Gastrointestinal Stromal Tumor (GIST) in Long Standing Crohn’s disease on Anti-TNF Therapy

Introduction Patients suffering from inflammatory bowel disease (IBD) are at increased risk for developing cancer. Adenocarcinomas are the most commonly observed tumors of the gastrointestinal tract whereas data on gastrointestinal stromal tumor (GIST) in IBD patients is limited. GIST is a neoplasm that originates from the interstitial cells of Cajal in the smooth muscle layers of the gastrointestinal tract. [1] The association between GIST and Crohn’s disease (CD) is debated, as the tumor inconsistently present in areas of inflammatory activity. We report an interesting case of CD maintained on Infliximab, who presented with a flare that revealed GIST in the stomach. To our knowledge, this is the first reported occurrence of GIST in stomach in a patient with CD maintained on anti-TNF therapy. Case Report A 40-year-old Caucasian man with a history of small bowel Crohn’s disease on infliximab therapy presented with a two-day history of abdominal pain, hematochezia, and diffuse joint pain. Upon admission, the patient was hemodynamically stable and afebrile, with a blood pressure of 140/70 mmHg, heart rate of 90 beats per minute, and respiratory rate of 14 per minute. Physical exam was remarkable for abdominal distension and diffuse abdominal tenderness. Complete blood count, comprehensive metabolic panel, and C-reactive protein were within normal range. The patient reported no history of alcohol abuse, smoking, recent abdominal procedures, or trauma. The patient had computed tomography (CT) of the abdomen done that revealed a 2.5-centimeter exophytic mass in the stomach with possible liver metastases (Fig. 1). Endoscopic ultrasound (EUS) guided biopsies of the exophytic mass confirmed gastrointestinal stromal tumor (GIST) on fine needle aspiration and flow cytometry results (Fig. 2,3). The patient underwent surgical resection without complication and is back to his usual state of health. Discussion GIST is the most common mesenchymal neoplasm in the gastrointestinal tract [1,2]. The annual incidence of GIST has been reported as 11-19.6 per million [3,4], however a more recent analysis in 2015 estimates the annual incidence to be 6.8 per million with a 53% predominance in males and 73% predominance in Caucasians [5]. Individuals are typically diagnosed with GIST in their seventh decade of life [5]. Immunologically, it is reported that 70-80% of GIST have a mutation in the KIT gene, leading to a continuously active KIT receptor, independent of its activating ligand [1]. KIT activation leads to overexpression of the protein CD117. In KIT-negative GIST, a small number are observed to have a mutation in platelet-derived growth factor receptor-a (PDGFRA). Dysregulated activation of either of these genes results in uncontrolled cell growth and survival. It is estimated that 10-15% of GIST do not have mutations in either KIT or PDGRFA, and while they are considered wild-type, they are shown to express high levels of KIT [1]. More recently, Novelli et al. found that the presence of proteins CD117 and DOG1 had the highest sensitivity and specificity for GIST [6]. The majority of GIST develop in the stomach (60%), with the jejunum and ileum representing the next most common site of involvement (30%) [7]. Several prognostic factors have been researched, most notably tumor location and mitotic index. Emory et al. found that GIST originating from the esophagus had the highest survival rate, followed by those that arose from the stomach, small bowel, colon/rectum, and omentum/mesentery in decreasing order [8]. Additionally, mitotic index, defined as the number of mitotic figures per high-power field (HPF), is reported an independent prognostic factor, with greater than 10 mitotic figures per 50 HPF showing the largest difference in survival in gastric GIST [8]. Small bowel GIST exhibited minimally different survival curves with respect to mitotic index. Age was also found to be an independent prognostic factor of survival in GIST [8]. Later research