Publications by authors named "Bruce D Greenwald"

42 Publications

Age-dependency of terminal ileum tissue resident memory T cell responsiveness profiles to S. Typhi following oral Ty21a immunization in humans.

Immun Ageing 2021 Apr 19;18(1):19. Epub 2021 Apr 19.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.

Background: The impact of aging on the immune system is unequivocal and results in an altered immune status termed immunosenescence. In humans, the mechanisms of immunosenescence have been examined almost exclusively in blood. However, most immune cells are present in tissue compartments and exhibit differential cell (e.g., memory T cells -T) subset distributions. Thus, it is crucial to understand immunosenescence in tissues, especially those that are exposed to pathogens (e.g., intestine). Using a human model of oral live attenuated typhoid vaccine, Ty21a, we investigated the effect of aging on terminal ileum (TI) tissue resident memory T (T) cells. T provide immediate adaptive effector immune responsiveness at the infection site. However, it is unknown whether aging impacts T S. Typhi-responsive cells at the site of infection (e.g., TI). Here, we determined the effect of aging on the induction of TI S. Typhi-responsive T subsets elicited by Ty21a immunization.

Results: We observed that aging impacts the frequencies of TI-lamina propria mononuclear cells (LPMC) T and T in both Ty21a-vaccinated and control groups. In unvaccinated volunteers, the frequencies of LPMC CD103- CD4+ T displayed a positive correlation with age whilst the CD4/CD8 ratio in LPMC displayed a negative correlation with age. We observed that elderly volunteers have weaker S. Typhi-specific mucosal immune responses following Ty21a immunization compared to adults. For example, CD103+ CD4+ T showed reduced IL-17A production, while CD103- CD4+ T exhibited lower levels of IL-17A and IL-2 in the elderly than in adults following Ty21a immunization. Similar results were observed in LPMC CD8+ T and CD103- CD8+ T cell subsets. A comparison of multifunctional (MF) profiles of both CD4+ and CD8+ T subsets between elderly and adults also showed significant differences in the quality and quantity of elicited single (S) and MF responses.

Conclusions: Aging influences tissue resident T S. Typhi-specific responses in the terminal ileum following oral Ty21a-immunization. This study is the first to provide insights in the generation of local vaccine-specific responses in the elderly population and highlights the importance of evaluating tissue immune responses in the context of infection and aging.

Trial Registration: This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304 , Registered 29 May 2019 - Retrospectively registered).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12979-021-00227-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053564PMC
April 2021

MicroRNA-141-3p regulates cellular proliferation, migration, and invasion in esophageal cancer by targeting tuberous sclerosis complex 1.

Mol Carcinog 2021 02 31;60(2):125-137. Epub 2020 Dec 31.

Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, USA.

MicroRNA (miR)-141-3p, which functions as an oncogene in multiple malignancies, has been shown to be highly overexpressed in esophageal cancer cells in our previous work. miR-141-3p is predicted to bind the messenger RNA (mRNA) of tuberous sclerosis complex 1 (TSC1), a tumor suppressor, with high affinity. In this study, we investigated the expression and functional interaction between miR-141-3p and TSC1 in esophageal cancer cells. Experiments were conducted in four esophageal cancer lines and in tumor cells isolated from human esophageal cancer specimens by laser capture microdissection. miR-141-3p expression was measured by real time and droplet digital PCR. Biotinylated RNA pull-down and luciferase reporter assays were used to assess binding. miR-141-3p function was tested by assessing proliferation, migration, invasion, and induction of autophagy following its silencing. We found that miR-141-3p levels were increased in TE7, OE33, and TE10 esophageal cancer cells compared to FLO-1 cells, with similar heterogeneity observed in human esophageal cancer specimens. Silencing of miR-141-3p led to increased TSC1 protein expression in these cells and was associated with increased TSC1 translation. Binding studies reveal that miR-141-3p binds to each of the predicted binding sites in the 3'-untranslated region of TSC1 mRNA. Following miR-141-3p silencing, TE7, OE33, and TE10 cells exhibited decreased proliferation, migration, and invasion, as well as enhanced autophagy. Importantly, these phenotypic effects were replicated by overexpression of TSC1 alone in these cells. Our results indicate that miR-141-3p functions in an oncogenic capacity in a subset of esophageal cancer cells, in part by suppressing TSC1 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mc.23274DOI Listing
February 2021

High-Flow Nasal Cannula Oxygen in Patients Having Anesthesia for Advanced Esophagogastroduodenoscopy: HIFLOW-ENDO, a Randomized Clinical Trial.

Anesth Analg 2021 03;132(3):743-751

From the Department of Anesthesiology.

Background: Over 6 million esophagogastroduodenoscopy (EGD) procedures are performed in the United States each year. Patients having anesthesia for advanced EGD procedures, such as interventional procedures, are at high risk for hypoxemia.

Methods: Our primary study aim was to evaluate whether high-flow nasal cannula (HFNC) oxygen reduces the incidence of hypoxemia during anesthesia for advanced EGD. Secondarily, we studied whether HFNC oxygen reduces hypercarbia or hypotension. After obtaining written informed consent, adults having anesthesia for advanced EGD, expected to last longer than 15 minutes, were randomly assigned to receive HFNC oxygen or standard nasal cannula (SNC) oxygen. The primary outcome was occurrence of one or more hypoxemia events during anesthesia, defined by arterial oxygen saturation <92% for at least 15 consecutive seconds. Secondary outcomes were occurrence of one or more hypercarbia or hypotension events. A hypercarbia event was defined by a transcutaneous CO2 measurement 20 mm Hg or more above baseline, and a hypotension event was defined by a mean arterial blood pressure measurement 25% or more below baseline.

Results: Two hundred seventy-one adult patients were enrolled and randomized, and 262 patients completed study procedures. Eight randomized patients did not complete study procedures due to changes in their anesthesia or endoscopy plan. One patient was excluded from analysis because their procedure was aborted after 1 minute. Patients who received HFNC oxygen (N = 132) had a significantly lower incidence of hypoxemia than those who received SNC oxygen (N = 130; 21.2% vs 33.1%; hazard ratio [HR] = 0.59 [95% confidence interval {CI}, 0.36-0.95]; P = .03). There was no difference in the incidence of hypercarbia or hypotension between the groups. The HR for hypercarbia with HFNC oxygen was 1.29 (95% CI, 0.89-1.88; P = .17), and the HR for hypotension was 1.25 (95% CI, 0.86-1.82; P = .25).

