T1 Rectal Adenocarcinoma: a Different Way to Measure Tumoral Invasion Based on the Healthy Residual Submucosa with Its Prognosis and Therapeutic Implications.

BACKGROUND: Surgical treatment of early rectal cancer T1 is either local excision or total mesorectal excision. The choice of surgery is based on the risk of metastatic lymph node involvement. The most important factor to consider is the degree of submucosal invasion. We present a different way to measure tumoral invasion derived from the measurement of the healthy residual submucosa with its prognosis and therapeutic implications METHODS: Observational study of tumor submucosal invasion in patients undergoing transanal endoscopic microsurgery was conducted. Parameters evaluated are submucosal invasion, measuring the healthy residual submucosa at the point of maximum invasion; macroscopic morphology of the tumor; presence of muscularis mucosa, muscularis propria, and measurement of submucosa in the tumor area and the healthy area. The classification proposed is compared with the ones previously published. RESULTS: Eighty consecutive patients diagnosed with T1 rectal cancer underwent transanal endoscopic microsurgery. Seventeen tumors (21.3%) were polypoid. En bloc resection was achieved in 77 (96.3%). The muscularis mucosa was present in 28 (35%), and the muscularis propria in 77 (96.3%) (p < 0.001). The healthy residual submucosa in the tumor area measured 2,343 ± 1,869 µm. Agreement was moderate with the Kikuchi classification (kappa 0.58) and very good with the Kudo classification (kappa 0.87). CONCLUSIONS: We describe a method for measuring submucosal invasion in T1 rectal cancer which does not depend on the morphology of the lesion or on the presence of the muscularis mucosa. It can be applied to all T1 classifications of the digestive tract in which the muscularis propria is present.

Target Enrichment Enables the Discovery of lncRNAs with Somatic Mutations or Altered Expression in Paraffin-Embedded Colorectal Cancer Samples.

Long non-coding RNAs (lncRNAs) play important roles in cancer and are potential new biomarkers or targets for therapy. However, given the low and tissue-specific expression of lncRNAs, linking these molecules to particular cancer types and processes through transcriptional profiling is challenging. Formalin-fixed, paraffin-embedded (FFPE) tissues are abundant resources for research but are prone to nucleic acid degradation, thereby complicating the study of lncRNAs. Here, we designed and validated a probe-based enrichment strategy to efficiently profile lncRNA expression in FFPE samples, and we applied it for the detection of lncRNAs associated with colorectal cancer (CRC). Our approach efficiently enriched targeted lncRNAs from FFPE samples, while preserving their relative abundance, and enabled the detection of tumor-specific mutations. We identified 379 lncRNAs differentially expressed between CRC tumors and matched healthy tissues and found tumor-specific lncRNA variants. Our results show that numerous lncRNAs are differentially expressed and/or accumulate variants in CRC tumors, thereby suggesting a role in CRC progression. More generally, our approach unlocks the study of lncRNAs in FFPE samples, thus enabling the retrospective use of abundant, well documented material available in hospital biobanks.

Droplet Digital PCR Detects Low-Density Infection in a Significant Proportion of Helicobacter Pylori-Negative Gastric Biopsies of Dyspeptic Patients.

INTRODUCTION: Helicobacter pylori-infected individuals may present low-density infection, undetectable by conventional tests such as histology, rapid urease test, or urea breath test. Droplet digital polymerase chain reaction (ddPCR) is more sensitive than other polymerase chain reaction methods. We aimed to evaluate the ability of ddPCR to detect H. pylori infection in patients diagnosed as negative by conventional tests. METHODS: Dyspeptic patients (n = 236) were tested for H. pylori by histology, urea breath test, and rapid urease test. Patients were classified as having 3 positive (n = 25, control group), 2 positive (n = 12), one positive (n = 41), or zero positive (n = 158) diagnostic tests. DNA was extracted from gastric biopsies. Triplicate ddPCR testing for each of the 16S rDNA, ureA, and vacA(s) genes was performed using a QX200 ddPCR system (Bio-Rad). A gene was considered positive when detected by at least 2 of 3 repeated ddPCRs. H. pylori positivity was defined as having 2 or more positive genes. RESULTS: All the biopsies of the control patients were positive for all 3 16S rDNA, ureA, and vacA(s) genes. H. pylori infection was detected in 57 (36%), 22 (54%), and 9 (75%) patients with zero, 1, and 2 positive diagnostic tests, respectively. The density of infection was 5, 121, 599, and 3,133 copies of H. pylori genome equivalents for patients with zero, 1, and 2 of 3 positive test results and for the control group, respectively. DISCUSSION: ddPCR detected low-density "occult" H. pylori infection in a significant proportion (36%) of patients diagnosed as negative by conventional methods. The number of conventional positive tests was related to the density of infection.