by Miettinen demonstrated that larger gastric GIST with a diameter of 10cm and 5 mitotic figures per 50 HPF carried a lower metastatic risk in comparison to gastric GIST with diameter of \u3e 5cm but with \u3e 5 mitotic figures per 50 HPF [9]. This may suggest that in gastric GIST, mitotic index carries the most prognostic value. Miettinen found that in intestinal GIST, a diameter of \u3e 5cm and \u3e 5 mitotic figures per HPF each independently carried a moderate or high risk of metastasis, respectively. Intestinal GIST carried a 39% tumor-related mortality rate, compared to 17% for gastric GIST [10,11]. Currently, surgery is the primary treatment modality for nonmetastatic GIST that is technically amenable to resection. Imatinib, a tyrosine kinase inhibitor (TKI), may be used as neoadjuvant therapy or as initial therapy for nonresectable disease [12]. Imatinib directly binds to the KIT protein and prevents further signaling [1]. This medication first demonstrated favorable treatment effects in 2002, with over 50% of the 147 patients showing at least a partial response to therapy [13]. Some patients develop resistance to Imatinib, prompting the development of alternative TKI therapy. Currently, Sunitinib is FDA approved for Imatinib-resistant GIST [14], with a host of other TKI’s and alternative therapies under investigation [1]. In 2012, Körner examined glucagon-like peptide-2 receptor (GLP-2) expression in a variety of neoplasm and found that 68% of the GISTs expressed this receptor in the intestinal myenteric plexus [15]. Additionally, this receptor was expressed in high density in patients with Crohn’s disease. Interestingly, this expression was absent in active or inactive ulcerative colitis as well as Hirschsprung’s disease [15]. Table 1: GIST with concurrent IBD. Author (ref) Age, Sex IBD Symptoms Location of GIST Imaging or operative findings Pfeffela, 1999 [16] 51, M CD Weight loss, Abdominal pain, Fever, Fatigue Ileum Large tumorous lesions in the right lower abdomen (terminal ileum) measuring 8 × 5 × 6 cm Grieco, 2002 [17] 57, F UC Melena, progressive anemia Ileum Solid mass in the left pelvic cavity with a diameter of 7 cm Mijandrusić Sincić, 2005 [18] 81, M CD Ileus Meckel’s diverticulum Dilated loops of intestine with large packets of gas and anti-peristalsis Kaiser, 2006 [19] 64, M UC Severe bleeding, abdominal distension Omentum 8 cm mass attached to greater omentum Ruffolo, 2010 [20] 59, M UC Rectal bleeding Rectum 0.5 cm GIST located 20 cm from anal adenocarcinoma Theodoropoulos, 2009 [21] 45, M CD Abdominal pain, vomiting, constipation, bloating Jejunum and Ileum 6 mm GIST within jejunoileal intussusception Bocker U, 2008 [22] 26, F CD Abdominal cramping, gastrointestinal bleeding Duodenum Ulcerated lesion noted 140 cm past proximal duodenum on enteroscopy Gianluca, 2016 [7] 38, M CD Asymptomatic Small bowel A mass found along the small bowel Gianluca, 2016 [7] 53, M UC Abrupt postoperative bleeding Stomach No evidences of masses at surgery. Gastric bleeding at endoscopy Present paper 40, M CD Abdominal pain, hematochezia Stomach 2.5 cm exophytic mass in the stomach with possible liver metastases CONCLUSION Our case of Crohn’s disease diagnosed with gastric GIST sheds light on a rare link between two separate disease entities native to the gastrointestinal system. While there exists a well-known association between inflammatory bowel disease and colon cancer, other malignancies are described much less frequently in the literature. The development of gastric GIST with underlying Crohn’s disease is a rare occurrence, but is one that should be kept in mind when evaluating patients with inflammatory bowel disease found to have new masses on imaging. References: 1. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: Origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865-878. doi:10.1038/nrc3143 2. Katzka DA, Loftus E V., Camilleri M. Evolving molecular targets in the treatment of nonmalignant gastrointestinal diseases. Clin Pharmacol Ther. 2012;92(3):306-320. doi:10.1038/clpt.2012.77 3. Nilsson B, Bümming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era - A population-based study in western Sweden. Cancer. 