Hypusination Maintains Intestinal Homeostasis and Prevents Colitis and Carcinogenesis by Enhancing Aldehyde Detoxification.

BACKGROUND & AIMS: The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis. METHODS: We used human colon tissue messenger RNA samples and publicly available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis. RESULTS: We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS messenger RNA and DHPS protein and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show down-regulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis. CONCLUSIONS: Hypusination in intestinal epithelial cells has a key role in the prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have a therapeutic impact.

The reverse transsulfuration pathway affects the colonic microbiota and contributes to colitis in mice.

Cystathionine γ-lyase (CTH) is a critical enzyme in the reverse transsulfuration pathway, the major route for the metabolism of sulfur-containing amino acids, notably converting cystathionine to cysteine. We reported that CTH supports gastritis induced by the pathogen Helicobacter pylori. Herein our aim was to investigate the role of CTH in colonic inflammation. First, we found that CTH is induced in the colon mucosa in mice with dextran sulfate sodium-induced colitis. Expression of CTH was completely absent in the colon of Cth-/- mice. We observed that clinical and histological parameters are ameliorated in Cth-deficient mice compared to wild-type animals. However, Cth deletion had no effect on tumorigenesis and the level of dysplasia in mice treated with azoxymethane-DSS, as a reliable model of colitis-associated carcinogenesis. Mechanistically, we determined that the deletion of the gene Slc7a11 encoding for solute carrier family 7 member 11, the transporter of the anionic form of cysteine, does not affect DSS colitis. Lastly, we found that the richness and diversity of the fecal microbiota were significantly increased in Cth-/- mice compared to both WT and Slc7a11-/- mice. In conclusion, our data suggest that the enzyme CTH represents a target for clinical intervention in patients with inflammatory bowel disease, potentially by beneficially reshaping the composition of the gut microbiota.

Ornithine Decarboxylase in Gastric Epithelial Cells Promotes the Immunopathogenesis of Helicobacter pylori Infection.

Colonization by Helicobacter pylori is associated with gastric diseases, ranging from superficial gastritis to more severe pathologies, including intestinal metaplasia and adenocarcinoma. The interplay of the host response and the pathogen affect the outcome of disease. One major component of the mucosal response to H. pylori is the activation of a strong but inefficient immune response that fails to control the infection and frequently causes tissue damage. We have shown that polyamines can regulate H. pylori-induced inflammation. Chemical inhibition of ornithine decarboxylase (ODC), which generates the polyamine putrescine from l-ornithine, reduces gastritis in mice and adenocarcinoma incidence in gerbils infected with H. pylori However, we have also demonstrated that Odc deletion in myeloid cells enhances M1 macrophage activation and gastritis. Here we used a genetic approach to assess the specific role of gastric epithelial ODC during H. pylori infection. Specific deletion of the gene encoding for ODC in gastric epithelial cells reduces gastritis, attenuates epithelial proliferation, alters the metabolome, and downregulates the expression of immune mediators induced by H. pylori Inhibition of ODC activity or ODC knockdown in human gastric epithelial cells dampens H. pylori-induced NF-κB activation, CXCL8 mRNA expression, and IL-8 production. Chronic inflammation is a major risk factor for the progression to more severe pathologies associated with H. pylori infection, and we now show that epithelial ODC plays an important role in mediating this inflammatory response.

Maximal Aerobic Power, Quality of Life, and Ejection Fraction in Survivors of Childhood Cancer Treated with Anthracyclines.

BACKGROUND: Anthracycline-induced cardiotoxicity is a frequent complication that can occur at any stage of treatment, even in survivors. OBJECTIVE: To determine maximum aerobic power, quality of life, and left ventricular ejection fraction in childhood cancer survivors treated with anthracyclines. DESIGN: Cross-sectional, observational study. METHODS: The left ventricular ejection fraction was obtained from the transthoracic echocardiogram report in the medical records. Each patient underwent a 6-minute walk test, assessment of maximum aerobic power on a cycle ergometer, and evaluation of perceived exertion using the EPInfant scale, and finally, their quality of life was evaluated using the pediatric quality of life inventory model. RESULTS: A total of 12 patients were studied, with an average of 16.2 years of age. All patients exhibited a left ventricular ejection fraction >60%, the mean distance covered in the 6-minute walk test was 516.7 m, and the mean of the maximum aerobic power was 70 W. Low quality of life scores were obtained in the physical and psychosocial aspects. In the Pearson test, a weak correlation without statistical significance was found between all the variables studied. CONCLUSIONS: Simultaneously with the detection of cardiotoxicity in childhood cancer survivors, it is pertinent to perform physical evaluations as physical condition and cardiotoxicity seem to be issues that are not necessarily dependent.

