Use of the National Institutes of Health Consensus Guidelines Improves the Diagnostic Sensitivity of Gastrointestinal Graft-Versus-Host Disease.

CONTEXT: - Graft-versus-host disease of the gastrointestinal tract is a common complication of hematopoietic stem cell transplant associated with significant morbidity and mortality. Accurate diagnosis can be difficult and is a truly clinicopathologic endeavor. OBJECTIVES: - To assess the diagnostic sensitivity of gastrointestinal graft-versus-host disease using the 2015 National Institutes of Health (NIH) histology consensus guidelines and to analyze histologic findings that support the guidelines. DESIGN: - Patients with allogeneic hematopoietic stem cell transplants were identified via a retrospective search of our electronic medical records from January 1, 2005, to January 1, 2011. Endoscopies with available histology were reviewed by 2 pathologists using the 2015 NIH guidelines. The clinical diagnosis was used as the gold standard. A nontransplant set of endoscopic biopsies was used as a control. RESULTS: - Of the 250 total endoscopies, 217 (87%) had a clinical diagnosis of gastrointestinal graft-versus-host disease. Use of the NIH consensus guidelines showed a sensitivity of 86% and a specificity of 65%. Thirty-seven of 58 (64%) cases with an initial false-negative histopathologic diagnosis were diagnosed as graft-versus-host disease on our review. CONCLUSIONS: - Use of the NIH histology consensus guidelines results in a high sensitivity and specificity, thereby decreasing false-negatives. Additionally, use of the NIH guidelines aids in creating uniformity and diagnostic clarity. Correlation with clinical and laboratory findings is critical in evaluating the differential diagnosis and to avoid false-positives. As expected, increased apoptosis with decreased inflammation was associated with a pathologic diagnosis of graft-versus-host disease and supports the NIH guidelines.

Late Gastrointestinal Complications of Allogeneic Hematopoietic Stem Cell Transplantation in Adults.

Gastrointestinal (GI) complications including graft-versus-host disease (GVHD) are a major cause of morbidity and mortality in allogenic stem transplant recipients. Although several studies have previously looked into the acute GI complications, fewer smaller studies have reported late complications. In this large study we focus on the late (100 days post-transplant) GI complications in allogenic stem transplant recipients. In this single-center, retrospective study of all adult allogenic stem cell transplant recipients who had their transplant at Duke University over a 6-year period, 479 patients underwent allogenic stem cell transplant, of whom 392 recipients survived for at least 100 days post-transplant. Late GI symptoms were noted in 71 patients, prompting endoscopic evaluation. The primary endpoint of our study was the diagnosis of GI-GVHD based on endoscopic findings, whereas overall survival and nonrelapse mortality were the secondary endpoints. Of the 71 patients who underwent endoscopy, 45 (63%) had GI-GVHD. Of these 45 patients, 39 (87%) had late acute GVHD, 1 (2%) had chronic GVHD, and 5 patients (11%) had overlap disease. Of the patients who did not have GVHD, the symptoms were mostly related to infectious and inflammatory causes. Less common causes included drug toxicity, food intolerance, disease relapse, and motility issues. In a multivariate analysis the factors most indicative of GI-GVHD were histologic findings of apoptosis on the tissue specimen (odds ratio, 2.35; 95% confidence interval, 1.18 to 4.70; P = .015) and clinical findings of diarrhea (odds ratio, 5.43; 95% confidence interval, 1.25 to 23.54; P = .024). The median survival time from the first endoscopy was 8.5 months. The incidence of nonrelapse mortality at 6 months was 31% in patients with GI-GVHD and 19% in patients without GI-GVHD (P = .42). All patients with GI-GVHD were on steroid therapy, and 31% of them received total parenteral nutrition. In our population close to one-fifth of allogenic transplant recipients experienced late GI complications, warranting endoscopic evaluation. Most of these patients were found to have GI-GVHD that had a high incidence of nonrelapse mortality at 6 months and close to one-third of these patients needed total parenteral nutrition.

The Diagnostic Yield of Site and Symptom-Based Biopsies for Acute Gastrointestinal Graft-Versus-Host Disease: A 5-Year Retrospective Review.