Conclusions: HFNC oxygen reduces the incidence of hypoxemia during anesthesia for advanced EGD and may offer an opportunity to enhance patient safety during these procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1213/ANE.0000000000004837DOI Listing
March 2021

Assessing Outcomes of Patients Treated With Re-Irradiation Utilizing Proton Pencil-Beam Scanning for Primary or Recurrent Malignancies of the Esophagus and Gastroesophageal Junction.

J Thorac Oncol 2020 06 4;15(6):1054-1064. Epub 2020 Mar 4.

Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland.

Introduction: Re-irradiation (re-RT) for locoregionally recurrent esophageal and gastroesophageal junction (GEJ) cancer and de novo esophageal + GEJ cancer arising in-field after a course of prior radiation poses considerable treatment challenges given the sensitivity of surrounding organs at risk (OARs). Guidelines for treatment of this presentation are not well established. Pencil-beam scanning (PBS) proton therapy has the ability to decrease radiation dose to OARs relative to photon plans. We present the first published series to date of re-RT with PBS for esophageal + GEJ malignancies and hypothesize that re-RT with proton PBS will be feasible and improve the safety profile of re-RT for this cohort of patients.

Methods: Consecutive esophageal + GEJ cancers treated with PBS re-RT within a single institution were analyzed. Comparative volumetric-modulated arc therapy photon plans were generated. A total of 17 patients were included for analysis.

Results: At a median follow-up of 11.6 months, 1-year local control was 75.3% and overall survival was 68.9%. There were five (27.8%) grade 3 or higher late toxicities. When matched for clinical target volume coverage, proton PBS plans delivered significantly lower doses to the spinal cord, lungs, liver, and heart (all p < 0.05); five volumetric-modulated arc therapy plans would have been undeliverable on the basis of physician-specified OAR constraints.

Conclusions: Re-RT for de novo or recurrent malignancies of the esophagus + GEJ, when delivered with PBS proton therapy, yields high rates of local control with acceptable acute and late toxicities in a high-risk population and decreased radiation dose to OARs relative to comparative photon plans. This is the largest series of proton re-RT for esophageal malignancies and the first that exclusively used PBS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2020.01.024DOI Listing
June 2020

Oral typhoid vaccine Ty21a elicits antigen-specific resident memory CD4 T cells in the human terminal ileum lamina propria and epithelial compartments.

J Transl Med 2020 02 25;18(1):102. Epub 2020 Feb 25.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.

Background: Salmonella enterica serovar Typhi (S. Typhi) is a highly invasive bacterium that infects the human intestinal mucosa and causes ~ 11.9-20.6 million infections and ~ 130,000-223,000 deaths annually worldwide. Oral typhoid vaccine Ty21a confers a moderate level of long-lived protection (5-7 years) in the field. New and improved vaccines against enteric pathogens are needed but their development is hindered by a lack of the immunological correlates of protection especially at the site of infection. Tissue resident memory T (T) cells provide immediate adaptive effector immune responsiveness at the infection site. However, the mechanism(s) by which S. Typhi induces T in the intestinal mucosa are unknown. Here, we focus on the induction of S. Typhi-specific CD4+T subsets by Ty21a in the human terminal ileum lamina propria and epithelial compartments.

Methods: Terminal ileum biopsies were obtained from consenting volunteers undergoing routine colonoscopy who were either immunized orally with 4 doses of Ty21a or not. Isolated lamina propria mononuclear cells (LPMC) and intraepithelial lymphocytes (IEL) CD4+T immune responses were determined using either S. Typhi-infected or non-infected autologous EBV-B cell lines as stimulator cells. T-CMI was assessed by the production of 4 cytokines [interferon (IFN)γ, interleukin (IL)-2, IL-17A and tumor necrosis factor (TNF)α] in 36 volunteers (18 vaccinees and 18 controls volunteers).

Results: Although the frequencies of LPMC CD103+ CD4+T were significant decreased, both CD103+ and CD103- CD4+T subsets spontaneously produced significantly higher levels of cytokines (IFNγ and IL-17A) following Ty21a-immunization. Importantly, we observed significant increases in S. Typhi-specific LPMC CD103+ CD4+T (IFNγ and IL-17A) and CD103- CD4+T (IL-2 and IL-17A) responses following Ty21a-immunization. Further, differences in S. Typhi-specific responses between these two CD4+T subsets were observed following multifunctional analysis. In addition, we determined the effect of Ty21a-immunization on IEL and observed significant changes in the frequencies of IEL CD103+ (decrease) and CD103- CD4+T (increase) following immunization. Finally, we observed that IEL CD103- CD4+T, but not CD103+ CD4+T, produced increased cytokines (IFNγ, TNFα and IL-17A) to S. Typhi-specific stimulation following Ty21a-immunization.

Conclusions: Oral Ty21a-immunization elicits distinct compartment specific immune responses in CD4+T (CD103+ and CD103-) subsets. This study provides novel insights in the generation of local vaccine-specific responses. Trial registration This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304, Registered 29 May 2019-Retrospectively registered, http://www.ClinicalTrials.gov/NCT03970304).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-020-02263-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043047PMC
February 2020

Spray cryotherapy for dysphagia palliation in esophageal cancer prior to systemic therapy: is it ready for prime time?

Endosc Int Open 2020 Feb 22;8(2):E122-E123. Epub 2020 Jan 22.

University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, United States.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-0966-8457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976331PMC
February 2020

Recognizing intrapancreatic accessory spleen via EUS: Interobserver variability.

Endosc Ultrasound 2019 Nov-Dec;8(6):392-397

Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA.

Background And Objective: Accessory spleen (AS) may be encountered as an intrapancreatic lesion on EUS. This can look similar to other pancreatic pathologies and may lead to unnecessary interventions. The goal of this study was to evaluate the accuracy of EUS in distinguishing intrapancreatic AS (IPAS) from other pancreatic lesions.

Materials And Methods: Twelve sets of endoscopic images of the spleen and various pancreatic lesions confirmed on histology or cytology were gathered. Ten endosonographers were asked to characterize and identify the lesions. The responses were analyzed via Excel and the interobserver agreement was analyzed using Gwet's agreement coefficient statistic via Stata I/C v15.

Results: In our sample, the interobserver agreement was 0.37 (-+1-1; 0-0.2 poor, 0.2-0.4 fair, 0.4-0.6 moderate, 0.6-0.8 substantial, and 0.8-1.0 almost perfect) for determining whether or not the pancreatic lesion is IPAS. The reviewers were able to correctly determine IPAS endosonographically with a sensitivity of 77%, specificity of 74%, and positive and negative predictive values of 50% and 92%, respectively.

