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Granular cell tumors (GCTs) are generally thought to be of Schwann cell origin and are typically S-100 positive. Up to 11% of these tumors affect the gastrointestinal tract, most commonly the esophagus, colon, and stomach. While GCTs are mostly benign, malignant and metastatic GCTs have been reported. GCTs are usually found incidentally during esophagogastroduodenoscopy, colonoscopy, imaging studies or during the evaluation of non-specific symptoms. Endoscopically, they are typically yellow in appearance with intact mucosa. On endoscopic ultrasound, they usually are hypoechoic, homogenous, smooth-edged lesions that appear to originate from the submucosal layer, although other endoscopic and ultrasound appearances have been described. There is no consensus on how to treat GCT. Surgical and conservative approaches have been described in the literature. GCTs can also affect the biliary tract, where patients may be misdiagnosed with cholangiocarcinoma. We explore the epidemiology, histology, clinical presentation, diagnosis and treatment of these tumors in the gastrointestinal tract, including the pharynx, esophagus, stomach, small intestine, large intestine and the perianal region. In addition, GCTs in the biliary tract are reviewed.

The main aim of this work is to compare Hindu and Arabic digits with respect to a machine’s ability to recognize them. This comparison is done on the raw representation (images) of the digits and on their features extracted using two feature selection methods. Three learning algorithms with different inductive biases were used in the comparison performed using the raw representation; two of them were also used to compare the digits using their extracted features. All classifiers gave better results for Hindu digits in both cases; when raw representation was used and when the selected features where used. The experiments also show that Hindu digits can be classified with better accuracy, higher confidence and using fewer features than Arabic digits. These results indicate that hand-written Hindu digits are actually easier to recognize than hand-written Arabic digits. The machine learning methods used in this work are instance based learning (the kNN algorithm), Naive Bayesian and neural networks. T...

T-cell non-Hodgkin lymphomas (NHLs) are a heterogeneous group of malignancies that represent 10%–15% of all NHLs. The prognosis of relapsed T-cell NHL is poor, especially for those relapsing after an autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT). Disease relapse post auto-HCT is best managed on a clinical trial. In the absence of an investigational protocol, the choice of salvage therapies should take into account patient performance status, eligibility for an allo-HCT, and surface CD30 expression. CD30-directed therapies or aggressive salvage regimens can be used as a bridge to allo-HCT in medically fit patients. In the elderly or more infirm patients, single-agent therapies could be offered, aiming at palliation. Similarly, relapse after an allo-HCT is not uncommon and is a real challenge. Reduction in ongoing immune suppression or donor lymphocyte infusion are often considered in this setting to augment graft-versus-lymphoma (GVL) effects and can occasionally provide durable disease control. Clinical trials designed to investigate novel therapeutic agents with immunomodulatory properties to augment GVL effects (eg, histone deacetylase [HDAC] inhibitors, proteasome inhibitor, lenalidomide) or targeted therapies (eg, aurora A kinase inhibitors, anaplastic lymphoma kinase [ALK] inhibitors) are sorely needed to improve the dismal outcomes of T-cell NHL relapsing after an allo-HCT.

Primary plasma cell leukemia (pPCL) is an uncommon but aggressive plasma cell malignancy associated with frequent extramedullary involvement, high-risk cytogenetic abnormalities, and frequent organ dysfunction, ultimately resulting in poor prognosis. Here we review recent advances in our understanding of the molecular and biological aspects of PCL and summarize therapeutic progress occurring over the past 2 decades. pPCL is distinguished from secondary PCL arising from multiple myeloma. The molecular and immunophenotypic changes of pPCL are often distinct from those seen in secondary PCL and multiple myeloma. The availability of novel agents (ie, proteasome inhibitors and immunomodulatory agents) and the increasing use of hematopoietic cell transplantation strategies have resulted in better outcomes, although long-term survival remains poor. Development of complex treatment algorithms that combine novel agents as induction therapy, as part of conditioning regimens for hematopoietic cell transplantation (autologous or allogeneic), or as post-transplantation remission strategies are logical and may translate into improved survival in patients with PCL.