Transverse colon volvulus in a young patient with wandering liver.

We present the case of a 26-year-old male patient with no history of interest who consulted the emergency department due to occlusive symptoms. Urgent CT showed the presence of a transverse colonic volvulus in the context of a heterotopic liver, located in the left hypochondrium. There were no clinical or radiological signs of perforation or ischemia, so urgent endoscopic decompression was performed with subsequent elective surgery with a favorable resolution of the condition. Transverse colonic volvulus is rare (<1%) and wandering liver is an exceptional predisposing factor, with less than a hundred published cases. In these patients, endoscopic decompression carries a risk of perforation with high recurrence rates, and surgical treatment should be considered. However, in this case, in the absence of severity criteria, decompressive colonoscopy was considered an urgent treatment and subsequent elective surgery with favorable results.

Protective Role of Spermidine in Colitis and Colon Carcinogenesis.

BACKGROUND & AIMS: Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX), which generates spermidine (Spd), regulates colitis. Here we determined whether Spd treatment reduces colitis and carcinogenesis. METHODS: SMOX was quantified in human colitis and associated dysplasia using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. We used wild-type (WT) and Smox-/- C57BL/6 mice treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Mice with epithelial-specific deletion of Apc were used as a model of sporadic colon cancer. Animals were supplemented or not with Spd in the drinking water. Colonic polyamines, inflammation, tumorigenesis, transcriptomes, and microbiomes were assessed. RESULTS: SMOX messenger RNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. DSS colitis and AOM-DSS-induced dysplasia and tumorigenesis were worsened in Smox-/- vs WT mice and improved in both genotypes with Spd. Tumor development caused by Apc deletion was also reduced by Spd. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of α-defensins, which was reduced by Spd. A shift in the microbiome, with reduced abundance of Prevotella and increased Proteobacteria and Deferribacteres, occurred in Smox-/- mice and was reversed with Spd. CONCLUSIONS: Loss of SMOX is associated with exacerbated colitis and CAC, increased α-defensin expression, and dysbiosis of the microbiome. Spd supplementation reverses these phenotypes, indicating that it has potential as an adjunctive treatment for colitis and chemopreventive for colon carcinogenesis.

Underwater versus conventional EMR of large nonpedunculated colorectal lesions: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: Underwater EMR (UEMR) is an alternative procedure to conventional EMR (CEMR) to treat large, nonpedunculated colorectal lesions (LNPCLs). In this multicenter, randomized controlled clinical trial, we aimed to compare the efficacy and safety of UEMR versus CEMR on LNPCLs. METHODS: We conducted a multicenter, randomized controlled clinical trial from February 2018 to February 2020 in 11 hospitals in Spain. A total of 298 patients (311 lesions) were randomized to the UEMR (n = 149) and CEMR (n = 162) groups. The main outcome was the lesion recurrence rate in at least 1 follow-up colonoscopy. Secondary outcomes included technical aspects, en bloc resection rate, R0 resection rates, and adverse events, among others. RESULTS: There were no differences in the overall recurrence rate (9.5% UEMR vs 11.7% CEMR; absolute risk difference, -2.2%; 95% CI, -9.4 to 4.9). However, considering polyp sizes between 20 and 30 mm, the recurrence rate was lower for UEMR (3.4% UEMR vs 13.1% CEMR; absolute risk difference, -9.7%; 95% CI, -19.4 to 0). The R0 resection showed the same tendency, with significant differences favoring UEMR only for polyps between 20 and 30 mm. Overall, UEMR was faster and easier to perform than CEMR. Importantly, the techniques were equally safe. CONCLUSIONS: UEMR is a valid alternative to CEMR for treating LNPCLs and could be considered the first option of treatment for lesions between 20 and 30 mm due to its higher en bloc and R0 resection rates. (Clinical trial registration number: NCT03567746.).

