The past, present, and future of immunotherapy for endometrial adenocarcinoma.

Incidences of endometrial adenocarcinoma are increasing in the USA with poor prognosis for patients with advanced disease. The current treatment standard is surgery including total hysterectomy and bilateral oophorectomy with surgical staging and adjunct treatment, such as chemotherapy or radiation. However, these methods do not present as an effective treatment option for poorly differentiated advanced cancers. Advancements in immunotherapy now offer a new approach for various types of cancer and specifically show promise in the treatment of endometrial adenocarcinoma. This review summarizes immunotherapeutic treatment options relevant to endometrial adenocarcinoma, such as immune checkpoint blockades, bispecific T-cell engager antibodies, vaccinations, and adoptive cell transfer. This study could be helpful for clinicians to identify treatment options more suitable for women with late-stage endometrial adenocarcinoma.

Prostate field cancerization and exosomes: Association between CD9, early growth response 1 and fatty acid synthase.

Intracapsular and well­defined adenocarcinomas of the prostate are often surrounded by tissue areas that harbor molecular aberrations, including those of genetic, epigenetic and biochemical nature. This is known as field cancerization, or a field effect and denotes a state of pre­malignancy. Such alterations in histologically normal tumor­adjacent prostatic tissues have been recognized as clinically important and are potentially exploitable as biomarkers of disease and/or targets for preventative/therapeutic intervention. The authors have previously identified and validated two protein markers of field cancerization: The expressional upregulation of the transcription factor early growth response 1 (EGR­1) and the lipogenic enzyme fatty acid synthase (FASN). However, the molecular etiology of prostate field cancerization, including EGR­1 and FASN upregulation, remains largely unknown. It was thus hypothesized that extracellular vesicles, notably exosomes, released by tumor lesions may induce molecular alterations in the surrounding tissues, resulting in field cancerization, priming the tissue, and ultimately promoting multifocal tumorigenesis, which is often observed in prostate cancer. Towards testing this hypothesis, the current study, to the best of our knowledge, for the first time, presents correlative protein expression data, generated in disease­free, tumor­adjacent and cancerous human prostate tissues by quantitative immunofluorescence, between the exosomal marker CD9, and EGR­1 and FASN. Despite the pilot character of the present study, and the static nature and heterogeneity of human tissues, the data suggest that CD9 expression itself is part of a field effect. In support of this hypothesis, the results suggest a possible contribution of exosomes to the induction of field cancerization in the prostate, particularly for EGR­1. These findings were corroborated in established cell models of cancerous (LNCaP) and non­cancerous (RWPE­1) human prostate epithelial cells. The findings of this study warrant further investigation into the functional interface between exosomes and field cancerization, as a detailed understanding of this characterization may lead to the development of clinical applications related to diagnosis and/or prognosis and targeted intervention to prevent progression from pre­malignancy to cancer.

The role of motion and intensity in deaf children's recognition of real human facial expressions of emotion.

There is substantial evidence to suggest that deafness is associated with delays in emotion understanding, which has been attributed to delays in language acquisition and opportunities to converse. However, studies addressing the ability to recognise facial expressions of emotion have produced equivocal findings. The two experiments presented here attempt to clarify emotion recognition in deaf children by considering two aspects: the role of motion and the role of intensity in deaf children's emotion recognition. In Study 1, 26 deaf children were compared to 26 age-matched hearing controls on a computerised facial emotion recognition task involving static and dynamic expressions of 6 emotions. Eighteen of the deaf and 18 age-matched hearing controls additionally took part in Study 2, involving the presentation of the same 6 emotions at varying intensities. Study 1 showed that deaf children's emotion recognition was better in the dynamic rather than static condition, whereas the hearing children showed no difference in performance between the two conditions. In Study 2, the deaf children performed no differently from the hearing controls, showing improved recognition rates with increasing rates of intensity. With the exception of disgust, no differences in individual emotions were found. These findings highlight the importance of using ecologically valid stimuli to assess emotion recognition.

