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.

Impact of subtrochanteric fractures in the geriatric population: better pre-fracture condition but poorer outcome than pertrochanteric fractures: evidence from the Spanish Hip Fracture Registry.

BACKGROUND: Clinical management in orthogeriatric units and outcome indicators are similar for extracapsular fragility hip fractures, without discriminating between subtrochanteric and pertrochanteric fractures. HYPOTHESIS: Geriatric patients, 75 years or older, with subtrochanteric fractures have worse clinical and functional outcomes than those with pertrochanteric fractures. MATERIALS AND METHODS: Retrospective observational study of data prospectively collected by the Spanish Hip Fracture Registry including patients 75 years or older, admitted for extracapsular hip fractures from January 2017 to June 2019. Demographic and baseline status, pre-operative, post-operative and 30-day follow-up data were included. RESULTS: A total of 13,939 patients with extracapsular hip fractures were registered: 12,199 (87.5%) pertrochanteric and 1740 (12.5%) subtrochanteric. At admission, patients with subtrochanteric fractures were younger (86.5 ± 5.8 versus 87.1 ± 5.6 years old), had better pre-fracture mobility (3.7 ± 2.7 versus 3.9 ± 2.8) (1-to-10 scale, 1 being independent) and were more likely to be living at home; those with pertrochanteric fractures had worse cognitive function (Pfeiffer 3.3 ± 3.3 versus 3.8 ± 3.5). The subtrochanteric fracture group showed worse post-fracture mobility (7.3 ± 2.7 versus 6.7 ± 2.7) and greater deterioration of mobility (3.7 ± 3.0 versus 2.9 ± 2.7). Among individuals living at home at baseline, those with subtrochanteric fractures were more likely to remain in an assisted facility at 30-day follow-up. In-hospital mortality during acute admission was higher for the subtrochanteric group (5.6% versus 4.5%) (p = 0.028). To our knowledge, this is the first paper highlighting the differences between these two fracture groups in the geriatric population. CONCLUSIONS: Subtrochanteric fractures in the older population are a different and worse entity, with greater morbimortality and functional decline than pertrochanteric fractures. Despite being younger and fitter at admission, older patients with subtrochanteric fractures have a higher risk of remaining non-weight bearing and undergoing re-operation and institutionalization. Orthogeriatric units should be aware of this and manage subtrochanteric fractures accordingly. LEVEL OF EVIDENCE: IV.

Magnetic Lateral Flow Immunoassay for Small Extracellular Vesicles Quantification: Application to Colorectal Cancer Biomarker Detection.

Colorectal cancer (CRC) is the third leading cause of cancer death and the fourth most common cancer in the world. Colonoscopy is the most sensitive test used for detection of CRC; however, their procedure is invasive and expensive for population mass screening. Currently, the fecal occult blood test has been widely used as a screening tool for CRC but displays low specificity. The lack of rapid and simple methods for mass screening makes the early diagnosis and therapy monitoring difficult. Extracellular vesicles (EVs) have emerged as a novel source of biomarkers due to their contents in proteins and miRNAs. Their detection would not require invasive techniques and could be considered as a liquid biopsy. Specifically, it has been demonstrated that the amount of CD147 expressed in circulating EVs is significant higher for CRC cell lines than for normal colon fibroblast cell lines. Moreover, CD147-containing EVs have been used as a biomarker to monitor response to therapy in patients with CRC. Therefore, this antigen could be used as a non-invasive biomarker for the detection and monitoring of CRC in combination with a Point-of-Care platform as, for example, Lateral Flow Immunoassays (LFIAs). Here, we propose the development of a quantitative lateral flow immunoassay test based on the use of magnetic nanoparticles as labels coupled to inductive sensor for the non-invasive detection of CRC by CD147-positive EVs. The results obtained for quantification of CD147 antigen embedded in EVs isolated from plasma sample have demonstrated that this device could be used as a Point-of-Care tool for CRC screening or therapy monitoring thanks to its rapid response and easy operation.

Complete Mesocolic Excision and D3 Lymphadenectomy versus Conventional Colectomy for Colon Cancer: A Systematic Review and Meta-Analysis.

BACKGROUNDS: Previous systematic reviews suggest that the implementation of 'complete mesocolon excision' (CME) for colon tumors entails better specimen quality but with limited long-term outcomes. We performed a meta-analysis to compare the pathological, perioperative, and oncological results of CME with conventional surgery (CS) in primary colon cancer. METHODS: Embase, MEDLINE and CENTRAL databases were searched using Medical Subject Headings for CME and D3 lymphadenectomy. The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 18,989 patients from 27 studies were included. Postoperative complications were higher in the CME group (relative risk [RR] 1.13, 95% confidence interval [CI] 1.04-1.22, I2 = 0%), while no differences were observed in terms of anastomotic leak (I2 = 0%) or perioperative mortality (I2 = 49%). CME was associated with a higher number of lymph nodes harvested (I2 = 95%), distance to high tie (I2 = 65%), bowel length (I2 = 0%), and mesentery area (I2 = 95%). CME also had positive effects on 3- and 5-year overall survival (RR 1.09, 95% CI 1.04-1.15, I2 = 88%; and RR 1.05, 95% CI 1.02-1.08, I2 = 62%, respectively) and 3-year disease-free survival (RR 1.10, 95% CI 1.04-1.17, I2 = 22%), as well as decreased local (RR 0.35, 95% CI 0.24-0.51, I2 = 51%) and distant recurrences (RR 0.71, 95% CI 0.60-0.85, I2 = 34%). CONCLUSIONS: Limited evidence suggests that CME improves oncological outcomes with a higher postoperative adverse events rate but no increase in anastomotic leak rate or perioperative mortality, compared with CS.