Patient Reported Outcome Following the Skoog Unilateral Cleft Lip Repair among Adults- a Long-Term Cohort Study and Comparison to a Non-cleft Population.

OBJECTIVE: The study primarily aimed to compare satisfaction with lip appearance among adults treated for unilateral cleft lip and palate (UCLP) with Skoog's primary lip repair procedure to those without clefts. The secondary aim was to determine whether satisfaction with lip appearance and the desire to change the lip/face appearance correlated with the number of secondary lip revisions performed. DESIGN: Long-term follow-up. PATIENTS/SETTINGS: All UCLP patients treated at the Uppsala University Hospital born between 1960- and 1987 (n = 109) were invited. At an average of 37 years following the primary lip repair, the participation rate was 76% (n = 83). A control group of adults without cleft (n = 67) completed the same study protocol for comparison. MAIN OUTCOME MEASURES: Satisfaction with appearance was measured with The Satisfaction with Appearance Questionnaire (SWA) and a modified version of the Body Cathexis -Scale was used to assess the desire to change the lip and facial appearance. RESULTS: UCLP patients were less satisfied with their lip, face, and overall appearance and reported a greater desire to change the appearance of their lips and face than non-cleft controls (p < 0.001). Dissatisfaction with lip appearance correlated to a greater willingness to change the appearance of the lip and face. No correlation was found between satisfaction with appearance and the number of the previously performed secondary lip revisions. CONCLUSION: Adults treated for UCLP are less satisfied with the appearance of their lips compared to the non-cleft population. The number of secondary revisions does not necessarily correlate to greater satisfaction with lip appearance.

The Colombian Chemoprevention Trial: 20-Year Follow-Up of a Cohort of Patients With Gastric Precancerous Lesions.

BACKGROUND & AIMS: Helicobacter pylori eradication and endoscopic surveillance of gastric precancerous lesions are strategies to reduce gastric cancer (GC) risk. To our knowledge, this study is the longest prospective cohort of an H pylori eradication trial in a Hispanic population. METHODS: A total of 800 adults with precancerous lesions were randomized to anti-H pylori treatment or placebo. Gastric biopsy samples taken at baseline and 3, 6, 12, 16, and 20 years were assessed by our Correa histopathology score. A generalized linear mixed model with a participant-level random intercept was used to estimate the effect of H pylori status on the score over time. Logistic regression models were used to estimate progression by baseline diagnosis and to estimate GC risk by intestinal metaplasia (IM) subtype and anatomic location. RESULTS: Overall, 356 individuals completed 20 years of follow-up. Anti-H pylori therapy (intention-to-treat) reduced progression of the Correa score (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.38-0.93). H pylori-negative status had a beneficial effect on the score over time (P = .036). Among individuals with IM (including indefinite for dysplasia) at baseline, incidence rates per 100 person-years were 1.09 (95% CI, 0.85-1.33) for low-grade/high-grade dysplasia and 0.14 (95% CI, 0.06-0.22) for GC. Incomplete-type (vs complete-type) IM at baseline presented higher GC risk (OR, 13.4; 95% CI, 1.8-103.8). Individuals with corpus (vs antrum-restricted) IM showed an OR of 2.1 (95% CI, 0.7-6.6) for GC. CONCLUSIONS: In a high-GC-risk Hispanic population, anti-H pylori therapy had a long-term beneficial effect against histologic progression. Incomplete IM is a strong predictor of GC risk.

Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis.

BACKGROUND & AIMS: Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis. METHODS: The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing. RESULTS: We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity. CONCLUSIONS: Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.

Targeted mobilization of Lrig1+ gastric epithelial stem cell populations by a carcinogenic Helicobacter pylori type IV secretion system.

Helicobacter pylori-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the cag type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within H. pylori-infected gastric mucosa. Lineage tracing was induced in Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) mice that were uninfected or subsequently infected with cag+H. pylori or an isogenic cagE- mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) H. pylori for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the cagE- mutant. WT H. pylori-infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT H. pylori In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic H. pylori infection stimulates Lrig1-expressing progenitor cells in a cag-dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.

Angiosarcoma of the aorta diagnosed via endoscopic ultrasound.

