Raavi Gupta

A Pilot Study of Omalizumab in Eosinophilic Esophagitis

Eosinophilic disorders of the gastrointestinal tract are an emerging subset of immune pathologies within the spectrum of allergic inflammation. Eosinophilic Esophagitis (EoE), once considered a rare disease, is increasing in incidence, with a rate of over 1 in 10,000 in the US, for unknown reasons. The clinical management of EoE is challenging, thus there is an urgent need for understanding the etiology and pathophysiology of this eosinophilic disease to develop better therapeutic approaches. In this open label, single arm, unblinded study, we evaluated the effects of an anti-IgE treatment, omalizumab, on local inflammation in the esophagus and clinical correlates in patients with EoE. Omalizumab was administered for 12 weeks to 15 subjects with long standing EoE. There were no serious side effects from the treatment. Esophageal tissue inflammation was assessed both before and after therapy. After 3 months on omalizumab, although tissue Immunoglobulin E (IgE) levels were significantly reduced in all but two of the subjects, we found that full remission of EoE, which is defined as histologic and clinical improvement only in 33% of the patients. The decrease in tryptase-positive cells and eosinophils correlated significantly with the clinical outcome as measured by improvement in endoscopy and symptom scores, respectively. Omalizumab-induced remission of EoE was limited to subjects with low peripheral blood absolute eosinophil counts. These findings demonstrate that in a subset of EoE patients, IgE plays a role in the pathophysiology of the disease and that anti-IgE therapy with omalizumab may result in disease remission. Since this study is open label there is the potential for bias, hence the need for a larger double blind placebo controlled study. The data presented in this pilot study provides a foundation for proper patient selection to maximize clinical efficacy. Trial Registration ClinicalTrials.gov NCT01040598

Quantification of hepatic iron deposition in patients with liver disease: comparison of chemical shift imaging with single-echo T2*-weighted imaging.

OBJECTIVE The purpose of this study was to determine the diagnostic performance of chemical shift imaging, compared with that of single-echo T2*-weighted imaging, for hepatic iron quantification in patients with liver disease, and to examine the confounding effect of steatosis. MATERIALS AND METHODS Sixty-three patients who underwent liver MRI and who had concomitant liver histopathologic analysis were retrospectively assessed. Chemical shift imaging and T2*-weighted imaging (n = 49) of the liver were reviewed by two independent observers. An iron index for each sequence (I(Fe-CSI) and I(Fe-T2*), respectively) was correlated with pathologic iron grade (0-4). Receiver operating characteristic curve analysis was performed to assess the accuracy of both sequences for the diagnosis of iron deposition (grades >or= 1, >or= 2, and >or= 3), and the impact of steatosis on accuracy was evaluated. RESULTS Forty-seven (74.6%) patients had hepatic siderosis. There was a significant correlation between both I(Fe-CSI) and I(Fe-T2*) with pathologic iron grade (r = 0.65 and -0.61, respectively; p < 0.0001 for both). I(Fe-CSI) and I(Fe-T2*) were significantly higher or lower in iron grades 2-4 versus grades 0-1 and in grades 3-4 versus grades 0-2 (p < 0.001). Area under the curve values for detecting iron grade >or= 1, >or= 2, and >or= 3 were 0.75, 0.88, and 0.90 for I(Fe-CSI) and 0.72, 0.81, and 0.98 for I(Fe-T2*). Accuracy was lower for both sequences in steatotic patients for detection of iron grades >or= 1 and >or= 2, without reaching significance. CONCLUSION Routine chemical shift imaging and single-echo T2*-weighted imaging have excellent diagnostic performance for detection of significant hepatic siderosis (grade >or= 2). Concomitant steatosis lowers the diagnostic performance of both sequences without reaching significance.

The numbers of FoxP3+ lymphocytes in sentinel lymph nodes of breast cancer patients correlate with primary tumor size but not nodal status.

Regulatory T cells, lymphocytes marked by expression of the transcription factor Forkhead Box Protein P3 (FoxP3), inhibit the activation of tumor-specific T cells in tumor-draining lymph nodes. Immunohistochemical analyses of sentinel lymph nodes (SLNs) from 104 breast cancer patients showed a significant association (p = .0028, Pearson correlation) between the number of FoxP3+ cells and the size of primary breast invasive ductal carcinoma. In contrast, there was no correlation between the number of FoxP3+ cells and the presence of SLN metastases, or other clinicopathological parameters. These results suggest the presence of an immune suppressive environment in SLNs of larger tumors.

