Machine Learning-Based Prediction of Responsiveness to Neoadjuvant Chemoradiotheapy in Locally Advanced Rectal Cancer Patients from Endomicroscopy.

The protocol for treating locally advanced rectal cancer consists of the application of chemoradiotherapy (neoCRT) followed by surgical intervention. One issue for clinical oncologists is predicting the efficacy of neoCRT in order to adjust the dosage and avoid treatment toxicity in cases when surgery should be conducted promptly. Biomarkers may be used for this purpose along with in vivo cell-level images of the colorectal mucosa obtained by probe-based confocal laser endomicroscopy (pCLE) during colonoscopy. The aim of this article is to report our experience with Motiro, a computational framework that we developed for machine learning (ML) based analysis of pCLE videos for predicting neoCRT response in locally advanced rectal cancer patients. pCLE videos were collected from 47 patients who were diagnosed with locally advanced rectal cancer (T3/T4, or N+). The patients received neoCRT. Response to treatment by all patients was assessed by endoscopy along with biopsy and magnetic resonance imaging (MRI). Thirty-seven patients were classified as non-responsive to neoCRT because they presented a visible macroscopic neoplastic lesion, as confirmed by pCLE examination. Ten remaining patients were considered responsive to neoCRT because they presented lesions as a scar or small ulcer with negative biopsy, at post-treatment follow-up. Motiro was used for batch mode analysis of pCLE videos. It automatically characterized the tumoral region and its surroundings. That enabled classifying a patient as responsive or non-responsive to neoCRT based on pre-neoCRT pCLE videos. Motiro classified patients as responsive or non-responsive to neoCRT with an accuracy of ~ 0.62 when using images of the tumor. When using images of regions surrounding the tumor, it reached an accuracy of ~ 0.70. Feature analysis showed that spatial heterogeneity in fluorescence distribution within regions surrounding the tumor was the main contributor to predicting response to neoCRT. We developed a computational framework to predict response to neoCRT by locally advanced rectal cancer patients based on pCLE images acquired pre-neoCRT. We demonstrate that the analysis of the mucosa of the region surrounding the tumor provides stronger predictive power.

Impact of radiotherapy on adverse events of self-expanding metallic stents in patients with esophageal cancer.

Self-expanding metallic stents (SEMS) are considered the treatment of choice for the palliation of dysphagia and fistulas in inoperable esophageal neoplasms. However, the safety of SEMSs in patients who received or who will be submitted to radiotherapy (RT) is uncertain. The study aimed to evaluate the impact of RT on adverse events (AEs) in patients with esophageal cancer with SEMSs. This is a retrospective study conducted at a tertiary cancer hospital from 2009 to 2018. We collected information regarding RT, the histological type of the tumor, the model of SEMSs and AEs after stent placement. Three hundred twenty-three patients with malignant stenosis or fistula were treated with SEMSs. The predominant histological type was squamous cell carcinoma (79.6%). A total of 282 partially covered and 41 fully covered SEMSs were inserted. Of the 323 patients, 182 did not received RT, 118 received RT before SEMS placement and 23 after. Comparing the group that received RT before stent insertion with the group that did not, the first one presented a higher frequency of severe pain (9/118 7.6% vs. 3/182 1.6%; P = 0.02). The group treated with RT after stent placement had a higher risk of global AEs (13/23 56.5% vs. 63/182 34.6%; P = 0.019), ingrowth/overgrowth (6/23 26.1% vs. 21/182 11.5%; P = 0.045) and gastroesophageal reflux (2/23 8.7% vs. 2/182 1.1%; P = 0.034). Treatment with RT before stent placement in patients with inoperable esophageal neoplasm prolongs survival and is associated with an increased risk of severe chest pain. Treatment with RT of patients with an esophageal stent increases the frequency of minor, not life-threatening AEs.

Tube-in-tube endoscopic vacuum therapy for the closure of upper gastrointestinal fistulas, leaks, and perforations.

