Endoscopic Intrapyloric Botulinum Toxin Injection with Pyloric Balloon Dilation for Symptoms of Delayed Gastric Emptying after Distal Esophagectomy for Esophageal Cancer: A 10-Year Experience.

Patients with esophageal cancer undergoing esophagectomy have an improved survival over time, however adverse events associated with the use of a gastric conduit are increasingly being reported. Delayed gastric emptying (DGE) is an esophagectomy-related complication which can decreased quality of life by causing debilitating gastrointestinal symptoms and malnutrition. The aim of our study was to evaluate the effect of endoscopic intrapyloric botulinum (BT) injection in combination with pyloric balloon dilation in patients with DGE following distal esophagectomy at our tertiary cancer center. Patients with a prior history of distal esophagectomy who had also undergone endoscopic BT injection with pyloric balloon dilation by a single endoscopist between 2007 and 2017 were included in the study. One hundred units of BT were injected endoscopically into the pylorus in four quadrants using an injection needle. Following BT injection, a standard through-the-scope balloon was passed to the pylorus and inflated to a maximum diameter of 12−20 mm. For patients who underwent repeat procedures, the symptomatic outcomes were assessed and documented by the endoscopist; for the other patients, the electronic medical records were reviewed. A total of 21 patients undergoing 44 endoscopic intrapyloric botox injections combined with balloon dilatations were identified. The patients underwent the procedures at a median of 22 months (range, 1−108 months) after esophagectomy. The procedures were performed only once in 43% of the patients; 43% patients underwent the procedure twice, while 14% had it multiple times (>2). Overall, intrapyloric BT injection coupled with balloon dilation was a safe procedure, without any major immediate or delayed (1 month) procedure-related adverse events. Eighteen patients (85%) reported a significant overall improvement in symptoms from the initial presentation. One patient (5%) showed no improvement, whereas in two (10%) patients responses were not available. In our particular cohort of patients, the interventions of endoscopic intrapyloric BT injection with pyloric balloon dilation proved to be very beneficial, leading to significant symptomatic improvement. The balloon dilation after BT injection might have resulted in better diffusion of the BT into the pyloric sphincter complex, possibly increasing its therapeutic effects. Further prospective studies are needed to validate these results.

Quality of life impact of EUS in patients at risk for developing pancreatic cancer.

BACKGROUND AND OBJECTIVES: The current knowledge about the psychological impact of pancreatic cancer (PC) screening is limited. We aimed to assess the changes in quality of life (QOL) and level of distress after undergoing EUS in individuals with pancreatic cystic lesions (PCLs) and in patients at high risk for PC based on genetic and familial factors. METHODS: Eighty patients with PCL and/or increased genetic or familial risk for PC who had undergone EUS were contacted. Fifty percent of those patients successfully completed the brief profile of mood states (POMS) and the linear analog scale assessment (LASA) QOL questionnaires to evaluate their pre/post-EUS overall QOL. The effect size (ES) method was used to assess clinically meaningful changes in the scores. RESULTS: There was a significant difference in patients' overall QOL scores before and after the EUS procedure (LASA, mean difference 0.73, standard deviation (SD) 1.76, ES 0.58, P < 0.01; brief POMS, mean difference -5.46, SD -6.72, ES 0.81, P < 0.01). CONCLUSIONS: QOL of patients with PCL or increased risk factors for PC is significantly improved after a EUS/EUS-guided fine-needle aspiration (FNA) negative for malignancy.

Recurrent Clostridium difficile infection is associated with treatment failure and prolonged illness in cancer patients.

