Acute GI Research Articles

Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG Oncology/RTOG 0415

Purpose/objectiveHypofractionated radiotherapy (HRT) regimens for prostate cancer are emerging, but tolerance doses for late adverse events are scarce. The purpose of this study is to define dose–volume predictors for late gastrointestinal and genitourinary (GI and GU) toxicities after HRT in the multi-center NRG Oncology/RTOG 0415 low-risk prostate cancer trial (N = 521). Material/methodsTreatment in the studied HRT arm was delivered as 70 Gy at 2.5 Gy/fraction with 3D-CRT/IMRT (N = 108/413). At a median follow-up of 5.9 years, the crude late ≥Grade 2 GI and GU toxicities were 19% and 29%, respectively. For modeling, the complete HRT cohort was randomly split into training and validation (70% and 30%; preserved toxicity rates). Within training, dose–response modeling was based on dose–volume cut-points (EQD2Gy; bladder/rectum: α/β = 6 Gy/3Gy), age, acute ≥Grade 2 toxicity, and treatment technique using univariate and multivariate logistic regression on bootstrapping (UVA and MVA). Candidate predictors were determined at p ≤ 0.05, and the selected MVA models were explored on validation where model generalizability was judged if the area under the receiver-operating curve in validation (AUCvalidation) was within AUCtraining ± SD with p ≤ 0.05, and with an Hosmer–Lemeshow p-value (pHL) > 0.05. ResultsThree candidate predictors were suggested for late GI toxicity: the minimum dose to the hottest 5% rectal volume (D5%[Gy]), the absolute rectal volume <35 Gy, and acute GI toxicity (AUC = 0.59–0.63; p = 0.02–0.04). The two generalizable MVA models, i.e., D5%[Gy] with or without acute GI toxicity (AUCvalidation = 0.64, 0.65; p = 0.01, 0.03; pHL = 0.45–0.56), suggest that reducing late GI toxicity from 20% to 10% would require reducing D5%[Gy] from ≤65 Gy to ≤62 Gy (logistic function argument: 17+(0.24D5%[Gy])). Acute GU toxicity showed only a trend to predict late GU toxicity (AUCtraining = 0.57; p = 0.07). ConclusionLate GI toxicity, following moderate HRT for low-risk prostate cancer, increases with higher doses to small rectal volumes. This work provides quantitative evidence that limiting small rectal dose ‘hotspots’ in clinical practice of such HRT regimens is likely to further reduce the associated rates of GI toxicity.

03:18 PM Abstract No. 337 Transcatheter embolization for upper GI bleed: outcomes of empiric vs. selective embolization

To compare clinical outcomes between empiric embolization for angiographically occult upper GI bleed with selective embolization for angiographically detectable upper GI bleed. This IRB-exempt retrospective study reviewed 47 patients who underwent gastroduodenal artery (GDA) and left gastric artery (LGA) embolization for acute upper GI bleed at our institution between June 2009 to April 2017. 22 patients underwent prophylactic embolization while 25 patients underwent selective embolization. Demographics, smoking history, alcohol use, ICU needs, 30-day mortality rates, endoscopic interventions, major IR complication rates, rebleed rates and transfusion requirements were compared between groups using student T test and Chi-square test. There were significant gender differences between the empiric embolization group (14% females) and the selective embolization group (48% females, p=.014). There was no significant difference in age distribution, smoking history, or past and current alcohol use between the two groups. There were no differences in major IR complication rates after embolization. In the empiric embolization group, ICU needs (86% vs. 44%, p=.003) were greater. The empiric embolization group had greater rebleeding rate (41% vs. 12%, p=.024) and had higher proportion of cases requiring greater than 5 units of PRBC after embolization (32% vs. 0%, p=.002). However, there were no significant differences in need for endoscopic intervention post embolization (14% vs. 8%, p=.5). There were no significant differences in 30 day mortality rates (22.7% vs. 20%, p=.82). Selective embolization is more clinically effective for cessation of upper GI bleeding when compared to empiric embolization of the GDA and LGA with less rebleeding rates and transfusion requirements. However, the difference in 30 day mortality rates and the need for endoscopic intervention post embolization between the two groups are insignificant.

03:27 PM Abstract No. 241 Effects of time to visceral angiography for gastrointestinal bleeding on angiographic success

Gastrointestinal bleeding (GIB) is a complex problem with a multitude of etiologies requiring a multidisciplinary approach to treatment. There is varying data regarding the role of urgent endoscopy (EGD), colonoscopy, CT, nuclear medicine tests, or conventional angiogram in the acute setting. This retrospective review was conducted to evaluate the effect of time to angiogram on angiographic outcomes. The RRSB at University of Rochester approved this retrospective cohort study. Visceral angiograms performed from Jan 2012 to Dec 2015 were evaluated. Index angiograms for GIB were identified. Exclusion criteria included recent abdominal surgery (30 days), empiric embolization, or incomplete arteriograms. Multiple factors were included in the analysis, age, gender, angiogram time, EGD, colonoscopy, anti platelet use, anticoagulant use, INR, CT, and Tc99m RBC scan (RBC Scan), among others. 118 angiograms were included in the final analysis. 44 angiograms resulted in identification and embolization of a bleed. (average age 67.4 yrs, 65% male) 74 angiograms failed to identify a bleed. 74 (average age 70.6yrs, 52% male) In cases with a positive RBC scan in the preceding 24 hours, successful identification and embolization was significantly statistically correlated with a shorter time to angiogram 4.6 hrs compared to 9.6 hrs for unsuccessful angiograms (p=.026). Patients with a bleed identified on EGD or colonoscopy prior to successful angiogram had a shorter time to angiogram 9.1 vs 10 hours for non-diagnostic angiograms, although not significant. CTA examinations were excluded due to low sample size. 92% of active bleeds seen on RBC scan and 93% of directly visualized bleeds corresponded to the embolized location. Visceral arteriography is a key tool in the identification and treatment of acute GI bleeding. Successful angiograms had a, statically significant, shorter time to angiogram from positive RBC scan compared to inconclusive angiograms. Angiography should be performed as soon as possible after a positive RBC scan. Successful embolization after EGD did not have a strong time dependence, likely owing to several factors.

