CRISPR/dCAS9-mediated DNA demethylation screen identifies functional epigenetic determinants of colorectal cancer.

BACKGROUND: Promoter hypermethylation of tumour suppressor genes is frequently observed during the malignant transformation of colorectal cancer (CRC). However, whether this epigenetic mechanism is functional in cancer or is a mere consequence of the carcinogenic process remains to be elucidated. RESULTS: In this work, we performed an integrative multi-omic approach to identify gene candidates with strong correlations between DNA methylation and gene expression in human CRC samples and a set of 8 colon cancer cell lines. As a proof of concept, we combined recent CRISPR-Cas9 epigenome editing tools (dCas9-TET1, dCas9-TET-IM) with a customized arrayed gRNA library to modulate the DNA methylation status of 56 promoters previously linked with strong epigenetic repression in CRC, and we monitored the potential functional consequences of this DNA methylation loss by means of a high-content cell proliferation screen. Overall, the epigenetic modulation of most of these DNA methylated regions had a mild impact on the reactivation of gene expression and on the viability of cancer cells. Interestingly, we found that epigenetic reactivation of RSPO2 in the tumour context was associated with a significant impairment in cell proliferation in p53-/- cancer cell lines, and further validation with human samples demonstrated that the epigenetic silencing of RSPO2 is a mid-late event in the adenoma to carcinoma sequence. CONCLUSIONS: These results highlight the potential role of DNA methylation as a driver mechanism of CRC and paves the way for the identification of novel therapeutic windows based on the epigenetic reactivation of certain tumour suppressor genes.

Linfografía como opción diagnóstica y terapéutica en la fuga quilosa posoperatoria de cáncer colorrectal.

La fuga quilosa es una complicación muy poco frecuente tras la cirugía colorrectal. Se presenta el caso de un paciente de 70 años con neoplasia de recto medio intervenido de forma electiva tras un ciclo largo de neoadyuvancia mediante una resección anterior de recto por laparoscopia. El cuarto día de posoperatorio presentó un drenaje pélvico de aspecto quiloso y el día 13 se confirmó la fuga quilosa en la linfografía. Posteriormente el débito se redujo de forma rápida. La linfografía no solo es un método diagnóstico, sino que en el 35-70% de los casos puede también ser terapéutica.Chylous leakage is an extremely rare complication after colorectal surgery. We report the case of a 70 year-old male with a mid-rectal cancer who underwent a laparoscopic anterior resection of the rectum after long course neoadjuvant therapy. On postoperative day 4 the patient presented with chylous pelvic drainage, and a chylous leakage was proved by lymphography on postoperative day 13. Hereinafter, the drainage was drastically reduced. The lymphography is not only a diagnostic technique, but it can be also a therapeutic method in up to 35-70% of the cases.

Post-nephrectomy diaphragmatic hernia. Increase suspicion and decrease morbi-mortality: two cases report.

Post-nephrectomy diaphragmatic hernia is an extremely rare condition. The symptoms may be acute or latent and will depend on the herniated organ, which makes it difficult to suspect. Therefore, it is necessary to know about this type of iatrogenic hernia to avoid a delay in diagnosis. A radiological confirmation with computed tomography and early surgical treatment greatly decreased the morbidity and mortality. We report two cases: a 76-year-old male, who underwent a right nephrectomy 18 days prior due to a renal carcinoma; and a 59-year-old woman, who underwent the procedure 4 years prior due to left renal atrophy.

Rectal linitis: A very unusual cause of stenosis / Linitis rectal: una causa muy inusual de estenosis

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Indications and Outcomes From 32 Consecutive Patients for the Treatment of Rectal Lesions by Transanal Minimally Invasive Surgery.

BACKGROUND: The aim of this study was to evaluate the feasibility, safety, perioperative morbidity, and short-term outcomes of the transanal minimally invasive surgery (TAMIS) technique. METHODS: This is a descriptive review of prospectively collected data from 32 consecutive patients who underwent TAMIS procedures in our colorectal unit over a 40-month period. GelPOINT Path port was used in all cases. Demographic data, indications, tumor characteristics, morbidity, and follow-up data were collected. Primary endpoints included feasibility, safety, perioperative morbidity, and resection quality. RESULTS: Fifteen adenomas, 12 carcinomas, 1 gastrointestinal stromal tumor, and 1 neuroendocrine tumor were locally excised. Additionally, 3 pelvic abscesses were drained transanally using the TAMIS port. Mean distance from the anal verge was 5.6 ± 1.5 cm. Early postoperative complications occurred in 22%, with only one case of major complication (3.1%) requiring reoperation, and no postoperative mortality. Four carcinomas were understaged (33.3%) and 1 adenoma overstaged (6.7%) preoperatively. Three carcinomas were not suspected preoperatively (25%). Microscopic positive lateral margin was found in one case, and no affected deep margin was found. Fragmentation rate was 6.9%, 2 cases, both lesions over 20 cm2. In cases of fit patients with high-risk carcinomas, 2 underwent immediate salvage surgery and another 2 refused and were treated with adjuvant radiotherapy. With a median follow-up of 26 months, the overall recurrence rate was 10.3%, 1 adenoma and 2 carcinomas. CONCLUSION: TAMIS seems to be a safe and reproducible procedure for local excision of well-selected rectal lesions with low morbidity and good functional outcomes.