Neoadjuvant therapy and transanal endoscopic surgery in T2-T3 superficial, N0, M0 rectal tumors. Local recurrence, complete clinical and pathological response. / Neoadyuvancia y cirugía endoscópica transanal en neoplasias de recto T2-T3 superficial, N0, M0. Recidiva local, respuesta clínica y patológica completa.

INTRODUCTION: The association of preoperative chemoradiotherapy and transanal endoscopic surgery in T2 and superficial T3 rectal cancers presents promising results in selected patients. The main objective is to evaluate the long-term loco-regional and systemic recurrence and, as secondary objectives, to provide results of postoperative morbidity and the correlation between complete clinical and pathological response. METHODS: This is a retrospective observational study including a consecutive series of patients with T2-T3 superficial rectal cancer, N0, M0 who refused radical surgery (2008-2016). The treatment consisted of preoperative chemotherapy (5-fluorouracil or capecitabine) combined with radiotherapy (50, 4Gy) and transanal endoscopic surgery after 8weeks. Preoperative, surgical, pathological and long-term oncologic results were analyzed. RESULTS: Twenty-four patients were included in the study. Two of them required rescue radical surgery for unfavorable pathological results. A local recurrence (4.5%) was observed and 2patients presented systemic recurrence (9%), with a median follow-up of 45 months. A complete clinical tumor response was achieved in 12 patients (50%), and complete pathological tumor response in 9 patients (37.5%). Postoperative complications were observed in 5 patients (20.8%), and they were mild except one. There was no postoperative mortality. CONCLUSIONS: In this stage of rectal cancer, our results seem to support this strategy, mainly when a complete pathological response is achieved. The complete clinical tumor response does not coincide with the pathological tumor response. Randomized prospective studies should be performed to standardize this treatment.

Neoadyuvancia y cirugía endoscópica transanal en neoplasias de recto T2-T3 superficial, N0, M0. Recidiva local, respuesta clínica y patológica completa / Neoadjuvant therapy and transanal endoscopic surgery in T2-T3 superficial, N0, M0 rectal tumors. Local recurrence, complete clinical and pathological response

INTRODUCCIÓN: La asociación de quimiorradioterapia preoperatoria y cirugía endoscópica transanal en el cáncer rectal T2-T3 superficial presenta resultados prometedores en pacientes seleccionados. El objetivo principal es evaluar la recurrencia locorregional y sistémica a largo plazo y los objetivos secundarios son aportar resultados de morbilidad postoperatoria y la correlación entre la respuesta patológica completa y clínica completa. MÉTODOS: Estudio observacional retrospectivo de una serie consecutiva de pacientes diagnosticados de cáncer de recto T2-T3 superficial, N0, M0 que se trataron con quimiorradioterapia neoadyuvante y escisión transanal del tumor (2008-2016). Se recogieron los datos de forma prospectiva. El tratamiento consistió en quimioterapia preoperatoria (5-fluorouracilo o capecitabina) combinada con radioterapia (50,4Gy) y cirugía endoscópica transanal tras 8semanas. Se analizaron las variables preoperatorias, quirúrgicas, patológicas y los resultados oncológicos a largo plazo. RESULTADOS: De los 24 pacientes incluidos, 2requirieron rescate a cirugía radical por resultados patológicos desfavorables. Con un seguimiento mediano de 45 meses, se observó recurrencia local en un paciente (4,5%) y 2pacientes presentaron recurrencias sistémicas (9%). La respuesta clínica tumoral completa se logró en 12 pacientes (50%) y la respuesta patológica tumoral completa en 9 pacientes (37,5%). Las complicaciones postoperatorias se apreciaron en 5 pacientes (20,8%), todas leves excepto una. No hubo mortalidad postoperatoria. CONCLUSIONES: En este estadio del cáncer rectal, nuestros resultados parecen apoyar esta estrategia, principalmente cuando se logra una respuesta patológica tumoral completa. La respuesta clínica tumoral completa no coincide con la respuesta patológica tumoral. Se deben llevar a cabo estudios prospectivos aleatorizados para estandarizar este tratamiento