BACKGROUND: Graft-versus-host disease (GVHD) complicates half of hematopoietic stem cell transplants (HCT), and the gastrointestinal tract is commonly affected. Endoscopic biopsies have a key role in the diagnosis. The optimal procedure(s) to perform and site(s) to biopsy remain unclear. METHODS: We retrospectively analyzed the charts of all adult patients who underwent allogeneic HCT at Duke University Medical Center between 1/1/05 and 1/1/11 and extracted data from those who underwent endoscopic biopsy for suspected GVHD. All histology was re-evaluated by blinded pathologists using 2006 NIH diagnostic criteria and then compared to the original clinical diagnosis of GVHD. RESULTS: A total of 169 adult patients underwent 250 endoscopic procedures to evaluate GVHD. The sensitivity of biopsies for clinical GVHD was 76 and 72% for upper and lower tract sites, respectively. In the presence of nausea, upper tract biopsies were positive for GVHD in 65%, 70% while lower tract biopsies were positive in 61-70%. In the presence of diarrhea, lower tract biopsies were positive in 65%, while upper tract sites were positive in 64-69%. Twenty six (40%) of the sixty-five endoscopies that simultaneously sampled upper and lower tract sites had discordant results. All were histologically positive for GVHD, yet 15% of upper tract biopsies and 25% of lower tract biopsies were negative. CONCLUSIONS: In this large review, the overall sensitivity of biopsies taken during EGD and Flex-Sig was 76 and 72%, respectively. A symptom-driven biopsy approach was not clearly supported as upper tract and lower tract biopsies were similarly diagnostic for GVHD regardless of symptoms.

Management of adverse events associated with idelalisib treatment: expert panel opinion.

Idelalisib is a first-in-class selective, oral, phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for the treatment of several types of blood cancer. Idelalisib has demonstrated significant efficacy and a tolerable safety profile in clinical trials. However, the US prescribing information contains a black box warning for fatal and/or severe diarrhea or colitis, hepatotoxicity, pneumonitis and intestinal perforation. An expert panel was convened to review the pathology of these treatment-emergent adverse events (TEAEs) to propose key management tools for patients receiving idelalisib therapy. This article provides an overview of idelalisib TEAEs reported in clinical trials, and a summary of the panel's recommendations for identification and management of idelalisib treatment-emergent diarrhea or colitis as well as a discussion of transaminitis and pneumonitis. For idelalisib-related diarrhea or colitis (including unresolved grade 2 and grade ≥ 3), after exclusion of infectious causes, the panel recommends individualized treatment with budesonide or oral or intravenous steroid therapy.

Pilot study of aprepitant for prevention of post-ERCP pancreatitis in high risk patients: a phase II randomized, double-blind placebo controlled trial.

CONTEXT: Animal studies have demonstrated a role for substance P binding to neurokinin-1 receptor in the pathogenesis of acute pancreatitis. OBJECTIVE: Our aim was to assess the efficacy of a neurokinin-1 receptor antagonist (aprepitant) at preventing post-ERCP pancreatitis in high risk patients. DESIGN: Randomized, double-blind, placebo controlled trial at a single academic medical center. INTERVENTION: Patients at high risk for post-ERCP pancreatitis received either placebo or oral aprepitant administered 4 hours prior to ERCP, 80 mg 24 hours after the first dose, and then 80 mg 24 hours after the second dose. PATIENTS: Thirty-four patients received aprepitant and 39 patients received placebo. STATISTICS: Fisher's exact test was used to compare incidence of post-ERCP pancreatitis in the two groups. RESULTS: Baseline characteristics were similar between the two groups. Incidence of acute pancreatitis was 7 in the aprepitant group and 7 in the placebo group. Hospitalization within 7 days post-procedure for abdominal pain that did not meet criteria for acute pancreatitis occurred in 6 and 9 patients in the aprepitant and placebo groups respectively (P=0.772). CONCLUSIONS: Aprepitant did not lower incidence of post-ERCP pancreatitis in this preliminary human study. Larger studies potentially using the recently available intravenous formulation are necessary to conclusively clarify the efficacy of aprepitant in this setting.  

A safety and survival analysis of neoadjuvant bevacizumab with standard chemoradiation in a phase I/II study compared with standard chemoradiation in locally advanced rectal cancer.

INTRODUCTION: Bevacizumab is increasingly being tested with neoadjuvant regimens in patients with localized cancer, but its effects on metastasis and survival remain unknown. This study examines the long-term outcome of clinical stage II/III rectal cancer patients treated in a prospective phase II study of bevacizumab with chemoradiation and surgery. As a benchmark, we used data from an analysis of 42 patients with locally advanced rectal cancer treated with a contemporary approach of preoperative fluoropyrimidine-based radiation therapy. MATERIALS AND METHODS: Outcome analyses were performed on 32 patients treated prospectively with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery as well as 42 patients treated with standard fluoropyrimidine-based chemoradiation. RESULTS: Overall survival, disease-free survival, and local control showed favorable trends in patients treated with bevacizumab with chemoradiation followed by surgery. Acute and postoperative toxicity appeared acceptable. CONCLUSIONS: Neoadjuvant bevacizumab with standard chemoradiation and surgery shows promising long-term efficacy and safety profiles in locally advanced rectal cancer patients.

Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer.

