Shaun Medlicott

Hypoxia-Inducible Factor Signaling Provides Protection in Clostridium difficile-Induced Intestinal Injury

BACKGROUND & AIMS Clostridium difficile is the leading cause of nosocomial infectious diarrhea. Antibiotic resistance and increased virulence of strains have increased the number of C difficile-related deaths worldwide. The innate host response mechanisms to C difficile are not resolved; we propose that hypoxia-inducible factor (HIF-1) has an innate, protective role in C difficile colitis. We studied the impact of C difficile toxins on the regulation of HIF-1 and evaluated the role of HIF-1alpha in C difficile-mediated injury/inflammation. METHODS We assessed HIF-1alpha mRNA and protein levels and DNA binding in human mucosal biopsy samples and Caco-2 cells following exposure to C difficile toxins. We used the mouse ileal loop model of C difficile toxin-induced intestinal injury. Mice with targeted deletion of HIF-1alpha in the intestinal epithelium were used to assess the effects of HIF-1alpha signaling in response to C difficile toxin. RESULTS Mucosal biopsy specimens and Caco-2 cells exposed to C difficile toxin had a significant increase in HIF-1alpha transcription and protein levels. Toxin-induced DNA binding was also observed in Caco-2 cells. Toxin-induced HIF-1alpha accumulation was attenuated by nitric oxide synthase inhibitors. In vivo deletion of intestinal epithelial HIF-1alpha resulted in more severe, toxin-induced intestinal injury and inflammation. In contrast, stabilization of HIF-1alpha with dimethyloxallyl glycine attenuated toxin-induced injury and inflammation. This was associated with induction of HIF-1-regulated protective factors (such as vascular endothelial growth factor-alpha, CD73, and intestinal trefoil factor) and down-regulation of proinflammatory molecules such as tumor necrosis factor and Cxcl1. CONCLUSIONS HIF-1alpha protects the intestinal mucosa from C difficile toxins. The innate protective actions of HIF-1alpha in response to C difficile toxins be developed as therapeutics for C difficile-associated disease.

Mitogen-activated protein kinase pathways contribute to hypercontractility and increased Ca2+ sensitization in murine experimental colitis.

Inflammatory bowel disease (IBD) is associated with intestinal smooth muscle dysfunction. Many smooth muscle contractile events are associated with alterations in Ca2+-sensitizing pathways. The aim of the present study was to assess the effect of colitis on Ca2+ sensitization and the signaling pathways responsible for contractile dysfunction in murine experimental colitis. Colitis was induced in BALB/c mice by providing 5% dextran sulfate sodium (DSS) in drinking water for 7 days. Contractile responses of colonic circular smooth muscle strips to 118 mM K+ and carbachol (CCh) were assessed. DSS induced a TH2 colitis [increased interleukin (IL)-4 and IL-6] with no changes in TH1 cytokines. Animals exposed to DSS had increased CCh-induced contraction (3.5-fold) and CCh-induced Ca2+-sensitization (2.2-fold) responses in intact and α-toxin permeabilized colonic smooth muscle, respectively. The contributions of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) to CCh-induced contractions were significantly increased during colitis. Ca2+-independent contraction induced by microcystin was potentiated (1.5-fold) in mice with colitis. ERK and p38MAPK (but not Rho-associated kinase) contributed to this potentiation. ERK1/2 and p38MAPK expression were increased in the muscularis propria of colonic tissue from both DSS-treated mice and patients with IBD (ulcerative colitis ≫ Crohns disease). Murine TH2 colitis resulted in colonic smooth muscle hypercontractility with increased Ca2+ sensitization. Both ERK and p38MAPK pathways contributed to this contractile dysfunction, and expression of these molecules was altered in patients with IBD.

Atypical fibroxanthoma with prominent sclerosis.

Background:  Malignant cutaneous spindle cell lesions with marked sclerosis are uncommon. Only a few cases of cutaneous leiomyosarcoma and dermatofibrosarcoma protuberans with sclerosis have been published.

Multimodal Immunosuppressant Therapy in Steroid-Refractory Common Variable Immunodeficiency Sprue: A Case Report Complicating Cytomegalovirus Infection

Immunodeficient patients can develop malabsorption, mimicking celiac disease clinically and histologically. Such individuals may also occasionally require immunosup pressive therapy for autoimmune disorders. We have identified a patient with common variable immunodeficiency (CVID)-associated sprue complicated by duodenal cytomegalovirus (CMV) infection following corticosteroid and ancillary immunomodulatory therapy. Ganciclovir and a modification of the immunosuppressant regimen improved both clinical symptoms and villous atrophy. To our knowledge, this is original documentation of duodenal CMV infection secondary to immunomodulatory therapy for steroid-refractory CVID-sprue.

Early post-transplant smooth muscle neoplasia of the colon presenting as diminutive polyps: a case complicating post-transplant lymphoproliferative disorder.

