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Purpose: Virtual reality (VR) allows for an immersive and interactive analysis of imaging data such as computed tomography (CT) and magnetic resonance imaging (MRI). The aim of this study is to assess the comprehensibility of VR anatomy and its value in assessing resectability of pancreatic ductal adenocarcinoma (PDAC)., Methods: This study assesses exposure to VR anatomy and evaluates the potential role of VR in assessing resectability of PDAC. Firstly, volumetric abdominal CT and MRI data were displayed in an immersive VR environment. Volunteering physicians were asked to identify anatomical landmarks in VR. In the second stage, experienced clinicians were asked to identify vascular involvement in a total of 12 CT and MRI scans displaying PDAC (2 resectable, 2 borderline resectable, and 2 locally advanced tumours per modality). Results were compared to 2D standard PACS viewing., Results: In VR visualisation of CT and MRI, the abdominal anatomical landmarks were recognised by all participants except the pancreas (30/34) in VR CT and the splenic (31/34) and common hepatic artery (18/34) in VR MRI, respectively. In VR CT, resectable, borderline resectable, and locally advanced PDAC were correctly identified in 22/24, 20/24 and 19/24 scans, respectively. Whereas, in VR MRI, resectable, borderline resectable, and locally advanced PDAC were correctly identified in 19/24, 19/24 and 21/24 scans, respectively. Interobserver agreement as measured by Fleiss κ was 0.7 for CT and 0.4 for MRI, respectively (p < 0.001). Scans were significantly assessed more accurately in VR CT than standard 2D PACS CT, with a median of 5.5 (IQR 4.75-6) and a median of 3 (IQR 2-3) correctly assessed out of 6 scans (p < 0.001)., Conclusion: VR enhanced visualisation of abdominal CT and MRI scan data provides intuitive handling and understanding of anatomy and might allow for more accurate staging of PDAC and could thus become a valuable adjunct in PDAC resectability assessment in the future., (© 2024. The Author(s).)

Muscarinic acetylcholine receptor M3 (M3R) has repeatedly been shown to be prominently expressed in human colorectal cancer (CRC), playing roles in proliferation and cell invasion. Its therapeutic targetability has been suggested in vitro and in animal models. We aimed to investigate the clinical role of MR3 expression in CRC for human survival. Surgical tissue samples from 754 CRC patients were analyzed for high or low immunohistochemical M3R expression on a clinically annotated tissue microarray (TMA). Immunohistochemical analysis was performed for established immune cell markers (CD8, TIA-1, FOXP3, IL 17, CD16 and OX 40). We used Kaplan-Meier curves to evaluate patients' survival and multivariate Cox regression analysis to evaluate prognostic significance. High M3R expression was associated with increased survival in multivariate (hazard ratio (HR) = 0.52; 95% CI = 0.35-0.78; p = 0.001) analysis, as was TIA-1 expression (HR = 0.99; 95% CI = 0.94-0.99; p = 0.014). Tumors with high M3R expression were significantly more likely to be grade 2 compared to tumors with low M3R expression (85.7% vs. 67.1%, p = 0.002). The 5-year survival analysis showed a trend of a higher survival rate in patients with high M3R expression (46%) than patients with low M3R expression CRC (42%) ( p = 0.073). In contrast to previous in vitro and animal model findings, this study demonstrates an increased survival for CRC patients with high M3R expression. This evidence is highly relevant for translation of basic research findings into clinically efficient treatments.

Objective: The novel picture archiving and communication system (PACS), compatible with virtual reality (VR) software, displays cross-sectional images in VR. VR magnetic resonance cholangiopancreatography (MRCP) was tested to improve the anatomical understanding and intraoperative performance of minimally invasive cholecystectomy (CHE) in surgical trainees., Design: We used an immersive VR environment to display volumetric MRCP data (Specto VR TM ). First, we evaluated the tolerability and comprehensibility of anatomy with a validated simulator sickness questionnaire (SSQ) and examined anatomical landmarks. Second, we compared conventional MRCP and VR MRCP by matching three-dimensional (3D) printed models and identifying and measuring common bile duct stones (CBDS) using VR MRCP. Third, surgical trainees prepared for CHE with either conventional MRCP or VR MRCP, and we measured perioperative parameters and surgical performance (validated GOALS score)., Setting: The study was conducted out at Clarunis, University Center for Gastrointestinal and Liver Disease, Basel, Switzerland., Participants: For the first and second study step, doctors from all specialties and years of experience could participate. In the third study step, exclusively surgical trainees were included. Of 74 participating clinicians, 34, 27, and 13 contributed data to the first, second, and third study phases, respectively., Results: All participants determined the relevant biliary structures with VR MRCP. The median SSQ score was 0.75 (IQR: 0, 3.5), indicating good tolerability. Participants selected the corresponding 3D printed model faster and more reliably when previously studying VR MRCP compared to conventional MRCP: We obtained a median of 90 s (IQR: 55, 150) and 72.7% correct answers with VR MRCP versus 150 s (IQR: 100, 208) and 49.6% correct answers with conventional MRCP, respectively ( p  < 0.001). CBDS was correctly identified in 90.5% of VR MRCP cases. The median GOALS score was higher after preparation with VR MRCP than with conventional MRCP for CHE: 16 (IQR: 13, 22) and 11 (IQR: 11, 18), respectively ( p  = 0.27)., Conclusions: VR MRCP allows for a faster, more accurate understanding of displayed anatomy than conventional MRCP and potentially leads to improved surgical performance in CHE in surgical trainees., Competing Interests: P.C. Cattin is the inventor and owner of the VR application (Specto VRTM) described in this study. The other authors have no conflicts of interest or financial ties to disclose., (© 2022 Staubli, Maloca, Kuemmerli, Kunz, Dirnberger, Allemann, Gehweiler, Soysal, Droeser, Däster, Hess, Raptis, Kollmar, von Flüe, Bolli and Cattin.)

