Search

The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune "cold" ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC. Integration of mathematical modeling, ecological analyses of patient biopsies, and neoantigen heterogeneity suggests recruitment of immunosuppressive cells is key to initializing transformation from adenoma to carcinoma in human colorectal cancer. [ABSTRACT FROM AUTHOR]

Purpose: Radiologic follow-up of patients with a meningioma at the skull base or near the venous sinuses with magnetic resonance imaging (MRI) after stereotactic radiotherapy (SRT) and neurosurgical resection(s) can be difficult to interpret. This study evaluates the addition of 11C-methionine positron emission tomography (MET-PET) to the regular MRI follow-up. Methods: This prospective pilot study included patients with predominantly WHO grade I meningiomas at the skull base or near large vascular structures. Previous SRT was part of their oncological treatment. A MET-PET in adjunct to their regular MRI follow-up was performed. The standardized uptake value (SUV) was determined for the tumor and the healthy brain, on the pre-SRT target delineation MET-PET and the follow-up MET-PET. Tumor-to-normal ratios were calculated, and 11C-methionine uptake over time was analyzed. Agreement between the combined MRI/MET-PET report and the MRI-only report was determined using Cohen's κ. Results: Twenty patients with stable disease underwent an additional MET-PET, with a median follow-up of 84 months after SRT. Post-SRT SUV T/N ratios ranged between 2.16 and 3.17. When comparing the pre-SRT and the post-SRT MET-PET, five categories of SUV T/N ratios did not change significantly. Only the SUVpeak T/Ncortex decreased significantly from 2.57 (SD 1.02) to 2.20 (SD 0.87) [p = 0.004]. A κ of 0.77 was found, when comparing the MRI/MET-PET report to the MRI-only report, indicating no major change in interpretation of follow-up data. Conclusion: In this pilot study, 11C-methionine uptake remained remarkably high in meningiomas with long-term follow-up after SRT. Adding MET-PET to the regular MRI follow-up had no impact on the interpretation of follow-up imaging. [ABSTRACT FROM AUTHOR]

Background: Tumour hypoxia is associated with metastatic disease, and while there have been many mechanisms proposed for why tumour hypoxia is associated with metastatic disease, it remains unclear whether one precise mechanism is the key reason or several in concert. Somatic evolution drives cancer progression and treatment resistance, fuelled not only by genetic and epigenetic mutation but also by selection from interactions between tumour cells, normal cells and physical micro-environment. Ecological habitats influence evolutionary dynamics, but the impact on tempo of evolution is less clear.Methods: We explored this complex dialogue with a combined clinical-theoretical approach by simulating a proliferative hierarchy under heterogeneous oxygen availability with an agent-based model. Predictions were compared against histology samples taken from glioblastoma patients, stained to elucidate areas of necrosis and TP53 expression heterogeneity.Results: Results indicate that cell division in hypoxic environments is effectively upregulated, with low-oxygen niches providing avenues for tumour cells to spread. Analysis of human data indicates that cell division is not decreased under hypoxia, consistent with our results.Conclusions: Our results suggest that hypoxia could be a crucible that effectively warps evolutionary velocity, making key mutations more likely. Thus, key tumour ecological niches such as hypoxic regions may alter the evolutionary tempo, driving mutations fuelling tumour heterogeneity. [ABSTRACT FROM AUTHOR]

Background: Esophageal adenocarcinoma carries a poor prognosis and therefore treatment of early neoplasia arising in the precursor condition Barrett's esophagus (BE) is desirable. Visible lesions arising in BE need endoscopic mucosal resection for accurate staging and removal. Resection modalities include a cap-based system with snare and custom-made multiband mucosectomy (MBM) devices (Duette, Cook Medical Ltd). A new MBM device has recently become available (Captivator, Boston Scientific Ltd).Objectives: A retrospective pilot study to compare the efficacy, safety, specimen size and histology of endoscopic mucosal resection (EMR) specimens resected with two MBM devices (Cook Duette and Boston Captivator) in treatment naive patients undergoing endoscopic therapy for BE neoplasia.Methods: Consecutive EMR procedures carried out by a single experienced endoscopist were analysed. All visible lesions were marked and resected using one of the two MBM devices. All resected specimens were analysed by the same two experienced pathologists. The resected specimens in both groups were analysed for maximum diameter, minimum diameter, surface area and depth.Results: Twenty consecutive patients were analysed (18M + 2F; mean age 74) in the Duette group and 20 (17M + 3F; mean age 72) in the Captivator group. A total of 58 specimens were resected in the Duette and 63 in the Captivator group. Min diameter, max diameter, surface area and depth of the ER specimens resected by the Captivator device were significantly larger than that by the Duette device [min diameter 9.89 mm vs 9.07 mm (p = 0.019); max diameter: 13.54 mm vs 12.38 mm (p = 0.024); surface area: 135.40 mm2 vs 113.89 mm2 (p = 0.005); depth 3.71 mm vs 2.89 (p = 0.001)].Conclusions: These two MBM devices showed equivalent efficacy and safety outcomes, but the EMR Captivator device resected specimens with a larger area in the esophagus when compared with the Duette device. A possible advantage of this is in situations where en bloc resections with fewer EMRs are desirable for larger lesions. [ABSTRACT FROM AUTHOR]