Reduced acute and late toxicities with intensity-modulated radiation therapy compared to three-dimensional conformal radiation therapy in post-operative gastric cancer

The role of intensity-modulated radiation therapy (IMRT) in post-operative gastric cancer is unknown. We evaluated the toxicity profiles of post-operative gastric cancer patients treated with IMRT or three-dimensional conformal radiation therapy (3D-CRT). We identified patients with gastric cancer treated with post-operative radiation at our institution between 2002 and 2016. Acute and late toxicities were evaluated per RTOG/EORTC Radiation Toxicity Grading Scale. Statistical analysis was performed using Chi-square tests, t tests, log-rank, and logistic regression. We identified 66 patients who underwent surgical resection as part of planned definitive treatment. Eighty percent of patients had T3 or higher disease, while 67% had N2+ disease. Thirty patients received 3D-CRT, while 36 received IMRT. Patients receiving 3D-CRT were younger in age than IMRT, treated longer ago, and did not receive neoadjuvant chemotherapy. Acute grade 2 lower GI toxicity was higher with 3D-CRT (40% vs 17%, p = 0.04). 3D-CRT had higher rates of late lung toxicity of any grade (23% vs 3%, p = 0.02), grade 3+ late esophageal toxicity (23% vs 3%, p = 0.02), and grade 2+ late intestinal toxicity (19% vs 0% p = 0.01). Dosimetric analysis showed that keeping Bowel V5 ≤ 93% protected against development of acute lower GI toxicity of any grade, with V5 ≤ 93% resulting in 10.5% incidence, and V5 > 93% resulting in 52% incidence (p = 0.004). Use of IMRT in post-operative gastric cancer is associated with reduced acute and late toxicities. Consideration should be given for prospective evaluation in the future.

Soluble CD64 Is a Novel Marker of Steroid Refractory Acute Gastrointestinal Graft Versus Host Disease in Pediatric Allogeneic Hematopoietic Stem Cell Transplant

Background CD64 is expressed on neutrophils and monocytes and is upregulated by mediators of inflammation such as interferon-gamma, G-CSF, infection or tissue injury. Soluble CD64 is elevated in new onset Crohn's disease and is a marker of intestinal inflammation. In Crohn's disease, elevated surface expression of CD64 has been associated with infliximab loss of response. The role of CD64 is not described in pediatric gastrointestinal graft versus host disease (GI GVHD). We hypothesized that CD64 would be elevated at diagnosis in children with acute GI GVHD at diagnosis. Methods Plasma CD64 was measured by ELISA in 40 patients (GI GVHD n=20, No GVHD n=20) at the following time points: before BMT and at diagnosis of acute GVHD or a comparable time point after BMT in controls (∼ day+35). Values were compared to new onset pediatric Crohn's disease (n=47) and non-inflammatory bowel disease (IBD) pediatric controls (n=42). Neutrophil CD64, measured by flow cytometry, was assessed in an independent group of 27 consecutive pediatric allogeneic BMT patients at diagnosis of GVHD or comparable time points in patients without GVHD. Results Patient demographics are shown in Table 1. Soluble CD64 was elevated in patients with GI GVHD at diagnosis compared to transplant patients without GVHD (p=0.003), Crohn's disease (p Nine of the 27 patients in the independent consecutive patient cohort had acute GVHD. Four patients had GI GVHD, 3 steroid refractory and one responsive. Median CD64 expression on neutrophils by flow cytometry was 14.3% in the GI GVHD patients compared to 4.92% in patients without GVHD (p=0.2) (Figure 2). Conclusion CD64 is a novel biomarker which could portend refractory acute gut GVHD in children. These findings need to be validated in a larger independent cohort.

α4β7 Integrin Is Upregulated on CD8+ Effector Memory T-Cells in Children with Gut Gvhd Prior to Clinical Symptoms and Represents a Therapeutic Target in Pediatric Allogeneic HSCT Patients

Background α4β7 integrin is expressed on T-cells which migrate to gut-associated lymphoid tissues. Expression of α4β7 integrin is elevated on memory T-cells in adult hematopoietic stem cell transplant (HSCT) recipients at diagnosis of GI GVHD. No pediatric data exist regarding α4β7 integrin expression before or at onset of GVHD. We hypothesized that α4β7 integrin expression on effector memory T-cells (TEMs) would be elevated in patients before acute GI GVHD symptoms compared to patients without GVHD and may be a useful therapeutic target for the prevention of acute GI GVHD. Methods Cryopreserved T-cells were characterized in 48 children who developed acute GI GVHD (n=22), isolated skin GVHD (n=12) and no GVHD (n=14). In patients with GVHD, T-cells were characterized prior to HSCT, one week before GVHD and at GVHD diagnosis. In patients without GVHD, samples were analyzed at baseline and day+30 after HSCT. Samples were incubated with fluorochrome conjugated monoclonal antibodies directed against CD3, CD8, CCR7, α4β7 integrin and CD45RA. TEMs were defined as CD3+, CCR7-, CD45RA- lymphocytes. Co-expression of trafficking markers implicated in GI GVHD (CCR5, CCR9), and liver GVHD (CXCR6 and CCR5) were also assessed. Samples were analyzed on an LSR Fortessa flow cytometer (BD Biosciences). Data were analyzed using FCS Express (De Novo Software). Surface expression of all markers were compared using the Mann Whitney U-test. Patients with skin GVHD and no GVHD were grouped for analysis. Patients with at least 200 absolute CD8+ T-cell events were deemed evaluable. Results Twenty patients with GI GVHD, 8 with skin GVHD and 10 patients without GVHD had at least 200 absolute CD8+ events and were evaluable. Demographics of patients are shown in Figure 1. Expression of α4β7 integrin on CD8+ TEMs was upregulated in patients with GI GVHD compared to the No GI GVHD (skin GVHD + no GVHD) group one week prior to clinical symptoms (p=0.02; Figure 2A). Co-expression of CCR5 and CCR9 with α4β7 integrin was also higher on CD8+ TEM cells in the GI GVHD group compared to No GI GVHD group (p Conclusion α4β7 integrin is elevated on CD8+ TEMs prior to acute GI GVHD symptoms and co-expression of intestinal trafficking-specific markers such as CCR5 and CCR9 are also elevated prior to acute GVHD in pediatric patients. Our data suggest a rationale for the blockade of α4β7 integrin or the dual blockade of α4β7 integrin and CCR5 with clinically available therapeutics (maraviroc and vedolizumab) for acute GI GVHD prevention in pediatric allogeneic HCT patients.