Purpose: Myeloperoxidase (MPO) is an enzyme secreted by neutrophil granulocytes as a result of phagocytosis during inflammation. In colorectal cancer, tumour infiltration by MPO expressing cells has been shown to be independently associated with a favourable prognosis. In this study, we explored the role of MPO-positive cell infiltration and its prognostic significance in invasive breast cancer., Methods: We performed immunohistochemical staining for MPO on multiple tissue microarrays comprising a total of 928 human breast cancer samples with detailed clinical-pathological annotation and outcome data., Results: MPO-positive cell infiltration (≥ 5 cells/tissue punch) was found in 150 (16%) of the 928 evaluable breast cancer cases. In univariate survival analyses, infiltration by MPO-positive cells was associated with a significantly better overall survival (p < 0.001). In subset univariate analyses, the infiltration by MPO-positive cells was associated with significantly better overall survival in the Luminal B/HER2-negative subtype (p = 0.005), the HER2 enriched subtype (p = 0.011), and the Triple Negative subtype (p < 0.001). In multivariate analysis, MPO expression proved to be an independent prognostic factor for improved overall survival (p < 0.001)., Conclusions: This is the first study to show that infiltration of MPO-positive cells is an independent prognostic biomarker for improved overall survival in human breast cancer.

Background: Despite improvements in therapy of colorectal cancer, some patients will present occurrence of recurrence either locally or distantly. Tumor metastasis constitutes the major cause of cancer-associated morbidity and mortality. Nectin-1 belongs to the family of immunoglobulin-like cell adhesion molecules that contribute to the formation of cell-cell adhesions and regulate a series of cellular activities including cell polarization, differentiation, movement, proliferation, and survival. Expression of Nectin-1 in malignant tumors has been associated with aggressive tumor phenotypes., Objectives: The aim of the present study was to assess Nectin-1 expression patterns in colorectal cancer and to investigate its clinical significance., Methods: Nectin-1 expression was assessed via immunohistochemistry in surgical specimens of a cohort comprised of 111 patients with primary resectable colorectal cancer. Results were correlated with clinicopathological characteristics and survival data. Progression-free survival was defined as the primary outcome of the present study., Results: Nectin-1 was strongly expressed in the cytoplasm of colorectal cancer cells. High Nectin-1 expression was associated with advanced stage of disease (p = 0.012) and lymph node metastasis (p = 0.007). Progression-free survival of patients exhibiting high expression of Nectin-1 in the first 36 months after surgery was significantly worse compared to patients with low expression of Nectin-1 (55.7%, 95% CI = 47-70, vs. 82.1%, 95% CI = 69-93, p = 0.014) and independent of other clinicopathological characteristics (HR = 0.389, 95% CI = 0.156-0.972, p = 0.043)., Conclusion: Nectin-1 expression in colorectal cancer is associated with a significantly worse 3-year progression-free survival identifying therefore a group of patients with high risk for early disease recurrence., (© 2019 S. Karger AG, Basel.)

