 24. The etiology of the rectovaginal fistulas was: obstetric trauma in 21 patients (55.2%), post-surgical in 5 (13.1%), traumatic in 5 (13.1%), after radiotherapy in 5 (13.1%) and malignant in 2 (5.2%). DISCUSSION: Rectovaginal fistula treatment relies on fistula classification (simple or complex), its location, and damage or not to the sphincter mechanisms and prior surgical repair. CONCLUSIONS: The most frequent surgical approach was the creation of a fourth degree perineum laceration and reconstruction (45.7%), followed by the advancement flap (25.7%). Complex fistulas were handled with a stoma. The surgical approach of rectovaginal fistula must rely on etiologic, anatomic and physiologic basis.

[Hemorrhoidal desarterialization guided by Doppler. A surgical alternative in hemorrhoidal disease management]. / Desarterialización hemorroidaria guiada por Doppler. Una alternativa quirúrgica en el manejo de la enfermedad hemorroidaria.

BACKGROUND: Hemorrhoidal disease is a common condition that includes 30% of patients seen for the first time at the Colon and Rectal Unit of the Gastroenterology Service, Hospital General in Mexico City. This study shows experience with hemorrhoidal desarterialization guided by Doppler in patients with internal hemorrhoidal disease stages II or III in the Coloproctology Units of the Hospital General in Mexico City and at the North Medical Unit in Monterrey, Nuevo Leon, Mexico. MATERIALS AND METHODS: A prospective, longitudinal, and descriptive study was performed in 56 patients with diagnosis of internal hemorrhoids stages II or III, not complicated, and treated by hemorrhoidal artery ligation guided by Doppler between July 1, 2002 and April 31, 2003. RESULTS: 49 patients were included, 32 male (66%) and 17 female (34%), aged between 21 and 75 years with mean age of 43.5 years; 40 patients had internal hemorrhoids stage II (82%) and nine, stage III (18%). With a follow-up of 4 months or longer, all patients were symptomless: bleeding and hemorrhoidal prolapse disappeared. CONCLUSIONS: Doppler-Guided hemorrhoidal desarterialization is indicated in patients with internal hemorrhoids stages II or III; it is a simple technique that requires a short learning curve, minimal anesthetic and surgical materials, and pain after the procedure is mild and short-lived in the majority of patients.

Leiomiosarcoma colorrectal: reporte de dos casos / Colorectal leiomyosarcoma: report of two cases

Casi todos los sarcomas colorrectales son leiomiosarcomas, que se originan en las células del músculo liso de la pared intestinal. Los síntomas de presentación y los hallazgos endoscópicos no son específicos, por lo que se requiere exploración quirúrgica para su diagnóstico. La resección completa es posible en el 50 a 60 por ciento de los casos. Las metástasis a la cavidad peritoneal e hígado son comunes. Sólo en 10 a 20 por ciento de los casos en quienes se practica resección completa presentan curación. Los pacientes con tumores de grado bajo de malignidad presentan una mayor supervivencia. A pesar de que los rangos de curación son bajos, la resección radical es un buen método paliativo. Ni la radioterapia ni la quimioterapia han mostrado ser efectivas como terapias adyuvantes. El papel de la resección preservadora de esfínteres y la excisión local en sarcomas rectales no es claro. El tratamiento convencional de las lesiones del tercio medio e inferior del recto es la resección abdominoperineal. En los tumores del colon, la resección segmentaria está indicada. La excisión local se fundamenta en la baja incidencia de metástasis a ganglios linfáticos locales en sarcomas colorrectales, pero la mayoría de los datos existentes sugieren que los rangos de recurrencia con excisión local son altos. Se presentan dos casos de pacientes masculinos atendidos en la Unidad de Coloproctología del Hospital General de México, los cuales presentaron rectorragia, pérdida de peso y marcadores inmunohistoquímicos positivos, con diagnóstico definitivo de leiomiosarcoma. La resección abdominoperineal para leiomiosarcoma del recto y la sigmoidectomía para leiomiosarcoma de sigmoides fueron los tratamientos quirúrgicos.Palabras clave: Leimiosarcoma colorrectal.

La fotocoagulación por rayos infrarrojos en el tratamiento de la enfermedad hemorroidaria / Infrared photocoagulation in hemorrhoidal disease treatment

Propósitos. Evaluar la eficacia de la fotocoagulación por rayos infrarrojos en el tratamiento de la enfermedad hemorroidaria grados I y II, en el Servicio de Coloproctología del Hospital General de México de la SSa. Material y métodos. Se incluyeron 60 pacientes con hemorragia transanal como síntoma único, sin patología anorrectal agregada. Fueron 30 pacientes del sexo femenino y 30 del sexo masculino, con una edad media de 39.9 años. Cada paciente recibió de 1 o 4 sesiones de fotocoagulación de acuerdo con los resultados que se obtuvieron en cada una. Se utilizó el fotocoagulador marca Redfield. Técnica. La aplicación de los disparos fue en forma de diamante o en arco iris, con una duración de 1.5 segundos cada uno. El tiempo de seguimiento fue de 24 meses. Resultados. Se obtuvo respuesta favorable en el 66.6 por ciento de los casos a partir de la segunda aplicación, y del 93.4 por ciento al término del estudio; en 4 pacientes (6.6 por ciento no hubo respuesta favorable y fueron tratados quirúrgicamente. Conclusiones. El tratamiento de la enfermedad hemorroidaria con fotocoagulación por rayos infrarrojos ofrece una buena alterantiva en los grados I y II, es indoloro, no requiere hospitalización y su costo es bajo

Fístulas anales complejas / Complex anal fistulae

Antecedentes: Las fístulas anorrectales ponen a prueba la experiencia de los cirujanos del colon y recto. Objetivo: Este artículo de revisión se realizó para discutir los avances más recientes en el diagnóstico y tratamiento de las fístulas anales complejas. Resultados: Las fallas en el tratamiento de las fístulas anorrectales pueden ser minimizadas mediante el conocimiento completo de la anatomía anorrectal y de los múltiples trayectos que pueden ocacionar las fístulas. Su complejidad está determinada por su tipo, especialmente con relación al aparato esfinteriano, que obliga a extremar el cuidado para su identificación correcta y la diferenciación de su origén. La planeación del tratamiento debe individualizarse a cada paciente que las padece. Conclusiones: El papel de las diferentes alternativas quirúrgicas dependerá de las características y relaciones del trayecto fistuloso y el esfínter