BACKGROUND : Although endoscopic vacuum therapy (EVT) has been successfully used to treat postoperative upper gastrointestinal (UGI) wall defects, its use demands special materials and several endoscopic treatment sessions. Herein, we propose a technical modification of EVT using a double tube (tube-in-tube drain) without polyurethane sponges for the drainage element. The tube-in-tube drainage device enables irrigation and application of suction. A flowchart for standardizing the management of postoperative UGI wall defects with this device is presented. METHODS : An EVT modification was made to achieve frequent fistula cleansing, with 3 % hydrogen peroxide rinsing, and the application of negative pressure. A tube-in-tube drain without polyurethane sponges can be inserted like a nasogastric tube or passed through a previously positioned surgical drain. This was a retrospective two-center observational study, with data collected from 30 consecutive patients. Technical success, clinical success, adverse events, time under therapy, interval time from procedure to fistula diagnosis and treatment start, size of transmural defect, volume of cavity, number of endoscopic treatment sessions, and mortality were reviewed. RESULTS : 30 patients with UGI wall defects were treated. The technical and clinical success rates were 100 % and 86.7 %, respectively. Three patients (10 %) had adverse events and three patients (10 %) died. The median time under therapy was of 19 days (range 1-70) and the median number of endoscopic sessions was 3 (range 1-9). CONCLUSIONS : This standardized approach and EVT modification using a tube-in-tube drain, with frequent fistula cleansing, were successful and safe in a wide variety of UGI wall defects.

Risk factors for adverse events of colorectal endoscopic submucosal dissection: a systematic review and meta-analysis.

Colorectal endoscopic submucosal dissection (ESD) is already an established treatment for superficial colorectal tumors. However, its technical difficulty and high adverse events rates, compared to endoscopic piecemeal mucosal resection, are a concern to some specialists and have probably contributed to discouragement in its widespread adoption. The debate mentioned above stimulated us to perform a systematic review aiming to identify risk factors for colorectal ESD-related adverse events. We conducted this study following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement and registered in the PROSPERO (University of York) international database (CRD42016042625). We searched MEDLINE, EMBASE, Cochrane Library and LILACS for the publications focused on risk factors for colorectal ESD-related adverse events from inception until April 2020. We included a total of 22 qualified studies in this analysis. We found that fibrosis had an odds ratio (OR) for perforation of 2.90 [95% confidence interval, (1.83-4.59)], right colon location of 2.35 (1.58-3.50), colonic location of 2.20 (1.44-3.35) and larger size of 2.17 (1.47-3.21), as well as one protective factor, the endoscopist experience OR = 0.62 (0.45-0.86). For bleeding, we considered rectal location a risk factor [OR = 3.55 (2.06-6.12)]. Through the several meta-analyses that we performed in this article, we could summarize the main risk factors for perforation and bleeding on colorectal ESD. Therefore, we provide insightful information for clinical judgment on regions where colorectal ESD is already widespread and help in the learning process of this challenging technique.

Role of Magnification Chromoendoscopy in the Management of Colorectal Neoplastic Lesions Suspicious for Submucosal Invasion.

