Abdominal Wall Reconstruction Utilizing the Combination of Absorbable and Permanent Mesh in a Retromuscular Position: A Multicenter Prospective Study.

BACKGROUND: Optimal mesh reinforcement for abdominal wall reconstruction (AWR) in complex hernias remains questionable. Use of biologic, absorbable and synthetic meshes has been described. The idea of using an absorbable mesh (AM) under a permanent mesh (PM) in a retromuscular position may help in these challenging situations. METHODS: Between 2011 and 2016, consecutive patients undergoing open AWR utilizing an AM as posterior layer reinforcement and configuration of a large PM were identified in a multicenter prospectively maintained database in four hospitals. Main outcomes included demographics, ventral hernia classifications, perioperative data, complications and recurrences. RESULTS: A total of 169 complex incisional hernias were analyzed. Mean age was 60.9, with mean body mass index 30.7 (range: 20-46). Location of incisional hernias (IH) was: 80 midline, 59 lateral and 30 midline and lateral. 78% were grade I and II in Ventral Hernia Working Group classification. 52% of patients were discharged with no complication. There were 19% seromas, 13% hematomas, 12% surgical-site infection and 10% skin dehiscence. Only partial mesh removal was necessary in one patient. After a mean follow-up of 26 months (range 15-59), there were five (3.2%) recurrences. Reoperations on patients showed a band of fibrosis separating the peritoneum from the PM. CONCLUSION: The combination of AM with very large PM in the same retromuscular position in AWR seems to be safe. The efficacy with recurrence rates below 4% in complex midline and lateral IH may be explained by the use of larger PMs that are extended and configured with the support of AMs. Reoperations on patients have confirmed the previous experimental reports on the use of the AM.

Revisión de las perforaciones duodenales tras colangiopancreatografía retrógrada endoscópica en el Hospital Puerta de Hierro de 1999 a 2014 / Review of duodenal perforations after endoscopic retrograde cholangiopancreatography in Hospital Puerta de Hierro from 1999 to 2014

Introducción: la colangiopancreatografía retrógrada endoscópica (CPRE) sigue siendo la prueba de elección para el diagnóstico y el tratamiento de la patología biliar y pancreática, pero cuenta con una tasa de morbimortalidad no desdeñable, por lo que se proponen algoritmos para el manejo y tratamiento de sus complicaciones. Objetivo: revisar las perforaciones post-CPRE tratadas en el Servicio de Cirugía General del Hospital Puerta de Hierro de 1999 a 2014, evaluando los resultados en función del tipo de perforación y el tratamiento. Métodos y resultados: se ha realizado un estudio descriptivo y observacional de todas las perforaciones post-CPRE comunicadas y tratadas por el Servicio de Cirugía General del Hospital Puerta de Hierro de 1999 a 2014, en relación a la indicación de la prueba y hallazgos, el tipo de perforación (clasificación de Stapfer), el tiempo hasta el diagnóstico y el método de diagnóstico, el tiempo hasta la intervención y la técnica empleada, las complicaciones posteriores, así como la evolución y el tiempo de ingreso. Los resultados se han evaluado en función del tipo de perforación (Stapfer) y del tipo de tratamiento realizado. Se comunicaron 36 perforaciones (21 de tipo I, ocho de tipo II, dos de tipo III y cinco de tipo IV), lo que supone una incidencia menor del 1%. El diagnóstico fue inmediato (en las primeras 24 horas) en el 67% de los casos, siendo las de tipo I las más frecuentes. Se intervino a 28 de los 36 pacientes (77,7%), realizándose en la mayoría una colecistectomía seguida, siempre que fue posible, de sutura, colangiografía intraoperatoria y exploración de la vía biliar y drenaje. Fallecieron cuatro pacientes (dos intervenidos y dos manejados de manera conservadora), todos con perforaciones de tipo I. La complicación más frecuente fue la colección/fístula, que apareció en el 21,42% de los pacientes intervenidos. Conclusiones: el tratamiento de las perforaciones periduodenales secundarias a CPRE debe orientarse en función de los hallazgos clínicos y radiológicos. Según nuestra experiencia, las perforaciones de tipo I requieren una intervención quirúrgica inmediata, mientras que las perforaciones tipo II y III permiten, en algunos casos, un manejo conservador, siempre ante la ausencia de complicaciones como colecciones abdominales asociadas y/o signos de sepsis o de irritación peritoneal. Las perforaciones tipo IV responden bien al manejo conservador