We explored plasma and urinary concentrations of two members of the vascular endothelial growth factor (VEGF) family and their receptors as potential response and toxicity biomarkers of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The concentrations of VEGF, placental growth factor (PlGF), soluble VEGF receptor 1 (sVEGFR-1), and sVEGFR-2 were measured in plasma and urine at baseline and during treatment. Pretreatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment as well as for acute toxicity in patients with locally advanced rectal cancer treated prospectively in 2002-2008 with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery in a phase I/II trial. Of all biomarkers, pretreatment plasma sVEGFR-1-an endogenous blocker of VEGF and PlGF, and a factor linked with "vascular normalization"-was associated with both primary tumor regression and the development of adverse events after neoadjuvant bevacizumab and chemoradiation. Based on the findings in this exploratory study, we propose that plasma sVEGFR-1 should be further studied as a potential biomarker to stratify patients in future studies of bevacizumab and/or cytotoxics in the neoadjuvant setting.

Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer.

Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti-vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell-derived factor 1alpha (SDF1alpha), its receptor CXCR4, and CXCL6, and down-regulated PlGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1alpha plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy.

Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study.

PURPOSE: To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response. PATIENTS AND METHODS: In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m(2)/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy. RESULTS: Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome. CONCLUSION: Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen.

Inflammatory bowel disease following solid organ transplantation.

Inflammatory bowel disease (IBD) is a T cell driven inflammatory condition of the gut. Following solid organ transplantation (SOT), de novo IBD has been reported despite anti-T cell therapy for the prevention of organ rejection. This paradox is illustrated with a case report, highlighting the difficult diagnostic criteria, the potential role of Damage or Pathogen Associated Molecular Pattern Molecules [DAMPs and PAMPs] that drives aspects of ongoing inflammation within the transplanted organ as well as the intestine, and the therapeutic strategies applied. Recurrent IBD is more common than de novo IBD following transplantation, with cumulative risks ten years after orthotopic liver transplantation of 70% and 30%, respectively. Furthermore, the annual incidence of de novo IBD following solid organ transplantation has been estimated to be 206 cases/100,000 or ten times the expected incidence of IBD in the general population (approximately 20 cases/100,000). The association of IBD with other autoimmune conditions such as primary sclerosing cholangitis and autoimmune hepatitis, both common indications for liver transplantation, may play a contributory role, particularly in view of the observation that IBD is more common following liver transplant than other solid organ transplants. Recurrent IBD following transplant appears to run a more aggressive course than de novo IBD, with a higher proportion requiring colectomy for medically refractory disease. Risk factors that have been associated with development of post-transplant IBD include acute CMV infection and the use of tacrolimus.

Using capsule endoscopy to identify GI tract lesions in cirrhotic patients with portal hypertension and chronic anemia.

GOALS: We aimed to evaluate the ability of capsule endoscopy (CE) to detect small intestine (SI) lesions, especially SI varices, in patients with intrahepatic cirrhosis, portal hypertension (PHTN), and chronic anemia. BACKGROUND: Gastroesophageal variceal bleeding is a well-recognized complication of cirrhosis and PHTN, yet methods of identifying lesions in the SI that may contribute to covert bleeding and anemia, such as small bowel enteroscopy and angiography, are invasive and may be inadequate. STUDY: In this observational pilot study, 19 consecutive patients presenting to a tertiary care, liver transplantation referral center with cirrhosis, PHTN, and chronic anemia after obliterative esophageal variceal therapy were evaluated with wireless CE using the GIVEN Pillcam SB M2A capsule. Two independent and blinded examiners reviewed the CE examinations. RESULTS: SI varices were identified in 15.8% (3/19) of patients. Other PHTN-related findings included portal hypertensive gastropathy (13/19, 68.4%), portal hypertensive enteropathy (12/19, 63.1%), and portal hypertensive colopathy (3/19, 15.8%). Two patients had nonbleeding esophageal varices (2/19, 10.5%). A potential source of gastrointestinal blood loss was identified in 89.5% (17/19) of patients. Active bleeding sites were identified in 15.8% (3/19). CONCLUSIONS: CE can identify potential bleeding sources and could have diagnostic utility in patients with end-stage liver disease and chronic anemia after obliterative esophageal variceal therapy.

Complete pathological response to bevacizumab and chemoradiation in advanced rectal cancer.

BACKGROUND: Localized rectal cancer responds well to 5-fluorouracil and radiation-based regimens. A phase I-II trial is currently testing the efficacy of adding bevacizumab, a VEGF-specific antibody, to standard chemoradiotherapy. The case presented here is a complete pathological response seen in a patient with extensive and locally invasive carcinoma after receiving this combined treatment. INVESTIGATIONS: Physical examination, rectal ultrasound, PET-CT scan, laboratory tests, proctoscopic examination, chest radiograph, rectal forcep biopsies with immunohistochemistry, and protein and flow cytometric analyses. DIAGNOSIS: Large, invasive, ultrasound stage T4 carcinoma of the rectum, which was positive for survivin. MANAGEMENT: One 2-week cycle of bevacizumab alone, followed by 3 cycles of bevacizumab with continuous 5-fluorouracil infusion, and external-beam radiation therapy given 5 days per week to the pelvis, abdominoperineal resection with posterior vaginectomy, hysterectomy and bilateral salpingo-oophorectomy.