MIPO helical pre-contoured plates in diaphyseal humeral fractures with proximal extension. Surgical technique and results.

INTRODUCTION: The aim of this study was to determine the feasibility of applying the MIPO technique with a helical-shaped plate in the treatment of humeral shaft fractures with proximal extension. PATIENTS AND METHODS: We present an observational prospective study of patients with a humeral shaft fracture involving the proximal humerus fixed with a long proximal humerus polyaxial locking plate with an anterior curvature and helical shape (ALPS® Zimmerbiomet, Warsaw, Indianapolis, USA), using a MIPO technique. Between January 2017 and July 2020, 15 patients were treated at our institution. Proximally a 4-5 cm anterolateral transdeltoid approach was made. And distally, a 5-7 cm incision was made 4 cm proximal to the elbow crease. At each follow-up, radiographs were taken to evaluate fracture healing. Funtional scales were applied to evaluate clinical results. RESULTS: Ten women and five men were included, with a mean age of 62 yo (range 26-86). All but one fracture healed uneventfully. The mean time to union was 28 weeks (range 12-48 weeks). Two out of 15 patients presented complications (an atrophic nonunion and a peri­implant distal fracture). None of the patients had a nerve palsy prior neither after the surgery. No other complications, including infection, were registered during follow-up. Shoulder range of motion showed the following means: abduction of 147° (range 50°-180°), anterior flexion of 144° (range 80°-180°), external rotation of 77,5 ° (range 70°-80°) and internal rotation of 54.5° (range 45°-60°). All patients recovered their pre-fracture elbow range of motion. All patients presented less than 10° of angular deviation in varus/valgus or ante/recurvatum after the surgical procedure. At the end of the follow-up, all final functional scores were "good" or "excellent": mean Constant-Murley score was 72 ± 13 (range 38-91), ASES score was 73 ± 12 (range 41-88), UCLA shoulder scale was 30 ± 3,5 (range 10-35), and Q-DASH score was 16.5 ± 0,11 (range 4-57). CONCLUSION: When applied correctly, the treatment of diaphyseal humeral fractures involving the proximal humerus using a polyaxial locking helical plate with a MIPO technique is a reliable treatment method. It has high union rates with low complications.

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.

Is my life going to change?-a review of quality of life after rectal resection.

Rectal resection is a common practice for colorectal surgeons. The causes of this procedure are varied. The most frequent is cancer, but also inflammatory bowel disease, endometriosis, and rectovaginal or rectourethral fistulas. The loss of the normal rectal reservoir function, urinary problems, sexual dysfunction or pelvic pain are frequently reported in patients after rectal surgery and these disorders markedly affect the overall quality of life (QoL). In the last decades, rectal surgery has radically changed, with the development of surgical techniques, and it has progressed from abdominoperineal resection (APR) with a permanent colostomy to sphincter-saving procedures. Nowadays, the use of sphincter-preserving surgery has increased, but all these surgical techniques can have important sequels that modify the QoL of the patients. Historically, surgical outcomes, such as complications, survival and recurrences, have been widely studied by surgeons. In the present day, surgical outcomes have improved, rectal cancer recurrence rate has decreased and survival has increased. For these reasons, it has begun to gain importance in aspects of the QoL of patients, such as body image, fecal continence and sexuality or urinary function. Therefore, physicians should know the influence of different techniques and approaches on functional outcomes and QoL, to be able to inform patients of the treatment benefits and risk of postoperative dysfunctions. The aim of our study is to review the current literature to determine to what degree the QoL of patients who underwent a rectal resection decreases, which domains are the most affected and, in addition, to establish the influence of different surgical techniques and approaches on functional outcomes.

Telemedicina, telementorización y evaluación telemática en cirugía. ¿Es su momento después de la COVID-19? / Telemedicine, telementoring and telematic evaluation in surgery. Is it your time after COVID-19?

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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.

Predictive markers of response to neoadjuvant therapy in rectal cancer.

BACKGROUND: Neoadjuvant therapy followed by radical surgery is the standard treatment in locally advanced rectal cancer. It is important to predict the response because the treatment has side effects and is costly. The aim of this study was to establish the relationship among clinical, pathologic, and molecular biomarkers and the response to neoadjuvant therapy. METHOD: A total of 130 patients with locally advanced mid and low rectal cancer who underwent long-course radiotherapy with 5-FU based chemotherapy followed by radical surgical resection were included in the study. Clinical and pathologic data were collected. Paraffin-embedded sections obtained in diagnostic biopsies were assessed by immunohistochemical staining for molecular markers and classified using a semiquantitative method. Results were related with T-downstaging and tumor regression grade using Mandard scoring system on surgical specimens. RESULTS: Pathologic complete response was found in 19 patients (14.6%), while in another 18 (13.8%) only minor residual disease was seen in the rectal wall. T-downstaging was observed in 63 (48.5%). The average of lymph node retrieval in the surgical specimens was 9.4. Regarding predictive markers of response, there was significant correlation between the expression of B-cell lymphoma 2 (P = 0.005), ß-catenin (P = 0.03), vascular endothelial growth factor (P = 0.048) and apoptotic protease activating factor 1 (P = 0.03), tumor differentiation grade (P < 0.001), and response in the univariate analysis. T-downstaging was associated with vascular endothelial growth factor expression (P = 0.03) and tumor differentiation grade (P < 0.001). Significant parameters found in the multivariate analysis were tumor differentiation grade and Bcl-2 expression. CONCLUSIONS: Pathologic and molecular biomarkers in the diagnostic biopsies may help us predict tumor response to chemoradiation in rectal cancer patients.

[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.