Analysis of tumor-infiltrating lymphocytes (TIL) in primary human colorectal cancer (CRC) by in situ immunohistochemical staining supports the hypothesis that the adaptive immune response influences ...the course of human CRC. Specifically, high densities of TILs in the primary tumor are associated with good prognosis independent of other prognostic markers. However, the prognostic role of TILs in metastatic CRC lesions is unknown, as is their role in response or resistance to conventional chemotherapy. We analyzed the association of TIL densities at the invasive margin of CRC liver metastases with response to chemotherapy and progression-free survival in a set of 101 large section samples. High-resolution automated microscopy on complete tissue sections was used to objectively generate cell densities for CD3, CD8, granzyme B, or FOXP3 positive immune cells. A predictive scoring system using TIL densities was developed in a training set and tested successfully in an independent validation set. TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. The association of high density values with longer progression-free survival under chemotherapy was statistically significant. Overall, these findings extend the impact of the local immune response on the clinical course from the primary tumor also to metastatic lesions. Because detailed quantification of TILs in metastatic lesions revealed a strong association with chemotherapy efficacy and prognosis, we suggest that the developed scoring system may be used as a predictive tool for response to chemotherapy in metastatic CRC.
The tumor edge of colorectal cancer and its adjacent peritumoral tissue is characterized by an invasion front‐specific expression of genes that contribute to angiogenesis or epithelial‐to‐mesenchymal ...transition. Dysregulation of these genes has a strong impact on the invasion behavior of tumor cells. However, the invasion front‐specific expression of microRNA (miRNA) still remains unclear. Therefore, the aim of the present study was to investigate miRNA expression patterns at the invasion front of colorectal liver metastases. Laser microdissection of colorectal liver metastases was performed to obtain separate tissue compartments from the tumor center, tumor invasion front, liver invasion front and pure liver parenchyma. Microarray expression analysis revealed 23 miRNA downregulated in samples from the tumor invasion front with respect to the same miRNA in the liver, the liver invasion front or the tumor center. By comparing samples from the liver invasion front with samples from pure liver parenchyma, the tumor invasion front and the tumor center, 13 miRNA were downregulated. By quantitative RT‐PCR, we validated the liver invasion front‐specific downregulation of miR‐19b, miR‐194, let‐7b and miR‐1275 and the tumor invasion front‐specific downregulation of miR‐143, miR‐145, let‐7b and miR‐638. Univariate analysis demonstrated that enhanced expression of miR‐19b and miR‐194 at the liver invasion front, and decreased expression of let‐7 at the tumor invasion front, is an adverse prognostic marker of tumor recurrence and overall survival. In conclusion, the present study suggests that invasion front‐specific downregulation of miRNA in colorectal liver metastases plays a pivotal role in tumor progression. (Cancer Sci 2011; 102: 1799–1807)
Highlights • Analysis of salinomycin in an orthotopic syngeneic pancreatic cancer mouse model. • Salinomycin significantly inhibits cancer cell migration. • Salinomycin affects the actin cytoskeleton ...disrupts stress fibers. • Loss of stress fiber integrity is caused by RhoA inactivation.
Background
Skill transfer represents an important issue in surgical education, and is not well understood. The aim of this randomized study is to assess the transferability of surgical skills between ...two laparoscopic abdominal procedures using the virtual reality simulator in surgical novices.
Methods
From September 2016 to July 2017, 44 surgical novices were randomized into two groups and underwent a proficiency-based basic training consisting of five selected simulated laparoscopic tasks. In group 1, participants performed an appendectomy training on the virtual reality simulator until they reached a defined proficiency. They moved on to the tutorial procedural tasks of laparoscopic cholecystectomy. Participants in group 2 started with the tutorial procedural tasks of laparoscopic cholecystectomy directly. Finishing the training, participants of both groups were required to perform a complete cholecystectomy on the simulator. Time, safety and economy parameters were analysed.
Results
Significant differences in the demographic characteristics and previous computer games experience between the two groups were not noted. Both groups took similar time to complete the proficiency-based basic training. Participants in group 1 needed significantly less movements (388.6 ± 98.6 vs. 446.4 ± 81.6;
P
< 0.05) as well as shorter path length (810.2 ± 159.5 vs. 945.5 ± 187.8 cm;
P
< 0.05) to complete the cholecystectomy compared to group 2. Time and safety parameters did not differ significantly between both groups.
Conclusion
The data demonstrate a positive transfer of motor skills between laparoscopic appendectomy and cholecystectomy on the virtual reality simulator; however, the transfer of cognitive skills is limited. Separate training curricula seem to be necessary for each procedure for trainees to practise task-specific cognitive skills effectively. Mentoring could help trainees to get a deeper understanding of the procedures, thereby increasing the chance for the transfer of acquired skills.
Purpose
Soft tissue deformation severely impacts the registration of pre- and intra-operative image data during computer-assisted navigation in laparoscopic liver surgery. However, quantifying the ...impact of target surface size, surface orientation, and mesh quality on non-rigid registration performance remains an open research question. This paper aims to uncover how these affect volume-to-surface registration performance.