INTRODUCTION: The association of preoperative chemoradiotherapy and transanal endoscopic surgery in T2 and superficial T3 rectal cancers presents promising results in selected patients. The main objective is to evaluate the long-term loco-regional and systemic recurrence and, as secondary objectives, to provide results of postoperative morbidity and the correlation between complete clinical and pathological response. METHODS: This is a retrospective observational study including a consecutive series of patients with T2-T3 superficial rectal cancer, N0, M0 who refused radical surgery (2008-2016). The treatment consisted of preoperative chemotherapy (5-fluorouracil or capecitabine) combined with radiotherapy (50, 4Gy) and transanal endoscopic surgery after 8weeks. Preoperative, surgical, pathological and long-term oncologic results were analyzed. RESULTS: Twenty-four patients were included in the study. Two of them required rescue radical surgery for unfavorable pathological results. A local recurrence (4.5%) was observed and 2patients presented systemic recurrence (9%), with a median follow-up of 45 months. A complete clinical tumor response was achieved in 12 patients (50%), and complete pathological tumor response in 9 patients (37.5%). Postoperative complications were observed in 5 patients (20.8%), and they were mild except one. There was no postoperative mortality. CONCLUSIONS: In this stage of rectal cancer, our results seem to support this strategy, mainly when a complete pathological response is achieved. The complete clinical tumor response does not coincide with the pathological tumor response. Randomized prospective studies should be performed to standardize this treatment

Hybrid NOTES: TEO for transanal total mesorectal excision: intracorporeal resection and anastomosis.

BACKGROUND: Laparoscopic surgery for rectal TME achieves better patient recovery, lower morbidity, and shorter hospital stay than open surgery. However, in laparoscopic rectal surgery, the overall conversion rate is nearly 20%. Transanal TME combined with laparoscopy, known as Hybrid NOTES, is a less invasive procedure that provides adequate solutions to some of the limitations of rectal laparoscopy. Transanal TME via TEO with technical variants (intracorporeal resection and anastomosis, TEO review of the anastomosis) attempts to standardize and simplify the procedure. METHOD: Prospective observational study was used describe and assess the technique in terms of conversion to open surgery, overall morbidity, surgical site infection and hospital stay. The sample comprised consecutive patients diagnosed with rectal tumor less than 10 cm from the anal verge who were candidates for low anterior resection using TME (except T4). Demographic, surgical, postoperative, and pathological variables were analyzed, as well as morbidity rates. RESULTS: From September 2012 to August 2014, 32 patients were included. The conversion rate was 0%. Overall morbidity was 31.3%, SSI rate was 9.4%, and mean hospital stay was 8 days. Oncological radical criteria were achieved with pathological parameters of 94% of complete TME and a median circumferential margin of 13 mm. CONCLUSION: The introduction of technical variants of TEO for transanal resection can facilitate a procedure that requires extensive experience in transanal and laparoscopic surgery. Studies of sphincter function, quality of life, and long-term oncological outcome are now necessary.

Occult H. pylori infection partially explains 'false-positive' results of (13)C-urea breath test.

BACKGROUND: In a previous study, UBiT-100 mg, (Otsuka, Spain), a commercial (13)C-urea breath test omitting citric acid pre-treatment, had a high rate of false-positive results; however, it is possible that UBiT detected low-density 'occult' infection missed by other routine reference tests. We aimed to validate previous results in a new cohort and to rule out the possibility that false-positive UBiT were due to an 'occult' infection missed by reference tests. METHODS: Dyspeptic patients (n = 272) were prospectively enrolled and UBiT was performed, according to the manufacturer's recommendations. Helicobacter pylori infection was determined by combining culture, histology and rapid urease test results. We calculated UBiT sensitivity, specificity, positive and negative predictive values (with 95% CI). In addition, we evaluated 'occult' H. pylori infection using two previously-validated polymerase chain reaction (PCR) methods for urease A (UreA) and 16 S sequences in gastric biopsies. We included 44 patients with a false-positive UBiT, and two control groups of 25 patients each, that were positive and negative for all H. pylori tests. RESULTS: UBiT showed a false-positive rate of 17%, with a specificity of 83%. All the positive controls and 12 of 44 patients (27%) with false-positive UBiT were positive for all two PCR tests; by contrast, none of our negative controls had two positive PCR tests. CONCLUSIONS: UBiT suffers from a high rate of false-positive results and sub-optimal specificity, and the protocol skipping citric acid pre-treatment should be revised; however, low-density 'occult' H. pylori infection that was undetectable by conventional tests accounted for around 25% of the 'false-positive' results.

Transanal endoscopic surgery with total wall excision is required with rectal adenomas due to the high frequency of adenocarcinoma.