Conclusion: There is a moderate-to-substantial interobserver agreement in describing the sonographic characteristics of the pancreatic lesions, such as the shape, echogenicity compared to spleen, echotexture, and border of the lesions. However, the interobserver agreement is only fair when deciding if the pancreatic lesion is an IPAS. The similar profile of IPAS and pancreatic neuroendocrine tumor could confound the diagnosis of IPAS, thus contributing to the decreased interobserver agreement. This study demonstrates that EUS criteria alone are not accurate for IPAS diagnosis. Fine-needle aspiration (FNA) may be required for a confirmatory diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/eus.eus_35_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927143PMC
August 2019

Attenuated Oral Typhoid Vaccine Ty21a Elicits Lamina Propria and Intra-Epithelial Lymphocyte Tissue-Resident Effector Memory CD8 T Responses in the Human Terminal Ileum.

Front Immunol 2019 14;10:424. Epub 2019 Mar 14.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States.

Tissue-resident memory T cells (T) are newly defined memory T cells (T) distinct from circulating T subsets which have the potential to mount rapid protective immune responses at the site of infection. However, very limited information is available regarding the role and contribution of T in vaccine-mediated immune responses in humans at the site of infection. Here, we studied the role and contribution of tissue resident memory T cells (T) located in the terminal ileum (TI) (favored site of infection for . Typhi) following oral Ty21a immunization in humans. We examined TI-lamina propria mononuclear cells (LPMC) and intra-epithelial lymphocytes (IEL) CD8+ T subsets obtained from healthy volunteers undergoing medically-indicated colonoscopies who were either immunized with Ty21a or unvaccinated. No significant differences in the frequencies of LPMC CD8+ T and CD8+CD69+CD103- T cells subsets were observed following Ty21a-immunization. However, LPMC CD8+ T exhibited significantly higher levels of cytokines (IFN-γ, IL-17A, and TNF-α) in Ty21a-vaccinated than in unvaccinated volunteers. LPMC CD8+ T. Typhi-specific responses were evaluated using . Typhi-infected targets and found to produce significantly higher levels of . Typhi-specific IL-17A. In contrast, LPMC CD8+CD69+CD103- T cells produced significantly increased . Typhi-specific levels of IFN-γ, IL-2, and IL-17A. Finally, we assessed CD8+ T in IEL and observed that the frequency of IEL CD8+ T is significantly lower following Ty21a immunization. However, IEL CD8+ T elicited by Ty21a immunization spontaneously produced significantly higher levels of cytokines (IFN-γ, IL-17A, IL-2, and TNF-α). This study provides the first demonstration of the effect of oral Ty21a vaccination on CD8+ T subsets (spontaneous and . Typhi-specific) responses in the LPMC and IEL compartment of the human terminal ileum mucosa, contributing novel information to our understanding of the generation of mucosal immune responses following oral Ty21a-immunization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.00424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426796PMC
August 2020

Association between . Typhi-specific memory CD4+ and CD8+ T responses in the terminal ileum mucosa and in peripheral blood elicited by the live oral typhoid vaccine Ty21a in humans.

Hum Vaccin Immunother 2019 2;15(6):1409-1420. Epub 2019 Apr 2.

a Center for Vaccine Development and Global Health , University of Maryland School of Medicine , Baltimore , MD , USA.

CD4+ and CD8+ T subsets are essential components of the adaptive immune system which act in concert at the site of infections to effectively protect against pathogens. Very limited data is available in humans regarding the relationship between CD4+ and CD8+ . Typhi responsive cells in the terminal ileum mucosa (TI) and peripheral blood following Ty21a oral typhoid immunization. Here, we compared TI lamina propria mononuclear cells (LPMC) and peripheral blood CD4+ and CD8+ T memory (T) subsets responses and their relationship by Spearman's correlation following Ty21a immunization in volunteers undergoing routine colonoscopy. We observed that Ty21a immunization (i) influences the homing and accumulation of both CD4+ and CD8+ T cells in the TI, particularly integrin α4β7+ CCR9+ CD8+ T cells, (ii) elicits significantly higher frequencies of LPMC . Typhi-responsive CD8+ T multifunctional (CD107a, IFNγ, IL-17A and/or MIP1β) cells than their CD4+ T counterparts, and (iii) results in the correlation of LPMC CD4+ Teffector/memory (T) . Typhi responses (CD107a, IFNγ, TNFα, IL-17A and/or MIP1β) to their LPMC CD8+ T counterparts. Moreover, we demonstrated that these positive correlations between CD4+ and CD8+ T occur primarily in TI LPMC but not in PBMC, suggesting important differences in responses between the mucosal and systemic compartments following oral Ty21a immunization. This study provides the first demonstration of the correlation of . Typhi-specific CD4+ and CD8+ T responses in the human terminal ileum mucosa and provides valuable information regarding the generation of mucosal and systemic immune responses following oral Ty21a-immunization which might impact future vaccine design and development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21645515.2018.1564570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663141PMC
March 2020

What Constitutes Optimal Management of T1N0 Esophageal Adenocarcinoma?

Ann Surg Oncol 2019 Mar 3;26(3):714-731. Epub 2019 Jan 3.

Cardiovascular and Thoracic Surgery, Integrated Health Associates, Ypsilanti, USA.

Purpose And Design: Esophageal adenocarcinoma (EAC) develops as a consequence of gastroesophageal reflux disease and Barrett's esophagus (BE). While combination therapy with chemotherapy or concurrent chemoradiotherapy followed by esophagectomy improves survival in more advanced tumors, the optimal treatment strategy for early-stage EAC is undefined. Endoscopic eradication therapy, consisting of endoscopic resection and mucosal ablation, has revolutionized therapy for superficial (T1a) EAC in BE and allows for esophageal preservation in appropriate patients at low risk for lymph node metastasis (LNM). This review critically examines the literature regarding evaluation, treatment, and outcomes in patients with T1 EAC.

Methods: The literature was queried via the PubMed database to include articles published between 1990 and 2017. Search terms were generated from the key statements "Endoscopic eradication therapy results in equivalent overall survival when compared to esophagectomy for clinical T1aN0 EAC" and "Esophagectomy provides better overall survival than endoscopic eradication therapy for cT1b EAC". Abstracts were reviewed and included according to predefined selection and exclusion criteria, and were then assessed according to the GRADE system.

Results And Conclusions: In patients with T1aN0 EAC, overall survival with endoscopic eradication therapy is equal to esophagectomy. Given the substantial risk of LNM in patients with submucosal (T1b) EAC, esophagectomy remains the standard of care for surgical candidates. In the case of inoperability or low-risk lesions, endoscopic resection may be considered adequate therapy. Chemotherapy and radiation can be offered as primary therapy for non-surgical candidates with lesions not amenable to endoscopic therapy, but does not have a clear role in the adjuvant setting after either endoscopic or surgical resection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-018-07118-5DOI Listing
March 2019

Effect of the live oral attenuated typhoid vaccine, Ty21a, on systemic and terminal ileum mucosal CD4+ T memory responses in humans.