Introduction: endoscopic retrograde cholangiopancreatography (ERCP) remains the gold standard in biliary and pancreatic pathology. Although the procedure has a significant morbidity and mortality rate. Algorithms are needed for the management and treatment of the associated complications. Objective: to review the post-ERCP perforations treated in the Department of General Surgery of the Hospital Puerta de Hierro from 1999 to 2014. The results were evaluated according to the types of perforation and treatment. Methods and results: this is a descriptive and observational study of all post-ERCP perforations reported and treated by the Department of General Surgery of the Hospital Puerta de Hierro from 1999 to 2014. The following data were collected: indication for the test and findings, type of perforation, time and method of diagnosis, time to surgery and the technique used; the subsequent complications as well as the evolution and time of admission were registered. Results were evaluated according to the type of perforation (Stapfer classification) and the treatment performed. Thirty-six perforations were reported (21 type I, eight type II, two type III and five type IV), with an associated incidence of less than 1%. The diagnosis was immediate (in the first 24 hours) in 67% of cases; type I was the most frequent: 28 of 36 patients (77.7%) required surgery. The majority underwent a cholecystectomy followed by suture, intraoperative cholangiography, bile duct exploration and drainage whenever possible. Four patients died with type I perforations; two were intervened and two were managed conservatively. The most frequent complication was a collection/fistula which occurred in 21.42% of patients who underwent surgery. Conclusions: periduodenal perforations secondary to ERCP treatment should be oriented according to the clinical and radiological findings. In our experience, type I perforations require immediate surgical intervention, whereas type II and III perforations can be managed conservatively in some cases when there are no complications such as associated abdominal collections, peritoneal irritation and/or sepsis. Type IV perforations respond to conservative management

Review of duodenal perforations after endoscopic retrograde cholangiopancreatography in Hospital Puerta de Hierro from 1999 to 2014.

INTRODUCTION: endoscopic retrograde cholangiopancreatography (ERCP) remains the gold standard in biliary and pancreatic pathology. Although the procedure has a significant morbidity and mortality rate. Algorithms are needed for the management and treatment of the associated complications. OBJECTIVE: to review the post-ERCP perforations treated in the Department of General Surgery of the Hospital Puerta de Hierro from 1999 to 2014. The results were evaluated according to the types of perforation and treatment. METHODS AND RESULTS: this is a descriptive and observational study of all post-ERCP perforations reported and treated by the Department of General Surgery of the Hospital Puerta de Hierro from 1999 to 2014. The following data were collected: indication for the test and findings, type of perforation, time and method of diagnosis, time to surgery and the technique used; the subsequent complications as well as the evolution and time of admission were registered. Results were evaluated according to the type of perforation (Stapfer classification) and the treatment performed. Thirty-six perforations were reported (21 type I, eight type II, two type III and five type IV), with an associated incidence of less than 1%. The diagnosis was immediate (in the first 24 hours) in 67% of cases; type I was the most frequent: 28 of 36 patients (77.7%) required surgery. The majority underwent a cholecystectomy followed by suture, intraoperative cholangiography, bile duct exploration and drainage whenever possible. Four patients died with type I perforations; two were intervened and two were managed conservatively. The most frequent complication was a collection/fistula which occurred in 21.42% of patients who underwent surgery. CONCLUSIONS: periduodenal perforations secondary to ERCP treatment should be oriented according to the clinical and radiological findings. In our experience, type I perforations require immediate surgical intervention, whereas type II and III perforations can be managed conservatively in some cases when there are no complications such as associated abdominal collections, peritoneal irritation and/or sepsis. Type IV perforations respond to conservative management.