BACKGROUND: Colorectal adenomatous polyps are considered premalignant lesions, although a high percentage are already malignant at the time of their removal. Full-thickness excision in patients with adenoma detected in preoperative biopsy enables much more accurate pathology examination and has shown that local surgery is appropriate for T1 adenocarcinoma. OBJECTIVE: To determine whether full-thickness excision during transanal endoscopic surgery is the treatment of choice for rectal adenoma, and to identify possible predictors of invasive adenocarcinoma associated with this type of lesion. DESIGN: Prospective, observational study. SETTING: The study was conducted at a university teaching hospital. PATIENTS: All patients scheduled for transanal endoscopic surgery after detection of adenoma in a preoperative biopsy between June 2004 and February 2013 entered the study. MAIN OUTCOME MEASURES: The principal variable was the presence of invasive adenocarcinoma in the pathology study. Other study variables were the epidemiological variables sex and age; the clinical variables tumor size, number of quadrants affected, distance from the anal verge, and tumor location; and the morphological variables tumor aspect, degree of dysplasia, preoperative biopsy (tubulo-villous), endorectal ultrasound, and pelvic MRI stage. Variables found to be related to the risk of malignancy in rectal adenomas were evaluated using univariate and multivariate analysis. RESULTS: Of 471 patients who underwent surgery, 277 had a preoperative diagnosis of adenoma. Final pathology studies showed 52 (18.8%) invasive adenocarcinomas, among which 27 were pT1 (52%), 16 pT2 (30.7%), and 9 pT3 (17.3%). Factors predictive of invasive adenocarcinoma were sessile morphology (OR 3.2, 95%CI 1.4-7.1), high-grade dysplasia (OR 2.3, 95%CI 1.2-4.8), and endorectal ultrasound stage uT2-T3 (OR 3.8, 95%CI 1.6-9). LIMITATIONS: The limitations are derived from the observational design. CONCLUSIONS: In this sample, half of the adenocarcinomas from adenomas were T1 adenocarcinomas. Because a high proportion of rectal adenomas are, in fact, invasive adenocarcinomas, full-thickness excision is appropriate.

microRNA expression profile in stage III colorectal cancer: circulating miR-18a and miR-29a as promising biomarkers.

Biomarkers that can facilitate disease detection, staging and prediction of outcome are highly desirable to improve survival and to help determine optimized treatment for colorectal cancer patients. microRNAs (miRNAs) are small non-coding RNAs that play a crucial role in gene regulatory networks. The deregulation of miRNA expression has been found in several types of cancer and may represent a novel class of cancer biomarkers. Our aim was to determine the miRNA signature of stage III colorectal cancer (CRC) tumors and to identify potential circulating miRNAs that may represent non-invasive biomarkers in CRC patients. Genome-wide microarray analysis of miRNA expression was performed on 12 paired tumor and non-tumor formalin-fixed paraffin-embedded tissues from stage III CRC patients. A selection of differentially overexpressed miRNAs was validated by quantitative real-time polymerase chain reaction (qRT-PCR) and determined in the serum of a set of 56 individuals (30 stage III CRC patients and 26 healthy individuals). Using 1.5-fold expression difference as a cut-off level, 43 miRNAs were identified as differentially expressed in tumor versus normal tissue. Using reverse transcription and qRT-PCR, 11 miRNAs (miR-135b, miR-141, miR-18a, miR-20a, miR-21, miR-224, miR-29a, miR-31, miR-34a, miR-92a and miR-96) were confirmed as significantly overexpressed in tumor samples when compared with normal samples. We were able to detect 9 of these 11 miRNAs in serum samples from CRC patients and healthy individuals. Serum levels of miR-18a and miR-29a were significantly higher in CRC patients when compared to levels in the controls (p<0.05). In conclusion, this study identified a substantial number of miRNAs which were differentially expressed in stage III colorectal tumors. Moreover, the findings provide relevant information concerning overexpressed tumoral miRNAs as potential circulating biomarkers and highlight serum miR-18a and miR-29a as promising biomarkers for the screening and monitoring of CRC patients.

Real-time PCR improves Helicobacter pylori detection in patients with peptic ulcer bleeding.

