Mehnaz A. Shafi

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.

The Gastrointestinal Complications of Oncologic Therapy

A spectrum of oncologic treatments including chemotherapy, radiotherapy, and molecular targeted therapies is available to combat cancer. These treatments are associated with adverse effects in several organ systems including the gastrointestinal (GI) tract. The immunocompromised state induced by oncologic therapy is also an important contributing factor underlying GI complications. This review discusses common GI complications that can result from cancer therapy. The pathologic mechanisms underlying each complication and the pharmacology of the agents used to treat these complications are discussed.

Mutational Profiles Reveal an Aberrant TGF-β-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-β 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-β signaling. We also define a functional role by which the CEA B3 domain interacts with TGFBR1, potentially inactivating the tumor suppressor function of TGF-β 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-β in high-risk adenomas and may lead to early detection of aggressive adenoma to CRC progression.

Impact of Hepatitis B Core Antibody Seropositivity on the Outcome of Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Hepatitis B core antibody (HBcAb) seropositivity has been associated with a higher rate of hepatitis B virus (HBV) reactivation after chemotherapy, even in patients who are hepatitis B surface antigen (HBsAg) negative. However, little is known about the risk of HBV reactivation after autologous hematopoietic stem cell transplantation (auto-HCT). We evaluated the incidence of HBV reactivation, liver toxicity, and survival in patients with multiple myeloma (MM) who received auto-HCT at our institution. We retrospectively identified 107 MM patients with resolved HBV infection (HBcAb positive, HBsAg negative) and 125 patients with negative HBV serology (control subjects) who were matched for age, timing of auto-HCT from diagnosis, cytogenetics, disease status at transplant, induction therapy, and preparative regimen. All patients underwent auto-HCT between 1991 and 2013. Primary endpoints were HBV reactivation, defined as HBsAg positivity or ≥10-fold increase in HBV DNA, and hepatotoxicity, as defined in the U.S. National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. In the resolved HBV infection group, 52 patients (49%) were HBsAb positive and 24 (22%) had detectable HBV DNA before auto-HCT. Only 1 patient with resolved HBV infection received pre-emptive antiviral therapy with lamivudine, whereas 4 patients received lamivudine (n = 3) or tenofovir (n = 1) at reactivation after auto-HCT for a median duration of 12 months. HBV reactivation occurred in 7 of 107 patients (6.5%) in the resolved HBV group. Median time to HBV reactivation from auto-HCT was 16 months. The cumulative incidence of grade 2 or greater hepatotoxicity was 30% in the resolved HBV infection group and 22% in the control group (hazard ratio, 1.3; 95% confidence interval, .7 to 2.3; P = .4). Nonrelapse mortality for the 2 groups was not statistically different at 2 years (P = .06), although it trended higher in the control group than in the resolved HBV infection group (8% versus 1%). The median progression-free survival (PFS) and overall survival (OS) durations in the resolved HBV infection and control groups were 21 versus 18 months (P = .5) and 53 versus 67 months (P = .2), respectively. Our data suggest that resolved HBV infection in patients undergoing auto-HCT for MM is associated with a low risk of HBV reactivation and hepatotoxicity; these complications were reversible and did not adversely affect the PFS or OS.

Role of argon plasma coagulation in management of bleeding GI tumors: evaluating outcomes and survival

BACKGROUND/AIMS Tumor related gastrointestinal (GI) bleeding is a challenging clinical problem in cancer patients. Argon plasma coagulation (APC) is preferred for the management of bleeding arterio-venous malformations. Our objective was to assess the role of APC in the management of bleeding GI tumors. MATERIALS AND METHODS This is a retrospective review of endoscopies performed at the UT MD Anderson Cancer Center over 3 consecutive years (2009-2011). This study involved patients with primary or metastatic gastrointestinal cancer with suspected GI bleeding and interventions included were endoscopies with APC. Our main outcome measurements were immediate hemostasis rate, change in transfusion requirements, re-bleeding rate, and 30-day mortality. RESULTS Immediate hemostasis was achieved in all 10 (100%) patients, with either APC performed alone (8 patients) or with adjuvant epinephrine (2 patients). There were no procedure related complications. The pooled transfusion requirements for all 10 patients 48 hours prior to the procedure were 26 packed red blood cells units, 11 platelet units and 6 fresh frozen plasma units, while the overall requirements in the 48 hours after the procedure were 5 packed red blood cells units, 6 platelet units and no fresh frozen plasma units. Re-bleeding occurred in 3 (30%) patients during follow up. Thirty day mortality rate was 0%. Total of 7 (70%) of patients were able to continue cancer specific therapy of either chemotherapy, radiation or both. CONCLUSION APC is feasible and safe in routine practice to manage bleeding GI tumors. It is very effective in achieving initial hemostasis (100%) and allows majority of the patients (70%) to undergo cancer specific therapy.