A 54-year-old man consulted for low back pain of 5 weeks of evolution, refractory to regular analgesics, and significant weight loss. The PET-CT revealed a retroperitoneal mass in contact with the anterior wall of the abdominal aorta. After consulting with the Endoscopy Unit, an endoscopic ultrasound-guided FNAP was performed due to the accessibility of the lesion and the less invasive nature of these procedures. The anatomopathological result was angiosarcoma of the aorta.

Location, morphology and invasiveness of lateral spreading tumors in the colorectum differ between two large cohorts from an eastern and western country.

BACKGROUND AND STUDY AIMS: Data from Japanese series show that surface morphology of laterally spreading tumors (LST) in the colon identifies lesions with different incidence and pattern of submucosal invasion. Such data from western countries are scarce. We compared clinical and histological features of LST in a western country and an eastern country, with special interest on mucosal invasiveness of LST, and investigated the effect of clinical factors on invasiveness in both countries. PATIENTS AND METHODS: Patients with LST lesions ≥20mm were included from a multicenter prospective registry in Spain and from a retrospective registry from the National Cancer Center Hospital East, Japan. The primary outcome was the presence of submucosal invasion in LST. The secondary outcome was the presence of high-risk histology, defined as high-grade dysplasia or submucosal invasion. RESULTS: We evaluated 1102 patients in Spain and 663 in Japan. Morphological and histological characteristics differed. The prevalence of submucosal invasion in Japan was six-fold the prevalence in Spain (Prevalence Ratio PR=5.66; 95%CI: 3.96, 8.08), and the prevalence of high-risk histology was 1.5 higher (PR=1.44; 95%CI: 1.31, 1.58). Compared to the granular homogeneous type and adjusted by clinical features, granular mixed, flat elevated, and pseudo-depressed types were associated with higher odds of submucosal invasion in Japan, whereas only the pseudo-depressed type showed higher risk in Spain. Regarding high-risk histology, both granular mixed and pseudo-depressed were associated with higher odds in Japan, compared with only the granular mixed type in Spain. CONCLUSION: This study reveals differences in location, morphology and invasiveness of LST in an eastern and a western cohort.

The Innate Immune Glycoprotein Lactoferrin Represses the Helicobacter pylori cag Type IV Secretion System.

Chronic infection with Helicobacter pylori increases risk of gastric diseases including gastric cancer. Despite development of a robust immune response, H. pylori persists in the gastric niche. Progression of gastric inflammation to serious disease outcomes is associated with infection with H. pylori strains which encode the cag Type IV Secretion System (cag T4SS). The cag T4SS is responsible for translocating the oncogenic protein CagA into host cells and inducing pro-inflammatory and carcinogenic signaling cascades. Our previous work demonstrated that nutrient iron modulates the activity of the T4SS and biogenesis of T4SS pili. In response to H. pylori infection, the host produces a variety of antimicrobial molecules, including the iron-binding glycoprotein, lactoferrin. Our work shows that apo-lactoferrin exerts antimicrobial activity against H. pylori under iron-limited conditions, while holo-lactoferrin enhances bacterial growth. Culturing H. pylori in the presence of holo-lactoferrin prior to co-culture with gastric epithelial cells, results in repression of the cag T4SS activity. Concomitantly, a decrease in biogenesis of cag T4SS pili at the host-pathogen interface was observed under these culture conditions by high-resolution electron microscopy analyses. Taken together, these results indicate that acquisition of alternate sources of nutrient iron plays a role in regulating the pro-inflammatory activity of a bacterial secretion system and present novel therapeutic targets for the treatment of H. pylori-related disease.

eXplainable Artificial Intelligence (XAI) for the identification of biologically relevant gene expression patterns in longitudinal human studies, insights from obesity research.

Until date, several machine learning approaches have been proposed for the dynamic modeling of temporal omics data. Although they have yielded impressive results in terms of model accuracy and predictive ability, most of these applications are based on "Black-box" algorithms and more interpretable models have been claimed by the research community. The recent eXplainable Artificial Intelligence (XAI) revolution offers a solution for this issue, were rule-based approaches are highly suitable for explanatory purposes. The further integration of the data mining process along with functional-annotation and pathway analyses is an additional way towards more explanatory and biologically soundness models. In this paper, we present a novel rule-based XAI strategy (including pre-processing, knowledge-extraction and functional validation) for finding biologically relevant sequential patterns from longitudinal human gene expression data (GED). To illustrate the performance of our pipeline, we work on in vivo temporal GED collected within the course of a long-term dietary intervention in 57 subjects with obesity (GSE77962). As validation populations, we employ three independent datasets following the same experimental design. As a result, we validate primarily extracted gene patterns and prove the goodness of our strategy for the mining of biologically relevant gene-gene temporal relations. Our whole pipeline has been gathered under open-source software and could be easily extended to other human temporal GED applications.