Lactic Acid Is an Independent Predictor of Mortality and Improves the Predictive Value of Existing Risk Scores in Patients Presenting With Acute Gastrointestinal Bleeding

BackgroundThere are validated clinical risk scores for risk stratifying patients presenting with acute upper gastrointestinal bleed (GIB), including Glasgow-Blatchford score (GBS), Pre-endoscopic Rockall score (RS-PE) and post-endoscopic complete Rockall Score (RS-C), and AIMS65. Several studies have explored the predictive value of lactic acid (LA) in the context of GI bleeding, but the prognostic role of LA and its incremental value in combination with existing clinical risk scores is not well defined.MethodsWe conducted a retrospective analysis of consecutive patients presenting to the emergency department of a single large academic tertiary care center from January 2014 to December 2015 with a charted diagnosis of acute GIB, inclusive of both upper and lower sources. We evaluated the independent role of LA as well as three clinical risk scores for predicting in-hospital mortality in these patients.ResultsOut of 704 patients admitted with acute GI bleeding, 366 patients had LA measured on presentation to the emergency department. The mean LA level, GBS, RS-PE and RS-C were found to be significantly higher in non-survivors, while there was no difference in the mean AIMS65 score between survivors and non-survivors. A multivariate logistic regression analysis showed that LA level was an independent predictor of in-hospital mortality. The area under the curve (AUC) for the receiver operator characteristic for RS-C, RS-PE, and GBS were 0.742, 0.675, and 0.652, respectively. When integrating LA into the above risk scores, the AUC for RS-C, RS-PE, and GBS showed statistical significance improvements to 0.780 (P = 0.04), 0.774 (P = 0.012), and 0.706 (P = 003), respectively.ConclusionsIn unselected patients with GIB who presented to the emergency department, LA is an independent predictor of in-hospital mortality. Integration of LA into RS-C, RS-PE, and GBS risk scores improved their ability to predict in-hospital mortality. The modified LA-based RS-PE (L-Rockall pre-endoscopic) score demonstrated predictive value comparable to the post-endoscopic RS-C.

Complete Rockall score in predicting outcomes in acute upper gastrointestinal bleeding

Background: Acute upper GI bleeding is a common medical emergency with a hospital mortality of approximately 10%. Higher mortality rate is associated with rebleeding. Complete Rockall scoring system identifies patients at higher risk of rebleed and mortality.&#x0D; Methods: This is a descriptive hospital based study conducted in Gastroenterology unit of College of Medical Sciences and Teaching Hospital, Bharatpur, Nepal from January 2012 to December 2014. It included 200 patients at random presenting with manifestations of UGI bleed. Complete Rockall score was calculated in each patient and its correlation with mortality and rebleed was determined. Scores of &gt;5 has been considered as one category as it comprises of patients with very high risks and scores of 0-4 as another category of low or lesser risks for the purpose of comparison of different risk factors.&#x0D; Results: Males were predominant (71%). Age ranged from 14 to 90 years, mean being 50.43+17.75 years. At presentation 110 patients (55%) had both hematemesis and malena, 56 patients (28%) had only malena and 34 patients (17%) had only hematemesis. Shock was detected in 21%, severe anemia and high blood urea were found in 31% and 41% respectively. Median hospital stay was 6.5+3.10 days. Comorbidities were present in 83.3%. Complete Rockall score ranged from 0 to 9, mean being 4.30+2.19. One hundred and thirteen (56.5%) had complete Rockall score &lt;4 and 87 (43.5%) &gt;5. Rebleeding was found in 16 (8%) patients. One hundred and eighty eight patients (94%) recovered and discharged from the hospital and 12 patients (6%) expired. The correlations between high Rockall scores (&gt;5) and the occurrence of rebleeding (p=0.001) and mortality (p=0.001) were statistically significant.&#x0D; Conclusion: Acute Upper GI bleeding is a medical emergency. Predictors of mortality in this series were high complete Rockall score &gt;5, esophageal varices with Child Pugh score C, massive initial bleed as well as rebleed and multiple comorbidities.&#x0D; Keywords: acute upper gastrointestinal bleed, complete Rockall score, comorbiditis, rebleed, mortality&#x0D; &#x0D; &#x0D; &#x0D;

Comparison of clinical prediction tools and identification of risk factors for adverse outcomes in acute lower GI bleeding