Abstract 67: Genomic and mutational profiling of human colon adenomas reveals early driver mutations and a TGF-β-CEA regulated profile

Introduction: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world with 143,700 newly diagnosed cases in 2012. The rapid development of cancers in small, sessile adenomas could be a contributing factor that may have been overlooked. Identifying high risk patients through genomic analysis of adenomas could potentially lead to an early intervention therapy. Methods: Whole Genome Sequence (WGS) and Whole Exome Sequence (WES) analyses were performed for 4 pairs of normal controls (two from proximal colon and two from the distal colon) and colorectal adenomas (2 sessile serrated (SSA) and 2 tubulovillous adenomas (TVA) less than 1 cm in size). Transcriptome sequence analysis was performed in seven pairs of control-test matched adenomas (6 TVA and 1 SSA). Expression level of CEA and TGF-β pathway members were carried out on 30 non dysplastic adenomas and normal colon tissues by immunohistochemistry. Results: 1. Hyper-mutator profiles were observed in two of the samples (1 SSA and 1 TVA) by WGS with 1709 mutations after normalization with normal paired samples. 2. The samples showed an average mutation frequency of 0.55 mutations per 10 6 bases. 3. Aberrant mutational profiles was detected in seven of the eleven adenomas, with distinct mutational signatures among the samples, two with high, two intermediate and three low mutational rates. 4. Six of the eleven adenomas (1 SSA and 4 TVAs) showed alteration in the Wnt and p53 pathway. 5. Transitional single nucleotide substitutions of C:T>G:A in the mutational spectrum were observed in 37% of the samples. 6. Subtle localized hyper mutation (kataegis) was observed among two of the samples. 7. Five out of eleven adenomas showed mutations in the TGF-β (transforming growth factor-β) and CEA pathways members, overlapping with Wnt/p53 mutations in four adenomas. 8. Analyses of expression level of CEA and TGF-β pathway members in 30 non dysplastic tissues revealed a marked increase (over 8 fold) in CEA expression in 25% of adenoma samples which was linked to concomitant loss of TGF-β signaling. 9. Further functional studies revealed that CEA associated with TGF-β Type I receptor and disruption of TGF-β tumor suppressor signaling with activation of STAT3. Conclusions: Our studies indicate that small adenomas both TVAs and SSAs can resemble CRCs in genomic profiling and may reflect a high risk population. Genetic and mechanistic analyses reveal that disruption of CEA/TGF-β pathway in early adenomas may reflect a new and early role for these pathways in CRC. This study further supports the biomarker driven targeting of CEA/TGF-β in high risk adenomas and can be used as a prognostic marker for early detection of aggressive adenoma-CRC progression. Citation Format: Vipin K. Menon, Raju S. Gottumukkala, Jian Chen, Xiaoping Su, Nipun Mistry, Avijit Majumdar, Ji-Hyun Shin, Shulin Li, Kirti Shetty, Xifeng Wu, Brian Weston, Ethan Miller, John R. Stroehlein, Marta L. Davila, Mehnaz A. Shafi, Asif Rashid, Bhaskar V. Kallakury, Selvi Thirumurthi, John S. McMurray, Sue-Hwa Lin, Wilma Jogunoori, Lopa Mishra. Genomic and mutational profiling of human colon adenomas reveals early driver mutations and a TGF-β-CEA regulated profile. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 67. doi:10.1158/1538-7445.AM2015-67

Mo1314 Gastric Electrical Stimulator and Its Impact on Symptom Reduction in Gastroparesis Patients With Prior Cholecystectomy

correlation of changes in gastric emptying in GES patients after PP with improvement of GP symptoms. Methods A total of 33 (13 DM, 7 ID, 13 P-V) consecutive GP patients [25F; mean age 43 (20-73 years); mean weight 148 lbs (86-245); mean duration of GP 4 years (1-10)] underwent GES implantation, and additionally all of them have received the HeinekeMikulicz PP. Total GP symptoms scores (TSS) assessing severity (S) and frequency (F) of nausea (N), early satiety (ES), bloating (B), vomiting (V), postprandial fullness (PF), epigastric pain (EP), and burning (EB) were obtained by using a 5-point Likert scale (max 28 points) at baseline and at last follow up visit, ranging from 3 to 18 months with mean 6 month. The 4-hrs scintigraphy method of GET was conducted before surgery and at F/U visits where GP was defined as > 60% retention of isotope at 2 hrs and >10% at 4 hrs. P-values are derived from Paired t-test and one-way ANOVA and Pearson correlation coefficient were also used to analyze data. Results Table: Changes in S and F of TTS of our study group (n= 33), and changes of 2 and 4 hrs retention of GET (n=26) before and after GES and PP procedures: There was a strong correlation between frequency of TSS and 2h GET r=0.454 (p=0.02). By analyzing each GP symptom and its possible correlation with gastric retention we identified that reduction in S and F of postprandial fullness correlated significantly with acceleration in GET at the 2nd hour time point r=0.39 (p=0.049) for both. 18 patients (70%) normalized their GET with <10% retention at 4 hrs. Conclusions: 1) In drug-refractory GP the combination of PP and GES markedly and significantly accelerated gastric emptying, and improved GP symptoms; 2) The increased rate of gastric emptying after PP correlated with symptoms improvements; 3) This comprehensive surgical approach addresses both the subjective and objective goals in treating drug refractory gastroparesis . Summary of the results