Int Immunol 2019 02;31(2):101-116

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.

Our current understanding of CD4+ T-cell-mediated immunity (CMI) elicited by the oral live attenuated typhoid vaccine Ty21a is primarily derived from studies using peripheral blood. Very limited data are available in humans regarding mucosal immunity (especially CD4+ T) at the site of infection (e.g. terminal ileum; TI). Here using multiparametric flow cytometry, we examined the effect of Ty21a immunization on TI-lamina propria mononuclear cells (LPMC) and peripheral blood CD4+ T memory (TM) subsets in volunteers undergoing routine colonoscopy. Interestingly, we observed significant increases in the frequencies of LPMC CD4+ T cells following Ty21a immunization, restricted to the T effector/memory (TEM)-CD45RA+ (TEMRA) subset. Importantly, Ty21a immunization elicited Salmonella Typhi-responsive LPMC CD4+ T cells in all major TM subsets [interferon (IFN)γ and interleukin (IL)-17A in TEM; IFNγ and macrophage inflammatory protein (MIP)1β in T central/memory (TCM); and IL-2 in TEMRA]. Subsequently, we analyzed LPMC S. Typhi-responsive CD4+ T cells in depth for multifunctional (MF) effectors. We found that LPMC CD4+ TEM responses were mostly MF, except for those cells exhibiting the characteristics associated with IL-17A responses. Finally, we compared mucosal to systemic responses and observed that LPMC CD4+S. Typhi-specific responses were unique and distinct from their systemic counterparts. This study provides the first demonstration of S. Typhi-specific CD4+ TM responses in the human TI mucosa and provides valuable information about the generation of mucosal immune responses following oral Ty21a immunization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/intimm/dxy070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376105PMC
February 2019

Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in Humans.

Cell Mol Gastroenterol Hepatol 2017 Nov 16;4(3):419-437. Epub 2017 Aug 16.

Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland.

Background & Aims: Systemic cellular immunity elicited by the Ty21a oral typhoid vaccine has been extensively characterized. However, very limited data are available in humans regarding mucosal immunity at the site of infection (terminal ileum [TI]). Here we investigated the host immunity elicited by Ty21a immunization on terminal ileum-lamina propria mononuclear cells (LPMC) and peripheral blood in volunteers undergoing routine colonoscopy.

Methods: We characterized LPMC-T memory (T) subsets and assessed serovar Typhi ( Typhi)-specific responses by multichromatic flow cytometry.

Results: No differences were observed in cell yields and phenotypes in LPMC CD8-T subsets following Ty21a immunization. However, Ty21a immunization elicited LPMC CD8 T cells exhibiting significant Typhi-specific responses (interferon-γ, tumor necrosis factor-α, interleukin-17A, and/or CD107a) in all major T subsets (T-effector/memory [T], T-central/memory, and T-CD45RA), although each T subset exhibited unique characteristics. We also investigated whether Ty21a immunization elicited Typhi-specific multifunctional effectors in LPMC CD8 T. We observed that LPMC CD8 T responses were mostly multifunctional, except for those cells exhibiting the characteristics associated with cytotoxic responses. Finally, we compared mucosal with systemic responses and made the important observation that LPMC CD8 Typhi-specific responses were unique and distinct from their systemic counterparts.

Conclusions: This study provides the first demonstration of Typhi-specific responses in the human terminal ileum mucosa and provides novel insights into the generation of mucosal immune responses following oral Ty21a immunization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcmgh.2017.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626924PMC
November 2017

Outcomes after liquid nitrogen spray cryotherapy in Barrett's esophagus-associated high-grade dysplasia and intramucosal adenocarcinoma: 5-year follow-up.

Gastrointest Endosc 2017 Oct 21;86(4):626-632. Epub 2017 Feb 21.

Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Background And Aims: Liquid nitrogen spray cryotherapy (LNSCT) has been shown to be a safe, well-tolerated, and effective therapy for Barrett's esophagus (BE)-associated high-grade dysplasia (BE-HGD) and intramucosal adenocarcinoma (IMC). Long-term follow-up is lacking.

Aims: The aim of this study was to assess the efficacy, durability, and rate of neoplastic progression after LNSCT in BE-HGD/IMC at 3 and 5 years.

Methods: In this single-center, retrospective study drawn from a prospective database, patients with BE-HGD/IMC of any length treated with LNSCT were followed with surveillance endoscopy with biopsy for 3 to 5 years. Patients with IMC completely removed by endoscopic resection were included. Outcome measures included complete eradication of HGD (CE-HGD), dysplasia, and intestinal metaplasia; incidence rates; durability of response; location of recurrent intestinal metaplasia and dysplasia; and rate of disease progression.

Results: A total of 50 and 40 patients were included in 3-year and 5-year analyses. Initial CE-HGD, dysplasia, and intestinal metaplasia achieved in 98%, 90%, and 60%, respectively. Overall CE-HGD, dysplasia, and intestinal metaplasia at 3 years were 96% (48/50), 94% (47/50), and 82% (41/50), and at 5 years were 93% (37/40), 88% (35/40), and 75% (30/40). Incidence rates of recurrent intestinal metaplasia, dysplasia, and HGD/esophageal adenocarcinoma per person-year of follow-up after initial complete eradication of intestinal metaplasia (CE-IM) were 12.2%, 4.0%, and 1.4% per person-year for the 5-year cohort. Most recurrences were found immediately below the neosquamocolumnar junction. Two of 7 HGD recurrences occurred later than 4 years after initial eradication, and 2 patients (4%) progressed to adenocarcinoma despite treatment.

Conclusions: In patients with BE-HGD/IMC, LNSCT is effective in eliminating dysplasia and intestinal metaplasia. Progression to adenocarcinoma was uncommon, and recurrence of dysplasia was successfully treated in most cases. Long-term surveillance is necessary to detect late recurrence of dysplasia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gie.2017.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565709PMC
October 2017

Should endoscopic ablation therapy for Barrett's-associated neoplasia be limited to academic or tertiary referral centers?

Endoscopy 2017 02 1;49(2):105-107. Epub 2017 Feb 1.

Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0042-123191DOI Listing
February 2017

Depth-resolved imaging of colon tumor using optical coherence tomography and fluorescence laminar optical tomography.

Biomed Opt Express 2016 Dec 21;7(12):5218-5232. Epub 2016 Nov 21.

Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; Key Laboratory of Optoelectronic Science and Technology for Medicine, Ministry of Education, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou 350007, China.