Bladder adenocarcinoma following gastrocystoplasty.

Bladder augmentation with segments of small bowel (ileocystoplasty), large intestine (colocystoplasty) or stomach (gastrocystoplasty) has been used to treat patients with small or noncompliant bladders by increasing the capacity or compliance. Carcinomas following gastrocystoplasty have been observed in the segments of stomach; however, to our knowledge, carcinoma arising in the residual native bladder has not been reported. We report the first case of adenocarcinoma arising in the residual native bladder in association with intestinal metaplasia and dysplasia of bladder mucosa 17 years following gastrocystoplasty. Intestinal metaplasia secondary to recurrent urinary infection, chronic inflammation, and some form of irritation may potentiate the development of native bladder adenocarcinoma. Patients with gastrocystoplasty are at an increased risk for carcinoma in stomach segments and require close long-term follow up; however, the risk of carcinoma in native bladder is still unclear.

Colon Necrosis Due to Sodium Polystyrene Sulfonate with and without Sorbitol: An Experimental Study in Rats.

Introduction Based on a single rat study by Lillemoe et al, the consensus has been formed to implicate sorbitol rather than sodium polystyrene sulfonate (SPS) as the culprit for colon necrosis in humans treated with SPS and sorbitol. We tested the hypothesis that colon necrosis by sorbitol in the experiment was due to the high osmolality and volume of sorbitol rather than its chemical nature. Methods 26 rats underwent 5/6 nephrectomy. They were divided into 6 groups and given enema solutions under anesthesia (normal saline, 33% sorbitol, 33% mannitol, SPS in 33% sorbitol, SPS in normal saline, and SPS in distilled water). They were sacrificed after 48 hours of enema administration or earlier if they were very sick. The gross appearance of the colon was visually inspected, and then sliced colon tissues were examined under light microscopy. Results 1 rat from the sorbitol and 1 from the mannitol group had foci of ischemic colonic changes. The rats receiving SPS enema, in sorbitol, normal saline, distilled water, had crystal deposition with colonic necrosis and mucosal erosion. All the rats not given SPS survived until sacrificed at 48 h whereas 11 of 13 rats that received SPS in sorbitol, normal saline or distilled water died or were clearly dying and sacrificed sooner. There was no difference between sorbitol and mannitol when given without SPS. Conclusions In a surgical uremic rat model, SPS enema given alone or with sorbitol or mannitol seemed to cause colon necrosis and high mortality rate, whereas 33% sorbitol without SPS did not.

Cryoglobulinemia in a patient with chronic lymphocytic leukemia - A case report and review of literature of renal involvement in CLL.

The incidence of glomerulonephritis, as a manifestation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), has always been considered low. Though renal infiltration is usually detected at post-mortem, it does not often interfere with kidney function [1]. Though immunoglobulin (Ig) levels in most CLL patients are subnormal, small monoclonal Ig peaks are occasionally detected in serum. They were present in a number of reported CLL nephropathy patients, and not all were cryoglobulins; serum and glomerular staining were concordant for Ig type [2,3,4]. Myeloma, which secretes monoclonal light chains, causes nephropathy in 25% of patients. But the little presumably secreted by small plasma cell clones, without myeloma, may also be nephrotoxic. The same is true of the low secretory CLL cells, which may occasionally be associated with cryoglobulins and other nephrotoxic Igs [5]. We report a patient with early stage CLL (Rai stage 0) with cryoglobulins, which led to membranoproliferative glomerulonephritis (MPGN), and death. We located reports of 51 patients with CLL-associated nephrotic syndrome or nephropathy, mostly from MPGN related to local Ig deposits. In those patients screened for cryoglobulins, about half tested positive. Many were early stage cases, where MPGN developed long after CLL presentation, and responded to its treatment. As early diagnosis and treatment CLL-related nephropathy may be curative, we propose a prospective study to determine the incidence of hyperalbuminuria development after presentation.