How we do it: down to up posterior components separation.

BACKGROUND: Posterior component separation with transversus abdominis release technique is increasingly being used for abdominal wall reconstruction in complex abdominal wall repair. The main purpose of this study is to present a modification of the surgical technique originally described that facilitates the surgical procedure and offers additional advantages. METHODS: Based on the knowledge of the anatomy of the retromuscular space and the preperitoneal aerolar tissue distribution, we start the incision on the posterior rectus sheath from the arcuate line in a down to up direction. The posterior rectus sheath is incised 0,5-1 cm medial to the linea semilunaris and cut longitudinally as far as the fibers of transversus abdominis muscle that are divided in the superior part of the abdomen. It is also possible to avoid cutting the fibers of this muscle if we incise the posterior rectus sheath in an oblique direction to the midline from the umbilical area. Since 2012 to 2016, 69 consecutive patients with down to up TAR have been prospectively followed. Main outcome measures included demographics, perioperative details, wound complications, and recurrences. RESULTS: Between 2012 and 2016, we have operated 69 patients with down to up TAR technique. Mean operative time was 251 (range 65-566) minutes. Mean hospital stay was 9,8 (2-98) days. 10 patients presented surgical site events (14,5%): 6 patients had superficial site infection, 3 deep and 1 organ space. During follow-up, 3 patients (4,3%) presented incisional hernia recurrence. CONCLUSIONS: This novel modification allows a simpler dissection of the preperitoneal retromuscular space and makes the TAR technique easier to perform. It also enables to incise only the insertion of the transversalis fascia cranially.

Duodenectomía total con preservación pancreática como tratamiento de la poliposis duodenal / Total duodenectomy with panceratic preservation for duodenal polyposis

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Hernia de Garengeot: hernia crural incarcerada conteniendo el apendice. Revisión de la literatura a proposito de 2 casos / De Garengeot's hernia: Incarcerated femoral hernia containing the vermiform appendix. Report of two cases and literature review

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Blocking the PAH2 domain of Sin3A inhibits tumorigenesis and confers retinoid sensitivity in triple negative breast cancer.

Triple negative breast cancer (TNBC) frequently relapses locally, regionally or as systemic metastases. Development of targeted therapy that offers significant survival benefit in TNBC is an unmet clinical need. We have previously reported that blocking interactions between PAH2 domain of chromatin regulator Sin3A and the Sin3 interaction domain (SID) containing proteins by SID decoys result in EMT reversal, and re-expression of genes associated with differentiation. Here we report a novel and therapeutically relevant combinatorial use of SID decoys. SID decoys activate RARα/ß pathways that are enhanced in combination with RARα-selective agonist AM80 to induce morphogenesis and inhibit tumorsphere formation. These findings correlate with inhibition of mammary hyperplasia and a significant increase in tumor-free survival in MMTV-Myc oncomice treated with a small molecule mimetic of SID (C16). Further, in two well-established mouse TNBC models we show that treatment with C16-AM80 combination has marked anti-tumor effects, prevents lung metastases and seeding of tumor cells to bone marrow. This correlated to a remarkable 100% increase in disease-free survival with a possibility of "cure" in mice bearing a TNBC-like tumor. Targeting Sin3A by C16 alone or in combination with AM80 may thus be a promising adjuvant therapy for treating or preventing metastatic TNBC.

Colecistitis hemorrágica perforada / Perforated hemorrhagic cholecystitis

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Identification of LMO2 transcriptome and interactome in diffuse large B-cell lymphoma.

