Frank McKeon

Cervical squamocolumnar junction-specific markers define distinct, clinically relevant subsets of low-grade squamous intraepithelial lesions

Low-grade cervical squamous abnormalities (low-grade squamous intraepithelial lesions [LSIL, CIN1]) can be confused with or followed by high-grade (HSIL, CIN2/3) lesions, expending considerable resources. Recently, a cell of origin for cervical neoplasia was proposed in the squamocolumnar junction (SCJ); HSILs are almost always SCJ+, but LSILs include SCJ+ and SCJ− subsets. Abnormal cervical biopsies from 214 patients were classified by 2 experienced pathologists (panel) as LSIL or HSIL using published criteria. SILs were scored SCJ+ and SCJ− using SCJ-specific antibodies (keratin7, AGR2, MMP7, and GDA). Assessments of interobserver agreement, p16ink4 staining pattern, proliferative index, and outcome were compared. The original diagnostician agreed with the panel diagnosis of HSIL and SCJ− LSIL in all cases (100%). However, for SCJ+ LSIL, panelists disagreed with each other by 15% and with the original diagnostician by 46.2%. Comparing SCJ− and SCJ+ LSILs, 60.2% and 94.9% were p16ink4 positive, 23% and 74.4% showed strong (full-thickness) p16ink4 staining, and 0/54 (0%) and 8/33 (24.2%) with follow-up had an HSIL outcome, respectively. Some SCJ+ LSILs are more likely to both generate diagnostic disagreement and be associated with HSIL. Conversely, SCJ− LSILs generate little observer disagreement and, when followed, have a very low risk of HSIL outcome. Thus, SCJ biomarkers in conjunction with histology may segregate LSILs with very low risk of HSIL outcome and conceivably could be used as a management tool to reduce excess allocation of resources to the follow-up of these lesions.

Quality Indicators for the Management of Barrett’s Esophagus, Dysplasia, and Esophageal Adenocarcinoma: International Consensus Recommendations from the American Gastroenterological Association Symposium

The development of and adherence to quality indicators in gastroenterology, as in all of medicine, is increasing in importance to ensure that patients receive consistent high-quality care. In addition, government-based and private insurers will be expecting documentation of the parameters by which we measure quality, which will likely affect reimbursements. Barretts esophagus remains a particularly important disease entity for which we should maintain up-to-date guidelines, given its commonality, potentially lethal outcomes, and controversies regarding screening and surveillance. To achieve this goal, a relatively large group of international experts was assembled and, using the modified Delphi method, evaluated the validity of multiple candidate quality indicators for the diagnosis and management of Barretts esophagus. Several candidate quality indicators achieved >80% agreement. These statements are intended to serve as a consensus on candidate quality indicators for those who treat patients with Barretts esophagus.

Mutational spectrum of Barrett's stem cells suggests paths to initiation of a precancerous lesion.

The precancerous lesion known as Barretts oesophagus can evolve to oesophageal adenocarcinoma in decades-long processes of regenerative growth. Here we report the isolation and propagation of distinct, patient-matched stem cells of Barretts, gastric and oesophageal epithelia that yield divergent tumour types following in vitro transformation and xenografting. Genomic analyses reveal a broad mutational spectrum unique to Barretts stem cells that likely reflects their risk for oncogenesis. Remarkably, 25% of cases show no cancer-related genomic changes, suggesting that Barretts initiates without driver mutations. Most cases, however, sustain patterns of deletions almost identical to adenocarcinoma though tumour-associated gene amplifications were absent. Notably, those suspected of low-grade dysplasia have p53 mutations or undergo amplifications of proto-oncogenes and receptor tyrosine kinases, implicating these events in lethal transitions. Our findings suggest paths for the initiation and progression of Barretts and define a discrete stem cell underlying its regenerative growth whose eradication could prevent oesophageal adenocarcinoma.

Adult stem cells underlying lung regeneration

Despite the massive toll in human suffering imparted by degenerative lung disease, including COPD, idiopathic pulmonary fibrosis and ARDS, the scientific community has been surprisingly agnostic regarding the potential of lung tissue, and in particular the alveoli, to regenerate. However, there is circumstantial evidence in humans and direct evidence in mice that ARDS triggers robust regeneration of lung tissue rather than irreversible fibrosis. The stem cells responsible for this remarkable regenerative process has garnered tremendous attention, most recently yielding a defined set of cloned human airway stem cells marked by p63 expression but with distinct commitment to differentiated cell types typical of the upper or lower airways, the latter of which include alveoli-like structures in vitro and in vivo. These recent advances in lung regeneration and distal airway stem cells and the potential of associated soluble factors in regeneration must be harnessed for therapeutic options in chronic lung disease.