Limited data exist on prediction of adverse outcomes in patients with acute lower GI bleeding (LGIB). The purpose of our study was to compare the ability of existing validated clinical risk scores to predict relevant outcomes in LGIB. We performed a prospective observational study of patients admitted with LGIB who underwent colonoscopy at a single center between April 2016 and September 2017. Seven risk scores were calculated at admission (Strate, NOBLADS, Sengupta, Oakland, Blatchford, AIMS65, and Charlson Comorbidity Index). The risk of severe LGIB was determined via univariable and multivariable logistic regression. Area under the receiver operating characteristic curve (AUC) analysis was used to compare the scores. We included 170 patients admitted with LGIB requiring colonoscopy. Fifty-two percent (n= 89) fit criteria for severe bleeding. Patients with severe bleeding had lower admission hemoglobin levels (8.6 g/dL vs 11.1 g/dL; P= .0001), were more likely to have blood transfusions (85% vs 36%; P< .0001), intensive care unit stays (49% vs 19%; P< .0001), and had a longer length of stay (6 days vs 4 days; P= .0009). The Oakland score was best for prediction of severe bleeding (AUC, .74), Blatchford score for blood transfusion (AUC, .87), and Strate score for in-hospital recurrent bleeding (AUC, .66) and endoscopic intervention (AUC, .62). The strongest individual predictors of severe bleeding were low admission hemoglobin (odds ratio, 1.28 per 1-g/dL decrease; P= .0015; 95% confidence interval, 1.10-1.49) and low albumin (odds ratio, 2.56 per 1-g/dL decrease; P= .02; 95% confidence interval, 1.16-5.56). Admission albumin and hemoglobin levels were the strongest predictors of severe bleeding. No singular clinical risk tool had the best predictive ability across all outcomes.

Bleeding Related Episodes, Thrombotic Events and Platelet Counts Among Immune Thrombocytopenia Patients Receiving Second Line Therapy

INTRODUCTION: Immune Thrombocytopenia (ITP) is a disease of immune-mediated destruction of platelets and suppression of platelet production. ITP has been historically treated with corticosteroids and/or immune globulins as first-line agents. There are several second-line treatments available, should patients fail to respond to initial treatment or relapse after it is tapered. This study utilizes a national electronic health record (EHR) database to understand clinical outcomes with use of second-line treatments including: thrombopoietin receptor agonists (specifically, eltrombopag and romiplostim), rituximab, and splenectomy.METHODS: Utilizing the Optum EHR database, we identified patients who initiated a second-line treatment from Jan. 1, 2009 to Sep. 30, 2016 for primary or unspecified ITP. Additionally, patients included in the analysis had the following characteristics: 18 years or older; previous treatment with corticosteroids or immune globulin products; and active in the database for at least 6 months prior to and 12 months post initiation of a second-line treatment. Evaluated outcomes included: (1) platelet counts; (2) bleeding related episodes (BREs); and (3) thrombotic events (TEs), including stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis, and pulmonary embolism. All outcomes were evaluated over the 12-month period following the initiation of second-line treatment. BREs and TEs were defined using ICD codes, collapsed to first three characters, indicating a form of bleeding or thrombotic events. Chi-square test and t-test were used to evaluate differences among the four treatment cohorts (eltrombopag, romiplostim, rituximab, and splenectomy).RESULTS: 2,047 patients met the inclusion criteria and used the second-line treatments as follows: eltrombopag, N=110 (5.4%); romiplostim, N=189 (9.2%); rituximab, N=1,488 (72.7%); splenectomy, N=260 (12.7%). The mean age was 60.8 years (standard deviation [SD]: 17.4), with 52.4% female and mean Charlson comorbidity score of 2.1 (SD: 2.1). Compared with platelet counts at the initiation of second-line treatments (collected within +/- 14 days of initiation of second-line treatments), mean platelet counts achieved during the 12 months post initiation of a second-line treatment increased in all treatment cohorts, ranging from an increase of 63,000/μL for rituximab to an increase of 157,000/μL for splenectomy. Mean platelet counts achieved during the 12 months post initiation of a second-line treatment differed significantly across treatment cohorts, ranging from 102,000/μL for eltrombopag to 240,000/μL for splenectomy (p<0.001) (Table 1). The proportion of patients who experienced BREs differed across the treatment cohorts, ranging from 25.5% for eltrombopag to 36.5% for romiplostim (p=0.038) (Table 2). Most common BREs observed included acute posthemorrhagic anemia, GI hemorrhage, hematuria, hemoptysis and hemorrhage, and rectal hemorrhage. TEs were observed in all treatment cohorts ranging from 11.6% for eltrombopag to 15.7% for splenectomy (p=0.744). (Table 2).CONCLUSIONS: This retrospective real world evidence study compares mean platelet response and burden of both BREs and TEs in ITP patients treated with different second-line treatments. Although there were significant differences in mean platelet counts achieved with the second-line treatments, TEs were observed with similar incidence across all treatments. Patients who received splenectomy had the highest mean platelet counts and also the highest proportion of patients who experienced TEs, though differences in TEs did not reach statistical significance. Incidence proportion of patients with BREs was lower in patients treated with eltrombopag than in patients treated with other second-line treatments. Such differences in outcomes may be useful when selecting treatment in the second-line setting. [Display omitted] DisclosuresSaid:Novartis Pharmaceuticals Corporation: Employment. Lal:Optum: Employment. Andrade:Optum: Employment. Nezami:Novartis Pharmaceuticals: Employment. Graves:Novartis: Employment. Roy:Novartis: Employment. Cuker:Kedrion: Membership on an entity's Board of Directors or advisory committees; Synergy: Consultancy; Genzyme: Consultancy; Spark Therapeutics: Research Funding.

