Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients.

Adipose mesenchymal stem cells (ASC) are considered minimally immunogenic. This is due to the low expression of human leukocyte antigens I (HLA-I), lack of HLA-II expression and low expression of co-stimulatory molecules such as CD40 and CD80. The low rate of observed immunological rejection as well as the immunomodulatory qualities, position ASC as a promising cell-based therapy for the treatment of a variety of inflammatory indications. Yet, few studies have addressed relevant aspects of immunogenicity such as ASC donor-to-patient HLA histocompatibility or assessment of immune response triggered by ASC administration, particularly in the cases of presensitization. The present study aims to assess allo-immune responses in a cohort of Crohn's disease patients administered with allogeneic ASC (darvadstrocel formerly Cx601) for the treatment of complex perianal fistulas. We identified donor-specific antibodies (DSA) generation in a proportion of patients and observed that patients showing preexisting immunity were prone to generating DSA after allogeneic therapy. Noteworthy, naïve patients generating DSA at week 12 (W12) showed a significant reduction in DSA titer at week 52 (W52), whereas DSA titer was reduced in pre-sensitized patients only with no specificities against the donor administered. Remarkably, we did not observe any correlation of DSA generation with ASC therapeutic efficacy. In vitro complement-dependent cytotoxicity (CDC) studies have revealed limited cytotoxic levels based upon HLA-I expression and binding capacity even in pro-inflammatory conditions. We sought to identify CDC coping mechanisms contributing to the limited cytotoxic killing observed in ASC in vitro. We found that ASC express membrane-bound complement regulatory proteins (mCRPs) CD55, CD46, and CD59 at basal levels, with CD46 more actively expressed in pro-inflammatory conditions. We demonstrated that CD46 is a main driver of CDC signaling; its depletion significantly enhances sensitivity of ASC to CDC. In summary, despite relatively high clearance, DSA generation may represent a major challenge for allogeneic cell therapy management. Sensitization may be a significant concern when evaluating re-treatment or multi-donor trials. It is still unknown whether DSA generation could potentially be the consequence of donor-to-patient interaction and, therefore, subsequently link to efficacy or biological activity. Lastly, we propose that CDC modulators such as CD46 could be used to ultimately link CDC specificity with allogeneic cell therapy efficacy.

Enfermedad de Paget perianal / Perianal Paget disease

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Repercusión diagnóstica y terapéutica del estudio ecográfico en los trayectos fistulosos perianales en pacientes con sospecha de hidradenitis supurativa / Diagnostic and Therapeutic Implications of Ultrasound Imaging of Perianal Fistulous Tracts in Patients with Suspected Hidradenitis Suppurativa

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Fístula perianal compleja / Complex Perianal Fistula

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Líquido cefalorraquídeo xantocrómico, ¿cómo puede ser posible? / Xanthochromic cerebrospinal fluid, how can it be possible?

La coloración amarillenta de una parte del cuerpo o de un líquido orgánico se denomina xantocromía. En el caso del líquido ce-falorraquídeo, que en condiciones fisiológicas es claro, incoloro e inodoro, la xantocromía indica que, además de otras causas, ha podido haber una liberación de hemoglobina por una hemorragia en alguna parte del sistema nervioso central. Se expone el caso clínico de una paciente con antecedentes de intervención lumbar diagnosticada de abceso perianal subsidiario de cirugía. Durante la anestesia intradural apareció líquido cefalorraquídeo xantocrómico. Se analiza la etiología, diagnóstico y procedimiento realizado en la paciente (AU)

The yellowish coloration of a body part or an organic liquid is called xanthochromia. Under physiological condi-tions cerebrospinal fluid is clear, colorless and odorless. Xanthochromia indicates that, in addition to other causes, there has been a release of hemoglobin from a hemorrhage somewhere in central nervous system. We report the case of a patient with a history of lumbar surgical intervention diagnosed as perianal abscess who needs surgery. During the intradural anesthesia, cerebrospinal fluid appeared xanthochromic. The etiology, diagnosis and procedure performed in the patient are analyzed (AU)

What is the optimal surgical strategy for complex perianal fistulous disease in pediatric Crohn's disease? A systematic review.

