Mucosal Spread Research Articles

Magnification linked color imaging characterization of the irregular vessel network of diffuse mucosal rectal metastatic spread from high-grade serous ovarian cancer

A 62-year-old female patient presented with lower abdominal pain in combination with a 2-kg weight loss and stool retention. Medical history was significant for ovarian cancer that was treated by curative-intent surgery and adjuvant chemotherapy two years before. Imaging studies were consistent with peritoneal carcinomatosis and suggested incipient large bowel obstruction, for which the patient underwent lower GI endoscopy. While a high-grade stricture at the rectosigmoidal junction due to external compression precluded scope advancement, apart from mild unspecific erythema multiple nodular aphthoid-like lesions were identified throughout the rectum (Fig.

Mucosal intralymphatic spread in a relapsed diffuse large B cell lymphoma

Intralymphatic spread is a rare finding and is associated with poor prognosis in diffuse large B cell lymphoma (DLBCL). Here, we report a case of relapsed DLBCL with mucosal intralymphatic spread. A 69-year-old man had been diagnosed with gastric DLBCL stage IIE at 57 years. He had a relapse with generalized lymphadenopathy and extranodal involvement at 61 years; then, second complete remission was achieved after salvage chemotherapy. He then had a second relapse with involvement of the terminal ileum, spinal cord, and left tonsil. The terminal ileum showed intralymphatic spread in the lamina propria of the intestinal villi, which was confirmed by D2–40 immunostaining. Eleven months later, another biopsy showed prominent intralymphatic spread in the mucosa of the terminal ileum. After salvage therapies, the spinal cord and tonsillar tumors resolved, but the intestinal tumors were refractory. The patient eventually died of progressive disease. In contrast to previously reported cases, the involved lymphatic vessels were observed in the mucosa, and the lymphoma cells expressed CD5 in the first colonoscopic biopsy. This rare case broadens the spectrum of intralymphatic spread in DLBCL.

Where in the World Did You Get That Rash?

1. Panteha Eshtiaghi, HBSc* 2. Miriam Weinstein, MD, FRCPC† 1. *Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada 2. †Hospital for Sick Children, Toronto, Ontario, Canada * Abbreviations: ACD: : allergic contact dermatitis CD: : cercarial dermatitis CL: : cutaneous leishmaniasis CLM: : cutaneous larva migrans DF: : dengue fever HFMD: : hand, foot, and mouth disease HSV: : herpes simplex virus KD: : Kawasaki disease PCR: : polymerase chain reaction PR: : pityriasis rosea RT-PCR: : reverse transcriptase polymerase chain reaction The challenge to diagnose cutaneous eruptions and lesions in patients who have spent time in foreign countries is increasingly common. With the advent of increased global travel, foreign adoptions, immigration, and refugee seekers, rashes that were once relegated to the realm of the exotic and likely to show up in a tropical diseases clinic may now present to a general pediatrician. Furthermore, the pediatric traveler is at increased risk for dermatoses. (1) It behooves the practitioner to be aware of these skin findings, to be able to recognize them and distinguish them from other skin conditions. After completing this article, readers should be able to: 1. Identify and classify rashes by main morphologic patterns. 2. Develop a broad differential diagnosis and diagnostic approach for a rash in a returned pediatric traveler based on initial morphology, history, epidemiology, and other clinical features. 3. Consider both infectious and noninfectious causes of skin disorders presenting in a patient with a travel history. 4. Outline the basic investigations and principles of management for travel-acquired and non–travel-acquired dermatologic illnesses. 5. Discuss …

Probing Clostridium difficile Infection in Complex Human Gut Cellular Models.