Successful hemostasis of active lower GI bleeding using a hemostatic powder as monotherapy, combination therapy, or rescue therapy

Acute lower GI bleeding is a frequent cause of hospital admission. The objective of this study was to evaluate the safety and performance of a hemostatic powder (TC-325/Hemospray) in the treatment of nonvariceal lower GI bleeding. Patients were enrolled into this prospective, multicenter, single-arm study at 4 tertiary care centers in Canada. Fifty patients with active lower GI bleeding of multiple different causes (52 bleeding sites) underwent topical endoscopic application of hemostatic powder. The primary endpoint was powder-related adverse events within 30 days of the index procedure. Secondary endpoints were initial hemostasis as well as recurrent bleeding and mortality within 30 days of the index procedure. Most patients (96%) had a single bleeding site, and most bleeding (73%) was due to polypectomy. Overall, the powder was applied as monotherapy in 13 bleeding sites (25%), as combination therapy in 22 bleeding sites (42.3%), and as rescue therapy in 17 bleeding sites (32.7%). Hemostasis was achieved in 98% of patients. No patient experienced a powder-related adverse event. Five patients (10%) developed recurrent bleeding within 30 days. One patient (2%) died within 30 days of powder application, but the death was not directly related to hemostatic powder use. The hemostatic powder is a safe and effective option for patients with lower GI bleeding of varying causes, and in particular, postpolypectomy hemorrhage. The hemostatic powder is effective as monotherapy, part of a combination approach, or as a rescue therapeutic option for the treatment of nonvariceal lower GI bleeding. (Clinical trial registration number: NCT02099435.).

Phase II Trial of Neoadjuvant Chemotherapy and Stereotactic Body Radiation Therapy (SBRT) for Resectable and Borderline Resectable (BLR) Pancreas Cancer

There is emerging interest in the role of SBRT in locally advanced pancreas cancer, however little prospective data exists examining the safety, efficacy, and optimal target volumes for SBRT in the neoadjuvant setting for resectable or BLR pancreatic cancer. The durability of local control and failure patterns following SBRT in the neoadjuvant setting are not well described. A phase II prospective trial was conducted in resectable and BLR pancreatic patients. Eighteen patients were enrolled from 11/2014-6/2017. All patients received 3 cycles of chemotherapy and restaging prior to radiation. SBRT was delivered to the tumor and abutting vessel with fiducials/compression and a 3 mm PTV margin to 33 Gy (6.6 Gyx5fxn) with an optional elective PTV to 25 Gy (5 Gyx5fxn) customized to the nodal space and mesenteric vessels. Patients without progression underwent surgery 4-6 weeks following SBRT. The primary endpoint is ≥ Grade 3 acute and late GI toxicity. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and cumulative incidence of local failure (LF). LF is defined as recurrence within conventional RT volumes from the time of resection to local failure or last CT with no progression. Local failures were fused to planning CTs for dose quantification. Thirteen patients had BLR tumors due to arterial abutment (n = 7) or SMV encasement (n = 6); 3 patients had resectable tumors. All patients received 4 months of gemcitabine/nab-paclitaxel (n = 13) or FOLFIRNOX (n = 5) prior to SBRT. There were no ≥ Grade 3 acute or late GI events. Following completion of SBRT, 6 patients progressed (33%) at restaging or surgery with liver metastases (n=5, 28%) or local disease (n=1, 5%). Surgery was performed in 12 patients (67%) with 11 (92%) R0 resections (median margin distance 1.75 mm [0-9mm]). Lymph nodes were involved in 4 (33%) patients. Median OS was 21 months for all patients. In patients undergoing resection median OS was 31 months compared to 9 months without resection (p=0.003). The median PFS was 11 months. Progression occurred in 75% (9/12) of resected patients with first site of failure as distant (n = 4, 44%), local only (n = 4, 44%), and local and distant (n = 1,11%). The cumulative incidence of LF at 12 months from resection was 56% with one patient surviving 15 months without LF. All LF were outside to the PTV33 with median D90 of 11.5 Gy (4-25 Gy), V25 Gy of 51% (0-90%), and V33 Gy of 45% (0-52%). In resected patients, LF occurred in 4/8(50%) patients treated with a 25 Gy elective PTV and in 4/5(80%) of patients treated to the primary only (p=0.56). SBRT as a component of neoadjuvant therapy was well tolerated. However, local failures were predominantly observed outside the PTV33 volume within conventional RT volumes. Therefore, the durability of local control after SBRT in the neoadjuvant setting using target volumes and dose as described merits close examination relative to chemoradiation prior to incorporation into routine practice.

The Effects of Dose Escalation on Pelvic Lymph Node Control in Patients with Node Positive Cervical Cancer

To review our institutional experience treating patients with node positive cervical cancer to assess whether RT dose was associated with pelvic lymph node control or GI toxicity. We retrospectively reviewed 390 patients with carcinoma of the uterine cervix treated with RT between October 1997 and October 2017. We included node positive patients and excluded those with <1 follow-up visit and those treated for palliative intent. Acute and late GI toxicity was recorded for all patients. A total of 77 patients with 206 lymph nodes were identified. Median stage at presentation was FIGO IIB. 13 patients were treated with definitive surgical resection followed by adjuvant radiation, of which 12 were treated to doses ≤50.4Gy. 64 patients were treated with definitive chemo-RT (CRT) of which 37 patients (57.8%) received ≤50.4Gy and 27 (42%) >50.4Gy. Patients treated definitively with pre-CRT LN ≥2cm had inferior pelvic LN control compared to patients with pre-CRT LN <2 cm (12 months, 88% vs 53%; p=0.05). While increased RT dose was not associated with pelvic LN control in patients with pre-RT lymph nodes measuring <2 cm (12 months, 88% vs 80%; p=0.53), RT dose was associated with pelvic lymph node control in patients with pre-RT pelvic LN ≥2 cm (12 months, 88% vs 31%; p=0.04). Acute grade 2 GI toxicity was not associated with RT dose (16% (n=46) vs 11% (n=4); p=0.88). 1 patient developed grade ≥2 late GI toxicity, treated to ≤50.4 Gy. Our experience treating patients with node positive cervical cancer supports the role of dose escalation for patients with regional LN ≥2cm. Higher pelvic LN dose is associated with improved regional control and does not seem to be associated with greater GI toxicity.