Chronic myelomonocytic leukemia is a heterogeneous disease with multifactorial molecular pathogenesis. Various recurrent somatic mutations have been detected alone or in combination in chronic myelomonocytic leukemia. Recently, recurrent mutations in spliceosomal genes have been discovered. We investigated the contribution of U2AF1, SRSF2 and SF3B1 mutations in the pathogenesis of chronic myelomonocytic leukemia and closely related diseases. We genotyped a cohort of patients with chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia for somatic mutations in U2AF1, SRSF2, SF3B1 and in the other 12 most frequently affected genes in these conditions. Chromosomal abnormalities were assessed by nucleotide polymorphism array-based karyotyping. The presence of molecular lesions was correlated with clinical endpoints. Mutations in SRSF2, U2AF1 and SF3B1 were found in 32%, 13% and 6% of cases of chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, respectively. Spliceosomal genes were affected in various combinations with other mutations, including TET2, ASXL1, CBL, EZH2, RAS, IDH1/2, DNMT3A, TP53, UTX and RUNX1. Worse overall survival was associated with mutations in U2AF1 (P=0.047) and DNMT3A (P=0.015). RAS mutations had an impact on overall survival in secondary acute myeloid leukemia (P=0.0456). By comparison, our screening of juvenile myelomonocytic leukemia cases showed mutations in ASXL1 (4%), CBL (10%), and RAS (6%) but not in IDH1/2, TET2, EZH2, DNMT3A or the three spliceosomal genes. SRSF2 and U2AF1 along with TET2 (48%) and ASXL1 (38%) are frequently affected by somatic mutations in chronic myelomonocytic leukemia, quite distinctly from the profile seen in juvenile myelomonocytic leukemia. Our data also suggest that spliceosomal mutations are of ancestral origin.

Myelodysplastic syndromes (MDSs) are chronic and often progressive myeloid neoplasms associated with remarkable heterogeneity in the histomorphology and clinical course. Various somatic mutations are involved in the pathogenesis of MDS. Recently, mutations in a gene encoding a spliceosomal protein, SF3B1, were discovered in a distinct form of MDS with ring sideroblasts. Whole exome sequencing of 15 patients with myeloid neoplasms was performed, and somatic mutations in spliceosomal genes were identified. Sanger sequencing of 310 patients was performed to assess phenotype/genotype associations. To determine the functional effect of spliceosomal mutations, we evaluated pre-mRNA splicing profiles by RNA deep sequencing. We identified additional somatic mutations in spliceosomal genes, including SF3B1, U2AF1, and SRSF2. These mutations alter pre-mRNA splicing patterns. SF3B1 mutations are prevalent in low-risk MDS with ring sideroblasts, whereas U2AF1 and SRSF2 mutations are frequent in chronic myelomonocytic leukemia and advanced forms of MDS. SF3B1 mutations are associated with a favorable prognosis, whereas U2AF1 and SRSF2 mutations are predictive for shorter survival. Mutations affecting spliceosomal genes that result in defective splicing are a new leukemogenic pathway. Spliceosomal genes are probably tumor suppressors, and their mutations may constitute diagnostic biomarkers that could potentially serve as therapeutic targets.