Interactions of anaerobic gut bacteria, such as Clostridium difficile, with the intestinal mucosa have been poorly studied due to challenges in culturing anaerobes with the oxygen-requiring gut epithelium. Although gut colonization by C. difficile is a key determinant of disease outcome, precise mechanisms of mucosal attachment and spread remain unclear. Here, using human gut epithelial monolayers co-cultured within dual environment chambers, we demonstrate that C. difficile adhesion to gut epithelial cells is accompanied by a gradual increase in bacterial numbers. Prolonged infection causes redistribution of actin and loss of epithelial integrity, accompanied by production of C. difficile spores, toxins, and bacterial filaments. This system was used to examine C. difficile interactions with the commensal Bacteroides dorei, and interestingly, C. difficile growth is significantly reduced in the presence of B. dorei. Subsequently, we have developed novel models containing a myofibroblast layer, in addition to the epithelium, grown on polycarbonate or three-dimensional (3D) electrospun scaffolds. In these more complex models, C. difficile adheres more efficiently to epithelial cells, as compared to the single epithelial monolayers, leading to a quicker destruction of the epithelium. Our study describes new controlled environment human gut models that enable host–anaerobe and pathogen–commensal interaction studies in vitro.

Natural History of Treated and Untreated Hypopharyngeal Cancer.

Patients with hypopharyngeal cancers frequently present at advanced stage and in poor general health status. Their natural history is characterised by diffuse local primary disease, mucosal and submucosal spread, early cervical nodal metastasis, and a relatively high rate of distant spread. By the time of initial diagnosis, some 60% of all hypopharyngeal cancer patients will be with stage IV disease, some 5% will present with distant metastases, and almost 40% will have a significant reduction in performance status. Less than 20% are diagnosed with a localised early stage disease. A long-standing social habit of excess of alcohol and tobacco usage leads to cancerisation and accounts for the multiple, synchronous primary malignant lesions that occur in many hypopharyngeal cancer patients. The natural history of untreated head and neck squamous cell carcinoma has infrequently been documented in the medical literature. However, without understanding the natural history of hypopharyngeal cancer, patient counselling and clinical management are difficult. Less than 20% of untreated patients survive for > 12 months and only a small proportion of patients will survive for more than 2 years after initial diagnosis. The natural course of the disease in patients treated for cure or, at least, for the relief of symptoms, is certainly more favourable than that of those who are not suited for, or not willing to accept the adverse effects of treatment. However, treatment results are still considerably less encouraging than those that are being reported for other sub-sites of the head and neck region. Among all head and neck cancer sites, 5-year age-standardised relative survival is currently the poorest for cancer of the hypopharynx and the highest for larynx cancers, 25 and 59%, respectively. Among the head and neck cancers, only hypopharynx showed a low outcome (25% at 5 years), with survival figures ranging between ≤30 (North Ireland and Italy) and 8% (Bulgaria). Recent studies from the United States indicate that overall 5-year survival rates for hypopharyngeal cancer have improved significantly in recent years, with the average survival being ≥40%.

Harnessing Novel Imaging Approaches to Guide HIV Prevention and Cure Discoveries-A National Institutes of Health and Global HIV Vaccine Enterprise 2017 Meeting Report.

Advances in imaging technologies have greatly increased our understanding of cellular and molecular interactions in humans and their corresponding animal models of infectious diseases. In the HIV/SIV field, imaging has provided key insights into mucosal viral transmission, local and systemic virus spread, host-virus dynamics, and chronic inflammation/immune activation and the resultant immunopathology. Recent developments in imaging applications are yielding physical, spatial, and temporal measurements to enhance insight into biological functions and disease processes, while retaining important cellular, microenvironmental, organ, and intact organism contextual details. Taking advantage of the latest advancements in imaging technologies may help answer important questions in the HIV field. The Global HIV Vaccine Enterprise in collaboration with the National Institutes of Health (NIH) sponsored a meeting on May 8 and 9, 2017 to provide a platform to review state-of-the-art imaging technologies and to foster multidisciplinary collaborations in HIV/AIDS research. The meeting covered applications of imaging in studies of early events and pathogenesis, reservoirs, and cure, as well as in vaccine development. In addition, presentations and discussions of imaging applications from non-HIV biomedical research areas were included. This report summarizes the presentations and discussions at the meeting.