Bladder-Sparing Hypofractionated Intensity Modulated Radiation Therapy plus Weekly Gemcitabine in Patients with Invasive Bladder Cancer

Trimodality therapy (TMT) is an effective and appealing alternative for bladder preservation in selected patients with muscle invasive bladder cancer (MIBC). Cisplatin has been frequently used as a radiosensitizer. However, in this usually elderly population with compromised renal function, the use of cisplatin may not be always feasible. We report results of hypofractionated IMRT (HypoIMRT) and weekly gemcitabine as components of a TMT regimen for patients with MIBC. From June 2008 to June 2017, 49 patients with T2-3N0M0 bladder cancer underwent treatment with HypoIMRT with concomitant weekly gemcitabine following maximal transurethral resection of bladder tumor (TURBT). HypoIMRT delivered a dose of 50 Gy in 20 fractions to the completely empty bladder and 40 Gy to pelvic nodes in the same 20 fractions. Weekly gemcitabine at a dose of 100 mg/m2 was given concomitantly. Patients treated with neoadjuvant chemotherapy or those treated with another chemotherapy agent were not included. Response rate was assessed by cystoscopy evaluation and bladder biopsy. The median age was 76 years (range: 58-91). A complete TURBT was achieved in 90% of patients. A complete response post-therapy was confirmed in 88% of the patients. At a median follow-up of 20 months, 20 patients had died, 10 of them from bladder cancer. Of those patients achieving a complete response, 29 patients (67.5%) have remained disease-free at a median follow-up of 21 months. The median time for either local or distant failure was 12 months. 8 patients (16%) failed in the bladder only (5 with superficial and 3 with invasive disease) with an actuarial local control projection of 75% at 3 years. Of the 8 patients failing locally, 3 of them presented with hydronephrosis and 2 had an incomplete TURBT; 13 patients (26.5%) failed distantly. The 3- and 5-year cancer-specific survival rate was 77%. Treatments were well tolerated with all patients completing HypoIMRT and 78% completing 4 cycles of gemcitabine. Grade 3 acute GU or GI toxicity was seen in 2% of patients (no grade 4 or 5). Late grade 2 or higher GI or GU toxicity was seen in 2% and 6%, respectively (no grade 4 or 5). HypoIMRT plus concurrent weekly gemcitabine post-TURBT is an effective, feasible and well-tolerated curative treatment strategy in selected patients with MIBC.

Stereotactic Body Radiation Therapy for Locally Recurrent Prostatic Carcinoma after Prior Therapeutic Irradiation: Prostate-Specific Antigen Response, Disease-Free Survival, and Toxicity

Salvage success with acceptable toxicity has been reported with high dose rate (HDR) brachytherapy in patients with locally recurrent adenocarcinoma of the prostate following prior radiation therapy (RT), though limitations include invasiveness and scarce availability in some regions. We prospectively evaluated PSA response, disease-free survival and toxicity using “HDR-like” prostate stereotactic body radiation therapy (SBRT) local salvage treatment. From 2/09 to 1/18, 50 patients with biopsy-proven local recurrent prostate cancer post-RT were enrolled in this IRB-approved trial and 47 treated. Pre-existing RT toxicity > grade 1 was an exclusion criteria. Median interval to SBRT salvage was 88 months post-RT (range 32-180) and 43/47 patients had prior “conventional fractionation only” RT, the remainder had brachytherapy, SBRT or post-radical prostatectomy plus prostate bed RT. Median recurrence Gleason score was 7 (34% ≥ 8). MRI-defined prostate volume plus any extraprostatic extension comprised the planning target volume (PTV). 34 Gy/5 fractions were given, delivering HDR-like intraprostatic dose escalation (Dmax ≥ 150% of prescribed). Concomitant androgen deprivation therapy (ADT), though not encouraged, was not specifically prohibited. 7/47 treated patients had ADT in addition to salvage SBRT. Toxicities were assessed using CTCAE v. 3.0. A total of 47 treated patients had a median 36-month follow-up (range, 0–96; 34 patients followed ≥ 1 year). Median pre-salvage SBRT baseline PSA of 3.7 ng/mL decreased to 0.1 ng/mL & <0.1 ng/mL by 2 and 5 years, respectively, excluding patients with relapse. Actuarial 2- and 5-year biochemical disease free survival (bDFS) measured 80% & 66%, respectively. Excluding the 7 patients treated with ADT resulted in a 2% decrease in 2-year bDFS, no change in the 5-year bDFS and no change in the 2- and 5-year median PSA result. RT toxicity > grade 1 was limited to the GU domain, with actuarial 19% grade 2+ and 9% grade 3+ rates by 5 years. Limiting the analysis to salvage of “conventional fractionation only” RT failures, grade 3+ GU toxicity incidence decreased to 3%. No acute or chronic GI toxicity > Grade 1 occurred. Post-SBRT salvage bDFS to 5 years is encouraging and appears comparable to published HDR brachytherapy results. The PSA response kinetic appears similar to that seen in de novo patients treated with SBRT; though with early biochemical relapse seen more commonly in this group (≤ 2 years out). Grade ≥ 3 SBRT-induced GU toxicity was rare in post “conventional fractionation only” SBRT salvage cases, appearing more frequently in the small subset treated after other prior RT situations (e.g. – post-brachytherapy). There was no serious GI toxicity in this series. SBRT salvage of post-radiotherapeutic local recurrence appears feasible, with larger patient numbers and longer median follow-up required to confirm this result. With IRB approval, the protocol has been expanded to a sample size n = 100 and the study continues.