Abstract 3566 MDS patients (pts) are destined to either progress to more aggressive disease or die of MDS-related complications. The International Prognostic Scoring System (IPSS) and other systems assess the survival and risk of evolution to acute myelogenous leukemia (AML), based in part on specific cytogenetic abnormalities. However, heterogeneity still exists even within cytogenetic groups, in part due to cryptic lesions, making predictions imperfect. In this respect, we and others have demonstrated that single nucleotide polymorphism array (SNP-A) karyotyping may improve the diagnostic yield, and that previously cryptic lesions can improve prognostic resolution of cytogenetic testing when compared to metaphase cytogenetics (MC) alone. Despite the recent identification of a variety of somatic mutations in MDS, their therapeutic value is unproven, and because of conflicting findings as to the risk for many mutations, they have not been routinely introduced into diagnostic algorithms. Mutational events may constitute suitable biomarkers that could strengthen current prognostic schemes. In addition, malignant progression is associated with acquisition of new molecular defects, which may impact our understanding of the molecular pathogenesis of MDS and allow for distinction of ancestral from facilitating defects. We hypothesized that serial cytogenetic testing for a comprehensive spectrum of mutations and cytogenetic defects would reveal which molecular event is associated with progression. We have analyzed a cohort of 76 MDS pts, 38 of whom experienced progression to AML (median age=68.5, IPSS = 0.5) matched to 38 pts (median age=69, IPSS =0.5) who did not experience progression. In addition to MC, we compared these groups for the presence of selected mutations, including TP53, RUNX1, TET2, ASXL1, DNMT3A, IDH1/2, NPM1, CBL and EZH2. The progressor group (PG) consisted of 20 (53%) low and intermediate-1 risk patients; the non-progressor group (NPG) had 22 (62%). In 60% of PG and 49% NPG at presentation, normal cytogenetics were present, while 16% and 14% had poor-risk cytogenetics, respectively. In addition, in 13% of PG and 11% of NPG, del7/7q was present. CBL, TP53, NPM1, ASXL1, IDH1, IDH2, RUNX1, DNMT3A, TET2 and EZH2 mutations were detected in (for PG vs. NPG): 0 (0/33) vs. 9% (3/35) p=1; 0 (0/29) vs. 5% (1/20) p=.4; 0 (0/33) vs N/A, 20% (6/30) vs. 18% (6/34) p=1; 9%(3/32) vs. 0 (0/39) p=.08; 0 (0/25) vs 0 (0/36) p=1; 0% (0/26) vs. 16% (1/6) p=.18; 7% (2/27) vs. 11% (4/37) p=1; 19% (4/21) vs. 37% (13/35) p=.23; and 5% (1/19) vs. 6% (2/32) p=1, respectively. We conclude that these pt groups had similar rates of mutations. We subsequently compared the cytogenetic and mutational status between initial presentation and at AML progression in the PG group. Progression was associated with occurrence of new cytogenetic lesions in 41% (14/34) while it remains stable in 53% (18/34) of pts. The most common new cytogenetics defects associated with evolution included trisomy 8, monosomy 7/del7q and monosomy 18. In 1, 2, and 1 pts, progression was associated with acquisition of CBL, TP53, and RUNX1 mutations, respectively. In contrast in 5, 3, 2 and 4 pts, ASXL1, IDH1, DNMT3A and TET2 mutations were present already at presentation. New mutations were detected upon leukemic evolution in 10/14 patients with abnormal MC and 3/14 with normal MC. We conclude that ASXL1 and TET2 (and perhaps IDH1 and DNMT3A) constitute early events while acquisition of TP53, CBL and possibly RUNX1 were events leading to progressive, advanced disease. Disclosures: Afable: Alexion: Speakers Bureau. Sekeres:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Celgene: Speakers Bureau; Alexion: Speakers Bureau; Celgene: Research Funding; Eisai: Research Funding; NIH: Research Funding; AA & MDS International Foundation: Research Funding.

e12525 Background: The objective of this study was to determine the clinicopathologic characteristics of Lebanese patients with breast cancer below 40 compared to those above 40 presenting to our institution. Methods: Using a cross-sectional study design, data were collected prospectively on a sample of 110 women newly diagnosed with breast cancer. Comparison between the groups was performed using Person Chi-square and Fishers exact test. Results: 28 patients were ≤ 40 years and 82 patients >40 years. 75% and 76.5% of patients above and below 40 years respectively presented with stage I or II disease, more patients above 40 presented with stage I compared to those below 40 (32.4% vs 8% respectively). 50% of the younger age group presented with a grade 3 tumor; however, more than the half of the older group presented with grade 1 or 2. The older age group had a higher incidence of concurrent lobular and intraductal carcinoma (0 vs 6.4%). The younger age group was more likely to present with nodal involvement (57.1% vs. 48.45 for younger and older age groups respectively). Similar proportions of the two age groups stained positive for cyclin B1, p53, and VEGFR. All patients stained positive for PDGFR. Mean value of Ki-67 was 21.8% and 24%in younger and older age groups respectively. These differences were not statistically significant. Methylene Tetrahydrofolate Reductase (MTHFR) single nuccleotide polymorphism (SNP) T677T was detected in 21% of the older group compared to 5% of the younger population. Stratified to age Vitamin D receptor (VDR) SNP ApaI A/A was found in similar proportion in both groups (35% and 33.3% in younger and older group) while 30% and 41.3 % carried the vitamin D receptor (SNP) BSMI b/b in younger and older group respectively. Conclusions: No significant differences in the clinicopathologic characteristics examined between patients younger or older than 40 years were found in this sample. Analysis of a larger sample size including BRCA gene mutation analysis is planned to determine differences between age groups and possibly explain the higher incidence of breast cancer in the younger age group in our population.