Methods
To find such evidence, we design three experiments that are evaluated using a three-step pipeline: (1) volume-to-surface registration using the physics-based shape matching method or PBSM, (2) voxelization of the deformed surface to a
1024
3
voxel grid, and (3) computation of similarity (e.g., mutual information), distance (i.e., Hausdorff distance), and classical metrics (i.e., mean squared error or MSE).
Results
Using the Hausdorff distance, we report a statistical significance for the different partial surfaces. We found that removing non-manifold geometry and noise improved registration performance, and a target surface size of only 16.5% was necessary.
Conclusion
By investigating three different factors and improving registration results, we defined a generalizable evaluation pipeline and automatic post-processing strategies that were deemed helpful. All source code, reference data, models, and evaluation results are openly available for download:
https://github.com/ghattab/EvalPBSM/
.
On a broader scale, T cell density and localization in colorectal cancer liver metastases have prognostic and predictive implications. As T cell distribution at higher resolutions has not been fully ...investigated, a detailed resolution analysis of T cell distribution was performed. Patient tissues were divided into 10 µm distance classes between the tumor border and adjacent normal liver. Thereby, distinct density patterns of T cell localization in relation to the malignant tissue could be detected. At a distance of 20 to 30 µm to the tumor, a decrease of CD3 T cells is common. Within this area, cytotoxic Granzyme B and CD8
+
T cells were found to be significantly reduced as well as CD163 macrophages were increased and identified to be in close contact with T cells. Our data suggests a physical or functional border within this region. Survival analysis revealed improved overall survival in patients with high T cells numbers at the direct tumor border. Interestingly, the decreased T cells in the 20 to 30 µm region were also found to be significantly associated with improved survival. Consequently, the detailed localization of T cells, despite blockade, could be associated with improved clinical outcome. The high-resolution analysis represents new insights into relevant heterogenous T cell distributions especially related to clinical responses. As the paradoxical observation of localization-dependent prognostic relevance of T cell densities is only detectable by detailed spatial analyses, this investigation of spatial profiles at higher resolutions is suggested as a new biomarker for survival and response to therapies.
T-regulatory cells (Treg) and mast cells (MC) are abundant in colorectal cancer (CRC) tumors. Interaction between the two is known to promote immune suppression or loss of Treg functions and ...autoimmunity. Here, we demonstrate that in both human CRC and murine polyposis the outcome of this interaction is the generation of potently immune suppressive but proinflammatory Treg (ΔTreg). These Treg shut down IL10, gain potential to express IL17, and switch from suppressing to promoting MC expansion and degranulation. This change is also brought about by direct coculture of MC and Treg, or culture of Treg in medium containing IL6 and IL2. IL6 deficiency in the bone marrow of mice susceptible to polyposis eliminated IL17 production by the polyp infiltrating Treg, but did not significantly affect the growth of polyps or the generation of proinflammatory Treg. IL6-deficient MC could generate proinflammatory Treg. Thus, MC induce Treg to switch function and escalate inflammation in CRC without losing T-cell-suppressive properties. IL6 and IL17 are not needed in this process.
Artificial intelligence (AI) and computer vision (CV) are beginning to impact medicine. While evidence on the clinical value of AI-based solutions for the screening and staging of colorectal cancer ...(CRC) is mounting, CV and AI applications to enhance the surgical treatment of CRC are still in their early stage. This manuscript introduces key AI concepts to a surgical audience, illustrates fundamental steps to develop CV for surgical applications, and provides a comprehensive overview on the state-of-the-art of AI applications for the treatment of CRC. Notably, studies show that AI can be trained to automatically recognize surgical phases and actions with high accuracy even in complex colorectal procedures such as transanal total mesorectal excision (TaTME). In addition, AI models were trained to interpret fluorescent signals and recognize correct dissection planes during total mesorectal excision (TME), suggesting CV as a potentially valuable tool for intraoperative decision-making and guidance. Finally, AI could have a role in surgical training, providing automatic surgical skills assessment in the operating room. While promising, these proofs of concept require further development, validation in multi-institutional data, and clinical studies to confirm AI as a valuable tool to enhance CRC treatment.
Abstract Background The International Study Group for Liver Surgery (ISGLS) proposed a definition for bile leak after liver surgery. A multicentre international prospective study was designed to ...evaluate this definition. Methods Data collected prospectively from 949 consecutive patients on specific datasheets from 11 international centres were collated centrally. Results Bile leak occurred in 69 (7.3%) of patients, with 31 (3.3%), 32 (3.4%) and 6 (0.6%) classified as grade A, B and C, respectively. The grading system of severity correlated with the Dindo complication classification system ( P < 0.001). Hospital length of stay was increased when bile leak occurred, from a median of 7 to 15 days ( P < 0.001), as was intensive care stay ( P < 0.001), and both correlated with increased severity grading of bile leak ( P < 0.001). 96% of bile leaks occurred in patients with intra-operative drains. Drain placement did not prevent subsequent intervention in the bile leak group with a 5–15 times greater risk of intervention required in this group ( P < 0.001). Conclusion The ISGLS definition of bile leak after liver surgery appears robust and intra-operative drain usage did not prevent the need for subsequent drain placement.
PDF