PURPOSE: Perianal fistulous disease is present in 10-15% of children with Crohn's disease (CD) and is frequently complex and refractory to treatment, with one-third of patients having recurrent lesions. We conducted a systematic review of the literature to examine the best surgical strategy or strategies for pediatric complex perianal fistulous disease (CPFD) in CD. METHODS: We searched CENTRAL, MEDLINE, EMBASE, and CINAHL for studies discussing at least one surgical strategy for the treatment of pediatric CPFD in CD. Reference lists of included studies were hand-searched. Two researchers screened all studies for inclusion, quality assessed each relevant study, and extracted data. RESULTS: One non-randomized prospective and two retrospective studies met our inclusion criteria. Combined use of setons and infliximab therapy shows promise as a first-line treatment. A specific form of fistulectomy, "cone-like resection," also shows promise when combined with biologics. Endoscopic ultrasound to guide medical and surgical management is feasible in the pediatric population, though it is unclear if it improves outcomes. CONCLUSION: There is a paucity of evidence regarding the treatment of CPFD in the pediatric population, and further research is required before recommendations can be made as to what, if any, surgical management is optimal.

Prospective Comparison of Magnetic Resonance Imaging, Transrectal and Transperineal Sonography, and Surgical Findings in Complicated Perianal Crohn Disease.

OBJECTIVES: Magnetic resonance imaging (MRI) and transrectal sonography are the two accepted imaging modalities for evaluation of perianal fistulas and abscesses. Transperineal sonography is a new technique that is easy to learn and can be performed at any time. The purpose of this study was to prospectively compare the diagnostic accuracy of MRI, transrectal sonography, and transperineal sonography with surgical findings in patients with perianal Crohn disease. METHODS: All patients with perianal Crohn disease underwent MRI, transrectal sonography, and transperineal sonography within a few days before surgery. Fistulas were classified as simple (43.8%) or complex (52.2%) based on surgical findings. RESULTS: Twenty-three patients with active perianal Crohn disease (12 women and 11 men; mean age, 29.9 years; current therapy: antibiotics, 69.6%; azathioprine, 56.5%; and biologics, 73.9%; previous surgery, 26.1%; and proportion of smokers, 39.1%) were included. Sensitivity values for MRI, transrectal sonography, and transperineal sonography for diagnosis of fistulas were 84.6%, 84.6%, and 100%, respectively. Transperineal sonography was more sensitive for diagnosis of perianal abscesses than MRI and transrectal sonography (100%, 58.8%, and 92.8%). CONCLUSIONS: Transperineal sonography is a very accurate diagnostic method with outstanding sensitivity compared with MRI and transrectal sonography for evaluation of complicated perianal Crohn disease. Due to its simplicity and low cost, it is recommended that transperineal sonography be the first diagnostic modality in these cases.

Carcinoma escamoso de ano en enfermedad de Crohn perianal severa de larga evolución / Anal squamous cell carcinoma in chronic severe perianal Crohn's disease

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Empleo de plasma autólogo rico en plaquetas en el tratamiento de fístulas perianales complejas / Using autologous platelet-rich plasma for the treatment of complex fistulas

Objetivo: este estudio tiene como objetivo demostrar la efectividad y seguridad de un gel de fibrina autóloga rico en factores de crecimiento plaquetario para el tratamiento de las fístulas perianales complejas. Material y métodos: estudio epidemiológico prospectivo descriptivo. Se incluyen pacientes que presentan fístula perianal compleja o fístula perianal simple con alteración de la continencia. Se realiza identificación de ambos orificios y del trayecto, legrado del mismo e instilación del Vivostat PRF® en el trayecto hasta observar exceso de material por el OFE. Las variables a analizar son: edad, sexo, uso de setón previo, clínica prevalente, tipo de fístula, complicaciones postoperatorias, cierre de la fístula y alteraciones en la calidad de vida mediante el test sf-36(v2). Resultados: desde enero del 2011 hasta mayo del 2013 se ha intervenido a 23 pacientes, 12 hombres y 11 mujeres, con una media de edad de 49 años y un seguimiento mínimo de 12 meses. Dos abandonaron el estudio. 17 pacientes presentaban fístula transesfinteriana baja; 2, transesfinteriana alta, y 2, interesfinteriana con alteración de la continencia. El síntoma más frecuente es la supuración. Doce pacientes llevaban un setón laxo (62%), de los cuales curaron nueve. De todos los pacientes que hemos intervenido el porcentaje de éxitos es de un 62%. Ningún paciente desarrolló incontinencia después del tratamiento. Sólo dos refieren una peor calidad de vida después de la intervención. Conclusión: este estudio demuestra que hay un claro beneficio con el uso de Vivostat PRF® como tratamiento para las fístulas perianales complejas. Es una técnica altamente reproductible con resultados aceptables y que no produce alteraciones de la continencia (AU)