Response to chemoradiotherapy and lymph node involvement in locally advanced rectal cancer.

AIM: To establish the association between lymph node involvement and the response to neoadjuvant therapy in locally advanced rectal cancer. METHODS: Data of 130 patients with mid and low locally advanced rectal adenocarcinoma treated with neoadjuvant chemoradiation followed by radical surgery over a 5-year period were reviewed. Tumor staging was done by endorectal ultrasound and/or magnetic resonance imaging. Tumor response to neoadjuvant therapy was determined by T-downstaging and tumor regression grading (TRG). Pathologic complete response (pCR) is defined as the absence of tumor cells in the surgical specimen (ypT0N0). The varying degrees TRG were classified according to Mandard's scoring system. The evaluation of the response is based on the comparison between previous clinico-radiological staging and the results of pathological evaluation. χ (2) and Spearman's correlation tests were used for the comparison of variables. RESULTS: Pathologic complete response (pCR, ypT0N0, TRG1) was observed in 19 cases (14.6%), and other 18 (13.8%) had only very few residual malignant cells in the rectal wall (TRG2). T-downstaging was found in 63 (48.5%). Mean lymph node retrieval was 9.4 (range 0-38). In 37 cases (28.5%) more than 12 nodes were identified in the surgical specimen. Preoperative lymph node involvement was seen in 77 patients (59.2%), 71 N1 and 6 N2. Postoperative lymph node involvement was observed in 41 patients (31.5%), 29 N1 and 12 N2, while the remaining 89 were N0 (68.5%). In relation to ypT stage, we found nodal involvement of 9.4% in ypT0-1, 22.2% in ypT2 and 43.7% in ypT3-4. Of the 37 patients considered "responders" to neoadjuvant therapy (TRG1 and 2), there were only 4 N+ (10.8%) and the remainder N0 (89.2%). In the "non responders" group (TRG 3, 4 and 5), 37 cases were N+ (39.8%) and 56 (60.2%) were N0 (P < 0.001). CONCLUSION: Response to neoadjuvant chemoradiation in rectal cancer is associated with lymph node involvement.

Local excision by transanal endoscopic surgery.

Transanal endoscopic surgery (TES) consists of a series of anorectal surgical procedures using different devices that are introduced into the anal canal. TES has been developed significantly since it was first used in the 1980s. The key point for the success of these techniques is how accurately patients are selected. The main indication was the resection of endoscopically unresectable adenomas. In recent years, these techniques have become more widespread which has allowed them to be applied in conservative rectal procedures for both benign diseases and selected cases of rectal cancer. For more advanced rectal cancers it should be considered palliative or, in some controlled trials, experimental. The role of newer endoscopic techniques available has not yet been defined. TES may allow for new strategies in the treatment of rectal pathology, like transanal natural orifice transluminal endoscopic surgery or total mesorectal excision.

[High-grade gastric epithelial dysplasia. Diagnostic and therapeutic controversies]. / Displasia epitelial gástrica de alto grado. Controversias diagnósticas y terapéuticas.

Gastric epithelial dysplasia is a premalignant lesion. Diagnostic and therapeutic criteria are controversial. We report the case of a 52-year-old woman admitted to our hospital.

Displasia epitelial gástrica de alto grado. Controversias diagnósticas y terapéuticas / High-grade gastric epithelial dysplasia. Diagnostic and therapeutic controversies

La displasia epitelial gástrica es una lesión premaligna. Hay controversia tanto en su diagnóstico como en su enfoque terapéutico. Presentamos un caso atendido en nuestro centro de una mujer de 52 años (AU)

Gastric epithelial dysplasia is a premalignant lesion. Diagnostic and therapeutic criteria are controversial. We report the case of a 52-year-old woman admitted to our hospital (AU)