A 44-year-old woman, 3 years post-transplant for pulmonary sarcoidosis, developed abdominal pain and diarrhea 13 months subsequent to an eradicated diffuse large B-cell-type, post-transplant lymphoproliferative disorder (PTLD) of the cecal region. Endoscopic examination identified multiple pale tan 5-to-9 mm rubbery nodules of the transverse and right colon in an otherwise unremarkable mucosa. Histology was characterized by bland smooth muscle proliferations, focally pushing into the mucosa. Immunohistochemistry (IHC), in situ hybridization (ISH), and polymerase chain reaction (PCR) of the sampled nodules confirmed Epstein-Barr virus (EBV) infection of neoplastic cells. To our knowledge, this is the first reported case of EBV-related post-transplant lymphoproliferative and smooth muscle neoplasms (PTSN) having distinct tropism for the colon. Endoscopic features of early PTSN, which in this case presented as diminutive polypoid lesions, have not been described previously

Vascular wall degeneration in doxycycline-related esophagitis.

To the Editor: We read with great interest the recently published article by Xiao et al1 describing the unique pattern of gastric mucosal injury occurring in the context of doxycycline exposure. In this article the authors report 2 cases of gastric ulceration with similar histomorphology and conclude that the unique pattern of findings relate to doxycycline exposure. Their conclusions are supported by clinical-pathologic correlation, which revealed a clinical history of oral doxycycline use in both patients. Receipt and evaluation of both specimens over a 6-month interval appears to have helped the authors in appreciating the unique features and similarities found in these cases, further assisting in rendering the presumptive diagnosis of drug-induced injury due to doxycycline. We were pleased to read their observations as we have recently had a similar experience and have noticed peculiar morphologic traits of doxycycline-related esophageal ulceration. In somewhat similar circumstances we received 2 cases of esophageal ulceration within a 3month interval, and both patients had confirmed doxycycline exposure in the days preceding clinical presentation and endoscopy. We wish to share the unique histologic findings of these cases, which overlap with those described in Xiao and colleagues’ article. The histologic findings in our cases were so striking that when the second case was presented blindly to my colleague, he immediately queried if the etiology for damage was doxycycline. The first individual was a 27-year-old woman who developed severe retrosternal chest pain 6 days subsequent to swallowing a doxycycline tablet. The antibiotic was prescribed for a urinary tract infection. Endoscopy revealed severe ulceration and inflammation in the upper esophagus. There was no preexisting stricture. There were no signs of eosinophilic esophagitis. The second patient was a 26year-old man who developed severe odynophagia 3 days subsequent to doxycycline exposure. Doxycycline was prescribed for acne. Endoscopy revealed a proximal esophageal ulcer with heaped edges. The proximal location of esophageal ulcer was deemed clinically suspicious for druginduced insult. In both of our cases, formalinfixed biopsies were processed as per routine protocol, and 4-mm-thick hematoxylin and eosin sections were reviewed. Histologically, both biopsies documented mucosal ulceration exposing inflammatory stroma containing abundant neutrophils, reactive lymphocytes, occasional eosinophils, and rare plasma cells. Most striking was peculiar changes of small-sized to medium-sized arterioles of the submucosa. In both cases there were perivascular zones of edema and reactive fibroblasts forming pale “halos” of stroma, readily visible at low magnification (Figs. 1A, 2A). These edematous halos contained large lymphocytes resembling lymphoblasts such that changes were somewhat reminiscent of the viral cytopathic effect (ie, Epstein-Barr virus). The reactive lymphoid infiltrate produced vasculitic changes with overt endotheliitis (Figs. 1B, 2B). There were no viral cytopathic changes identified, and stains for yeast and fungi were negative in both cases. In our experience, these ulcerations were unique and quite distinct from those encountered in the context of reflux or other suspected pill esophagitis. Upon review of the available literature at the time of evaluation of

Synchronous appendiceal and intramucosal gastric signet ring cell carcinomas in an individual with CDH1-associated hereditary diffuse gastric carcinoma: a case report of a novel association and review of the literature

BackgroundHereditary diffuse gastric carcinoma is an autosomal dominant cancer syndrome associated with mutations of the E-cadherin gene (CDH1). E-cadherin is normally involved in cell-cell adhesion, so it not surprising that individuals with this syndrome are predisposed to develop malignancies with dyshesive morphologies at a young age, such as diffuse (signet ring cell) gastric carcinoma and lobular breast carcinoma. Herein we describe the first reported case of primary appendiceal signet ring cell carcinoma arising in a CDH1-associated hereditary diffuse gastric carcinoma kindred with synchronous primary diffuse gastric carcinoma.Case presentationA 51- year old woman, with known CDH1 mutation carrier status and a prior history of lobular breast carcinoma underwent prophylactic total gastrectomy which revealed multifocal intramucosal signet ring cell carcinoma. An appendectomy was performed at the same time due to a prior episode of presumed appendicitis, with pathologic examination significant for a primary signet ring cell carcinoma of the appendix.ConclusionAs appendiceal signet ring cell carcinoma is exceedingly rare, the occurrence of this neoplasm in this patient, with this particular morphology, provides credence for it being part of the hereditary diffuse gastric carcinoma spectrum of malignancies.