Methotrexate and actinomycin D chemotherapy in a patient with porphyria: a case report

BackgroundDespite their broadly recommended use as chemotherapeutic agents, the porphyrogenicity of methotrexate and actinomycin D have not been confirmed. Accordingly, it is not known whether these agents are safe for use in patients with porphyria.Case presentationIn this report, we present a case of an invasive mole with lung metastasis in a 49-year-old Japanese woman who had previously been diagnosed with acute intermittent porphyria at 27 years of age but had no recent history of acute intermittent porphyria attacks. Her serum human chorionic gonadotropin level was elevated 1 month after hysterectomy, and she was referred to our center for chemotherapy. After she received 100 mg of methotrexate, drug eruptions were observed starting on day 3 and grew progressively worse. Erythema and mucosal erosion spread throughout her body, whereupon she was administered prednisolone. In addition, our patient experienced febrile neutropenia and required granulocyte colony- stimulating factor treatment. No changes in our patient’s urinary coproporphyrin or uroporphyrin levels were detected during this entire episode. Methotrexate was replaced by actinomycin D (0.5 mg/body intravenously on days 1–5 every 2 weeks). After five uneventful cycles of actinomycin D, our patient achieved and maintained a normal serum human chorionic gonadotropin level for 3 years.ConclusionsMethotrexate and actinomycin D did not induce acute porphyric attacks in this patient with acute intermittent porphyria; however, severe adverse effects were noted with methotrexate. Although further investigation is required, our data suggest that these agents are nonporphyrinogenic and can therefore be used to treat patients with comorbid porphyria.

Replication characteristics of infectious laryngotracheitis virus in the respiratory and conjunctival mucosa

Avian infectious laryngotracheitis virus (ILTV) is an alphaherpesvirus of poultry that is spread worldwide. ILTV enters its host via the respiratory tract and the eyes. Although ILTV has been known for a long time, the replication characteristics of the virus in the respiratory and conjunctival mucosa are still poorly studied. To study these characteristics, two in vitro explant models were developed. Light microscopy and fluorescent terminal deoxynucleotidyl transferase dUTP nick end-labelling staining were used to evaluate the viability of mucosal explants, which were found to be viable up to the end of the experiment at 96 h of cultivation. The tracheal and conjunctival mucosal explants were inoculated with ILTV and collected at 0, 24, 48 and 72 h post inoculation (p.i.). ILTV spread in a plaque-wise manner in both mucosae. A reproducible quantitative analysis of this mucosal spread was evaluated by measuring plaque numbers, plaque latitude and invasion depth underneath the basement membrane. No major differences in plaque numbers were observed over time. Plaque latitude progressively increased to 70.4 ± 12.9 μm in the trachea and 97.8 ± 9.5 μm in the conjunctiva at 72 h p.i. The virus had difficulty crossing the basement membrane and was first observed only at 48 h p.i. The virus was observed at 72 h p.i. in 56% (trachea) and 74% (conjunctiva) of the plaques. Viability analysis of infected explants indicated that ILTV blocks apoptosis in infected cells of both mucosae but activates apoptosis in bystander cells.

Whipple made simple for surgical pathologists: orientation, dissection, and sampling of pancreaticoduodenectomy specimens for a more practical and accurate evaluation of pancreatic, distal common bile duct, and ampullary tumors.

Pancreaticoduodenectomy (PD) specimens present a challenge for surgical pathologists because of the relative rarity of these specimens, combined with the anatomic complexity. Here, we describe our experience on the orientation, dissection, and sampling of PD specimens for a more practical and accurate evaluation of pancreatic, distal common bile duct (CBD), and ampullary tumors. For orientation of PDs, identification of the "trapezoid," created by the vascular bed at the center, the pancreatic neck margin on the left, and the uncinate margin on the right, is of outmost importance in finding all the pertinent margins of the specimen including the CBD, which is located at the upper right edge of this trapezoid. After orientation, all the margins can be sampled. We submit the uncinate margin entirely as a perpendicular inked margin because this adipose tissue-rich area often reveals subtle satellite carcinomas that are grossly invisible, and, with this approach, the number of R1 resections has doubled in our experience. Then, to ensure proper identification of all lymph nodes (LNs), we utilize the orange-peeling approach, in which the soft tissue surrounding the pancreatic head is shaved off in 7 arbitrarily defined regions, which also serve as shaved samples of the so-called "peripancreatic soft tissue" that defines pT3 in the current American Joint Committee on Cancer TNM. With this approach, our LN count increased from 6 to 14 and LN positivity rate from 50% to 73%. In addition, in 90% of pancreatic ductal adenocarcinomas there are grossly undetected microfoci of carcinoma. For determination of the primary site and the extent of the tumor, we believe bisectioning of the pancreatic head, instead of axial (transverse) slicing, is the most revealing approach. In addition, documentation of the findings in the duodenal surface of the ampulla is crucial for ampullary carcinomas and their recent site-specific categorization into 4 categories. Therefore, we probe both the CBD and the pancreatic duct from distal to the ampulla and cut the pancreatic head to the ampulla at a plane that goes through both ducts. Then, we sample the bisected pancreatic head depending on the findings of the case. For example, for proper staging of ampullary carcinomas, it is imperative to take the sections perpendicular to the duodenal serosa at the "groove" area, as ampullary carcinomas often extend to this region. Amputative (axial) sectioning of the ampulla, although good for documentation of the peri-Oddi spread of the intra-ampullary tumors, unfortunately disallows documentation of mucosal spread of the papilla of Vater tumors (those arising from the edge of the ampulla, where the ducts transition to duodenal mucosa and extending) into the neighboring duodenum. Axial sectioning also often fails to document tumor spread to the "groove" area. In conclusion, knowledge of the gross characteristics of the anatomic hallmarks is essential for proper dissection of PD specimens. The approach described above allows practical and accurate documentation and staging of pancreas, distal CBD, and ampullary cancers.