BACKGROUND: Correctly predicting the depth of tumor invasion in the colorectal wall is crucial for successful endoscopic resection of superficial colorectal neoplasms. OBJECTIVE: The aim of this study was to assess the accuracy of magnifying chromoendoscopy in a Western medical center to predict the depth of invasion by the pit pattern classification in patients with colorectal neoplasms with a high risk of submucosal invasion. DESIGN: This single-center retrospective study, from a prospectively collected database, was conducted between April 2009 and June 2015. SETTINGS: The study was conducted at a single academic center. PATIENTS: Consecutive patients with colorectal neoplasms with high risk of submucosal invasion were included. These tumors were defined by large (≥20 mm) sessile polyps (nonpedunculated), laterally spreading tumors, or depressed lesions of any size. INTERVENTIONS: Patients underwent magnifying chromoendoscopy and were classified according to the Kudo pit pattern. The therapeutic decision, endoscopic or surgery, was defined by the magnification assessment. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values of magnifying chromoendoscopy for assessment of these lesions were determined. RESULTS: A total of 123 lesions were included, with a mean size of 54.0 ± 37.1 mm. Preoperative magnifying chromoendoscopy with pit pattern classification had 73.3% sensitivity, 100% specificity, 100% positive predictive value, 96.4% negative predictive value, and 96.7% accuracy to predict depth of invasion and consequently to guide the appropriate treatment. Thirty-three rectal lesions were also examined by MRI, and 31 were diagnosed as T2 lesions. Twenty two (70.1%) of these lesions were diagnosed as noninvasive by magnifying colonoscopy, were treated by endoscopic resection, and met the curative criteria. LIMITATIONS: This was a single-center retrospective study with a single expert endoscopist experience. CONCLUSIONS: Magnifying chromoendoscopy is highly accurate for assessing colorectal neoplasms suspicious for submucosal invasion and can help to select the most appropriate treatment. See Video Abstract at http://links.lww.com/DCR/A920.

Epithelial cell turnover is increased in the excluded stomach mucosa after Roux-en-Y gastric bypass for morbid obesity.

BACKGROUND: Mucosal alterations after Roux-en-Y gastric bypass for morbid obesity have not been clearly evaluated. This study aims to analyze the mucosal alterations (proliferative status (Ki-67); apoptosis (caspase-3 and BCL-2); hormonal function (gastrin)) in the excluded stomach. METHODS: Double-balloon enteroscopy was performed in 35 patients who underwent Roux-en-Y gastric bypass longer than 36 months. Multiple biopsies of the proximal pouch and the excluded gastric mucosa were collected. Gastric biopsies from 32 non-operated obese patients were utilized as controls. Endoscopic biopsies were cut from tissue blocks fixed in formalin and embedded in paraffin. Sections 4 µm thick were examined for immunoexpression using the streptavidin-biotin-peroxidase method. RESULTS: The two groups were comparable for age, gender, gastritis, intestinal metaplasia, and Helicobacter pylori. The mean number of positive gastrin cells was 55.5 (standard deviation (SD) = 11.7) in the control group and 29.6 (SD = 7.9) in the cases, p = 0.0003. Ki-67 proliferative index in cases (body = 24.7%, antrum = 24.9%) was significantly higher compared to controls (body = 15.0% and antrum = 17.7%), p = 0.002 and 0.01, respectively. Caspase-3 immunoexpression was higher in the controls compared to the excluded stomach (46 vs. 31%), p = 0.02. There was no statistical difference between CD3, CD8, and Bcl-2 immunoexpressions in the control and cases. CONCLUSIONS: Cell proliferation is increased and apoptosis is downregulated in the excluded gastric mucosa compared to the non-operated obese controls. Alterations in cell turnover and in hormonal secretions in these conditions may be of relevance in long-term follow-up.

Endoscopic findings in the excluded stomach after Roux-en-Y gastric bypass surgery.

HYPOTHESIS: After gastric bypass surgery performed because of morbid obesity, the excluded stomach can rarely be endoscopically examined. With the advent of a new apparatus and technique, possible mucosal changes can be routinely accessed and monitored, thus preventing potential benign and malignant complications. DESIGN: Prospective observational study in a homogeneous population with nonspecific symptoms. SETTING: Outpatient clinic of a large public academic hospital. PATIENTS: Forty consecutive patients (mean +/- SD age, 44.5 +/- 10.0 y ears; 85.0% women) were seen at a mean +/- SD of 77.3 +/- 19.4 months after Roux-en-Y gastric bypass surgery. INTERVENTION: Elective double-balloon enteroscopy of the excluded stomach was performed. MAIN OUTCOME MEASURES: Rate of successful intubation, endoscopic findings, and complications. RESULTS: The excluded stomach was reached in 35 of 40 patients (87.5%). Mean +/- SD time to enter the organ was 24.9 +/- 14.3 minutes (range, 5-75 minutes). Endoscopic findings were normal in 9 patients (25.7%), whereas in 26 (74.3%), various types of gastritis (erythematous, erosive, hemorrhagic erosive, and atrophic) were identified, primarily in the gastric body and antrum. No cancer was documented in the present series. Tolerance was good, and no complications were recorded during or after the intervention. CONCLUSIONS: The double-balloon method is useful and practical for access to the excluded stomach. Although cancer was not noted, most of the studied population had gastritis, including moderate and severe forms. Surveillance of the excluded stomach is recommended after Roux-en-Y gastric bypass surgery performed because of morbid obesity.