Utility of CT Angiography (CTA) in Diagnosis and Treatment of Acute Lower GI Bleeding (LGIB)

Introduction: To investigate the diagnostic performance of CTA in identifying the cause of acute lower GI bleeding and to determine the clinical features associated with positive test result of CTA. Acute Lower GI bleed warrants quick detection and localization of the bleed. Various studies have shown that CTA can detect active hemorrage at rate of 0.3 ml/min (compared to bleeding scan detection rate of 0.2 ml/min) Methods: Retrospective chart review study of all patients who had CTA performed for suspected acute LGIB in last 5 years in a community hospital in Brooklyn Results: 84 patients with mean age of 69 years were included. 41% were male and 59% were females. 49% were on antiplatelet therapy.29% had history of diverticulosis. Mean Hb value was 8.34 g/dL. Presenting complaints were lower GI bleeding in 86%, upper GI bleeding in 9.5%, abdominal pain with anemia in 4.5%. On abd CTA, 86% had no active bleeding and 14% had active bleeding. 9/12 had LGI and 3/12 had upper GI bleeding. EGD showed antral/duodenal ulcers in patients where CT had localized disease to upper GI tract. 5/9 with localized bleeding to lower GI tract had colonoscopy done. Colonoscopy showed diverticulosis in 3, mass in 1 and colitis in 1. CTA was negative in 44%, non-specific colitis 13%, diverticulosis in 15%. 20% patients had bleeding scan done. 11/17 had positive bleeding scan. In patients with positive bleeding scan,10/11 had initial negative CTA, 6/11 had EGD done which did not show active bleeding. 7 had colonoscopy done which did not show active bleeding. EGD was done in 41/84 patients. No active bleeding was identified in all patient who had EGD done. Conclusion: In patients with acute LGIB, CTA lacks sensitivity and was positive only in14% of the patients. Bleeding scan was more sensitive however, lacked specificity in localizing the bleeding. Patients who had positive CT scan for active bleeding, only one had active bleeding on Colonoscopy. All the patients who had CT evidence of diverticulosis, were found to have diverticulosis on colonoscopy.Diverticular bleeding is most common cause of LGIB. CTA should only be reserved for patients with continued bleeding despite usual standard of care and in patients in whom vascular intervention is needed. Majority of patients can be spared from radiation and IV contrast exposure from CTA. However, further large prospective studies are needed to define the role of CT in acute GI bleeding when other investigations are unable to provide a diagnosis.

Hepatocelluar Carcinoma Invading the Gallbladder - A Rare Cause of Hemobilia

Bleeding from the hepatobiliary tract (hemobilia) is a rare cause of acute upper GI bleed. It should be considered in any patient with recent history of hepatic parenchymal or biliary intervention, angioembolization, blunt abdominal trauma or hepatic malignancy. We describe a rare case of hemobilia due to hepatocellular carcinoma (HCC) invading the gall bladder wall. A 52- year old female with Laennec's cirrhosis complicated by HCC status post transarterial chemoembolization (TACE) presented with black tarry stools, dizziness and abdominal pain. Physical examination was significant for right upper quadrant tenderness to palpation and melanotic stools. Labs were consistent with severe anemia, thrombocytopenia and liver profile derangement. An MRI performed the month prior to admission, demonstrated a 3.1 cm oval-shaped, arterial phase enhancing lesion in the lateral aspect of the right hepatic lobe, suspicious for residual HCC (Fig A). She was aggressively transfused multiple blood products, placed on a proton pump inhibitor and started on octreotide. An emergent EGD was performed which identified blood oozing from the ampulla of vater; consistent with a diagnosis of hemobilia (Fig B). A CTA was negative for active extravasation. The presumed etiology was invasion of the residual HCC into the gall bladder wall given the close proximity identified on MRI. Given her history of TACE and severe liver dysfunction, she was not a candidate for embolization and she was medically managed. First recorded in 1654 by Francis Glisson, hemobilia is an exceedingly rare condition with unknown exact incidence. Traumatic etiology accounts for 40-80 percent of all cases. In patients with HCC, invasion into the blood vessels is a frequent feature, however gallbladder and ductal invasion is widely unrecognized. One study involving 24 patients with HCC was performed to describe the features of intra-biliary duct invasion. 21 percent developed hemobilia; one patient subsequently died from hemorrhagic shock. Approximately one-third of all patients will present with quinke's Triad: acute upper GI bleed (100 percent), biliary colic (70 percent) and jaundice (60 percent). Diagnosis is by visualizing blood from the Ampulla of vater via EGD or ERCP. The best diagnostic and therapeutic intervention is angiography with embolization (success rate > 95 percent). Despite aggressive intervention, severe hemobilia has been shown to have a mortality as high as 25 percent.1950_A Figure 1. A 3.1 cm oval shaped arterial phase enhancing lesion in the lateral aspect of the right hepatic lobe (arrow) suspicious for residual HCC within close proximity of the gall bladder.1950_B Figure 2. EGD oozing from the ampulla of vater (A) and showing blood oozing within the second part of the duodenum (B).

Traumatic Nasogastric Tube Placement Causing Acute Upper GI Bleeding in a Black Esophagus: A Warning to Gastroenterologists and Clinicians