Mimicking Herpes Simplex Virus 1 and Herpes Simplex Virus 2 Mucosal Behavior in a Well-Characterized Human Genital Organ Culture

We developed and morphologically characterized a human genital mucosa explant model (endocervix and ectocervix/vagina) to mimic genital herpes infections caused by herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Subsequent analysis of HSV entry receptor expression throughout the menstrual cycle in genital tissues was performed, and the evolution of HSV-1/-2 mucosal spread over time was assessed. Nectin-1 and -2 were expressed in all tissues during the entire menstrual cycle. Herpesvirus entry mediator expression was limited mainly to some connective tissue cells. Both HSV-1 and HSV-2 exhibited a plaque-wise mucosal spread across the basement membrane and induced prominent epithelial syncytia.

Enhanced in vivo fitness of carbapenem-resistant oprD mutants of Pseudomonas aeruginosa revealed through high-throughput sequencing

An important question regarding the biologic implications of antibiotic-resistant microbes is how resistance impacts the organism's overall fitness and virulence. Currently it is generally thought that antibiotic resistance carries a fitness cost and reduces virulence. For the human pathogen Pseudomonas aeruginosa, treatment with carbapenem antibiotics is a mainstay of therapy that can lead to the emergence of resistance, often through the loss of the carbapenem entry channel OprD. Transposon insertion-site sequencing was used to analyze the fitness of 300,000 mutants of P. aeruginosa strain PA14 in a mouse model for gut colonization and systemic dissemination after induction of neutropenia. Transposon insertions in the oprD gene led not only to carbapenem resistance but also to a dramatic increase in mucosal colonization and dissemination to the spleen. These findings were confirmed in vivo with different oprD mutants of PA14 as well as with related pairs of carbapenem-susceptible and -resistant clinical isolates. Compared with OprD(+) strains, those lacking OprD were more resistant to killing by acidic pH or normal human serum and had increased cytotoxicity against murine macrophages. RNA-sequencing analysis revealed that an oprD mutant showed dramatic changes in the transcription of genes that may contribute to the various phenotypic changes observed. The association between carbapenem resistance and enhanced survival of P. aeruginosa in infected murine hosts suggests that either drug resistance or host colonization can cause the emergence of more pathogenic, drug-resistant P. aeruginosa clones in a single genetic event.

Incidental Gall Bladder Carcinoma in Laparoscopic Cholecystectomy: A Report of 6 Cases and a Review of the Literature