Purpose: Tumor infiltration by different T lymphocyte subsets is known to be associated with favorable prognosis in colorectal cancer. Still debated is the role of innate immune system. We investigated clinical relevance, phenotypes, and functional features of colorectal cancer-infiltrating CD66b + neutrophils and their crosstalk with CD8 + T cells. Experimental Design: CD66b + and CD8 + cell infiltration was analyzed by IHC on a tissue microarray including >650 evaluable colorectal cancer samples. Phenotypic profiles of tissue-infiltrating and peripheral blood CD66b + cells were evaluated by flow cytometry. CD66b + /CD8 + cells crosstalk was investigated by in vitro experiments. Results: CD66b + cell infiltration in colorectal cancer is significantly associated with increased survival. Interestingly, neutrophils frequently colocalize with CD8 + T cells in colorectal cancer. Functional studies indicate that although neutrophils are devoid of direct antitumor potential, coculture with peripheral blood or tumor-associated neutrophils (TAN) enhances CD8 + T-cell activation, proliferation, and cytokine release induced by suboptimal concentrations of anti-CD3 mAb. Moreover, under optimal activation conditions, CD8 + cell stimulation in the presence of CD66b + cells results in increasing numbers of cells expressing CD45RO/CD62L "central memory" phenotype. Importantly, combined tumor infiltration by CD66b + and CD8 + T lymphocytes is associated with significantly better prognosis, as compared with CD8 + T-cell infiltration alone. Conclusions: Neutrophils enhance the responsiveness of CD8 + T cells to T-cell receptor triggering. Accordingly, infiltration by neutrophils enhances the prognostic significance of colorectal cancer infiltration by CD8 + T cells, suggesting that they might effectively promote antitumor immunity. Clin Cancer Res; 23(14); 3847-58. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Internal hernias (IH) after laparoscopic Roux-en-Y gastric bypass (LRYGB) have been reported with an incidence of 11 %. IH can lead to bowel incarceration and potentially bowel necrosis. The aim of this study was to analyze reoperations and intraoperative findings in a cohort of patients with unclosed mesenteric defects., Methods: From a prospective database of patients with LRYGB, we selected as primary cohort patients with non-closure of mesenteric defects and abdominal reoperation for analysis. The data included pre-, intra- and post-operative findings, computed tomogram results and laboratory test results. This group underwent a very very long limb LRYGB, at that time the institutional standard technique. Additionally, a more recently operated cohort with primary closure of mesenteric defects was also analyzed., Results: We identified 146 patients with primary non-closure and reoperation, mean age of 43.8 years. The main indication for reoperation was unclear abdominal pain in 119 patients with 27 patients undergoing a reoperation for other reasons (weight regain, prophylactic surgical inspection of mesenteric defects). Median time and mean excess weight loss from RYGB to reoperation were 41.1 months and 62.7 %, respectively. The incidence of IH was 14.4 %, with all patients with an IH being symptomatic. Conversion rate from laparoscopic to open surgery was 5.5 %, mortality 0.7 % and morbidity 3.4 %. Thirty-one patients underwent a second re-look laparoscopy. Eleven patients had recurrent open mesenteric defects. Three hundred and sixteen patients who underwent primary closure of the mesenteric defects had a reoperation rate of 13.6 % and an IH rate of 0.6 %., Conclusion: The incidence of IH in patients without closure of mesenteric defects and reoperation is high and substantially higher compared to patients with primary closure of mesenteric defects. Patients with or without closure of mesenteric defects following LRYGB with acute, chronic or recurrent pain should be referred to a bariatric surgeon for diagnostic laparoscopy.

Background: It remains a matter of debate whether colorectal cancer resection in an emergency setting negatively impacts on survival. Our objective was therefore to assess the impact of urgent versus elective operation on overall and disease-free survival in patients undergoing resection for colorectal cancer by using propensity score adjusted analysis., Methods: In a single-center study patients operated for colorectal cancer between 1989 and 2013 were identified from a prospectively maintained database. Median follow-up was 44 months. Patients with neoadjuvant treatment were excluded. The impact of urgent operation on overall and disease-free survival was assessed using both Cox regression and propensity score analyses., Results: Of 747 patients with colorectal cancer, 84 (11%) had urgent and 663 elective cancer resection. The propensity score revealed strongly biased patient characteristics (0.22 ± 0.16 vs. 0.10 ± 0.09; P < 0.001). In unadjusted analysis urgent operation was associated with a 35% increased risk of overall mortality (hazard ratio(HR) of death = 1.35, 95% confidence interval(CI):1.02-1.78, P = 0.045). In risk-adjusted Cox regression analysis urgent operation was not associated with poor overall (HR = 1.08, 95%CI:0.79-1.48; P = 0.629) or disease-free survival (HR = 1.02, 95%CI:0.76-1.38; P = 0.877). Similarly in propensity score analysis urgent operation did not influence overall (HR = 0.98, 95% CI:0.74-1.29), P = 0.872) and disease-free survival (HR = 0.89, 95%CI:0.68 to 1.16, P = 0.387)., Conclusions: This study provides evidence that worse oncologic outcomes after urgent operation for colorectal cancer are caused by clinical circumstances and not due to the urgent operation itself. Urgent operation is not a risk factor for colorectal cancer resection.

