miR-21 mediates hematopoietic suppression in MDS by activating TGF-ß signaling.

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis that leads to peripheral cytopenias. We observed that SMAD7, a negative regulator of transforming growth factor-beta (TGF-ß) receptor-I kinase, is markedly reduced in MDS and leads to ineffective hematopoiesis by overactivation of TGF-ß signaling. To determine the cause of SMAD7 reduction in MDS, we analyzed the 3'UTR of the gene and determined that it contains a highly conserved putative binding site for microRNA-21. We observed significantly elevated levels of miR-21 in MDS marrow samples when compared with age-matched controls. miR-21 was shown to directly bind to the 3'UTR of SMAD7 and reduce its expression in hematopoietic cells. Next, we tested the role of miR-21 in regulating TGF-ß signaling in a TGF-ß-overexpressing transgenic mouse model that develops progressive anemia and dysplasia and thus serves as a model of human bone marrow failure. Treatment with a chemically modified miR-21 inhibitor led to significant increases in hematocrit and led to an increase in SMAD7 expression in vivo. Inhibition of miR-21 also led to an increase in erythroid colony formation from primary MDS bone marrow progenitors, demonstrating its ability in stimulating hematopoiesis in vitro. Taken together, these studies demonstrate the role of miR-21 in regulating overactivated TGF-ß signaling in MDS.

Successful Diagnosis of Epithelial Thymic Cancer Case Using EBUS-TBNA.

Mediastinal masses are relatively uncommon. Surgical approach is often needed to diagnose mediastinal masses. Using endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) toward approaching a mediastinal mass has yet to be established. Here, we present a case of successful diagnosis of thymic cancer with the use of EBUS-TBNA.

Two Cases of Pelvic Diffuse Large B-Cell Lymphoma.

Primary diffuse large B-cell lymphoma presenting as an extranodal site in the pelvis is rare and can mimic a gynecological malignancy. Although management for diffuse large B-cell lymphoma is standardized and curative, prognosis depends on timely diagnosis and therapy. Diagnosis can be challenging as patients lack classical symptoms of fever, night sweats, weight loss, and lymphadenopathy associated with lymphoma. A multidisciplinary approach is recommended to diagnose and treat judiciously. In this article, we present cases of 2 females who presented with pelvic masses with initial suspicion of a gynecological malignancy but were ultimately diagnosed as diffuse large B-cell lymphoma of the pelvis and managed accordingly.

Isolated myeloid sarcoma of lumbar spine without bone marrow involvement: a rare case report and treatment dilemma.

Granulocytic sarcoma, chloroma, myeloblastoma, or here referred as myeloid sarcoma (MS), is a rare extramedullary tumor composed of immature myeloid cells called myeloblasts. MS is seen most commonly in patients with acute myeloid leukemia and less frequently in chronic myeloid leukemia, myelodysplastic syndrome. In rarer instances, MS has been shown to precede the development of myeloid tumors by acute myeloblastic leukemia (AML). In particular, isolated MS involving spine is extremely rare. We herein present a rare case of isolated spinal MS in non-leukemic patient. This is a previously relatively healthy 47-year-old man who presented with signs of lumbar spinal cord compression, initially reported as schwannoma on imaging, later diagnosed with spinal MS on pathology. Further workup did not reveal any evidence of bone marrow or other hematological involvement. The patient successfully treated by L4/L5 laminectomy and debulking with subsequent radiation resulting in substantial decrease in size of tumor with significant improvement in symptoms during follow up. This case not only describes a rare case of isolated MS of lumbar spine, but also highlights the potential treatment challenges of such a rare diagnosis. We review the available literature, discuss available treatment options, and highlight the need for further investigations along with increased clinician awareness.

Lemierre Syndrome in a Patient With Splenectomy Secondary to Pyruvate Kinase Deficiency, Complicated by Heparin Resistance.

Lemierre syndrome was first documented in the literature in 1936, and is defined as septic thrombophlebitis of the internal jugular vein. It is typically a result of oropharyngeal infection causing local soft tissue inflammation, which spreads to vasculature, and promotes formation of septic thrombi within the lumen, persistent bacteremia, and septic emboli. We present the case of a 24-year-old incarcerated man, who presented with leukocytosis and a right-sided tender, swollen neck after undergoing left mandibular molar extraction for an infected tooth. Computed tomography revealed a persistent thrombus in the transverse and sigmoid sinuses bilaterally, extending downwards, into the upper jugular veins. He was started on empiric intravenous vancomycin, zosyn, and heparin, but subsequently demonstrated heparin resistance, and was thus anticoagulated with a lovenox bridge to warfarin. Throughout his hospital course, hemocultures demonstrated no growth, so antibiotic treatment was deescalated to oral metronidazole and ceftriaxone. On discharge, the patient was transitioned to oral amoxicillin and metronidazole for an additional 4 weeks with continuation of anticoagulation with warfarin for a total of 3 to 6 months. This case report details a unique presentation of Lemierre syndrome with bilateral transverse sinus, sigmoid sinus, and internal jugular vein thrombosis that was presumably secondary to an odontogenic infectious focus.

An Unusual Presentation of Spinal Giant Cell Glioblastoma in a 21-Year-Old Female.

Primary spinal cord giant cell glioblastoma multiforme of the thoracic spinal cord is a rarely-diagnosed primary spinal cord tumor in comparison to neoplasms in intracranial locations. In this article, we highlight a young adult who was diagnosed with intramedullary giant cell glioblastoma, IDH wild-type, World Health Organization grade IV/IV of the thoracic spinal cord. This case report describes the treatment approach with a postsurgical combination of radiation therapy and temozolomide, which resulted in the patient to return to her baseline of health only to later develop neurological symptoms significant for a recurrence of malignancy. In a review of the literature of described cases of primary spinal cord glioblastoma multiforme, prognosis continues to be unfavorable as current treatment options of the aggressive malignancy remain absent of a cure.