Gall bladder carcinoma accounts for 98% of all the gall bladder malignancies and it is the sixth most common malignancy of the gastrointestinal tract worldwide. The incidence of incidental gall bladder carcinoma which is diagnosed during or after a laparoscopic cholecystectomy is reported to be around 0.19-3.3% in the literature. This study was aimed at detecting the incidence of gall bladder carcinomas which were diagnosed incidentally during or after laparoscopic cholecystectomies which were done for gall stone disease and cholecystitis. We analyzed the medical records of patients with symptomatic gallstone disease and acute or chronic cholecystitis, who underwent laparoscopic cholecystectomies at the Hakeem Abdul Hameed Centenary Hospital during the period from January 2007 to June 2012. A total of 622 laparoscopic cholecystectomies were performed at our institute during the study period of five and a half years. In 6 (0.96%) cases, incidental carcinomas of the gallbladder were discovered. A laparoscopic cholecystectomy which is performed for benign gall bladder disease rarely results in a diagnosis of unexpected gallbladder cancer. The microscopic examination of the specimens, with special attention to the depth of invasion, range of the mucosal spread and the lymphovascular involvement, is critical in diagnosing the incidental malignancies as well as for the subsequent management of the cases.

Extent of local invasion and safe resection in cT1–2 tonsil cancer

Although intraoral resection of small-sized tonsil cancer achieves excellent tumor control, the extent of local invasion and adequate safety margin in resection have not been studied. Thus, we aim to determine the extent of local invasion in terms of mucosal spread and deep infiltration in stage T1-2 tonsil cancer. We re-analyzed the surgical specimens from 49 cT1-2 tonsil cancers. Microscopic tumor cell extension from the tumor gross boundary of specimens was assessed in representative sections of each tumor. We also tested whether local extension correlates with human papilloma virus (HPV) status of tumors. The extent of microscopic deep invasion from the gross tumor border was 0.52 ± 0.41 mm, which was significantly less than that of mucosal spread (0.83 ± 0.61 mm, P = 0.01) in cT1-2 tonsil cancer. The microscopic deep invasion correlated with tumor size (rho = 0.703, P < 0.001). We found tumor invasion into superior constrictor muscles in 58.1%, no cases of tumor invasion into the deep fascia. In terms of HPV status (genotyping plus p16 staining), there were no differences in microscopic tumor extension. Our detailed pathologic analyses confirm that an oropharyngectomy including the superior constrictor muscle is an oncologically safe procedure for stage T1-2 tonsil cancer.

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Treatment of Fallopian Tube Metastasis in Cervical Cancer after Laparoscopic Ovarian Transposition

A 40-year-old woman, gravida 2, para 2, with squamous cell carcinoma of the cervix, stage IIB, underwent ovarian transposition. Bilateral salpingectomy was performed as part of the operative technique. Histopathologic analysis revealed mucosal spread of the tumor to one of the fallopian tubes. The patient underwent radiation of the ovaries in their new location in addition to standard chemoradiotherapy to the pelvis. There has been no evidence of disease for more than 5 years. Inasmuch as performance of bilateral salpingectomy in ovarian transposition is not standard practice, the finding of fallopian tube metastasis presented a dilemma to the clinician. It remains to be proved whether the finding of metastasis to the fallopian tubes can be evidence for ovarian metastasis in grossly normal-appearing ovaries to validate this practice. Literature review demonstrates that fallopian tube metastasis is usually associated with endometrial involvement.

Seminal Vesicle Involvement by Urothelial Carcinoma in Situ of the Bladder with Mucosal Spread Pattern: A Case Report

Mucosal spreading of urothelial tumors to the seminal vesicles is very rare. We experienced a case of mucosal involvement of the seminal vesicles by a bladder tumor in a 72-year-old man. The patient had a history of transurethral resection for invasive urothelial carcinoma of the bladder 8 years previously. Radical cystoprostatectomy was performed owing to recurrent and multiple urothelial carcinoma in situ. Microscopically, the urothelial carcinoma in situ was throughout the mucosa of the urinary bladder, both ureters, the prostate, and the left seminal vesicle. To date, the implication of mucosal involvement of the seminal vesicles by urothelial carcinoma is unclear. However, careful microscopic examination is needed to avoid an erroneous diagnosis.