Barrett's oesophagus surveillance biopsies represent a significant share of the daily workload for a busy histopathology department. Given the emphasis on endoscopic detection and dysplasia grading, it is easy to forget that the benefits of these screening programs remain unproven. The majority of patients are at low risk of progression to oesophageal adenocarcinoma, and periodic surveillance of these patients is burdensome and costly. Here, we investigate the parallels in the development of Barrett's oesophagus and other scenarios of wound healing in the intestine. There is now increased recognition of the full range of glandular phenotypes that can be found in patients' surveillance biopsies, and emerging evidence suggests parallel pathways to oesophageal adenocarcinoma. Greater understanding of the conditions that favour progression to cancer in the distal oesophagus will allow us to focus resources on patients at increased risk. [ABSTRACT FROM AUTHOR]

Intra-tumor heterogeneity (ITH) is a major underlying cause of therapy resistance and disease recurrence, and is a read-out of tumor growth. Current genetic ITH analysis methods do not preserve spatial context and may not detect rare subclones. Here, we address these shortfalls by developing and validating BaseScope--a novel mutation-specific RNA in situ hybridization assay. We target common point mutations in the BRAF, KRAS and PIK3CA oncogenes in archival colorectal cancer samples to precisely map the spatial and morphological context of mutant subclones. Computational modeling suggests that subclones must arise sufficiently early, or carry a considerable fitness advantage, to form large or spatially disparate subclones. Examples of putative treatment-resistant cells isolated in small topographical areas are observed. The BaseScope assay represents a significant technical advance for in situ mutation detection that provides new insight into tumor evolution, and could have ramifications for selecting patients for treatment. [ABSTRACT FROM AUTHOR]

Colon cancer is a clinically diverse disease. This heterogeneity makes it difficult to determine which patients will benefit most from adjuvant therapy and impedes the development of new targeted agents. More insight into the biological diversity of colon cancers, especially in relation to clinical features, is therefore needed. We demonstrate, using an unsupervised classification strategy involving over 1,100 individuals with colon cancer, that three main molecularly distinct subtypes can be recognized. Two subtypes have been previously identified and are well characterized (chromosomal-instable and microsatellite-instable cancers). The third subtype is largely microsatellite stable and contains relatively more CpG island methylator phenotype-positive carcinomas but cannot be identified on the basis of characteristic mutations. We provide evidence that this subtype relates to sessile-serrated adenomas, which show highly similar gene expression profiles, including upregulation of genes involved in matrix remodeling and epithelial-mesenchymal transition. The identification of this subtype is crucial, as it has a very unfavorable prognosis and, moreover, is refractory to epidermal growth factor receptor-targeted therapy. [ABSTRACT FROM AUTHOR]

Familial cancer syndromes present rare insights into malignant tumor development. The molecular background of polyp formation and the cancer prone state in Peutz-Jeghers syndrome remain enigmatic to this day. Previously, we proposed that Peutz-Jeghers polyps are not pre-malignant lesions, but an epiphenomenon to the malignant condition. However, Peutz-Jeghers polyp formation and the cancer-prone state must both be accounted for by the same molecular mechanism. Our contribution focuses on the histopathology of the characteristic Peutz-Jeghers polyp and recent research on stem cell dynamics and how these concepts relate to Peutz-Jeghers polyposis. We discuss a protracted clonal evolution scenario in Peutz-Jeghers syndrome due to a germline LKB1 mutation. Peutz-Jeghers polyp formation and malignant transformation are separately mediated through the same molecular mechanism played out on different timescales. Thus, a single mechanism accounts for the development of benign Peutz-Jeghers polyps and for malignant transformation in Peutz-Jeghers syndrome. [ABSTRACT FROM AUTHOR]

The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome and exome sequencing of 24 benign and malignant colorectal tumours, we investigate the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations-considered to be functionally important in the carcinogenic process-that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a 'punctuated' fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilizing selection.