Long-term Evaluation of Fistulotomy and Immediate Sphincteroplasty as a Treatment for Complex Anal Fistula.

BACKGROUND: Fistulotomy with immediate sphincteroplasty is a technique that can heal fistulas and decrease fecal incontinence more effectively than fistulotomy alone, in selected patients. OBJECTIVE: We aimed to perform a long-term evaluation of fecal incontinence after fistulotomy and immediate sphincteroplasty in patients with complex anal fistula. DESIGN: This prospective study included patients undergoing fistulotomy and immediate sphincteroplasty for complex anal fistula from January 2000 to December 2010. SETTINGS: The study was conducted by 2 colorectal surgeons in the coloproctology unit of the General Hospital of Elche. PATIENTS: We included patients aged ≥18 years with complex anal fistulas of cryptoglandular origin. MAIN OUTCOME MEASURES: Main outcomes were recurrence and continence after fistulotomy and immediate sphincteroplasty, according to fistula tract height and preoperative continence status. RESULTS: A total of 107 patients were included; 68.2% were men, with a mean age of 48 years and mean fistula duration of 12.8 months. The range and median follow-up period were 84 to 204 and 96 months. Thirty-seven fistulas were not primary. The overall healing rate was 84.1%. Primary fistulas healed by the end of follow-up in 58 (82.9%) of 70 patients; recurrent fistulas healed in 32 (86.5%) of 37; high tracts healed in 31 (83.8%) of 37, and nonhigh fistulas healed in 59 (84.3%) of 70. Male sex (OR = 0.66 (95% CI, 0.20-2.13); p > 0.05) and recurrent fistulas (OR = 0.43 (95% CI, 0.11-1.68); p > 0.05) could have a protective effect against postoperative fecal incontinence; however, more studies with larger sample sizes are necessary to confirm this result, whereas high fistulas showed a 4-fold increased risk of incontinence (range, 1.22-13.06; p < 0.01). One in 5 high-tracts patients experienced continence deterioration. LIMITATIONS: This was a prospective study, and randomized clinical trials with more patients and longer follow-up are needed to compare fistulotomy and immediate sphincteroplasty with other sphincter-preserving techniques. CONCLUSIONS: Fistulotomy and immediate sphincteroplasty are good options for treating complex anal fistulas, especially for recurrent fistulas, men, and patients with nonhigh tracts, with acceptable recurrence and incontinence rates. See Video Abstract at http://links.lww.com/DCR/B498. EVALUACIN A LARGO PLAZO DE LA FISTULOTOMA Y LA ESFINTEROPLASTIA INMEDIATA COMO TRATAMIENTO PARA LA FSTULA ANAL COMPLEJA: ANTECEDENTES:La fistulotomía y la esfinteroplastia inmediata es una técnica que puede curar las fístulas y disminuir la incontinencia fecal de manera más efectiva que la fistulotomía sola, en pacientes seleccionados.OBJETIVO:Nuestro objetivo fue realizar una evaluación a largo plazo de la incontinencia fecal después de la fistulotomía y la esfinteroplastia inmediata en pacientes con fístula anal compleja.DISEÑO:Este estudio prospectivo incluyó pacientes sometidos a fistulotomía y esfinteroplastia inmediata por fístula anal compleja, desde enero de 2000 hasta diciembre de 2010.ENTORNO CLINICO:El estudio fue realizado por dos cirujanos colorrectales de la Unidad de Coloproctología del Hospital General de Elche.PACIENTES:Se incluyeron pacientes ≥ 18 años con fístulas anales complejas de origen criptoglandular.PRINCIPALES MEDIDAS DE VALORACION:Los principales resultados fueron la recurrencia y la continencia después de la fistulotomía y la esfinteroplastia inmediata, de acuerdo con la altura del trayecto de la fístula y el estado de continencia preoperatoria.RESULTADOS:Se incluyeron un total de 107 pacientes; El 68,2% eran varones, con una edad media de 48 años y una duración media de la fístula de 12,8 meses. El rango y la mediana del período de seguimiento fue de 84-204 y 96 meses, respectivamente. Treinta y siete fístulas no fueron primarias. La tasa de curación general fue del 84,1%. Las fístulas primarias cicatrizaron al final del seguimiento en 58/70 (82,9%) pacientes; las fístulas recurrentes cicatrizaron en 32/37 (86,5%); los tractos altos cicatrizaron en 31/37 (83,8%) y las fístulas no altas cicatrizaron en 59/70 (84,3%). El sexo masculino (razón de posibilidades: 0,66 [0,20-2,13], p > 0,05) y las fístulas recurrentes (razón de posibilidades: 0,43 [0,11-1,68], p > 0,05) podrían tener un efecto protector contra la incontinencia fecal postoperatoria, sin embargo, más estudios con una muestra más grande son necesarios para confirmar este resultado. Fistulas altas mostraron un riesgo cuatro veces mayor de incontinencia ([1.22-13.06], p < 0.01). Uno de cada cinco pacientes con tractos altos experimentó un deterioro de la continencia.LIMITACIONES:Este fue un estudio prospectivo y se necesitan ensayos clínicos aleatorios con más pacientes y un seguimiento más prolongado para comparar la fistulotomía y la esfinteroplastia inmediata con otras técnicas de preservación del esfínter.CONCLUSIÓN:La fistulotomía y la esfinteroplastia inmediata son buenas opciones para el tratamiento de fístulas anales complejas, especialmente para fístulas recurrentes, varones y pacientes con tractos no altos, con tasas aceptables de recurrencia e incontinencia. Consulte Video Resumen en http://links.lww.com/DCR/B498.