HIV portends a poor prognosis in myelodysplastic syndromes.

Even though HIV is associated with worse prognosis in many malignancies, the clinical course of myelodysplastic syndrome (MDS) in HIV + patients has not been well studied. Determining the clinical presentation and outcomes of MDS in these patients would be important for future diagnostic strategies, as anemia and other cytopenias are commonly seen in HIV + patients. Unique data mining software was used to identify cases of MDS or AML in adult patients who were also HIV + at Albert Einstein/Montefiore Medical Center between 1 January 2003 and 1 January 2017. Using Chi-Square and Fisher's exact test, characteristics of the HIV + MDS patients were compared to 135 HIV - MDS patients from the same institution diagnosed between 1997 and 2011. Fourteen biopsy proven MDS patients were identified with concomitant HIV. HIV + MDS patients presented at a younger age (59 vs. 71 yrs, p = .001) had higher risk disease, faster progression to acute leukemia, and worse overall survival (median survival 11.2 vs. 69.1 mo, p < .001) compared to HIV - MDS controls. Additionally, there was a higher prevalence of clonal-hematopoiesis related mutations (ASXL1, DNMT3A) and a higher proportion of patients with high risk cytogenetics. Analysis of the largest single center cohort of HIV + MDS patients demonstrated that these individuals present at a significantly younger age and with higher risk disease than their HIV - counterparts.

Comparative Effectiveness Research: The Impact of Biologic Agents in Ethnic Minorities With Metastatic Colorectal Cancer.

BACKGROUND: Biologic agents have improved the outcomes of patients with metastatic colorectal cancer (mCRC). However, the clinical trials included a predominately white population (85%), with Hispanic and black patients underrepresented. Thus, the real world benefit for the latter remains unknown. Comparative effectiveness research is a tool allowing for this exploration. PATIENTS AND METHODS: The demographic and clinical characteristics of patients treated for mCRC from 2000 to 2011 were extracted from the medical records of Montefiore Medical Center. A semiparametric accelerated failure time model was used to assess the survival differences between patients receiving chemotherapy (CT) alone versus CT plus biologic agents (CBT). RESULTS: Of the 290 patients (black, 45.9%; Hispanic, 26.2%; and white, 27.9%), 53.8% received biologic agents. The median overall survival was 15.2 months in the CT-alone group and 25.6 months in CBT group (P = .004). On univariate analysis, a lower number of metastatic sites, carcinoembryonic antigen < 41 ng/mL, and more lines of CT were associated with improved overall survival. In a propensity score-based analysis of the entire cohort, CBT offered a survival benefit compared with CT alone (increased median survival, 1.44-fold; 95% confidence interval [CI], 1.11-1.86; P = .038). The results of the subgroup analysis suggested a survival benefit for white patients (2.01; 95% CI, 1.26-3.23; P = .031) but not for Hispanic (1.42; 95% CI, 0.91-2.20; P = .370) or black (1.12; 95% CI, 0.76-1.66; P = .596) patients. CONCLUSION: In the present cohort, CBT was associated with longer survival, with the effect mainly driven by the outcomes for white patients, with black patients not appearing to benefit. These data are provocative and warrant further confirmation. Efforts to increase ethnic minority patients' enrollment in clinical trials is required to prospectively define the benefit from novel therapies.

Targeting chemokine pathways in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US and needs newer therapeutic and diagnostic strategies. Chronic inflammation plays a role in the pathogenesis of EAC and contributes to the dysplastic conversion of normal esophageal epithelium to Barrett's esophagus and frank adenocarcinoma. Chemokines play important roles in mediating inflammation and recent evidence implicates these ligands and their receptors in the development and spread of various tumors. We demonstrated that the chemokines IL8, CXCL1 and CXCL3 are significantly overexpressed during esophageal carcinogenesis and accompanied by amplification and demethylation of the chr4q21 gene locus. We also demonstrated that IL8 levels can be detected in serum of patients with EAC and can serve as potential biomarkers. We now demonstrate that inhibition of IL8 receptor, CXCR2, leads to decreased invasiveness of esophageal adenocarcinoma derived cells without affecting cellular proliferation. Taken together, these studies reveal the important roles that chemokines play in development of esophageal cancer and demonstrate that these pathways can serve as potential therapeutic targets.

Role of epigenetic alterations in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma.

Barrett's esophagus, a pre-malignant condition that can lead to esophageal adenocarcinoma, is characterized by histological changes in the normal squamous epithelium of the esophagus. Numerous molecular changes occur during the multistage conversion of Barrett's metaplasia to dysplasia and frank adenocarcinoma. Epigenetic changes, especially changes in DNA methylation are widespread during this process. Aberrant DNA methylation has been shown to occur at promoters of tumor suppressor genes, adhesion molecules and DNA repair genes during Barrett's esophagus. These epigenetic alterations can be used as molecular biomarkers for risk stratification and early detection of esophageal adenocarcinoma. We also show that genome wide analysis of methylation surprisingly reveals that global hypomethylation and not hypermethylation is the dominant change during Barrett's metaplasia. The transformation of Barrett's esophagus to frank adenocarcinoma is in turn characterized by much smaller wave of selective promoter hypermethylation. These studies reveal many novel, potential targets for new therapies and illustrate the utility of incorporating these epigenetic changes as biomarkers during endoscopic surveillance interval for patients with Barrett's esophagus.