Early detection of neoplastic changes remains a critical challenge in clinical cancer diagnosis and treatment. Many cancers arise from epithelial layers such as those of the gastrointestinal (GI) tract. Current standard endoscopic technology is difficult to detect the subsurface lesions. In this research, we investigated the feasibility of a novel multi-modal optical imaging approach including high-resolution optical coherence tomography (OCT) and high-sensitivity fluorescence laminar optical tomography (FLOT) for structural and molecular imaging. The C57BL/6J-Apc/J mice were imaged using OCT and FLOT, and the correlated histopathological diagnosis was obtained. Quantitative structural (scattering coefficient) and molecular (relative enzyme activity) parameters were obtained from OCT and FLOT images for multi-parametric analysis. This multi-modal imaging method has demonstrated the feasibility for more accurate diagnosis with 88.23% (82.35%) for sensitivity (specificity) compared to either modality alone. This study suggested that combining OCT and FLOT is promising for subsurface cancer detection, diagnosis, and characterization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/BOE.7.005218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175565PMC
December 2016

Mucosal-Associated Invariant T Cells in the Human Gastric Mucosa and Blood: Role in Helicobacter pylori Infection.

Front Immunol 2015 17;6:466. Epub 2015 Sep 17.

Center for Vaccine Development, University of Maryland School of Medicine , Baltimore, MD , USA ; Department of Pediatrics, University of Maryland School of Medicine , Baltimore, MD , USA ; Department of Medicine, University of Maryland School of Medicine , Baltimore, MD , USA.

Mucosal-associated invariant T (MAIT) cells represent a class of antimicrobial innate-like T cells that have been characterized in human blood, liver, lungs, and intestine. Here, we investigated, for the first time, the presence of MAIT cells in the stomach of children, adults, and the elderly undergoing routine endoscopy and assessed their reactivity to Helicobacter pylori (H. pylori - Hp), a major gastric pathogen. We observed that MAIT cells are present in the lamina propria compartment of the stomach and display a similar memory phenotype to blood MAIT cells. We then demonstrated that gastric and blood MAIT cells are able to recognize H. pylori. We found that CD8(+) and CD4(-)CD8(-) (double negative) MAIT cell subsets respond to H. pylori-infected macrophages stimulation in a MR-1 restrictive manner by producing cytokines (IFN-γ, TNF-α, IL-17A) and exhibiting cytotoxic activity. Interestingly, we observed that blood MAIT cell frequency in Hp(+ve) individuals was significantly lower than in Hp(-ve) individuals. However, gastric MAIT cell frequency was not significantly different between Hp(+ve) and Hp(-ve) individuals, demonstrating a dichotomy between blood and gastric tissues. Further, we observed that the majority of gastric MAIT cells (>80%) expressed tissue-resident markers (CD69(+) CD103(+)), which were only marginally present on PBMC MAIT cells (<3%), suggesting that gastric MAIT cells are readily available to respond quickly to pathogens. These results contribute important new information to the understanding of MAIT cells function on peripheral and mucosal tissues and its possible implications in the host response to H. pylori.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2015.00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585133PMC
October 2015

Characterization and functional properties of gastric tissue-resident memory T cells from children, adults, and the elderly.

Front Immunol 2014 19;5:294. Epub 2014 Jun 19.

Center for Vaccine Development, University of Maryland School of Medicine , Baltimore, MD , USA ; Department of Pediatrics, University of Maryland School of Medicine , Baltimore, MD , USA ; Department of Medicine, University of Maryland School of Medicine , Baltimore, MD , USA.

T cells are the main orchestrators of protective immunity in the stomach; however, limited information on the presence and function of the gastric T subsets is available mainly due to the difficulty in recovering high numbers of viable cells from human gastric biopsies. To overcome this shortcoming we optimized a cell isolation method that yielded high numbers of viable lamina propria mononuclear cells (LPMC) from gastric biopsies. Classic memory T subsets were identified in gastric LPMC and compared to peripheral blood mononuclear cells (PBMC) obtained from children, adults, and the elderly using an optimized 14 color flow cytometry panel. A dominant effector memory T (TEM) phenotype was observed in gastric LPMC CD4(+) and CD8(+) T cells in all age groups. We then evaluated whether these cells represented a population of gastric tissue-resident memory T (TRM) cells by assessing expression of CD103 and CD69. The vast majority of gastric LPMC CD8(+) T cells either co-expressed CD103/CD69 (>70%) or expressed CD103 alone (~20%). Gastric LPMC CD4(+) T cells also either co-expressed CD103/CD69 (>35%) or expressed at least one of these markers. Thus, gastric LPMC CD8(+) and CD4(+) T cells had the characteristics of TRM cells. Gastric CD8(+) and CD4(+) TRM cells produced multiple cytokines (IFN-γ, IL-2, TNF-α, IL-17A, MIP-1β) and up-regulated CD107a upon stimulation. However, marked differences were observed in their cytokine and multi-cytokine profiles when compared to their PBMC TEM counterparts. Furthermore, gastric CD8(+) TRM and CD4(+) TRM cells demonstrated differences in the frequency, susceptibility to activation, and cytokine/multi-cytokine production profiles among the age groups. Most notably, children's gastric TRM cells responded differently to stimuli than gastric TRM cells from adults or the elderly. In conclusion, we demonstrate the presence of gastric TRM, which exhibit diverse functional characteristics in children, adults, and the elderly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2014.00294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062881PMC
July 2014

Liquid nitrogen spray cryotherapy in Barrett's esophagus with high-grade dysplasia: long-term results.

Gastrointest Endosc 2013 Aug 24;78(2):260-5. Epub 2013 Apr 24.

Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Background: Liquid nitrogen endoscopic spray cryotherapy can safely and effectively eradicate high-grade dysplasia in Barrett's esophagus (BE-HGD). Long-term data on treatment success and safety are lacking.

Objective: To assess the long-term safety and efficacy of spray cryotherapy in patients with BE-HGD.

Design: Single-center, retrospective study.

Setting: Tertiary-care referral center.

Patients: A total of 32 patients with BE-HGD of any length.

Intervention: Patients were treated with liquid nitrogen spray cryotherapy every 8 weeks until complete eradication of HGD (CE-HGD) and intestinal metaplasia (CE-IM) was found by endoscopic biopsy. Surveillance endoscopy with biopsies was performed for at least 2 years.

Main Outcome Measurements: CE-HGD, CE-IM, durability of response, disease progression, and adverse events.