BACKGROUND: Cancer patients are susceptible to recurrent Clostridium difficile infection (CDI) that is increasing globally, necessitating new approaches to prevent fatal consequences. We examined the clinical characteristics of cancer patients with recurrent CDI (RCDI). PATIENTS AND METHODS: A retrospective review of cancer patients with C. difficile-positive test between January 2015 and May 2017 was carried out. CDI was defined as diarrhea and toxigenic C. difficile detection in the stool by nucleic acid amplification test and enzyme immunoassay. Patients having two CDI episodes were categorized as single recurrent CDI (SRCDI), and those having three or more CDI episodes were categorized as multiple recurrent CDI (MRCDI). Treatment failure was defined as the requirement of antimicrobial alteration or repetition. RESULTS: We included 170 patients having 270 CDI episodes; 85 patients had non-RCDI, and 85 had RCDI; 14 of them had MRCDI. Previous hospitalization and immunosuppressant use were more frequent in MRCDI group than in SRCDI group (P=0.009 and 0.002, respectively). Physicians treated more SRCDI episodes than MRCDI episodes with metronidazole alone (P=0.017), whereas, more MRCDI episodes needed combination antimicrobials (P=0.072). The mean duration of CDI treatment was longer in the MRCDI group than in the SRCDI group (P=0.030). MRCDI was associated with treatment failure more than SRCDI (P=0.021). The risk for a recurrent episode of CDI was increased in patients who had the following features of the first CDI episode: previous use of antibiotic, NSAID, immunosuppressant, chemotherapy, comorbidities, CDI treatment failure, and severe CDI (P<0.05). CONCLUSION: Risk factors for RCDI in cancer patients are similar to those without cancer, with the exception of chemotherapy that is only given to cancer patients. Long CDI treatment and CDI treatment failure are associated with MRCDI.

Author Correction: Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis.

In the version of this article originally published, an author was missing from the author list. Alexander J. Lazar should have been included between Jorge M. Blando and James P. Allison. The author has been added to the list, and the author contributions section has been updated to include Alexander J. Lazar's contribution to the study. The error has been corrected in the print, PDF and HTML versions of the manuscript.

Safety of endoscopy in cancer patients with thrombocytopenia and neutropenia.

BACKGROUND AND AIMS: Cancer patients are prone to thrombocytopenia and neutropenia, which increase the risk of bleeding and infection. We assessed the safety of endoscopic procedures in cancer patients with thrombocytopenia and/or neutropenia. METHODS: We studied consecutive cancer patients with thrombocytopenia and/or neutropenia who underwent endoscopic procedures from 2010 through 2015. Neutropenia was defined as an absolute neutrophil count (ANC) <1000 cells/µL, and thrombocytopenia as a platelet count <100 × 103/µL. Univariate and multivariate generalized estimating equation models were used to assess factors associated with risk of adverse events (AEs) or death. RESULTS: We identified 588 patients who underwent 783 procedures; 608 procedures were performed in the setting of thrombocytopenia and 675 procedures in the setting of neutropenia. Concurrent neutropenia and thrombocytopenia were recorded in 500 endoscopies. Twenty-four patients (4.1%) experienced infectious AEs, whereas 29 (4.9%) experienced bleeding AEs within 1 week of the procedure. On multivariate analysis, platelet count ≤50 × 103/µL was associated with risk of bleeding AEs. In contrast, poor performance status was associated with increased risk of infection AEs (P < .01). No association was observed between low ANC and infectious AEs. Poor performance status (P < .01) and platelet count ≤100 × 103/µL (P < .05) were associated with increased risk of 30-day mortality. A persistent platelet count <20 × 103/µL after the procedure, with a baseline platelet count of ≤20 × 103/µL before the procedure, was associated with significant risk of bleeding AEs compared with a platelet count >20 × 103/µL after the procedure (P < .01); furthermore, if the platelet count increased to >50 × 103/µL after the procedure, the bleeding risk after the procedure was greatly reduced (P < .01). CONCLUSIONS: Endoscopic procedures are relatively safe in cancer patients with platelet count >50 × 103/µL. Nevertheless, a platelet count of ≥20 × 103/µL could be an appropriate threshold for platelet transfusion if 50 × 103/µL is difficult to achieve. The functional status of the patient, in the absence of the need for urgent or necessary endoscopic interventions, should be considered when deciding whether to perform endoscopy. The risk of procedure and the ANC did not seem to affect the outcomes.

Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis.

We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.

Context-dependent functions of KLF4 in cancers: Could alternative splicing isoforms be the key?

Krüppel-like factor 4 (KLF4) is an important transcription factor that is expressed in a variety of tissues and regulates many critical physiologic and cellular processes, including cell proliferation, differentiation, stem cell reprogramming, maintenance of genomic stability, and normal tissue homeostasis. KLF4 has both tumor suppressive and oncogenic functions in gastrointestinal and other cancers. These functions are thought to be context dependent, but how KLF4 exerts these differential functions and the molecular mechanisms behind them remain poorly understood. Recent studies have shown that the KLF4 gene undergoes alternative splicing, and the protein products of certain transcripts antagonize wild-type KLF4 function, suggesting an additional layer of regulation of KLF4 function. Therefore, detailed study of KLF4 alternative splicing may not only provide new insights into the complexity of KLF4 functions but also lead to rational targeting of KLF4 for cancer prevention and therapy.