Iron addiction: a novel therapeutic target in ovarian cancer

Ovarian cancer is a lethal malignancy that has not seen a major therapeutic advance in over 30 years. We demonstrate that ovarian cancer exhibits a targetable alteration in iron metabolism. Ferroportin (FPN), the iron efflux pump, is decreased, and transferrin receptor (TFR1), the iron importer, is increased in tumor tissue from patients with high grade but not low grade serous ovarian cancer. A similar profile of decreased FPN and increased TFR1 is observed in a genetic model of ovarian cancer tumor-initiating cells (TICs). The net result of these changes is an accumulation of excess intracellular iron and an augmented dependence on iron for proliferation. A forced reduction in intracellular iron reduces the proliferation of ovarian cancer TICs in vitro, and inhibits both tumor growth and intraperitoneal dissemination of tumor cells in vivo. Mechanistic studies demonstrate that iron increases metastatic spread by facilitating invasion through expression of matrix metalloproteases and synthesis of interleukin 6 (IL-6). We show that the iron dependence of ovarian cancer TICs renders them exquisitely sensitive in vivo to agents that induce iron-dependent cell death (ferroptosis) as well as iron chelators, and thus creates a metabolic vulnerability that can be exploited therapeutically.

A Summary of the 2016 James W. Freston Conference of the American Gastroenterological Association: Intestinal Metaplasia in the Esophagus and Stomach: Origins, Differences, Similarities and Significance

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 A Summary of the 2016 James W. Freston Conference of the American Gastroenterological Association: Intestinal Metaplasia in the Esophagus and Stomach: Origins, Differences, Similarities and Significance 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 Stuart J. Spechler, Juanita L. Merchant, Timothy C. Wang, Parakrama Chandrasoma, James G. Fox, Robert M. Genta, James R. Goldenring, Yoku Hayakawa, Ernst J. Kuipers, Pauline K. Lund, Frank McKeon, Jason Mills, Robert D. Odze, Richard M. Peek, Jr., Thai Pham, Jianwen Que, Anil K. Rustgi, Nicholas J. Shaheen, Ramesh A. Shivdasani, Rhonda Souza, Peter Storz, Andrea Todisco, David H. Wang, and Nicholas A. Wright

CEACAM 6, a novel marker for the diagnosis of Barrett's esophagus

Barretts esophagus (BE) is a premalignant condition associated with the development of esophageal adenocarcinoma (EAC). Despite the low risk of progression to EAC, evidence highlights the notably poor survival rates of this malignancy. The mainstay form of diagnosis of BE is endoscopy and biopsy sampling. However, research emphasizes limitations with regards to the histological detection of BE and associated dysplasia. The aim of this study is to evaluate the clinical significance of CEACAM6 as a potential biomarker for the diagnosis of BE and beyond. Retrospective tissue samples were obtained from columnar lined esophagus without goblet cells (n = 27), BE (n = 18), BE associated dysplasia (n = 16), and EAC (n = 24). Standardized immunohistochemistry for CEACAM6 was performed followed by quantitative staining analysis. Statistical analysis across the BE spectrum for CEACAM6 was undertaken and a P value <0.05 was considered significant. CEACAM6 expression increased from columnar lined epithelium (CLE) to BE with a subsequent decrease to dysplasia and adenocarcinoma. The expression of CEACAM6 was significant from CLE to BE at p 0.001, CLE to dysplasia at p 0.001, BE to dysplasia at p 0.006, CLE to adenocarcinoma at p 0.001 and BE to adenocarcinoma at p 0.001. There was no significant difference in expression between dysplasia and adenocarcinoma (P = 0.15). Our findings highlight the increasing expression of CEACAM6 from CLE to BE with a subsequent decrease to dysplasia and adenocarcinoma. In view of this, we advocate the utilization of this marker for the enhanced diagnosis of BE and for the distinction of BE and dysplasia.

TAp63 as a guardian of female germ line integrity

A new study reveals how the oocyte-specific transcription factor TAp63 ensures female germ line fidelity and describes approaches to circumvent premature ovarian insufficiency in women receiving cytotoxic chemotherapy.

Demise of lung transplants: exposing critical gaps in understanding lung stem cells

Lung transplantation is the only potentially curative therapy for end-stage chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF), which together claim the lives of 150,000 patients each year in the USA (1). Yet less than 2,000 of these procedures are performed each year in the US due to donor availability, the need of specialized surgical and medical teams, and the overall unit costs that are approaching one million dollars.

Abstract 114: Study of the high-grade ovarian cancer precursors in the oviduct

The discovery that many high-grade ovarian cancers originate in the oviduct has generated a paradigm shift in the field of ovarian cancer. The description of new entities in the oviduct that signify early phases of ovarian carcinogenesis, including both serous tubal intraepithelial carcinomas and their precursors the p53 signatures, has provided a tangible sequence of events leading to malignancy that can be linked to DNA damage and p53 mutations. However, it has become clear that other pathway disturbances also play a critical role in the early development of ovarian cancer. We hypothesize that molecular alterations present in morphologically normal oviductal epithelium from ovarian cancer patients reflect the earliest events in ovarian carcinogenesis and may be markers of increased cancer risk as well as targets for risk reduction. Whole-genome transcriptome analysis of laser microdissected oviductal epithelium from histologically normal ovarian cancer patients and controls was performed. We identified a set of aberrantly expressed genes in the oviductal epithelium from women who developed high-grade ovarian cancer and demonstrated some of these genes are also abnormally expressed in the ovarian cancers due to the genomic alterations. We further examined the function of these genes using three-dimensional cell culture system and mouse models. Our work demonstrates the synergistic effects of defective p53 pathway and other newly found pathways in driving early steps of ovarian cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 114. doi:1538-7445.AM2012-114