Results: CE-HGD was 100% (32/32), and CE-IM was 84% (27/32) at 2-year follow-up. At last follow-up (range 24-57 months), CE-HGD was 31/32 (97%), and CE-IM was 26/32 (81%). Recurrent HGD was found in 6 (18%), with CE-HGD in 5 after repeat treatment. One patient progressed to adenocarcinoma, downgraded to HGD after repeat cryotherapy. BE segment length ≥3 cm was associated with a higher recurrence of IM (P = .004; odds ratio 22.6) but not HGD. No serious adverse events occurred. Stricture was seen in 3 patients (9%), all successfully dilated.

Limitations: Retrospective study design, small sample size.

Conclusion: In patients with BE-HGD, liquid nitrogen spray cryotherapy has an acceptable safety profile and success rate for eliminating HGD and IM and is associated with a low rate of recurrence or progression to cancer with long-term follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gie.2013.03.002DOI Listing
August 2013

Endoscopic management of esophageal cancer after definitive chemoradiotherapy.

Dig Dis Sci 2013 Jun 17;58(6):1477-85. Epub 2013 Jan 17.

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Background: Concurrent chemoradiotherapy (CRT) is a potentially curative non-surgical option for locally advanced esophageal cancer, with pathological complete response (CR) ranging from 13 to 49 %. The rate of persistent and recurrent disease within the esophagus remains high at 40-60 %, and treatment of these tumors may improve disease-free survival. The aim of this review is to assess the efficacy of salvage endoscopic therapies for recurrent esophageal cancer.

Methods: Medline and Embase were searched for relevant studies published in the English-language literature that reported use of endoscopic modalities, including photodynamic therapy (PDT), endoscopic mucosal resection (EMR), and spray cryotherapy, as salvage therapies for esophageal cancer.

Results: A total of 12 studies were identified. In small case series of PDT, CR varied from 20 to 100 %, with 1-, 3-, and 5-year overall survival rates of 65-80, 34-47, and 36 %, respectively. Data from three studies of EMR in squamous cell cancer show CR in 50 % of cases, with 3- and 5-year overall survival of 56-81 and 49 %, respectively. Endoscopic spray cryotherapy has recently been used in this setting with an observed CR of 37.5 %.

Conclusions: Endoscopic salvage therapies are options for those patients with disease limited to the superficial esophageal wall and those who are unfit to undergo salvage esophagectomy. Widespread application of endoscopic salvage therapies is limited by the lack of awareness and guidelines for endoscopic surveillance post-CRT and limited data on the effectiveness of endoscopic therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10620-012-2554-0DOI Listing
June 2013

Barrett's esophagus: endoscopic treatments II.

Ann N Y Acad Sci 2011 Sep;1232:156-74

Division of Gastroenterology and Hepatology, Department of Medicine and Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.

The following on endoscopic treatments of Barrett's esophagus includes commentaries on animal experiments on cryotherapy; indications for cryotherapy, choice of dosimetry, number of sessions, and role in Barrett's esophagus and adenocarcinoma; recent technical developments of RFA technology and long-term effects; the comparative effects of diverse ablation procedures and the rate of recurrence following treatment; and the indications for treatment of dysplasia and the role of radiofrequency ablation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1749-6632.2011.06050.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632386PMC
September 2011

Anatomic classification of the endoscopic appearance of the normal appendiceal orifice: a novel tool for recognition and documentation of cecal intubation.

Clin Anat 2012 May 12;25(4):496-502. Epub 2011 Sep 12.

Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

Complete colonoscopy for cancer screening requires cecal intubation. Failure to reach and examine the cecum may result in missed right colon pathology. We developed and validated a novel classification scheme for the endoscopic appearance of the normal appendiceal orifice (AO). We analyzed 1,456 AO images and grouped them into four categories based on distinguishing features: "diverticuloid," "umbilicoid," "crescent," and "linear." An expert panel classified the images and modified these categories, combining crescent and linear categories into "curvilinear." A 100-image subset was classified twice by a validation cohort consisting of gastroenterology faculty and fellows. Inter-observer agreement among the expert panel, and intra- and inter-observer agreement among the validation cohort were analyzed using Fleiss' kappa statistic. The distribution of AO images was 67% curvilinear, 19% umbilicoid, and 10% diverticuloid; 85 images (4%) were not classifiable. There was substantial inter-observer agreement among the expert panel (κ, 0.72). Inter-observer agreement among the validation cohort was moderate (κ, 0.53 and 0.55 for the first and second viewing, respectively). Intra-observer κ values among the validation cohort were 0.69 for the overall classification, 0.65 for diverticuloid, 0.70 for umbilicoid, and 0.70 for curvilinear, indicating substantial agreement. This simple, validated classification scheme for the endoscopic appearance of the normal AO can be used both as a research and clinical tool to measure endoscopic quality, improve cecal examination, and document successful cecal intubation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ca.21276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041536PMC
May 2012

Pneumoperitoneum after esophageal cryoablation in a patient with a PEG.

Surg Laparosc Endosc Percutan Tech 2011 Jun;21(3):e141-2

Department of Gastroenterology and Nutrition, Geisinger Medical Center, Danville, PA, USA.

There is an increasing use of cryotherapy in the gastrointestinal tract for ablation of a variety of lesions. There is only a single reported case of perforation with spray cryotherapy, which was in a patient with Marfan syndrome. In this report, we describe pneumoperitoneum in a patient with a percutaneous endoscopic gastrostomy tube undergoing cryoablation. It is postulated that barotrauma at the percutaneous endoscopic gastrostomy site led to the pneumoperitoneum, and this can occur even with apparently adequate gas-venting procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SLE.0b013e31821a9034DOI Listing
June 2011

Cryotherapy for Barrett's esophagus and esophageal cancer.

Curr Opin Gastroenterol 2011 Jul;27(4):363-7

Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine and Greenebaum Cancer Center, Baltimore, Maryland 21201, USA.

Purpose Of Review: To summarize the recent literature on endoscopic spray cryotherapy for the treatment of Barrett's esophagus and esophageal cancer.

Recent Findings: Endoscopic spray cryotherapy is a relatively new ablative modality for the treatment of gastrointestinal diseases. Spray cryotherapy rapidly cools tissues by spraying them with either liquid nitrogen or rapidly expanding carbon dioxide gas. Initial, nonrandomized and uncontrolled studies show success rates comparable to other ablative modalities for the treatment of Barrett's esophagus with high-grade dysplasia, with complete eradication of dysplasia seen in 87-96% and complete eradication of intestinal metaplasia in 57-96% of treated patients. In early-stage esophageal cancer, spray cryotherapy appears to have a unique role, eliminating mucosal cancer in 75% of patients, including those who have failed other modalities. Patient tolerance of the procedure is very good. Limitations of current studies include small sample sizes and short durations of follow-up, and further studies are needed to validate the promising early results.