Carcinogenic Helicobacter pylori Strains Selectively Dysregulate the In Vivo Gastric Proteome, Which May Be Associated with Stomach Cancer Progression.

Helicobacter pylori is the strongest risk factor for gastric cancer. Initial interactions between H. pylori and its host originate at the microbial-gastric epithelial cell interface, and contact between H. pylori and gastric epithelium activates signaling pathways that drive oncogenesis. One microbial constituent that increases gastric cancer risk is the cag pathogenicity island, which encodes a type IV secretion system that translocates the effector protein, CagA, into host cells. We previously demonstrated that infection of Mongolian gerbils with a carcinogenic cag+H. pylori strain, 7.13, recapitulates many features of H. pylori-induced gastric cancer in humans. Therefore, we sought to define gastric proteomic changes induced by H. pylori that are critical for initiation of the gastric carcinogenic cascade. Gastric cell scrapings were harvested from H. pylori-infected and uninfected gerbils for quantitative proteomic analyses using isobaric tags for relative and absolute quantitation (iTRAQ). Quantitative proteomic analysis of samples from two biological replicate experiments quantified a total of 2764 proteins, 166 of which were significantly altered in abundance by H. pylori infection. Pathway mapping identified significantly altered inflammatory and cancer-signaling pathways that included Rab/Ras signaling proteins. Consistent with the iTRAQ results, RABEP2 and G3BP2 were significantly up-regulated in vitro, ex vivo in primary human gastric monolayers, and in vivo in gerbil gastric epithelium following infection with H. pylori strain 7.13 in a cag-dependent manner. Within human stomachs, RABEP2 and G3BP2 expression in gastric epithelium increased in parallel with the severity of premalignant and malignant lesions and was significantly elevated in intestinal metaplasia and dysplasia, as well as gastric adenocarcinoma, compared with gastritis alone. These results indicate that carcinogenic strains of H. pylori induce dramatic and specific changes within the gastric proteome in vivo and that a subset of altered proteins within pathways with oncogenic potential may facilitate the progression of gastric carcinogenesis in humans.

From conventional two-stage hepatectomy to ALPPS: Fifteen years of experience in a hepatobiliary surgery unit.