The somatic mutation landscape of premalignant colorectal adenoma.

OBJECTIVE: There are few studies which characterised the molecular alterations in premalignant colorectal adenomas. Our major goal was to establish colorectal adenoma genome atlas and identify molecular markers of progression from colorectal adenoma to adenocarcinoma. DESIGN: Whole-exome sequencing and targeted sequencing were carried out in 149 adenoma samples and paired blood from patients with conventional adenoma or sessile serrated adenoma to characterise the somatic mutation landscape for premalignant colorectal lesions. The identified somatic mutations were compared with those in colorectal cancer (CRC) samples from The Cancer Genome Atlas. A supervised random forest model was employed to identify gene panels differentiating adenoma from CRC. RESULTS: Similar somatic mutation frequencies, but distinctive driver mutations, were observed in sessile serrated adenomas and conventional adenomas. The final model included 20 genes and was able to separate the somatic mutation profile of colorectal adenoma and adenocarcinoma with an area under the curve of 0.941. CONCLUSION: The findings of this project hold potential to better identify patients with adenoma who may be candidates for targeted surveillance programmes and preventive interventions to reduce the incidence of CRC.

Non-Meckel Small Intestine Diverticulitis.

Non-Meckel small intestine diverticulitis can have many manifestations and its management is not well-defined. We report 4 unselect cases of small intestine diverticulitis; all patients were seen by the same physician at the Emergency Center at The University of Texas MD Anderson Cancer Center between 1999 and 2014. The median age at diagnosis of these patients was 82 years (range, 76-87 years). All 4 patients presented with acute onset of abdominal pain, and computed tomography scans showed characteristics of small intestine diverticulitis unrelated to cancer. Most of the diverticula were found in the region of the duodenum and jejuno-ileal segments of the small intestine. The patients, even those with peripancreatic inflammation and localized perforation, were treated conservatively. Non-Meckel diverticulitis can be overlooked in the initial diagnosis because of the location of the diverticulosis, the age of the patient, and the rarity of the disease. Because patients with non-Meckel small intestine diverticulitis can present with acute abdominal pain, non-Meckel small intestine diverticulitis should be considered in the differential diagnosis of patients with acute abdominal pain, and computed tomography scans can help identify the condition. Because of the rarity of non-Meckel small intestine diverticulitis, few studies have been published, and the data are inconclusive about how best to approach these patients. Our experience with these 4 elderly patients indicates that non-Meckel small intestine diverticulitis can be treated conservatively, which avoids the potential morbidity and mortality of a surgical approach.

Loss of the transforming growth factor-ß effector ß2-Spectrin promotes genomic instability.

Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor ß/mothers against decapentaplegic homolog 3 adaptor ß2-Spectrin (ß2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. ß2SP supports DNA repair through ß2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of ß2SP leads to decreased Fancd2 levels and sensitizes ß2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor ß stimulation is regulated by the ß2SP/mothers against decapentaplegic homolog 3 complex. CONCLUSION: Dysfunctional transforming growth factor ß/ß2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2017;65:678-693).

Mutational Profiles Reveal an Aberrant TGF-ß-CEA Regulated Pathway in Colon Adenomas.

Mutational processes and signatures that drive early tumorigenesis are centrally important for early cancer prevention. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. Here, we describe surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Transitional single nucleotide substitutions of C:G>T:A predominate in the adenoma mutational spectrum. Strikingly, we observe mutations in the TGF-ß pathway and CEA-associated genes in 4 out of 11 adenomas, overlapping with the Wnt pathway. Immunohistochemical labeling reveals a nearly 5-fold increase in CEA levels in 23% of adenoma samples with a concomitant loss of TGF-ß signaling. We also define a functional role by which the CEA B3 domain interacts with TGFBR1, potentially inactivating the tumor suppressor function of TGF-ß signaling. Our study uncovers diverse mutational processes underlying the transition from early adenoma to cancer. This has broad implications for biomarker-driven targeting of CEA/TGF-ß in high-risk adenomas and may lead to early detection of aggressive adenoma to CRC progression.

Outcome of EMR as an alternative to surgery in patients with complex colon polyps.