Summary: Endoscopic spray cryotherapy is a promising ablative modality for treatment of Barrett's esophagus and esophageal cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MOG.0b013e328347bae8DOI Listing
July 2011

Endoscopic ultrasound does not accurately stage early adenocarcinoma or high-grade dysplasia of the esophagus.

Clin Gastroenterol Hepatol 2010 Dec 8;8(12):1037-41. Epub 2010 Sep 8.

National Naval Medical Center, Bethesda, Maryland 20889, USA.

Background & Aims: Patients with esophageal high-grade dysplasia or mucosal esophageal cancer can be successfully treated by endoscopy. We performed a systematic review of the literature to determine whether endoscopic ultrasound (EUS) correctly predicts the T-stage of early esophageal cancers, compared with pathology specimens obtained by using endoscopic mucosal resection (EMR) or surgery.

Methods: Standard systematic review methods were used to perform reference searches, determine eligibility, abstract data, and analyze data. When possible, individual patient-level data were abstracted, in addition to publication-level aggregate data.

Results: Twelve studies had sufficient information to abstract and review for quality; 8 had individual patient-level data (n = 132). Compared with surgical or EMR pathology staging, EUS had T-stage concordance of 65%, including all studies (n = 12), but only 56% concordance when limited to individual patient-level data. Factors such as initial biopsy pathology (high-grade dysplasia vs early-stage cancer) did not appear to affect the concordance of staging between EUS and EMR/surgical staging.

Conclusions: EUS is not sufficiently accurate in determining the T-stage of high-grade dysplasias or superficial adenocarcinomas; other means of staging, such as EMR, should be used.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cgh.2010.08.020DOI Listing
December 2010

Outcomes after trimodality therapy for esophageal cancer: the impact of histology on failure patterns.

Am J Clin Oncol 2011 Jun;34(3):259-64

Department of Radiation Oncology, The Marlene and Stewart Greenebaum Cancer Center, The University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Objectives: This retrospective analysis of patients undergoing neoadjuvant chemoradiation followed by surgical resection was performed to determine if histology or pathologic response affected local-regional control (LRC), survival outcomes or patterns of failure.

Methods: We performed a review of 164 patients who underwent neoadjuvant chemoradiation followed by surgical resection from 1992 to 2006 for esophageal cancer. Information on patient characteristics, pathologic response, failure patterns, and survival was collected. Survival was estimated by the Kaplan-Meier method, and Cox multivariable Regression model was used to analyze trends.

Results: The median follow-up was 18 months and 27 months in surviving patients. The 3-year overall survival (OS) and LRC was 46% and 79%. The overall response for the entire cohort included a pathologic complete response (pCR) rate of 41.4%, 21.3% with microscopic residual disease (mRD) and 36.3% with gross residual disease (gRD). The 3-year OS of patients who achieved a pCR versus mRD versus gRD was 58%, 53%, and 29%. OS was significantly improved in patients with a pCR and mRD compared with gRD (P = 0.001). On multivariate analysis both pCR and mRD correlated with an improved OS. Squamous cell cancers (SCC) had a higher rate of pCR than adenocarcinomas (AC), 54% versus 34.8% (P = 0.01). The 3 year LRC for patients with SCC and AC was 100% and 71% (P = 0.03). Among SCC with recurrence, there were no local failures and all failed distantly (P = 0.001).

Conclusions: Patients with microscopic residual disease following trimodality therapy had similar outcomes to patients achieving a pCR. Patients with SCC were more likely to achieve a pCR, and had a higher propensity to fail distantly when compared with patients with AC. This data should be considered in the design of future clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/COC.0b013e3181e841ceDOI Listing
June 2011

Endoscopic spray cryotherapy for esophageal cancer: safety and efficacy.

Gastrointest Endosc 2010 Apr;71(4):686-93

Division of Gastroenterology and Hepatology, University of Maryland School of Medicine and Greenebaum Cancer Center, Baltimore, Maryland 21201-1595, USA.

Background: Few options exist for patients with localized esophageal cancer ineligible for conventional therapies. Endoscopic spray cryotherapy with low-pressure liquid nitrogen has demonstrated efficacy in this setting in early studies.

Objective: To assess the safety and efficacy of cryotherapy in esophageal carcinoma.

Design: Multicenter, retrospective cohort study.

Setting: Ten academic and community medical centers between 2006 and 2009.

Patients: Subjects with esophageal carcinoma in whom conventional therapy failed and those who refused or were ineligible for conventional therapy.

Interventions: Cryotherapy with follow-up biopsies. Treatment was complete when tumor eradication was confirmed by biopsy or when treatment was halted because of tumor progression, patient preference, or comorbid condition.

Main Outcome Measurements: Complete eradication of luminal cancer and adverse events.

Results: Seventy-nine subjects (median age 76 years, 81% male, 94% with adenocarcinoma) were treated. Tumor stage included T1-60, T2-16, and T3/4-3. Mean tumor length was 4.0 cm (range 1-15 cm). Previous treatment including endoscopic resection, photodynamic therapy, esophagectomy, chemotherapy, and radiation therapy failed in 53 subjects (67%). Forty-nine completed treatment. Complete response of intraluminal disease was seen in 31 of 49 subjects (61.2%), including 18 of 24 (75%) with mucosal cancer. Mean (standard deviation) length of follow-up after treatment was 10.6 (8.4) months overall and 11.5 (2.8) months for T1 disease. No serious adverse events were reported. Benign stricture developed in 10 (13%), with esophageal narrowing from previous endoscopic resection, radiotherapy, or photodynamic therapy noted in 9 of 10 subjects.

Limitations: Retrospective study design, short follow-up.

Conclusions: Spray cryotherapy is safe and well tolerated for esophageal cancer. Short-term results suggest that it is effective in those who could not receive conventional treatment, especially for those with mucosal cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gie.2010.01.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144145PMC
April 2010

Safety and efficacy of endoscopic spray cryotherapy for Barrett's esophagus with high-grade dysplasia.

Gastrointest Endosc 2010 Apr;71(4):680-5

Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7080, USA.

Background: Endoscopic ablation to treat Barrett's esophagus (BE) with high-grade dysplasia (HGD) is associated with a decreased incidence of esophageal adenocarcinoma. Endoscopic spray cryotherapy (CRYO) demonstrates promising preliminary data.

Objective: To assess the safety and efficacy of CRYO in BE with HGD.

Design: Multicenter, retrospective cohort study.

Setting: Nine academic and community centers; treatment period, 2007 to 2009.

Patients: Subjects with HGD confirmed by 2 pathologists. Previous EMR was allowed if residual HGD remained.

Interventions: CRYO with follow-up biopsies.