BACKGROUND: Hepatectomy in patients with large tumor load may result in postoperative liver failure and associated complications due to excessive liver parenchyma removal. Conventional two-stage hepatectomy (TSH) and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) technique are possible solutions to this problem. Colorectal liver metastases (CRLM) is the most frequent indication, and there is a need to assess outcomes for both techniques to improve surgical and long-term oncological outcomes in these patients. METHODS: A single-center retrospective study was designed to compare TSH with ALPPS in patients with initially unresectable bilateral liver tumors between January 2005 and January 2020. ALPPS was performed from January 2012 onwards as the technique of choice. Long-term overall survival (OS) and disease-free survival (DFS) were evaluated as primary outcome in CRLM patients. Postoperative morbidity, mortality and liver growth in all patients were also evaluated. RESULTS: A total of 38 staged hepatectomies were performed: 17 TSH and 21 ALPPS. Complete resection rate was 76.5% (n = 13) in the TSH group and 85.7% (n = 18) in the ALPPS group (P = 0.426). Overall major morbidity (Clavien-Dindo ≥ 3a) (stage 1 + stage 2) was 41.2% (n = 7) in TSH and 33.3% (n = 7) in ALPPS patients (P = 0.389), and perioperative 90-day mortalities were 11.8% (n = 2) vs. 19.0% (n = 4) in each group, respectively (P = 0.654). Intention-to-treat OS rates at 1 and 5 years in CRLM patients for TSH (n = 15) were 80% and 33%, and for ALPPS (n = 17) 76% and 35%, respectively. DFS rates at 1 and 5 years were 36% and 27% in the TSH group vs. 33% and 27% in the ALPPS group, respectively. CONCLUSIONS: ALPPS is an effective alternative to TSH in bilateral affecting liver tumors, allowing higher resection rate, but patients must be carefully selected. In CRLM patients similar long-term OS and DFS can be achieved with both techniques.

Managing esophageal strictures following endoscopic resection of superficial neoplastic lesions.

Over the last few years early esophageal tumors, whether squamous-cell or associated with Barrett's esophagus, have been excised using endoscopic resection techniques, primarily endoscopic submucosal dissection (ESD). Esophageal surgery-associated morbidity and mortality are thus avoided with similar oncologic outcomes. ESD is not without complications, many of which arise and are endoscopically solved during the procedure itself (bleeding, perforation, etc.). Other complications develop within days or weeks after resection, these including mainly esophageal stricture. Esophageal strictures following ESD are initially managed with endoscopic balloon dilation (EBD). Preventive measures have been suggested to alleviate this complication, primarily by using local or systemic steroids in association with early dilation. Even so, not always may they be prevented. Such complications are called refractory strictures, which require either esophageal stents (in a majority of cases) or surgery.

Radiological evaluation in patients with clinical suspicion of cerebral venous sinus thrombosis presenting with nontraumatic headache - a retrospective observational study with a validation cohort.

BACKGROUND: Clinical suspicion of cerebral venous sinus thrombosis (CVST) is imprecise due to non-specific symptoms such as headache. The aim was to retrospectively assess the diagnostic value of nonenhanced CT (neCT) in patients with nontraumatic headache and clinically suspected CVST. METHODS: A retrospective consecutive series of patients referred 2013-2015 for radiology were evaluated. Eligible patients had nontraumatic headache and suspicion of CVST stated in the referral, investigated with CT venography (CTV) and nonenhanced CT (neCT). neCT scans were re-evaluated for the presence of CVST or other pathology. All CTVs were checked for the presence of CVST. The validation cohort consisted of 10 patients with nontraumatic CVT (2017-2019). RESULTS: Less than 1% (1/104) had a suspected thrombus on neCT, confirmed by subsequent CTV. The remaining 99% had a CTV excluding CVST. Eleven percent had other imaging findings explaining their symptoms. In the patient with CVST, the thrombosed dural sinus was high attenuating (maximum HU 89) leading to the suspicion of CVST confirmed by CTV. The validation cohort (n = 10) confirmed the presence of a high attenuating (HU > 65) venous structure in the presence of a confirmed thrombus in all patients presenting within 10 days (suspicion written in referral, 10%). CONCLUSIONS: Despite clinical suspicion, imaging findings of CVST in nontraumatic headache are uncommon. Evaluating neCT for high attenuation in dural sinuses, followed by CTV for confirmation in selected cases seems reasonable. CVST should be recognized by all radiologists and requires a high level of awareness when reading neCT for other indications.