BACKGROUND AND AIMS: Histological and rapid urease tests to detect H. pylori in biopsy specimens obtained during peptic ulcer bleeding episodes (PUB) often produce false-negative results. We aimed to examine whether immunohistochemistry and real-time PCR can improve the sensitivity of these biopsies. PATIENTS AND METHODS: We selected 52 histology-negative formalin-fixed paraffin-embedded biopsy specimens obtained during PUB episodes. Additional tests showed 10 were true negatives and 42 were false negatives. We also selected 17 histology-positive biopsy specimens obtained during PUB to use as controls. We performed immunohistochemistry staining and real-time PCR for 16S rRNA, ureA, and 23S rRNA for H. pylori genes on all specimens. RESULTS: All controls were positive for H. pylori on all PCR assays and immunohistochemical staining. Regarding the 52 initially negative biopsies, all PCR tests were significantly more sensitive than immunohistochemical staining (p<0.01). Sensitivity and specificity were 55% and 80% for 16S rRNA PCR, 43% and 90% for ureA PCR, 41% and 80% for 23S rRNA PCR, and 7% and 100% for immunohistochemical staining, respectively. Combined analysis of PCR assays for two genes were significantly more sensitive than ureA or 23S rRNA PCR tests alone (p<0.05) and marginally better than 16S rRNA PCR alone. The best combination was 16S rRNA+ureA, with a sensitivity of 64% and a specificity of 80%. CONCLUSIONS: Real-time PCR improves the detection of H. pylori infection in histology-negative formalin-fixed paraffin-embedded biopsy samples obtained during PUB episodes. The low reported prevalence of H. pylori in PUB may be due to the failure of conventional tests to detect infection.

Clinical patterns and outcomes of ischaemic colitis: results of the Working Group for the Study of Ischaemic Colitis in Spain (CIE study).

BACKGROUND: There is a lack of prospective studies evaluating the natural history of colonic ischaemia (CI). We performed such a study to evaluate the clinical presentation, outcome, and mortality as well as clinical variables associated with poor prognosis. METHODS: An open, prospective, and multicentre study was conducted in 24 Spanish hospitals serving a population of 3.5 million people. The study included only patients who met criteria for definitive or probable CI. A website (www.colitisisquemica.org) provided logistical support. RESULTS: A total of 364 patients met criteria for inclusion. CI was suspected clinically in only 24.2% of cases. The distribution of clinical patterns was as follows: reversible colopathy (26.1%), transient colitis (43.7%), gangrenous colitis (9.9%), fulminant pancolitis (2.5%), and chronic segmental colitis (17.9%). A total of 47 patients (12.9%) had an unfavorable outcome as defined by mortality and/or the need for surgery. Multivariate analysis identified the following signs as independent risk factors for an unfavorable outcome: abdominal pain without rectal bleeding [odds ratio (OR) 3.9; 95% confidence interval (CI) = 1.6-9.3], non-bloody diarrhoea (OR 10; 95% CI = 3.7-27.4), and peritoneal signs (OR 7.3; 95% CI = 2.7-19.6). Unfavorable outcomes also were more frequent in isolated right colon ischaemia (IRCI) compared with non-IRCI (40.9 vs. 10.3%, respectively; p < 0.0001). The overall mortality rate was 7.7%. CONCLUSIONS: The clinical presentation of CI is very heterogeneous, perhaps explaining why clinical suspicion of this disease is so low. The presence of IRCI, and occurrence of peritoneal signs or onset of CI as severe abdominal pain without bleeding, should alert the physician to a potentially unfavorable course.

Accuracy of diagnostic tests for Helicobacter pylori: a reappraisal.

BACKGROUND: Despite many changes, no large studies comparing the different diagnostic tests for Helicobacter pylori have been performed in the past 10 years. In this time, monoclonal stool antigen immunoassays and in-office 13C-urea breath tests (UBTs) have appeared. The aim of this study was to evaluate the accuracy of invasive and noninvasive tests in a large series of dyspeptic patients. METHODS: A total of 199 dyspeptic patients who had not previously been treated for H. pylori infection were prospectively enrolled. Noninvasive analyses included a commercial infrared-based UBT and a commercially available stool test. Biopsy-based tests included histological examination and a rapid urease test. A patient was considered to be infected when at least 2 test results were positive. Sensitivity, specificity, positive and negative predictive values, and 95% confidence intervals were calculated. The test results were compared using the McNemar test. RESULTS: Rates of positive test results were similar (54%) for the rapid urease test, histopathological examination, and the stool test. By contrast, 75% of UBT results were positive, and the UBT was associated with a very low specificity (60%). For this reason, the delta cutoff value for the UBT was recalculated as 8.5%. Sensitivities and specificities with this new cutoff value were 95% and 100%, respectively, for the rapid urease test; 94% and 99%, respectively, for histopathological examination; 90% and 93%, respectively, for the stool test; and 90% and 90%, respectively, for the UBT. CONCLUSIONS: Histological examination and rapid urease testing showed excellent diagnostic reliability. The stool test seems to be a good, noninvasive alternative to endoscopy-based tests. By contrast, the infrared-based UBT evaluated in our study showed a lower than expected performance, which was partially corrected when the cutoff value for the test was recalculated.

Convulsiones y lesión frontoparietal izquierda en una mujer de 20 años / Convulsions and left frontotemporal lesion in a 20-yars-old woman

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