Objective: This study aims to demonstrate the effectiveness and safety of autologous fibrin gel rich in platelet growth factors for the treatment of complex perianal fistulas. Material and Methods: Prospective epidemiological study. Patients with complex perianal fistula or perianal fistula mere alteration of continence are included. identification of both holes and the journey, curettage of it and instillation of Vivostat PRF® in the way it is done to observe excess material by OFE. The variables analyzed were: age, sex, use of prior Seton clinic prevalent type of fistula, postoperative complications, fistula closure and impaired quality of life using the SF-36 test (v2). Results: From January 2011 to May 2013 have involved 23 patients, 12 men and 11 women, with an average age of 49 years and a minimum follow-up of 12 months. Two dropped out. 17 patients had low transsphincteric fistulas, 2 and 2 high transsphincteric intersphincteric with impaired continence. The most common symptom is the discharge. Twelve patients had a loose seton (62%), of which nine cured. Of all the patients we have operated the success rate is 62%. No patient developed incontinence after treatment. Only two reported a worse quality of life after surgery. Conclusion: This study demonstrates that there is a clear benefit to the use of Vivostat PRF® as a treatment for complex perianal fistulas. It is a highly reproducible technique with acceptable results and does not produce impairment of continence (AU)

Multiple perianal infundibular follicular cysts in a dog.

This case report describes a 7-year-old male cocker spaniel dog with multiple perianal infundibular follicular cysts. Clinically the dog had moderate anal sacculitis, peri-anal pruritus causing it to 'scoot' and lick the area. On examination of the perianal area, there were over 100 firm, well circumscribed papules, ranged from 0.2 to 0.5 cm in diameter with a central pore, and were found in the perianal region. Alopecia was present in the perianal region. The skin tissue in the perianal region resected surgically was submitted for histological examination. Microscopically, the tissue revealed multiple dilated cysts filled with keratins and the papules corresponded to infundibular follicular cysts. The affected dog showed moderate anal sacculitis. Anal sacculitis commonly causes repeated scooting or licking the area around the anus. Therefore, the multiple follicular cysts in the present case appear to be primarily a sequela to chronic external trauma to the perianal area, probably in response to anal sacculitis. To the best of the authors' knowledge, the present report is the first documented case of multiple perianal infundibular follicular cysts in a dog.

Long-term prospective evaluation of topically applied 0.1% tacrolimus ointment for treatment of perianal sinuses in dogs.

OBJECTIVE: To evaluate effectiveness of a combination of topically applied tacrolimus, orally administered prednisone, and a novel-protein diet for treatment of perianal sinuses in dogs and to monitor clinical progress and owner management of the condition for 2 years. DESIGN: Noncontrolled clinical trial. Animals-19 dogs with perianal sinuses. Procedures-Perianal sinuses were diagnosed during physical examination, and dogs were placed on a 16-week treatment protocol consisting of topically applied 0.1% tacrolimus ointment, orally administered prednisone (tapering dose), and a novel-protein diet. Metronidazole was orally administered for the first 2 weeks. Anal sacculectomy was recommended whenever anal sacs were involved. Dogs were evaluated every month for the first 4 months and then every 6 to 12 weeks for 2 years. RESULTS: Perianal sinuses resolved completely in 15 of 19 dogs during the 16 weeks. In the remaining 4 dogs, the lesions markedly improved but failed to completely resolve. Three of these had anal sac involvement, and the owner of 1 dog had complied poorly with treatment instructions. During the 2 years following treatment, all dogs were maintained on intermittently applied tacrolimus ointment, 4 dogs also received prednisone every other day, and 11 dogs remained on the novel-protein diet. At the conclusion of the study, 13 of the 15 dogs that survived to that point were free of perianal disease. CONCLUSIONS AND CLINICAL RELEVANCE: The described protocol was effective and economical for resolving perianal sinuses. Dogs maintained on intermittent medications were unlikely to redevelop lesions. When the anal sacs were involved, anal sacculectomy appeared to improve the outcome.