2005;103(4):821-829. doi:10.1002/cncr.20862 4. Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RMC, Hogendoorn PCW. Incidence of gastrointestinal stromal tumours is underestimated: Results of a nation-wide study. Eur J Cancer. 2005;41(18):2868-2872. doi:10.1016/j.ejca.2005.09.009 5. Ma GL, Murphy JD, Martinez ME, Sicklick JK. Epidemiology of gastrointestinal stromal tumors in the era of histology codes: Results of a population-based study. Cancer Epidemiol Biomarkers Prev. 2015;24(1):298-302. doi:10.1158/1055-9965.EPI-14-1002 6. Novelli M, Rossi S, Rodriguez-Justo M, et al. DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours. Histopathology. 2010;57(2):259-270. doi:10.1111/j.1365-2559.2010.03624.x 7. Pellino G, Marcellinaro R, Candilio G, et al. The experience of a referral centre and literature overview of GIST and carcinoid tumours in inflammatory bowel diseases. Int J Surg. 2016;28:S133-S141. doi:10.1016/j.ijsu.2015.12.051 8. Emory TS, Sobin LH, Lukes L, Lee DH, O’Leary TJ. Prognosis of gastrointestinal smooth-muscle (stromal) tumors: Dependence on anatomic site. Am J Surg Pathol. 1999;23(1):82-87. doi:10.1097/00000478-199901000-00009 9. Miettinen M, Lasota J. Gastrointestinal stromal tumors: Pathology and prognosis at different sites. Semin Diagn Pathol. 2006. doi:10.1053/j.semdp.2006.09.001 10. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: A clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005;29(1):52-68. doi:10.1097/01.pas.0000146010.92933.de 11. Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the jejunum and ileum: A clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol. 2006;30(4):477-489. doi:10.1097/00000478-200604000-00008 12. Demetri GD, Benjamin R, Blanke CD, et al. NCCN Task Force Report: Optimal Management of Patients with Gastrointestinal Stromal Tumor (GIST)--Expansion and Update of NCCN Clinical Practice Guidelines. Vol 2 Suppl 1.; 2004. 13. Eorge D Emetri GD, Argaret Von Ehren MM, Harles B Lanke CD, et al. The New Eng Land Jour Nal of Medicine EFFICACY AND SAFETY OF IMATINIB MESYLATE IN ADVANCED GASTROINTESTINAL STROMAL TUMORS A BSTRACT Background Constitutive Activation of KIT Receptor. Vol 347.; 2002. www.nejm.org. Accessed January 29, 2020. 14. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329-1338. doi:10.1016/S0140-6736(06)69446-4 15. Körner M, Rehmann R, Reubi JC. GLP-2 receptors in human disease: High expression in gastrointestinal stromal tumors and Crohn’s disease. Mol Cell Endocrinol. 2012;364(1-2):46-53. doi:10.1016/j.mce.2012.08.008 16. Pfeffel F, Stiglbauer W, Depisch D, Oberhuber G, Raderer M, Scheithauer W. Coincidence of Crohn’s disease and a high-risk gastrointestinal stromal tumor of the terminal ileum. Digestion. 1999. doi:10.1159/000007684 17. Grieco A, Cavallaro A, Potenza AE, et al. Gastrointestinal stromal tumor (GIST) and ulcerative colitis. J Exp Clin Cancer Res. 2002. 18. Mijandrusic Sincic BM, Kovać D, Jašić M, Grbas H, Uravić M, Depolo A. Crohn’s disease and a gastrointestinal stromal tumor in an 81-year-old man - A rare coincidence. Zentralbl Chir. 2005. doi:10.1055/s-2005-918206 19. Kaiser AM, Kang JC, Tolazzi AR, Sherrod AE, Beart RW. Primary solitary extragastrointestinal stromal tumor of the greater omentum coexisting with ulcerative colitis. Dig Dis Sci. 2006;51(10):1850-1852. doi:10.1007/s10620-006-9217-y 20. Ruffolo C, Massani M, Rossi S, Caratozzolo E, Antoniutti M, Bassi N. Adenocarcinoma and GIST in ulcerative colitis. Int J Colorectal Dis. 2010;25(8):1027-1028. doi:10.1007/s00384-010-0905-x 21. Theodoropoulos GE, Linardoutsos D, Tsamis D, et al. Gastrointestinal stromal tumor causing small bowel intussusception in a patient with Crohn’s disease. World J Gastroenterol. 2009;15(41):5224-5227. doi:10.3748/wjg.15.5224 22. Böcker U, Löhr JM, Marx A. Twenty-six-year-old female with assumed Crohn’s disease and a gastrointestinal stromal tumor: Response. Inflamm Bowel Dis. 2009;15(4):489-490. doi:10.1002/ibd.2065