Increased expression of enhancer of Zeste Homolog 2 (EZH2) differentiates squamous cell carcinoma from normal skin and actinic keratosis

BackgroundEnhancer of Zeste Homolog 2 (EZH2) is a polycomb group protein that has been shown to be involved in the progression of multiple human cancers including melanoma. The expression of EZH2 in normal skin and in pre-malignant and malignant cutaneous squamous cell carcinoma (SCC) has not been studied.ObjectivesWe examined the expression of EZH2 in normal skin, actinic keratosis (AK), SCC in situ, well-differentiated (SCC-WD), moderately-differentiated (SCC-MD) and poorly-differentiated SCC (SCC-PD) to ascertain whether EZH2 expression differentiates these conditions.Materials and MethodsImmunohistochemical staining for EZH2 was performed on formalin-fixed paraffin-embedded biopsies and a tissue microarray containing normal skin, AK, SCC in situ, and SCC of different grades.ResultsIn comparison to the normal skin, EZH2 expression in actinic keratosiswas increased (p = 0.03). Similarly, EZH2 expression in all of the neoplastic conditions studied (SCC in situ, SCC-WD, SCC-MD and SCC-PD) was greatly increased in comparison to both the normal skin and actinic keratosis (p≤0.001).ConclusionEZH2 expression increases incrementally from normal skin to AK and further to SCC, suggesting a role for EZH2 in the progression and differentiation of SCC. EZH2 expression may be used as a diagnostic marker for differentiating SCC from AK or normal skin.

Characterization of Trypanosoma cruzi infectivity, proliferation, and cytokine patterns in gut and pancreatic epithelial cells maintained in vitro

Trypanosoma cruzi infects all nucleated cells in both humans and experimental animals. As a prelude to our studies of T. cruzi pathogenesis in the gastrointestinal system, we have initiated in vitro cultures of gut (Caco-2 and HT-29) and pancreatic (Panc-1) epithelial cells. We show that along with primary human fibroblasts, all three cell lines are susceptible to infection and support proliferation of T. cruzi. Infection with T. cruzi modified dramatically the cytokines elaborated by these cells. Substantially greater quantities of IL-5 and TGF-β1 were produced by fibroblasts and Caco-2 and Panc-1 cells, whereas secretion of IFN-γ and TNF-α was greatly reduced in all three cell types. Since these cells are not known to be the primary sources of IFN-γ, we examined IFN-γ mRNA expression in these cells. Both Caco-2 and Panc-1 cells were found to express IFN-γ mRNA, validating its secretion. These findings may provide insight into signaling pathways that mediate innate immunity to T. cruzi and pathogenesis of gastrointestinal and pancreatic alterations in Chagas disease.

Determinants of reactivation of inapparent Strongyloides stercoralis infection in patients hospitalized for unrelated admitting diagnosis.

Background Clinical presentation of strongyloidiasis in humans is highly variable, ranging from clinically inapparent infection to life-threatening multisystem disease. The course of infection is dependent on the immune status of the patient. Our objective was to ascertain the clinical characteristics of patients who developed reactivated strongyloidiasis from a primary infection acquired in the past, and to evaluate risk factors that contributed to its exacerbation. Methods We identified 31 patients diagnosed with strongyloidiasis by stool examination at our institution from January 2007 to June 2012. We reviewed their clinical records and selected eight patients whose admitting diagnosis was not suggestive of strongyloidiasis-associated gastrointestinal disease. However, they developed symptoms consistent with strongyloidiasis during their hospitalization, and stool examinations revealed diagnostic larvae. Results and conclusion We have identified immunosuppressive therapy, viral infection-associated immunodeficiency, alcoholism, and diabetes mellitus as risk factors for reactivation of chronic inapparent strongyloidiasis. Analysis of hemogram data suggests the low sensitivity of hypereosinophilia to be a marker for this helminthiasis.

Pediatric Helicobacter pylori gastropathy demonstrates a unique pattern of gastric foveolar hyperplasia

Helicobacter pylori (Hp) are the most common agents causing gastric mucosal injury worldwide. Foveolar hyperplasia is a key component of the stomachs reaction to injury. This study examines histopathologic characteristics associated with Helicobacter pylori and with non‐ Helicobacter pylori‐associated gastropathy in children and adolescents, and compares the prevalence of foveolar hyperplasia among these disease subgroups and normal control subjects.