Enterocolic Lymphocytic Phlebitis: Statistical Analysis of Histology Features in Viable and Ischemic Bowel

Enterocolic lymphocytic phlebitis is a rare cause of segmental ischemic enterocolitis. This artery-sparing transmural vasculitis is classically a circumferential phlebitis with perivenular lymphocyte cuffing and thrombi in the absence of systemic manifestations. Myointimal hyperplasia may represent a chronic phase of enterocolic lymphocytic phlebitis. Subclinical or early stage enterocolic lymphocytic phlebitis is not well delineated. We analyzed 600 submucosal and subserosal veins from both ischemic and intact bowel segments to discern if vascular morphology varied between sites. Crescentic and circumferential lymphocytic phlebitis is more common in viable bowel than in the ischemic segment. A nonsignificant trend was found for increased crescentic morphology between intact bowel remote from the ischemic focus compared with that adjacent to the ischemic focus. Hallmarks of ischemic bowel are necrotizing phlebitis and thrombi formation. Thrombophlebitis morphology is distinctly different in viable and ischemic bowel, changing from the classic lymphocytic to necrotizing lesions respectively.

Mixed Epithelial-Stromal Tumor (MEST) of Seminal Vesicle: A Proposal for Unified Nomenclature

In contrast to the common tumors of the prostate, seminal vesicle demonstrates low potential for neoplastic proliferation. Of the rare primary seminal vesicle tumors, adenocarcinoma is the most common, but there are also rare seminal vesicle neoplasms which demonstrate epithelial and stromal components. These neoplasms have been described in the literature under various names, including “epithelial-stromal tumor,” “cystic epithelial-stromal tumor,” “cystadenoma,” “cystomyoma,” “mesenchymoma,” “Müllerian adenosarcoma-like tumor,” “phyllodes tumor,” and “cystosarcoma phyllodes.” The spectrum of reported mixed epithelial-stromal tumors (MEST) of seminal vesicle encompasses low, intermediate and high-grade tumors, but the precise distinction and nomenclature for these tumors remain unsettled. We propose a common nomenclature for these tumors, based on the review of published cases and 2 index cases from our practice, which represent the low-grade category. The first patient was 46 years old and presented with seminal vesicle neoplasm detected on routine rectal examination. The neoplasm measured 4 cm in greatest dimension, and completely replaced the left seminal vesicle. The tumor was circumscribed and consisted of multiple cysts separated by spindle-cell stroma. The second patient was a 60-year-old man, who had an incidental seminal vesicle neoplasm, which was discovered when he underwent a radical prostatectomy for a prostatic adenocarcinoma, (Gleason score 3+4, stage 3a). Both neoplasms contained hypercellular stroma, which was composed of uniform spindle cells, arranged in fascicles and interspersed between the glands. Both tumors lacked worrisome morphology, such as infiltrative borders, cell atypia, increased mitotic activity, hemorrhage, and necrosis. The stromal cells were reactive for estrogen and progesterone receptors, and desmin. The cysts and dilated glands were lined by epithelial cells, which were positive for cytokeratin 7 and were negative for prostate-specific antigen and prostate-specific acid phosphatase. The first patient underwent prostatectomy and was alive and without evidence of disease recurrence or progression after 11 years of follow-up. Similarly, the second patient had no evidence of disease recurrence or progression after 8 months of follow-up. We propose that term seminal vesicle “mixed epithelial-stromal tumor” be used to designate the tumors of the seminal vesicle containing epithelial and stromal components, with a distinction of grade based on the histologic features and the biological behavior. Histologic features to be evaluated for grade separation include stromal atypia, mitotic activity, nuclear pleomorphism, and tumor necrosis. Designations “low-grade MEST,” “intermediate-grade MEST (uncertain malignant potential),” and “high-grade MEST” of seminal vesicle can be applied to these tumors to better characterize and study them in the future.

Intramuscular myxoid lipoma in the proximal forearm presenting as an olecranon mass with superficial radial nerve palsy: a case report

BackgroundExtremity lipomas may occur in any location, including the proximal forearm. We describe a case of a patient with an intramuscular lipoma presenting as an unusual posterior elbow mass.Case presentationWe discuss the case of a 57-year-old Caucasian man who presented with a tender, posterior elbow mass initially diagnosed as chronic olecranon bursitis. A minor sensory disturbance in the distribution of the superficial radial nerve was initially thought to be unrelated, but was likely caused by mass effect from the lipoma. No pre-operative advanced imaging was obtained because the diagnosis was felt to have already been made. At the time of surgery, a fatty mass originating in the volar forearm muscles was found to have breached the dorsal forearm fascia and displaced the olecranon bursa. Tissue diagnosis was made by histopathology as a myxoid lipoma with no aggressive features. Post-operative recovery was uneventful.ConclusionWe present a case of an unusual elbow mass presenting with symptoms consistent with chronic olecranon bursitis, a relatively common condition. The only unexplained pre-operative finding was the non-specific finding of a transient superficial radial nerve deficit. We remind clinicians to be cautious when diagnosing soft tissue masses in the extremities when unexplained physical findings are present.