Comments on: Interval Type-2 Fuzzy Sets are generalization of Interval-Valued Fuzzy Sets: Towards a Wider view on their relationship

This Letter makes some observations about [2] that further support the distinction between an interval type-2 fuzzy set (IT2 FS) and an interval-valued fuzzy set (IV FS), points out that all operations, methods and systems that have been developed and published about IT2 FSs are, so far, only valid in the special case when IT2 FS = IVFS, and suggests some research opportunities

Parallel Metric Tree Embedding based on an Algebraic View on Moore-Bellman-Ford

A \emph{metric tree embedding} of expected \emph{stretch~$\alpha \geq 1$} maps a weighted $n$-node graph $G = (V, E, \omega)$ to a weighted tree $T = (V_T, E_T, \omega_T)$ with $V \subseteq V_T$ such that, for all $v,w \in V$, $\operatorname{dist}(v, w, G) \leq \operatorname{dist}(v, w, T)$ and $operatorname{E}[\operatorname{dist}(v, w, T)] \leq \alpha \operatorname{dist}(v, w, G)$. Such embeddings are highly useful for designing fast approximation algorithms, as many hard problems are easy to solve on tree instances. However, to date the best parallel $(\operatorname{polylog} n)$-depth algorithm that achieves an asymptotically optimal expected stretch of $\alpha \in \operatorname{O}(\log n)$ requires $\operatorname{\Omega}(n^2)$ work and a metric as input. In this paper, we show how to achieve the same guarantees using $\operatorname{polylog} n$ depth and $\operatorname{\tilde{O}}(m^{1+\epsilon})$ work, where $m = |E|$ and $\epsilon > 0$ is an arbitrarily small constant. Moreover, one may further reduce the work to $\operatorname{\tilde{O}}(m + n^{1+\epsilon})$ at the expense of increasing the expected stretch to $\operatorname{O}(\epsilon^{-1} \log n)$. Our main tool in deriving these parallel algorithms is an algebraic characterization of a generalization of the classic Moore-Bellman-Ford algorithm. We consider this framework, which subsumes a variety of previous "Moore-Bellman-Ford-like" algorithms, to be of independent interest and discuss it in depth. In our tree embedding algorithm, we leverage it for providing efficient query access to an approximate metric that allows sampling the tree using $\operatorname{polylog} n$ depth and $\operatorname{\tilde{O}}(m)$ work. We illustrate the generality and versatility of our techniques by various examples and a number of additional results

The Savvidy ``ferromagnetic vacuum'' in three-dimensional lattice gauge theory

The vacuum effective potential of three-dimensional SU(2) lattice gauge theory in an applied color-magnetic field is computed over a wide range of field strengths. The background field is induced by an external current, as in continuum field theory. Scaling and finite volume effects are analyzed systematically. The first evidence from lattice simulations is obtained of the existence of a nontrivial minimum in the effective potential. This supports a ``ferromagnetic'' picture of gluon condensation, proposed by Savvidy on the basis of a one-loop calculation in (3+1)-dimensional QCD.Comment: 9pp (REVTEX manuscript). Postscript figures appende

Protein engineering of Pseudomonas fluorescens peroxidase Dyp1B for oxidation of phenolic and polymeric lignin substrates

Directed evolution was applied to dye-decolourizing peroxidase Dyp1B from Pseudomonas fluorescens Pf-5, in order to enhance the activity for oxidation of phenolic and lignin substrates. Saturation mutagenesis was used to generate focused libraries at 7 active site residues in the vicinity of the heme cofactor, and the libraries were screened for activity towards 2,6-dichlorophenol. Mutants N193 L and H169 L were found to show 7–8 fold enhanced kcat/KM towards DCP, and replacements at Val205 and Ala209 also showed enhanced activity towards alkali Kraft lignin. Residues near the predicted Mn(II) binding site were also investigated by site-directed mutagenesis, and mutants S223 N and H127R showed 4-7-fold increased kcat/KM for Mn(II) oxidation. Mutant F128R also showed enhanced thermostability, compared to wild-type Dyp1B. Testing of mutants for low molecular weight product release from Protobind alkali lignin revealed that mutant H169 L showed enhanced product release, compared with WT enzyme, and the formation of three low molecular weight metabolites by this mutant was detected by reverse phase HPLC analysis

Using level-2 fuzzy sets to combine uncertainty and imprecision in fuzzy regions

In many applications, spatial data need to be considered but are prone to uncertainty or imprecision. A fuzzy region - a fuzzy set over a two dimensional domain - allows the representation of such imperfect spatial data. In the original model, points of the fuzzy region where treated independently, making it impossible to model regions where groups of points should be considered as one basic element or subregion. A first extension overcame this, but required points within a group to have the same membership grade. In this contribution, we will extend this further, allowing a fuzzy region to contain subregions in which not all points have the same membership grades. The concept can be used as an underlying model in spatial applications, e.g. websites showing maps and requiring representation of imprecise features or websites with routing functions needing to handle concepts as walking distance or closeby