Clinicopathologic and immunohistochemistry characterization of synchronous multiple primary gastric adenocarcinoma.

The aim of this investigation was to evaluate clinicopathologic and immunohistochemical characteristics of synchronous primary gastric adenocarcinomas. Immunohistochemistry for p53 (suppressor pathway) and for hMLH1, hMSH2, and hMSH6 (mutator pathway) was performed using ABC-technique amplification by biotinylated tyramide. Synchronous primary gastric adenocarcinomas were detected in 19/553 (3.43%) of the patients. The tumors were localized in distal stomach in 22, body in 14, and proximal in five. There was a predominance of intestinal type in the group of synchronic tumors compared to the solitary lesions, 73.2 vs 37.3%, p = 0.001. Synchronous neoplasias were diagnosed in earlier stage than solitary neoplasias, T1-T2 = 60.9% vs T1-T2 = 28.4%, p = 0.0001; and N0 = 68.4% vs N0 = 26.2%, p = 0.001. p53 was detected in 52.6% of the patients with synchronous tumors. Altered hMLH1 immunoexpression occurred in 26.3% of the patients and hMSH6 in 5.3%. hMSH2 immunoreactivity was positive in all tumors. p53 was solely detected in 17 tumors, while hMLH1 was altered in 10/24 negative p53 tumors, p = 0.01. Synchronous gastric adenocarcinomas presented higher frequency of intestinal type and early gastric cancer in comparison to solitary gastric cancer. Two routes of carcinogenesis, mutator, and suppressor appear to be involved independently in the development of synchronous tumors.

Prognostic value of immunohistochemistry in gastric neuroendocrine (carcinoid) tumors.

UNLABELLED: Three subtypes of enterochromaffin-like cell tumors (carcinoids) have been described: type I, associated with chronic atrophic gastritis; type II, multiple endocrine neoplasia 1 and Zollinger-Ellison syndrome; and type III, sporadic tumors. OBJECTIVES: (i) To investigate the immunoexpression of Ki-67, p53 and Bcl-2 proteins in enterochromaffin-like cell (carcinoid) tumors and (ii) to evaluate the prognostic value of these markers. METHODS: Fifty-four samples from 21 patients with gastric carcinoid tumors were sectioned and immunostained using avidin-biotin peroxidase method. RESULTS: The mean age was 62.2+/-11.4 years (36-83 years-old) and 13 (61.9%) were women. Type I lesions were detected in 61.9% and type III in 38.1%. Tumors were single in 10 (47.6%) and were multiple and/or multicentric in 11 (52.4%). Nuclear p53 immunoreactivity was observed in 6/21 patients (28.6%), and all of them were type III tumors (6/8), compared with no p53 expression in type I (0/13), P=0.0002. p53 expression was also associated with high degree of cell proliferation (Ki-67-positive nuclear cells), P=0.00001. Bcl-2 expression was either unreactive or weakly positive in all tumor lesions. The mean follow-up period was 50.4 months (SD=45.2), varying from 6 to 144 months. Overall survival time of patients with positive p53 expression and high proliferative rate was significantly lower than that of negative patients (14.4 vs 123 months, P=0.0007). CONCLUSIONS: (i) p53 immunoexpression associated with high proliferative rate was useful to distinguish between type I and type III gastric carcinoid tumors and (ii) these markers were able to predict a shorter survival.

Does the intraoperative peritoneal lavage cytology add prognostic information in patients with potentially curative gastric resection?