Long-term evaluation of canine perianal fistula disease treated with exclusive fish and potato diet and surgical excision.

The records of 33 dogs that had perianal fistula disease treated with en bloc surgical excision and bilateral anal saculectomy, and that were perioperatively administered an exclusive white fish and potato diet, were reviewed to determine outcome. By 1 year after surgery, 87.9% of the dogs had complete or near-complete resolution of visible fistula disease, while only 20.7% continued to have mild intermittent clinical signs. Fecal incontinence was not reported in any dog. Overall, complications were considerably less in both severity and frequency when compared with previous reports.

Nuevo caso de retroneumoperitoneo secundario al lavado con agua oxigenada de un absceso perianal / A new case of retropneumoperitoneum following washout with oxygenated water of a perianal abscess

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Perirenal expanding haematoma in a cat.

A four-year-old, entire male domestic cat was referred for assessment of a large abdominal mass of three-weeks duration. Diagnostic imaging suggested the presence of either splenic neoplasia, an abdominal abscess or haematoma. A coeliotomy was performed and an enlarged, irregular mass, including the left kidney and adrenal gland, was identified. The mass was removed, requiring a left adrenalo-uretero-nephrectomy. The aorta was accidentally punctured during the procedure, resulting in paraplegia. Given a poor prognosis, the owners decided to have the cat euthanased. Histological examination of the mass was characteristic of a chronic expanding haematoma.

Lipoma fusocelular de localización perineal / Spindle cell lipoma in the perineal region

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Use of the carbon dioxide laser for perianal and rectal surgery.

The skin of the perianal region is very thin and sensitive. The carbon dioxide laser is a very effective tool for removing tumors and treating conditions of this area. It offers a "no touch" method of treatment for conditions of the perianal region. There is less bleeding, less pain, less swelling with the use of the carbon dioxide laser. The carbon dioxide laser is an effective tool for excising perianal tumors, rectal tumors, performing anal sacculectomies and treating perianal fistulas.

Randomized controlled trial of cyclosporine for treatment of perianal fistulas in dogs.

OBJECTIVE: To evaluate efficacy of cyclosporine for treatment of perianal fistulas in dogs. DESIGN: Randomized, controlled trial. ANIMALS: 20 German Shepherd Dogs with naturally developing perianal fistulas. PROCEDURE: 10 dogs were treated with cyclosporine; the other 10 dogs were given a placebo. Overall improvement and change in total surface area of involvement and depth of the deepest fistula were determined after 4 weeks. Thereafter, cyclosporine-group dogs were treated for an additional 12 weeks and control-group dogs were treated with cyclosporine for 16 weeks. RESULTS: All cyclosporine-group dogs, but none of the control-group dogs, were subjectively improved after 4 weeks. Mean total surface area and mean fistula depth decreased 78 and 62%, respectively, in the cyclosporine-group dogs but increased 29 and 11%, respectively, in the control-group dogs. After 16 weeks of cyclosporine treatment, fistulas had healed in 17 (85%) dogs. However, fistulas recurred in 7 of 17 dogs, and additional cyclosporine treatment or anal sacculectomy and surgical excision of fistulas was necessary. CLINICAL IMPLICATIONS: Cyclosporine appeared to be effective in dogs with perianal fistulas. Even in dogs in which fistulas were not completely healed, cyclosporine administration appeared to be beneficial, because the surgical procedures that were required were less extensive than those that would have been necessary if cyclosporine had not been given.