Association and regulation of protein factors of field effect in prostate tissues.

Field effect or field cancerization denotes the presence of molecular aberrations in structurally intact cells residing in histologically normal tissues adjacent to solid tumors. Currently, the etiology of prostate field­effect formation is unknown and there is a prominent lack of knowledge of the underlying cellular and molecular pathways. We have previously identified an upregulated expression of several protein factors representative of prostate field effect, i.e., early growth response-1 (EGR­1), platelet-derived growth factor­A (PDGF­A), macrophage inhibitory cytokine­1 (MIC­1), and fatty acid synthase (FASN) in tissues at a distance of 1 cm from the visible margin of intracapsule prostate adenocarcinomas. We have hypothesized that the transcription factor EGR­1 could be a key regulator of prostate field­effect formation by controlling the expression of PDGF­A, MIC­1, and FASN. Taking advantage of our extensive quantitative immunofluorescence data specific for EGR­1, PDGF­A, MIC­1, and FASN generated in disease­free, tumor­adjacent, and cancerous human prostate tissues, we chose comprehensive correlation as our major approach to test this hypothesis. Despite the static nature and sample heterogeneity of association studies, we show here that sophisticated data generation, such as by spectral image acquisition, linear unmixing, and digital quantitative imaging, can provide meaningful indications of molecular regulations in a physiologically relevant in situ environment. Our data suggest that EGR­1 acts as a key regulator of prostate field effect through induction of pro­proliferative (PDGF­A and FASN), and suppression of pro­apoptotic (MIC­1) factors. These findings were corroborated by computational promoter analyses and cell transfection experiments in non­cancerous prostate epithelial cells with ectopically induced and suppressed EGR­1 expression. Among several clinical applications, a detailed knowledge of pathways of field effect may lead to the development of targeted intervention strategies preventing progression from pre-malignancy to cancer.

Confronting the language barrier: Theory of mind in deaf children.

UNLABELLED: The current study addressed deaf children's Theory of Mind (ToM) development as measured by a battery of first- and second-order belief tasks. Both a chronological age-matched control group and a younger group of pre-school aged hearing children were compared to a group of deaf children born to hearing parents. A hearing native signer enacted each of the tasks, which were pre-recorded in video clips in English (SSE), British Sign Language (BSL) and spoken English, in order to consider all communication preferences of the deaf children. Results revealed no differences in performance between the deaf and the young hearing children. However, despite the inclusion of ToM tasks based on their preferred mode of communication, the deaf children performed significantly worse at the unexpected-content and second-order belief task compared with their age-matched controls. These findings imply a delay rather than a deficit in ToM in deaf children that could be attributed to limited opportunities to converse and overhear conversations about mental states. LEARNING OUTCOMES: None.

Prostate field cancerization: deregulated expression of macrophage inhibitory cytokine 1 (MIC-1) and platelet derived growth factor A (PDGF-A) in tumor adjacent tissue.

Prostate field cancerization denotes molecular alterations in histologically normal tissues adjacent to tumors. Such alterations include deregulated protein expression, as we have previously shown for the key transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS). Here we add the two secreted factors macrophage inhibitory cytokine 1 (MIC-1) and platelet derived growth factor A (PDGF-A) to the growing list of protein markers of prostate field cancerization. Expression of MIC-1 and PDGF-A was measured quantitatively by immunofluorescence and comprehensively analyzed using two methods of signal capture and several groupings of data generated in human cancerous (n = 25), histologically normal adjacent (n = 22), and disease-free (n = 6) prostate tissues. A total of 208 digitized images were analyzed. MIC-1 and PDGF-A expression in tumor tissues were elevated 7.1x to 23.4x and 1.7x to 3.7x compared to disease-free tissues, respectively (p<0.0001 to p = 0.08 and p<0.01 to p = 0.23, respectively). In support of field cancerization, MIC-1 and PDGF-A expression in adjacent tissues were elevated 7.4x to 38.4x and 1.4x to 2.7x, respectively (p<0.0001 to p<0.05 and p<0.05 to p = 0.51, respectively). Also, MIC-1 and PDGF-A expression were similar in tumor and adjacent tissues (0.3x to 1.0x; p<0.001 to p = 0.98 for MIC-1; 0.9x to 2.6x; p<0.01 to p = 1.00 for PDGF-A). All analyses indicated a high level of inter- and intra-tissue heterogeneity across all types of tissues (mean coefficient of variation of 86.0%). Our data shows that MIC-1 and PDGF-A expression is elevated in both prostate tumors and structurally intact adjacent tissues when compared to disease-free specimens, defining field cancerization. These secreted factors could promote tumorigenesis in histologically normal tissues and lead to tumor multifocality. Among several clinical applications, they could also be exploited as indicators of disease in false negative biopsies, identify areas of repeat biopsy, and add molecular information to surgical margins.