Peritoneal recurrence is the foremost pattern of failure after potentially curative resection for gastric cancer. Our aim was to evaluate the prognostic value of intraperitoneal free cancer cells (IFCCs) in peritoneal lavage of patients who underwent potentially curative resection for gastric carcinoma. Two hundred twenty patients with gastric cancer stage I, II, or III were prospectively evaluated with peritoneal lavage and cytologic examination. Aspirated fluid from the abdominal cavity was centrifuged and subjected to Papanicolaou staining. The mean age was 60.9 years (range, 21-89 years), and 63.6% were men. IFCCs were detected in 6.8% of the patients; suspicious in 2.7%, and negative in 84.5%. No judgment could be given in 5.9% of the cases. Invasion of the gastric serosa (pT3) was observed in all positive cytology patients. Patients with IFCCs had a mean survival time of 10.5 months, while those with negative IFCC had a mean survival time of 61 months (P = 0.00001). There was no correlation between the presence of IFCCs and tumor size, histology, pN, or tumor site. Our conclusions are that (1) positive cytology indicates a poor prognosis in patients who underwent potentially curative gastric resection and (2) peritoneal lavage cytology improves staging in assessing these patients and may alter their therapeutic approach.

Hiperexpressão e mutação do gene p53 em biópsias endoscópicas de pacientes com megaesôfago chagásico / Overexpression and mutation of gene p53 in endoscopic biopsies of patients with Chagas megaesophagus

O câncer do esôfago é mais prevalente em pacientes com megaesôfago chagáscio do que na população normal. Marcadores desse maior risco não são conhecidos. Objetivos: Correlacionar as alterações do p53 (gene supressor de tumor) e do PCNA (antígeno nuclear de células em proliferação) com as alterações histólogiacas da mucosa em pacientes com megaesôfago avançado. Métodos:Quatro carcinomas epidermóides do esôfago e áreas adjacentes correspondentes, provenietes de pacientes com megaesôfago, foram analisados através de imuno-histoquimica para p53 e PCNA. Concomitantemente, 128 biópsias, de diferentes níveis do esôfago, de 16 pacientes com megaesôfago avançado (sem tumor) foram prospectivamente coletados e avaliadas quanto ao grau de inflamação, hiperplasia, displasia e imuno-histoquímica para p53 e PCNA. Todos os tecidos positivos para o p53 foram submetidos à análise gênica topográfica através de microdissecção, amplicifacção por PCR e direito sequenciamento dos exons 5 a 8. Resultados: Reatividade forte e difusa para o p53 foi observada em 2/4 tumores (exon 7,238 CH e exon 5, 146WC). Em um paciente, a área adjacente ao tumor apresentou forte positividade para o p53. Na mucosa adjacente, as mesmas áreas mostrando hiperexpressão do p53 também apresentaram maior positividade ao PCNA. No grupo prospectivo, 7/16 (43,7por cento) pacientes ou 53/128(41,4por cento) biópsias expressaram o p53. Hiperplasia foi diagnosticada em 4/16pacientes ou em 10 biópsias e associada a hiperexpressão do p53 em todos os casos . Displasia não esteve presente nesse grupo. Foi observada positividade ao p53 em 15,4por cento das biópsias sem inflamação em 31,4por cento com inflamação leve, 78,3por cento com moderada e 88,9poe cento com intensa (p<0,00001). A expressão do PCNA foi detectada na camada basal da mucosa e aumento da positividade foi associada à hiperexpressão da p53 (p=0,00018). A genotipagem revelou mutação em exon 5 códon 213 RG, em um paciente (1/16, 6,2por cento). Conclusão: 1) A expressão e mutação do p53 em biópsias de pacientes de alto risco indicam que este gene representa um evento inicial no desenvolvimento do câncer esôfago: 2)A inflamação frequentemente observada nesses pacientes parece estar associada às alterações da proteína p53; 3) A expressão do gene supressor de tumor está aumentada em áreas mostrando proliferação celular