The Isgur-Wise function in a relativistic model for qQˉq\bar Q system

We use the Dirac equation with a ``(asymptotically free) Coulomb + (Lorentz scalar) linear '' potential to estimate the light quark wavefunction for $q\bar Q$ mesons in the limit $m_Q\to \infty$. We use these wavefunctions to calculate the Isgur-Wise function $\xi (v.v^\prime )$ for orbital and radial ground states in the phenomenologically interesting range $1\leq v.v^ \prime \leq 4$. We find a simple expression for the zero-recoil slope, $\xi^ \prime (1) =-1/2- \epsilon^2 /3$, where $\epsilon$ is the energy eigenvalue of the light quark, which can be identified with the $\bar\Lambda$ parameter of the Heavy Quark Effective Theory. This result implies an upper bound of $-1/2$ for the slope $\xi^\prime (1)$. Also, because for a very light quark $q (q=u, d)$ the size $\sqrt {}$ of the meson is determined mainly by the ``confining'' term in the potential $(\gamma_\circ \sigma r)$, the shape of $\xi_{u,d}(v.v^\prime )$ is seen to be mostly sensitive to the dimensionless ratio $\bar \Lambda_{u,d}^2/\sigma$. We present results for the ranges of parameters $150 MeV <\bar \Lambda_{u,d} <600 MeV$ $(\bar\Lambda_s \approx \bar\Lambda_{u,d}+100 MeV)$, $0.14 {GeV}^2 \leq \sigma \leq 0.25 {GeV}^2$ and light quark masses $m_u, m_d \approx 0, m_s=175 MeV$ and compare to existing experimental data and other theoretical estimates. Fits to the data give: ${\bar\Lambda_{u,d}}^2/\sigma =4.8\pm 1.7$, $-\xi^\prime_{u,d}(1)=2.4\pm 0.7$ and $\vert V_{cb} \vert \sqrt {\frac {\tau_B}{1.48 ps}}=0.050\pm 0.008$ [ARGUS '93]; ${\bar\Lambda_{u,d}}^2/\sigma = 3.4\pm 1.8$, $-\xi^\prime_{u,d}(1)=1.8\pm 0.7$ and $\vert V_{cb} \vert \sqrt { \frac {\tau_B}{1.48 ps}}=0.043\pm 0.008$ [CLEO '93]; ${\bar\Lambda_{u,d}}^2/Comment: 22 pages, Latex, 4 figures (not included) available by fax or via email upon reques

Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis

Supported by the Global Alliance for TB Drug Development with support from the Bill and Melinda Gates Foundation, the European and Developing Countries Clinical Trials Partnership, U.S. Agency for International Development, U.K. Department for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and National Institutes of Health, AIDS Clinical Trials Group and by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (UM1AI068634, UM1 AI068636, and UM1AI106701) and by NIAID grants to the University of KwaZulu Natal, South Africa, AIDS Clinical Trials Group (ACTG) site 31422 (1U01AI069469); to the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, South Africa, ACTG site 12301 (1U01AI069453); and to the Durban International Clinical Trials Unit, South Africa, ACTG site 11201 (1U01AI069426); Bayer Healthcare for the donation of moxifloxacin; and Sanofi for the donation of rifampin.Background: Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis. Methods: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization. Results: Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group. Conclusions: The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.)Publisher PDFPeer reviewe

Scalars from Top-condensation Models at Hadron Colliders

We study the production and decay of neutral scalars and pseudo-scalars at hadron colliders, in theories where the top-quark mass is the result of a $t\bar t$ condensate. We show that the dominant decay channel for masses below the $t\bar t$ threshold is the flavor changing mode $tc$. This is a consequence of the non-universal nature of the underlying interactions in all top-condensation models and provides a model-independent signature of these scenarios. We show that an upgraded Tevatron is sensitive to a sizeable region of the interesting parameter space and that the LHC will highly constrain these models through this flavor violating channel.Comment: 4 pages, 4 figures. Minor changes in figures for readibility. final version to appear in PR