Markers of field cancerization: proposed clinical applications in prostate biopsies.

Field cancerization denotes the occurrence of genetic, epigenetic, and biochemical aberrations in structurally intact cells in histologically normal tissues adjacent to cancerous lesions. This paper tabulates markers of prostate field cancerization known to date and discusses their potential clinical value in the analysis of prostate biopsies, including diagnosis, monitoring progression during active surveillance, and assessing efficacy of presurgical neoadjuvant and focal therapeutic interventions.

Early growth response 1 and fatty acid synthase expression is altered in tumor adjacent prostate tissue and indicates field cancerization.

BACKGROUND: Field cancerization denotes the occurrence of molecular alterations in histologically normal tissues adjacent to tumors. In prostate cancer, identification of field cancerization has several potential clinical applications. However, prostate field cancerization remains ill defined. Our previous work has shown up-regulated mRNA of the transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS) in tissues adjacent to prostate cancer. METHODS: Immunofluorescence data were analyzed quantitatively by spectral imaging and linear unmixing to determine the protein expression levels of EGR-1 and FAS in human cancerous, histologically normal adjacent, and disease-free prostate tissues. RESULTS: EGR-1 expression was elevated in both structurally intact tumor adjacent (1.6× on average) and in tumor (3.0× on average) tissues compared to disease-free tissues. In addition, the ratio of cytoplasmic versus nuclear EGR-1 expression was elevated in both tumor adjacent and tumor tissues. Similarly, FAS expression was elevated in both tumor adjacent (2.7× on average) and in tumor (2.5× on average) compared to disease-free tissues. CONCLUSIONS: EGR-1 and FAS expression is similarly deregulated in tumor and structurally intact adjacent prostate tissues and defines field cancerization. In cases with high suspicion of prostate cancer but negative biopsy, identification of field cancerization could help clinicians target areas for repeat biopsy. Field cancerization at surgical margins on prostatectomy specimen should also be looked at as a predictor of cancer recurrence. EGR-1 and FAS could also serve as molecular targets for chemoprevention.

Breast field cancerization: isolation and comparison of telomerase-expressing cells in tumor and tumor adjacent, histologically normal breast tissue.

Telomerase stabilizes chromosomes by maintaining telomere length, immortalizes mammalian cells, and is expressed in more than 90% of human tumors. However, the expression of human telomerase reverse transcriptase (hTERT) is not restricted to tumor cells. We have previously shown that a subpopulation of human mammary epithelial cells (HMEC) in tumor-adjacent, histologically normal (TAHN) breast tissues expresses hTERT mRNA at levels comparable with levels in breast tumors. In the current study, we first validated a reporter for measuring levels of hTERT promoter activity in early-passage HMECs and then used this reporter to compare hTERT promoter activity in HMECs derived from tumor and paired TAHN tissues 1, 3, and 5 cm from the tumor (TAHN-1, TAHN-3, and TAHN-5, respectively). Cell sorting, quantitative real-time PCR, and microarray analyses showed that the 10% of HMECs with the highest hTERT promoter activity in both tumor and TAHN-1 tissues contain more than 95% of hTERT mRNA and overexpress many genes involved in cell cycle and mitosis. The percentage of HMECs within this subpopulation showing high hTERT promoter activity was significantly reduced or absent in TAHN-3 and TAHN-5 tissues. We conclude that the field of "normal tissue" proximal to the breast tumors contains a population of HMECs similar in hTERT expression levels and in gene expression to the HMECs within the tumor mass and that this population is significantly reduced in tissues more distal to the tumor.

Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors.

Previous studies have shown that a field of genetically altered but histologically normal tissue extends 1 cm or more from the margins of human breast tumors. The extent, composition and biological significance of this field are only partially understood, but the molecular alterations in affected cells could provide mechanisms for limitless replicative capacity, genomic instability and a microenvironment that supports tumor initiation and progression. We demonstrate by microarray, qRT-PCR and immunohistochemistry a signature of differential gene expression that discriminates between patient-matched, tumor-adjacent histologically normal breast tissues located 1 cm and 5 cm from the margins of breast adenocarcinomas (TAHN-1 and TAHN-5, respectively). The signature includes genes involved in extracellular matrix remodeling, wound healing, fibrosis and epithelial to mesenchymal transition (EMT). Myofibroblasts, which are mediators of wound healing and fibrosis, and intra-lobular fibroblasts expressing MMP2, SPARC, TGF-ß3, which are inducers of EMT, were both prevalent in TAHN-1 tissues, sparse in TAHN-5 tissues, and absent in normal tissues from reduction mammoplasty. Accordingly, EMT markers S100A4 and vimentin were elevated in both luminal and myoepithelial cells, and EMT markers α-smooth muscle actin and SNAIL were elevated in luminal epithelial cells of TAHN-1 tissues. These results identify cellular processes that are differentially activated between TAHN-1 and TAHN-5 breast tissues, implicate myofibroblasts as likely mediators of these processes, provide evidence that EMT is occurring in histologically normal tissues within the affected field and identify candidate biomarkers to investigate whether or how field cancerization contributes to the development of primary or recurrent breast tumors.

Endoscopy has minimal impact on mortality from upper gastrointestinal cancer in patients older than 55 years with uncomplicated dyspepsia.

INTRODUCTION: The objective of the study was to determine the effectiveness of endoscopy to detect curable upper gastrointestinal malignancy in patients older than 55 years presenting with uncomplicated dyspepsia. METHODS: A cohort study was performed in North Glasgow Health Trust. One hundred and thirty-one patients older than 55 years of age, diagnosed to have upper gastrointestinal cancer within the North Glasgow Trust between January 1995 and December 1997, identified by the West of Scotland Cancer Registry were included. The main outcome measures were the proportion of upper gastrointestinal cancers that present in patients older than 55 years with uncomplicated dyspepsia, and the proportion of patients that presented with uncomplicated dyspepsia who have curable upper gastrointestinal cancer. RESULTS: Of the 131 cancer cases identified, only 30 (23%) had dyspepsia (complicated or uncomplicated) as their predominant symptom and only eight (6%) patients presented with uncomplicated dyspepsia. Of those eight patients presenting with uncomplicated dyspepsia and found to have upper gastrointestinal cancer, six were found to have lymph node metastases and/or extensive metastases at the time of diagnosis. Each of these six patients died from their cancer within 39 months of diagnosis. Of the two patients presenting with uncomplicated dyspepsia without evidence of lymph node spread, one died 55 days after diagnosis. Only one patient presenting with uncomplicated dyspepsia and found to have cancer remains alive at 5-year follow-up. CONCLUSIONS: Of the 131 patients diagnosed with upper gastrointestinal cancer, only eight presented with uncomplicated dyspepsia and only one of these was cured. Consequently a policy of endoscoping patients older than 55 years with uncomplicated dyspepsia will reduce death from upper gastrointestinal cancers by less than 1% in our population.