Th17 cells in pathogenic simian immunodeficiency virus infection of macaques

We discuss studies on a subset of CD4T cells, designated Th17, and their role in the pathogenesis of human and simian acquired immune deficiency, caused by infection with HIV and simian immunodeficiency virus (SIV), respectively. Most of the Th17 cells are lost within 2 weeks from infection at mucosal sites of SIV-infected macaques and are not replenished over time. Comparison of simian pathogenic and nonpathogenic models of SIV infection suggests that Th17 cells contribute to the pathogenesis of AIDS. Th17 cells, a recently identified subset of T helper cells, play a major role in both inducing autoimmune disorders and fencing off extracellular pathogens. Several groups have reported that the number of Th17 cells is decreased in the gut of HIV-infected and SIV-infected hosts. The loss of Th17 cells from the mucosal compartment has been associated with the dissemination of Salmonella typhimurium that is normally contained locally by the host immune system. It is believed that microbial translocation sustains immune activation in HIV infection and contributes to AIDS. Understanding the mechanisms that lead to disruption of mucosal integrity, viral spread, and chronic immune activation is of crucial importance for the design of efficient vaccines and therapeutic intervention for HIV.

GM-CSF-Facilitated Dendritic Cell Recruitment and Survival Govern the Intestinal Mucosal Response to a Mouse Enteric Bacterial Pathogen

Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes dendritic cell (DC) differentiation and survival in vitro. However, its role in host defense at the intestinal mucosa is unknown. We report that infection with the mouse enteric pathogen, Citrobacter rodentium, increased colonic GM-CSF production and CD11c(+) DC recruitment. After infection, GM-CSF(-/-) mice had fewer mucosal CD11c(+) DCs, greater bacterial burden, increased mucosal inflammation and systemic spread of infection, decreased antibody responses, and delayed pathogen clearance. This defective mucosal response was rescued by GM-CSF administration to GM-CSF(-/-) mice and mimicked by CD11c(+) DC depletion in wild-type animals. Diminished mucosal DC numbers in infected GM-CSF(-/-) mice reflected decreased DC recruitment and survival, with the recruitment defect being related to a failure to upregulate epithelial cell production of the DC chemoattractant, CCL22. Thus, GM-CSF produced in the intestinal mucosa acts to enhance host protection against an enteric bacterial pathogen through regulating recruitment and survival of DCs.

Differential modulation of CCR5-tropic human immunodeficiency virus–1 transfer from macrophages towards T cells under interleukin-4/interleukin-13 microenvironment

Macrophages constitute major human immunodeficiency virus type 1 (HIV-1) reservoirs at the mucosal level, and their functional activity is modulated by cytokine environments that could play a role in HIV-1 mucosal spread. As proof of concept, we herein evaluated the modulation of HIV/macrophages interactions associated with two ubiquitous T h2 cytokines, namely, interleukin (IL)–4 and IL-13, using the in vitro model of R5-HIV-1 transfer from macrophages to T lymphocytes. Monocyte-derived macrophages differentiated in the presence of IL-4 (M-4) transferred the virus to T cells more efficiently than those differentiated in the presence of interleukin-13 (M-13), likely because to their high capacity to capture and produce HIV-1 and to recruit HIV-1 target T cell. However, M-13 harbored high levels of HIV DNA, similarly to M-4, and secreted HIV-activating factors. Notably, uninfected macrophages recruited HIV-1 target T cells (CCR4 +IL-13 + T h2 cells and CD4 +CCR5 + T cells), indicating their role in facilitating the HIV-1 spread by a passive manner. Strikingly, R5-HIV-1 reprogrammed macrophages toward a T h1 secretion pattern. Thus, T h2 microenvironment facilitates the emergence of HIV-1 macrophage reservoir and HIV-1 spread. In conclusion, secreted cytokines within mucosae may differentially influence both the HIV-1 production within the mucosal target cells reservoir and its spread thorough the mucosal tissue.

Pagetoid spread to oral mucosa from submandibular gland salivary duct carcinoma: a case report

Salivary duct carcinoma is a high-grade malignant tumor arising predominantly in the major salivary glands. We describe herein a rare presentation of salivary duct carcinoma arising in the submandibular gland and showing pagetoid spread to the oral mucosa. A 46-year-old man was admitted with a 2-year history of swelling in the floor of the mouth. Resection of the submandibular gland tumor was followed by mucosal biopsy around the aperture of the right Wharton's duct. The tumor recurred in the oral mucosa with pagetoid spread and extended widely in the oral cavity for the following 10 years, despite chemo- and radiotherapy. Mucosal spread, although a relatively remote possibility, can occur in the setting of salivary duct carcinoma.