BACKGROUND AND AIMS: Patients with complex colon polyps were traditionally referred for surgery to avoid adverse events associated with endoscopic resection. Recent advances in endoscopic imaging as well as endoscopic hemostasis and clip closure allow for the use of EMR as an alternative to surgery for such lesions. To determine the outcome of treatment of complex colon polyps with EMR as an alternative to surgery, we conducted a retrospective observational study. METHODS: Two hundred three patients with complex colon polyps were referred to an EMR center as an alternative to surgery. Patients underwent a protocol-driven EMR. The primary endpoint was the complete resection rate. Secondary endpoints were safety, residual adenoma rate, and incidence of missed synchronous polyps. RESULTS: EMR was performed in 155 patients and was deferred in 48 patients who were referred to surgery. EMR specimens revealed benign polyps in 149 and cancer in 6 patients. EMR adverse events occurred in 7 patients, requiring hospitalization in 5 of them. None of the patients died as a result of their adverse events. Surveillance colonoscopy at 4 to 6 months after resection of a benign lesion in 137 patients revealed residual adenoma at the scar site in 6 patients and additional synchronous precancerous lesions in 117 patients that were not removed by the referring endoscopist. None underwent surgery for failure of EMR. The overall precancerous lesion burden was 2.83 per patient, the adenoma burden was 2.13 per patient, and the serrated polyp burden was .69 per patient. CONCLUSIONS: EMR can be used instead of surgery for complex colon polyps in 75% of patients with few adverse events and few residual adenomas at resection sites. In addition, careful repeat examination of the entire colon for synchronous lesions overlooked by the referring endoscopist is required for most patients. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01827241.).

Mutations of Chromatin Structure Regulating Genes in Human Malignancies.

Chromatin structure regulating processes mediated by the adenosine triphosphate (ATP) - dependent chromatin remodeling complex and the covalent histone-modifying complexes are critical to gene transcriptional control and normal cellular processes, including cell stemness, differentiation, and proliferation. Gene mutations, structural abnormalities, and epigenetic modifications that lead to aberrant expression of chromatin structure regulating members have been observed in most of human malignancies. Advances in next-generation sequencing (NGS) technologies in recent years have allowed in-depth study of somatic mutations in human cancer samples. The Cancer Genome Atlas (TCGA) is the largest effort to date to characterize cancer genome using NGS technology. In this review, we summarize somatic mutations of chromatin-structure regulating genes from TCGA publications and other cancer genome studies, providing an overview of genomic alterations of chromatin regulating genes in human malignancies.

Natural language processing as an alternative to manual reporting of colonoscopy quality metrics.

BACKGROUND AND AIMS: The adenoma detection rate (ADR) is a quality metric tied to interval colon cancer occurrence. However, manual extraction of data to calculate and track the ADR in clinical practice is labor-intensive. To overcome this difficulty, we developed a natural language processing (NLP) method to identify adenomas and sessile serrated adenomas (SSAs) in patients undergoing their first screening colonoscopy. We compared the NLP-generated results with that of manual data extraction to test the accuracy of NLP and report on colonoscopy quality metrics using NLP. METHODS: Identification of screening colonoscopies using NLP was compared with that using the manual method for 12,748 patients who underwent colonoscopies from July 2010 to February 2013. Also, identification of adenomas and SSAs using NLP was compared with that using the manual method with 2259 matched patient records. Colonoscopy ADRs using these methods were generated for each physician. RESULTS: NLP correctly identified 91.3% of the screening examinations, whereas the manual method identified 87.8% of them. Both the manual method and NLP correctly identified examinations of patients with adenomas and SSAs in the matched records almost perfectly. Both NLP and the manual method produced comparable values for ADRs for each endoscopist and for the group as a whole. CONCLUSIONS: NLP can correctly identify screening colonoscopies, accurately identify adenomas and SSAs in a pathology database, and provide real-time quality metrics for colonoscopy.

Hippo coactivator YAP1 upregulates SOX9 and endows esophageal cancer cells with stem-like properties.