Acute necrotizing esophagitis (Black Esophagus) is a rare and sometimes fatal syndrome, typically affecting older males, with a prevalence of up to 0.01% of all endoscopy cases. In our tertiary referral center, we describe the case of a 57-year-old male with a history of hypertension, diabetes mellitus type II, and renal cell carcinoma who presented for an elective partial nephrectomy. His post-operative course was complicated by gross hematuria requiring multiple blood transfusions, and he was found to have a AV fistula and pseudoaneurysm of his kidney. He then developed fevers and hypotension and was found to have bacteremia and a urinary tract infection. On post-op day 12, the patient became obtunded and a nasogastric tube was placed which aspirated copious coffee-ground materials. Overnight, the patient had frank hematemesis and was transferred to the ICU; an emergent EGD was performed. Diffuse esophagitis with necrosis was found in the mid and distal esophagus (Image 1A). His nasogastric tube was removed, which unveiled a pulsatile arterial bleed 4 cm proximal to the GE junction (Image 1B). Hemostasis was achieved with BICAP cautery (Image 1D). He was made strict NPO, IV PPI was started, and antifungals were added. A follow up EGD on post-op day 14 demonstrated a sharp demarcation of normal healthy esophageal mucosa in the proximal esophagus to necrotic black esophagus distally (Image 2B). A final endoscopy was performed 6 days later, with the majority of esophagus demonstrating signs of healing (Image 2 C,D). Black esophagus is thought to be due to a “two hit” phenomenon, where an initial event such as a low flow vascular state predisposes the esophageal mucosa to severe topical injury from acid reflux. With concomitant gastric outlet obstruction, accumulation of gastric fluids results in direct tissue injury and necrosis of the esophageal mucosa, with the distal third of the esophagus being most vulnerable to ischemic injury due to its relative hypovascularity. This elusive diagnosis should not be missed in critically ill patients with hemorrhagic or septic shock who develop upper GI bleeding during their hospitalization. We recommend that before urgent nasogastric tube placement for gastric decompression, a bedside endoscopy should be considered to rule out acute necrotizing esophagitis, as placement of a foreign body in a severely diseased esophagus could lead to direct tissue injury and significant GI bleeding as was the case in our patient.1723_A Figure 1. Initial EGD A. Necrotizing Esophagitis (Black Esophagus) - B. Active arterial bleeding in distal esophagus from NGT trauma C. Large clot burden in esophagus D. NG trauma s/p BICAP treatment1723_B Figure 2. A, B. EGD #2 (48 hours later) - distal esophageal necrosis (A) with proximal sharp demarcation from necrotic esophagus to normal mucosa (B). C, D. EGD #3 (8 days after initial EGD) - healthy, healing esophageal mucosa with viable granulation tissue

Donʼt Stop Looking: Lower Gastrointestinal Hemorrhage Secondary to Appendiceal Orifice Bleeding

The patient is a 53 year old male who presented to the hospital with anemia and gastrointestinal hemorrhage. The decision was made to pursue an endoscopic work up with upper endoscopy and a colonoscopy. The upper endoscopy was nondiagnostic, however a large amount of hematochezia noted during his colonoscopy. Further work up with a bleeding scan did not reveal active bleeding, prompting us to pursue a capsule endoscopy. There was an area of active bleeding noted in the distal small bowel which led to patient being scheduled for retrograde double balloon enteroscopy. During this procedure, diligent attention was made to irrigate and suction remaining blood throughout the colon. After the cecum was thoroughly cleaned, a slow ooze was noted emanating from the appendiceal orifice. Withdrawal of the scope did not reveal any other potential source of bleeding. The patient subsequently underwent an appendectomy resulting in successful treatment of his hemorrhage. The specimens from surgical pathology did not reveal any obvious abnormality. The patient was subsequently discharged without any signs of overt hemorrhage. Appendiceal orifice hemorrhage is a rare cause of lower gastrointestinal hemorrhage, as there are only few case reports noted in the literature. This type of bleeding can result from ulcers, erosions, angiodysplasias, or malignancy. Appendectomy is generally curative as it was in our patient's case. This case highlights the need to remain persistent while attempting to diagnose an acute lower GI bleed

A Rare Case of Massive Gastrointestinal Bleeding From a Rectal Dieulafoy Lesion

A Dieulafoy lesion (DL) is defined as a dilated sub-mucosal vessel that erodes the overlying epithelium without evidence of a primary ulcer or erosion. DL lesions of the rectum are a rare cause of gastrointestinal bleeding that is difficult to identify and subsequently manage. We present an 84-year-old man, who presented with lower gastrointestinal bleeding secondary to a DL of the rectum. An 84-year-old man with a medical history significant for End-stage renal disease(ESRD), and hypertension presented to our emergency department with multiple episodes of rectal bleeding mixed with bowel movements. On physical examination, he was hemodynamically stable, with rectal examination notable for bright red blood on the examining finger. His initial complete blood count showed a hemoglobin of 8.4 g/dL, with other normal indices. The patient was rapidly prepped for colonoscopy. Colonoscopy revealed an actively spurting Dieulafoy lesion in the distal rectum just proximal to the pectinate line associated with underlying friable mucosa. Hemostasis was achieved with injection of 3cc of 1:10000 epinephrine, and application of 3 hemostatic clips. He remained stable, with no subsequent rectal bleeding and was discharged home. DLs first described by Gallard in 1884, is a rare cause of gastrointestinal bleeding.They are believed to account for an estimated 1-2% of all cases of acute GI bleeding and can be associated with high mortality rate. The etiology of Dieulafoy lesions are unknown. Risk factors associated with their development include male gender, hypertension, and ESRD, which were present in our patient. With regards to location, DLs are most commonly encountered in the stomach and the gastroesophageal junction. DLs of the rectum is a rare entity, observed in a mere 2% of reported cases in the literature. Bleeding episodes of DL are usually self-limited, however, they are usually recurrent and can lead to profuse rectal bleeding. Diagnosis of DLs, both gastric and rectal, can often time be challenging for the clinician. Endoscopy is the gold standard for diagnosis, but is only successful in 70% of cases, requiring the need for repeat endoscopy to establish the diagnosis. Treatment of rectal DLs is best accomplished endoscopically using a combination of epinephrine injection with bipolar probe coagulation, hemoclip placement, or thermal coagulation. Rarely angiograph and surgery is indicated in failed endoscopic therapy.1991_A Figure 1. An actively bleeding dieulafoy lesion in the distal rectum, just proximal to the pectinate line.1991_B Figure 2. Hemostasis achieved with 3 hemostatic clips.