Maria T. Perez

Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis

Background: Chronic intestinal inflammation culminates in cancer and a link to Toll‐like receptor‐4 (TLR4) has been suggested by our observation that TLR4 deficiency prevents colitis‐associated neoplasia. In the current study we address the effect of the aberrant activation of epithelial TLR4 on induction of colitis and colitis‐associated tumor development. We take a translational approach to address the consequences of increased TLR signaling in the intestinal mucosa. Methods: Mice transgenic for a constitutively active TLR4 under the intestine‐specific villin promoter (villin‐TLR4 mice) were treated with dextran sodium sulfate (DSS) for acute colitis and azoxymethane (AOM)‐DSS TLR4 expression was analyzed by immunohistochemistry in colonic tissue from patients with ulcerative colitis (UC) and UC‐associated cancer. The effect of an antagonist TLR4 antibody (Ab) was tested in prevention of colitis‐associated neoplasia in the AOM‐DSS model. Results: Villin‐TLR4 mice were highly susceptible to both acute colitis and colitis‐associated neoplasia. Villin‐TLR4 mice had increased epithelial expression of COX‐2 and mucosal PGE2 production at baseline. Increased severity of colitis in villin‐TLR4 mice was characterized by enhanced expression of inflammatory mediators and increased neutrophilic infiltration. In human UC samples, TLR4 expression was upregulated in almost all colitis‐associated cancer and progressively increased with grade of dysplasia. As a proof of principle, a TLR4/MD‐2 antagonist antibody inhibited colitis‐associated neoplasia in the mouse model. Conclusions: Our results show that regulation of TLRs can affect the outcome of both acute colitis and its consequences, cancer. Targeting TLR4 and other TLRs may ultimately play a role in prevention or treatment of colitis‐associated cancer. (Inflamm Bowel Dis 2010;)

Temporal relationships between acute cellular rejection features and increased mucosal fibrosis in the early posttransplant period of human small intestinal allografts.

BACKGROUND Intestinal allograft biopsies limit histopathological analysis to the superficial layers of the bowel. These biopsies allow a reasonable assessment of the histological features of acute rejection, but characteristics of chronic injury in mucosal layers remain poorly defined because of the limitations posed by endoscopic sampling. Experimental work has inferred that intestinal mucosal fibrosis may be indicative of chronic rejection; however, a temporal, graded study of mucosal fibrosis has not been performed. METHODS A total of 79 endoscopic intestinal allograft biopsies from 12 patients obtained at 3 to 120 days posttransplantation were evaluated. Fibrosis and individual parameters of acute cellular rejection were graded according to a semiquantitative scoring system and were evaluated for potential relationships with each other. RESULTS We found that while acute rejection tends to occur early in the posttransplant period, fibrosis of the lamina propria increases at a later time, particularly in the third and fourth month. Several individual graded parameters of acute rejection had an association with fibrosis at the same time points. CONCLUSIONS Fibrous replacement of the lamina propria in human endoscopic allograft biopsies occurs with advancing time after transplantation. Acute rejection precedes and may have some eventual impact upon the amount of fibrosis present. A measurement of the connective tissue component of bowel transplant tissue may serve as a harbinger of long-term enteral allograft dysfunction.

Extranodal lymphoplasmacytoid lymphoma (immunocytoma) presenting as small intestinal obstruction

A 57-year-old woman presented with intermittent symptoms of intestinal obstruction. Workup provided nondiagnostic radiologic studies. An exploratory laparotomy revealed a segmental dilatation in the proximal ileum, which showed diffuse thickening of the intestinal wall. Microscopic examination of the affected area disclosed a diffuse transmural infiltrate composed of small lymphocytes, mature plasma cells, and lymphoplasmacytoid cells in different stages of maturation associated with extracellular periodic acid-Schiff-positive material. In addition, serum protein electrophoresis showed a monoclonal immunoglobulin M kappa paraprotein. Postoperative workup did not demonstrate evidence of systemic involvement. The morphologic features and immunohistochemical and molecular analyses were consistent with lymphoplasmacytoid lymphoma (immunocytoma). We report an unusual case of primary extranodal immunocytoma involving the small intestine and discuss its clinicopathologic features.

Pleural body cavity-based lymphoma

We report a case of recurrent body cavity-based non-Hodgkins lymphoma in a patient with advanced acquired immunodeficiency syndrome who presented with bilateral pleural effusions, without evidence of an associated tumor mass. The lymphoma cells were large and pleomorphic, lacking pan-T- and pan-B-cell markers, but expressing activation markers (CD30, CD38, and HLA-DR). The purpose of this article is to discuss the radiological-pathological correlation of body cavity-based lymphoma with a review of the entities that should be included in the differential diagnosis of patients with malignant pleural effusions.

In silico and Ex vivo approaches identify a role for toll-like receptor 4 in colorectal cancer

BackgroundInflammation increases the risk of colorectal cancer (CRC). We and others have described a role for TLR4, the receptor for LPS, in colon cancer. To explore the relationships between TLR4 expression and CRC, we combined the strength of transcriptome array data and immunohistochemical (IHC) staining.MethodsTLR4 signal intensity was scored in the stromal and epithelial compartments. Detection of differential expression between conditions of interest was performed using linear models, Cox proportional hazards models, and empirical Bayes methods.ResultsA strong association between TLR4 expression and survival was noted, though a dichotomous relationship between survival and specific TLR4 transcripts was observed. Increasing TLR4 expression was seen with advancing tumor stage and was also over-expressed in some adenomas. IHC staining confirmed the positive relationship between TLR4 staining score in the CRC tumor stroma and epithelium with tumor stage, with up to 47% of colon cancer stroma positive for TLR4 staining. Increased TLR4 expression by IHC was also marginally associated with decreased survival. We now also describe that pericryptal myofibroblasts are responsible for a portion of the TLR4 stromal staining.ConclusionsIncreased TLR4 expression occurs early in colonic neoplasia. TLR4 is associated with the important cancer-related outcomes of survival and stage.