Cancer stem cells (CSC) are purported to initiate and maintain tumor growth. Deregulation of normal stem cell signaling may lead to the generation of CSCs; however, the molecular determinants of this process remain poorly understood. Here we show that the transcriptional coactivator YAP1 is a major determinant of CSC properties in nontransformed cells and in esophageal cancer cells by direct upregulation of SOX9. YAP1 regulates the transcription of SOX9 through a conserved TEAD binding site in the SOX9 promoter. Expression of exogenous YAP1 in vitro or inhibition of its upstream negative regulators in vivo results in elevated SOX9 expression accompanied by the acquisition of CSC properties. Conversely, shRNA-mediated knockdown of YAP1 or SOX9 in transformed cells attenuates CSC phenotypes in vitro and tumorigenicity in vivo. The small-molecule inhibitor of YAP1, verteporfin, significantly blocks CSC properties in cells with high YAP1 and a high proportion of ALDH1(+). Our findings identify YAP1-driven SOX9 expression as a critical event in the acquisition of CSC properties, suggesting that YAP1 inhibition may offer an effective means of therapeutically targeting the CSC population.

Genetic and intermediate phenotypic susceptibility markers of gastric cancer in Hispanic Americans: a case-control study.

BACKGROUND: Hispanics are the largest nonwhite ethnic group in the US population, and they have higher incidence and mortality rates for gastric cancer (GC) than whites and Asians. Studies have identified several genetic susceptibility loci and intermediate phenotypic biomarkers for GC in whites and Asians. No studies have evaluated genetic susceptibility and intermediate phenotypic biomarkers in Hispanics. METHODS: In a case-control study of 132 Hispanic patients with GC (cases) and a control group of 125 Hispanics (controls), the authors evaluated the association of 5 single nucleotide polymorphisms (SNPs) that predispose whites and/or Asians to GC and of 2 intermediate phenotypic markers in peripheral blood leukocytes, ie, telomere length and mitochondrial DNA (mtDNA) copy number, with the GC risk. RESULTS: The variant C allele of the reference SNP rs2294008 in the PSCA gene was associated with a significantly reduced risk of GC (per allele-adjusted odds ratio [aOR], 0.51; 95% confidence interval [CI], 0.33-0.77; P = .002). Leukocyte mtDNA copy numbers were significantly lower in GC cases (mean ± standard deviation, 0.91 ± 0.28) than in controls (1.29 ± 0.42; P < .001). When individuals were dichotomized into high and low mtDNA copy number groups based on the median mtDNA copy number value in the controls, those who had a low mtDNA copy number had a significantly increased risk of GC (aOR, 11.00; 95% CI, 4.79-25.23; P < .001) compared with those who had a high mtDNA copy number. Telomere length was not associated significantly with the risk of GC (aOR, 1.21; 95% CI, 0.65-2.27; P = .551). CONCLUSIONS: Hispanics share certain genetic susceptibility loci and intermediate phenotypic GC biomarkers with whites and Asians and may also have distinct genetic susceptibility factors.

Adenoma detection in patients undergoing a comprehensive colonoscopy screening.

Measures shown to improve the adenoma detection during colonoscopy (excellent bowel preparation, cecal intubation, cap fitted colonoscope to examine behind folds, patient position change to optimize colon distention, trained endoscopy team focusing on detection of subtle flat lesions, and incorporation of optimum endoscopic examination with adequate withdrawal time) are applicable to clinical practice and, if incorporated are projected to facilitate comprehensive colonoscopy screening program for colon cancer prevention. To determine adenoma and serrated polyp detection rate under conditions designed to optimize quality parameters for comprehensive screening colonoscopy. Retrospective analysis of data obtained from a comprehensive colon cancer screening program designed to optimize quality parameters. Academic medical center. Three hundred and forty-three patients between the ages of 50 years and 75 years who underwent first screening colonoscopy between 2009 and 2011 among 535 consecutive patients undergoing colonoscopy. Comprehensive colonoscopy screening program was utilized to screen all patients. Cecal intubation was successful in 98.8% of patients. The Boston Bowel Preparation Scale for quality of colonoscopy was 8.97 (95% confidence interval [CI]; 8.94, 9.00). The rate of adenoma detection was 60% and serrated lesion (defined as serrated adenomas or hyperplastic polyps proximal to the splenic flexure) detection was 23%. The rate of precancerous lesion detection (adenomas and serrated lesions) was 66%. The mean number of adenomas per screening procedure was 1.4 (1.2, 1.6) and the mean number of precancerous lesions (adenomas or serrated lesions) per screening procedure was 1.6 (1.4, 1.8). Retrospective study and single endoscopist experience. A comprehensive colonoscopy screening program results in high-quality screening with high detection of adenomas, advanced adenomas, serrated adenomas, and multiple adenomas.