LMO2 regulates gene expression by facilitating the formation of multipartite DNA-binding complexes. In B cells, LMO2 is specifically up-regulated in the germinal center (GC) and is expressed in GC-derived non-Hodgkin lymphomas. LMO2 is one of the most powerful prognostic indicators in diffuse large B-cell (DLBCL) patients. However, its function in GC B cells and DLBCL is currently unknown. In this study, we characterized the LMO2 transcriptome and transcriptional complex in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly, and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners, such as LDB1, E2A, HEB, Lyl1, ETO2, and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, nuclear factor of activated T-cells (NFATc1), and lymphoid enhancer-binding factor1 (LEF1) proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provides a platform for future elucidation of LMO2 function in GC B cells and DLBCL pathogenesis.

miR-155 regulates HGAL expression and increases lymphoma cell motility.

HGAL, a prognostic biomarker in patients with diffuse large B-cell lymphoma and classic Hodgkin lymphoma, inhibits lymphocyte and lymphoma cell motility by activating the RhoA signaling cascade and interacting with actin and myosin proteins. Although HGAL expression is limited to germinal center (GC) lymphocytes and GC-derived lymphomas, little is known about its regulation. miR-155 is implicated in control of GC reaction and lymphomagenesis. We demonstrate that miR-155 directly down-regulates HGAL expression by binding to its 3'-untranslated region, leading to decreased RhoA activation and increased spontaneous and chemoattractant-induced lymphoma cell motility. The effects of miR-155 on RhoA activation and cell motility can be rescued by transfection of HGAL lacking the miR-155 binding site. This inhibitory effect of miR-155 suggests that it may have a key role in the loss of HGAL expression on differentiation of human GC B cells to plasma cell. Furthermore, this effect may contribute to lymphoma cell dissemination and aggressiveness, characteristic of activated B cell-like diffuse large B-cell lymphoma typically expressing high levels of miR-155 and lacking HGAL expression.

PRDM1/Blimp1 downregulates expression of germinal center genes LMO2 and HGAL.

Human germinal center-associated lymphoma (HGAL) and LIM domain only-2 (LMO2) are proteins highly expressed in germinal center (GC) B lymphocytes. HGAL and LMO2 are also expressed in GC-derived lymphomas and distinguish biologically distinct subgroups of diffuse large B-cell lymphomas (DLBCL) associated with improved survival. However, little is known about their regulation. PRDM1/Blimp1 is a master regulator of terminal B cell differentiation and may also function as a tumor suppressor in the pathogenesis of DLBCL, where it is frequently inactivated by mutations and deletions. We now demonstrate that both HGAL and LMO2 are directly regulated by the transcription repressor PRDM1. In vivo studies demonstrate that PRDM1 directly binds to the recognition sites within the upstream promoters of both HGAL and LMO2. PRDM1 binding suppresses endogenous protein and mRNA levels of HGAL and LMO2. In addition, promoter analysis reveals that site-specific binding of PRDM1 to the promoters is capable of repressing transcriptional activity. This inhibitory effect of PRDM1 suggests that it has a key role in the loss of HGAL and LMO2 expression upon differentiation of GC B cells to plasma cells and may also contribute to absence of HGAL and LMO2 expression in post-GC lymphoid tumors.

HGAL, a germinal center specific protein, decreases lymphoma cell motility by modulation of the RhoA signaling pathway.

HGAL is a germinal center (GC)-specific gene that negatively regulates lymphocyte motility and whose expression predicts improved survival of patients with diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). We demonstrate that HGAL serves as a regulator of the RhoA signaling pathway. HGAL enhances activation of RhoA and its down-stream effectors by a novel mechanism - direct binding to the catalytic DH-domain of the RhoA-specific guanine nucleotide exchange factors (RhoGEFs) PDZ-RhoGEF and LARG that stimulate the GDP-GTP exchange rate of RhoA. We delineate the structural domain of HGAL that mediates its interaction with the PDZ-RhoGEF protein. These observations reveal a novel molecular mechanism underlying the inhibitory effects of GC-specific HGAL protein on the motility of GC-derived lymphoma cells. This mechanism may underlie the limited dissemination and better outcome of patients with HGAL-expressing DLBCL and cHL.

Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas.

miRNAs are small RNA molecules binding to partially complementary sites in the 3'-UTR of target transcripts and repressing their expression. miRNAs orchestrate multiple cellular functions and play critical roles in cell differentiation and cancer development. We analyzed miRNA profiles in B-cell subsets during peripheral B-cell differentiation as well as in diffuse large B-cell lymphoma (DLBCL) cells. Our results show temporal changes in the miRNA expression during B-cell differentiation with a highly unique miRNA profile in germinal center (GC) lymphocytes. We provide experimental evidence that these changes may be physiologically relevant by demonstrating that GC-enriched hsa-miR-125b down-regulates the expression of IRF4 and PRDM1/BLIMP1, and memory B cell-enriched hsa-miR-223 down-regulates the expression of LMO2. We further demonstrate that although an important component of the biology of a malignant cell is inherited from its nontransformed cellular progenitor-GC centroblasts-aberrant miRNA expression is acquired upon cell transformation. A 9-miRNA signature was identified that could precisely differentiate the 2 major subtypes of DLBCL. Finally, expression of some of the miRNAs in this signature is correlated with clinical outcome of uniformly treated DLBCL patients.

Synthesis and biological evaluation of 2,4,6-functionalized derivatives of pyrido[2,3-d]pyrimidines as cytotoxic agents and apoptosis inducers.

In the search for new derivatives with anticancer activity that are able to induce a selective pro-apoptotic mechanism in cancer cells, we have designed, synthesized, and evaluated a series of new 2-(alkylsulfanyl)-N-alkylpyrido[2,3-d]pyrimidine-4-amine derivatives as cytotoxic and apoptosis inducers. The potential antitumor activity of the compounds was evaluated in vitro by examining their cytotoxic effects against human breast, colon, and bladder cancer-cell lines. The IC(50)values of the compounds that showed cytotoxic activity were calculated. The cytotoxic compounds were then tested for their ability to induce caspase-3 activation and nuclear-chromatin degradation. Some compounds, such as 6c, 6d, 6e, 6j, 6o, and 6p, show significant in-vitro cytotoxicity in at least two of the three tested cell lines, induced apoptosis, and also produced a rapid dose-dependent increase in the caspase-3 level in some of the cell lines tested. In order to test the selectivity of the compounds, two non-tumoral human cell lines were used. Several compounds of the did not show cytotoxicity in these cell lines.

A gene signature of 8 genes could identify the risk of recurrence and progression in Dukes' B colon cancer patients.

The benefit of postoperative adjuvant chemotherapy in patients with Dukes' B colorectal cancer is still uncertain and its routine use is not recommended. The five-year relapse rate is approximately 25-40% and the identification of patients at high risk of recurrence would represent an important strategy for the use of adjuvant chemotherapy. We retrospectively analyzed gene expression profiles in frozen tumor specimens from patients with Dukes' B colorectal cancer by using high density oligonucleotide microarrays. Our results show a subset of 48 genes differentially expressed with an associated probability <0.001 in the t-test. Another statistical procedure based on the Fisher criterion resulted in 11 genes able to separate both groups. We selected the 8 genes present in both subsets. The differential expression of five genes (CHD2, RPS5, ZNF148, BRI3 and MGC23401) in colon cancer progression was confirmed by real-time PCR in an independent set of patients of Dukes' B and C stages.

Biological profile of new apoptotic agents based on 2,4-pyrido[2,3-d]pyrimidine derivatives.

In order to obtain less toxic antitumoral compounds we have looked for novel compounds with anticancer activity based on proapoptotic mechanisms. The compounds studied in this work are derivatives of bicyclic aromatic systems like pyrido[2,3-d]pyrimidines. The potential antitumoral activity of the compounds was evaluated in vitro by examining their cytotoxic effects against human breast, colon, and bladder cancer lines (MD-MBA-231, HT-29, and T-24). The data indicate that HC-6 is a potent anticancer drug showing dose-dependent cytostatic and proapoptotic effects through activation of two different signaling pathways namely a pathway leading to cell cycle arrest and a transcription-independent route leading to rapid apoptosis.