Main Outcome Measurements: Complete eradication of HGD with persistent low-grade dysplasia, complete eradication of all dysplasia with persistent nondysplastic intestinal metaplasia, and complete eradication of all intestinal metaplasia.

Results: Ninety-eight subjects (mean age 65.4 years, 83% male) with BE and HGD (mean length 5.3 cm) underwent 333 treatments (mean 3.4 treatments per subject). There were no esophageal perforations. Strictures developed in 3 subjects. Two subjects reported severe chest pain managed with oral narcotics. One subject was hospitalized for bright red blood per rectum. Sixty subjects had completed all planned CRYO treatments and were included in the efficacy analysis. Fifty-eight subjects (97%) had complete eradication of HGD, 52 (87%) had complete eradication of all dysplasia with persistent nondysplastic intestinal metaplasia, and 34 (57%) had complete eradication of all intestinal metaplasia. Subsquamous BE was found in 2 subjects (3%).

Limitations: Nonrandomized, retrospective study with no control group, short follow-up (10.5 months), lack of centralized pathology, and use of surrogate outcome for decreased cancer risk.

Conclusions: CRYO is a safe and well-tolerated therapy for BE and HGD. Short-term results suggest that CRYO is highly effective in eradicating HGD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gie.2010.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094022PMC
April 2010

Cryotherapy in the management of esophageal dysplasia and malignancy.

Gastrointest Endosc Clin N Am 2010 Jan;20(1):75-87, vi-vii

Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, MD 21201-1595, USA.

Accumulating evidence highlights the promising results seen with endoscopic spray cryotherapy in the treatment of dysplasia associated with Barrett esophagus and esophageal carcinoma. Published studies show that the success of spray cryotherapy to eradicate Barrett high-grade dysplasia is comparable to that for other therapies, with a favourable safety profile and high levels of patient comfort. For patients with untreatable esophageal cancer, spray cryotherapy offers a therapeutic option with the potential for complete eradication in early-stage disease and palliation in advanced cases. The mechanism of tissue injury in cryotherapy is unique, with direct cytotoxic effects and ischemic effects from vascular injury. Increased tumor cell death through induction of apoptosis and immunologic effects require further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.giec.2009.07.009DOI Listing
January 2010

Clinical utility of postchemoradiation endoscopic brush cytology and biopsy in predicting residual esophageal adenocarcinoma.

Cancer 2009 Dec;117(6):463-72

Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA.

Background: Esophageal adenocarcinoma generally carries a poor prognosis. Treatment with combination chemoradiation (CRT) followed by esophagectomy is becoming common. A pathologic complete response is uncommon but predicts improved survival. Identifying the subset of patients with residual carcinoma has potential management implications. Post-CRT endoscopic brush cytology and biopsy may detect residual tumor; however, the accuracy and clinical value of these methods remain unclear.

Methods: Sixty-seven patients with esophageal adenocarcinoma who underwent preoperative CRT and post-CRT endoscopic brush cytology and biopsy followed by esophagectomy were identified. By using esophagectomy histology as the gold standard, the performance of cytology and biopsy was evaluated in diagnosing residual carcinoma. Two pathologists independently reviewed all false-negative and false-positive cases and resolved disagreements by consensus.

Results: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of cytology for diagnosing residual carcinoma were 26%, 95%, 92%, 35%, and 45%, respectively. For biopsy, these rates were 13%, 90%, 75%, 31%, and 36%, respectively. Sampling error accounted for false-negative diagnoses in approximately 66% of cytology analyses and 98% of biopsy analyses. Approximately 33% of false-negative cytology analyses and 1 false-negative biopsy analysis were caused by the under-recognition of tumor cells. Major diagnostic pitfalls included obscuring acute inflammation, necrosis, tumor cells that mimicked benign cells with radiation/reactive atypia, and the under recognition of mucin-containing adenocarcinoma cells.

Conclusions: Brush cytology and biopsy were specific but not sensitive methods for predicting residual cancer after CRT. However, cytology was superior. The current results indicated that brush cytology can be used alone to diagnose residual esophageal carcinoma, and awareness of specific diagnostic pitfalls will help pathologists improve its accuracy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncy.20051DOI Listing
December 2009

Safety, tolerability, and efficacy of endoscopic low-pressure liquid nitrogen spray cryotherapy in the esophagus.

Dis Esophagus 2010 Jan 9;23(1):13-9. Epub 2009 Jun 9.

Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine and Greenebaum Cancer Center, Baltimore, Maryland 21201-1595, USA.

Endoscopic cryotherapy is a new technique for ablation of esophageal dysplasia and neoplasia. Preliminary studies have shown it to be safe and effective for this indication. The objective of this study is to characterize safety, tolerability, and efficacy of low-pressure liquid nitrogen endoscopic spray cryotherapy ablation in a large cohort across multiple study sites. Parallel prospective treatment studies at four tertiary care academic medical centers in the U.S. assessed spray cryotherapy in patients with Barrett's esophagus with or without dysplasia, early stage esophageal cancer, and severe squamous dysplasia who underwent cryotherapy ablation of the esophagus. All patients were contacted between 1 and 10 days after treatment to assess for side effects and complications of treatment. The main outcome measurement was the incidence of serious adverse events and side effects from treatment. Complete response for high-grade dysplasia (HGD) (CR-HGD), all dysplasia (CR-D), intestinal metaplasia (CR-IM) and cancer (CR-C) were assessed in patients completing therapy during the study period. A total of 77 patients were treated for Barrett's high-grade dysplasia (58.4%), intramucosal carcinoma (16.9%), invasive carcinoma (13%), Barrett's esophagus without dysplasia (9.1%), and severe squamous dysplasia (2.6%). Twenty-two patients (28.6%) reported no side effects throughout treatment. In 323 procedures, the most common complaint was chest pain (17.6%) followed by dysphagia (13.3%), odynophagia (12.1%), and sore throat (9.6%). The mean duration of any symptoms was 3.6 days. No side effects were reported in 48% of the procedures (155/323). Symptoms did not correlate with age, gender, diagnosis, or to treatment early versus late in the patient's or site's experience. Logit analysis showed that symptoms were greater in those with a Barrett's segment of 6 cm or longer. Gastric perforation occurred in one patient with Marfan's syndrome. Esophageal stricture developed in three, all successfully treated with dilation. In 17 HGD patients, cryotherapy produced CR-HGD, CR-D, and CR-IM of 94%, 88%, and 53%, respectively. Complete regression of cancer and HGD was seen in all seven patients with intramucosal carcinoma or stage I esophageal cancer. Endoscopic spray cryotherapy ablation using low-pressure liquid nitrogen in the esophagus is safe, well-tolerated, and efficacious.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1442-2050.2009.00991.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144029PMC
January 2010