Resistant Herpes Simplex Virus Infection and HIV: A Potential Diagnostic and Therapeutic Dilemma

Herpes simplex virus (HSV) is the most frequent cause of genital ulcer disease worldwide. It is also 1 of the leading infections among HIV-infected individuals. Though HSV-2 is the principal etiologic agent of genital HSV infections (GH), HSV-1 has increasingly become a more common cause of GH, particularly in those with concurrent HIV. The clinical presentation of HSV in HIV-infected patients is often atypical. Individuals with depressed CD4 T-cell lymphocyte counts frequently present with more severe and protracted GH. Extensive, ulcerated, and necrotic lesions may make for a confusing initial clinical diagnosis. Furthermore, treatment with routine anti-herpetic viral agents may result in failure to resolve infection. Motivated by our recent experience involving an AIDS patient with a difficult-to-diagnose genital HSV infection that proved unresponsive to standard treatment, we review the topic of HSV anti-viral medication resistance with particular attention to its association in the HIV/HSV co-infected patient.

Intraductal carcinoma (Carcinoma in situ) of the pancreas with microinvasion

We report a case of predominantly intraductal carcinoma of the pancreas with microscopic foci of invasive carcinoma in a patient with chronic pancreatitis. In this article, we discuss the pathologic and prognostic features of pancreatic carcinoma in situ. This entity is probably overlooked due to a number of reasons, including the fact that, in most cases, pancreatic ductal carcinomas are extensively infiltrative at the time of surgical removal; the atypical epithelial changes in the intraductal carcinoma had been overlooked in the presence or absence of an invasive component; epithelial changes may be missed due to insufficient sampling; and last, the differentiation with atypical epithelial hyperplasia is a subjective matter. Intraductal carcinoma of the pancreas is a distinct pathological entity with characteristic morphologic changes restricted to the ductal epithelium, bearing important prognostic implications.

Testing for Tuberculosis: The Roles of Tuberculin Skin Tests and Interferon Gamma Release Assays

The identification of latent tuberculosis infection (LTBI) in any individual or population has proven to carry significant importance not only for that person’s health, but also for the control and eventual elimination of tuberculosis (TB) in the United States. Traditionally, the tuberculin skin test (TST) has served as the standard of care for the identification of prior exposure to Mycobacterium tuberculosis (MTB). However, the specificity of a positive test is less than optimal. It is either due to previous vaccination intended to prevent TB or infection with nontuberculous mycobacterium (NTM). Newer tests classified as interferon-gamma release assays (IGRA) possess potential advantages over the TST when used for identifying those with MTB infection. We recently diagnosed a case of pleuropulmonary infection involving an unusual NTM, Mycobacterium interjectum (M. interjectum) , in an immunocompromised man diagnosed 1 year after he had been treated for LTBI based on a reactive TST. A propos this experience, we discuss the beneficial role of IGRAs and review the literature on infection with M. interjectum . * LTBI : latent tuberculosis infection TST : tuberculin skin test MTB : Mycobacterium tuberculosis NTM : nontuberculous mycobacterium IGRA : interferon gamma release assays PPD : purified protein derivative BCG : Bacillus Calmette-Guerin FDA : Food and Drug Administration IFN-γ : interferon-gamma IGRAs : interferon-gamma release assays INH : isoniazid TNF-α : tumor necrosis factor alpha CXR : chest radiograph CT : computerized tomographic AFB : acid-fast bacilli TB : tuberculosis RA : rheumatoid arthritis MTX : methotrexate DMARDs : disease-modifying antirheumatic drugs CDC : Centers for Disease Control and Prevention DTH : delayed-type hypersensitivity QFT : QuantiFERON-TB QFT-G : QuantiFERON-TB Gold QFT-GIT : QuantiFERON-TB Gold In-Tube ELISA : enzyme-linked immunosorbent assay ESAT-6 : early secretory antigenic target-6 CFP-10 : culture filtrate protein-10 ELISpot : enzyme-linked immunospot assay PBMCs : peripheral blood mononuclear cells MOTT : mycobacteria other than tuberculosis

Primary gastroesophageal-ileal hodgkin lymphoma.

Primary Hodgkin lymphoma of the gastrointestinal tract is exceedingly rare to the point that some authors regard with skepticism the existence of this entity. Cases of gastrointestinal Hodgkin lymphoma have been reported previously; however, most of these cases represented secondary involvement of the digestive tract in the context of systemic disease. Other cases have been reclassified in retrospective studies as non-Hodgkin lymphomas after the application of immunohistochemical techniques. We report a case of primary Hodgkin lymphoma of the gastrointestinal tract in a patient who presented with obstructive symptoms at the site of a gastroileal bypass; the bypass had been performed years earlier because of morbid obesity. Some non-Hodgkin lymphomas may morphologically mimic Hodgkin lymphoma and vice versa; therefore, an accurate pathologic diagnosis is important, since the therapeutic approach and prognostic implications differ significantly for these diseases. In this context, immunohistochemistry should be used to confirm or to exclude the histologic diagnosis of Hodgkin lymphoma.

Probiotic-Associated Bifidobacterium Septic Prosthetic Joint Arthritis

AbstractProbiotics are claimed to provide some preventative and/or therapeutic health benefits. However, many of these assertions are based on scarce or no objective data. Generally believed to be safe, few adverse events have been associated with their use. We report the first case of septic prosthetic joint arthritis due to Bifidobacterium species presumed secondary to probiotic consumption.