Recent evidence suggests that natural killer (NK) cells are typically defective in infiltrating solid tumors, with the exception of gastrointestinal stromal tumors (GIST). Interestingly, however, infrequently infiltrating NK cells do not appear to have a direct effect on tumor progression. Here, prompted by the recent evidence that NK cell and T cell crosstalk may trigger, or enhance, tumor antigen-specific immune responses, we have tested the clinical significance of this reciprocal signaling. To this end, a tissue microarray constructed with 1410 colorectal carcinoma (CRC) patient specimens was stained with NK and T cell antigen-specific monoclonal antibodies, utilizing the immunoperoxidase staining technique. Cut-off scores for positive (>4 NK cells) and negative (≤4 NK cells) NK cell CRC patient samples were determined using receiver operating characteristic curve analysis. Using this approach, NK cells were detected in 423 (30%) of the 1410 CRC specimens evaluated. The number of NK cells was >4 in only 132 (9%) of CRC samples. Correlation of the immunohistochemical staining results together with analysis of the clinical course of the disease revealed that the infiltration of colorectal tumors with both NK cells and CD8+ T cells is associated with prolonged patient survival. In contrast, infiltration of tumors with NK cells in combination with CD3 + and CD4 + T lymphocytes had no detectable effect on the clinical course of the disease. These results suggest that NK cell and CD8 + T cell crosstalk in the tumor microenvironment may benefit patient outcome and further, that the enumeration of infiltrating NK and CD8 + T cells in CRC tumors may provide useful prognostic information.

The goal of this study was to determine the frequency of HLA class II antigen expression in colorectal carcinoma (CRC) tumors, its association with the clinical course of the disease, and the underlying mechanism(s). Two tissue microarrays constructed with 220 and 778 CRC tumors were stained with HLA-DR, DQ, and DP antigen-specific monoclonal antibody LGII-612.14, using the immunoperoxidase staining technique. The immunohistochemical staining results were correlated with the clinical course of the disease. The functional role of HLA class II antigens expressed on CRC cells was analyzed by investigating their in vitro interactions with immune cells. HLA class II antigens were expressed in about 25% of the 220 and 21% of the 778 tumors analyzed with an overall frequency of 23%. HLA class II antigens were detected in 19% of colorectal adenomas. Importantly, the percentage of stained cells and the staining intensity were significantly lower than those detected in CRC tumors. However, HLA class II antigen staining was weakly detected only in 5.4% of 37 normal mucosa tissues. HLA class II antigen expression was associated with a favorable clinical course of the disease. In vitro stimulation with interferon gamma (IFNγ) induced HLA class II antigen expression on two of the four CRC cell lines tested. HLA class II antigen expression on CRC cells triggered interleukin-1β (IL-1β) production by resting monocytes. HLA class II antigen expression in CRC tumors is a favorable prognostic marker. This association may reflect stimulation of IL-1β production by monocytes.

Background: Clinical relevance of tumor infiltrating lymphocytes (TILs) in breast cancer is controversial. Here, we used a tumor microarray including a large series of ductal and lobular breast cancers with long term follow up data, to analyze clinical impact of TIL expressing specific phenotypes and distribution of TILs within different tumor compartments and in different histological subtypes., Methods: A tissue microarray (TMA) including 894 ductal and 164 lobular breast cancers was stained with antibodies recognizing CD4, FOXP3, and IL-17 by standard immunohistochemical techniques. Lymphocyte counts were correlated with clinico-pathological parameters and survival., Results: CD4(+) lymphocytes were more prevalent than FOXP3(+) TILs whereas IL-17(+) TILs were rare. Increased numbers of total CD4(+) and FOXP3(+) TIL were observed in ductal, as compared with lobular carcinomas. High grade (G3) and estrogen receptor (ER) negative ductal carcinomas displayed significantly (p < 0.001) higher CD4(+) and FOXP3(+) lymphocyte infiltration while her2/neu over-expression in ductal carcinomas was significantly (p < 0.001) associated with higher FOXP3(+) TIL counts. In contrast, lymphocyte infiltration was not linked to any clinico-pathological parameters in lobular cancers. In univariate but not in multivariate analysis CD4(+) infiltration was associated with significantly shorter survival in patients bearing ductal, but not lobular cancers. However, a FOXP3(+)/CD4(+) ratio > 1 was associated with improved overall survival even in multivariate analysis (p = 0.033)., Conclusions: Ductal and lobular breast cancers appear to be infiltrated by different lymphocyte subpopulations. In ductal cancers increased CD4(+) and FOXP3(+) TIL numbers are associated with more aggressive tumor features. In survival analysis, absolute numbers of TILs do not represent major prognostic indicators in ductal and lobular breast cancer. Remarkably however, a ratio > 1 of total FOXP3(+)/CD4(+) TILs in ductal carcinoma appears to represent an independent favorable prognostic factor.

The prognostic significance of macrophage and natural killer (NK) cell infiltration in colorectal carcinoma (CRC) microenvironment is unclear. We investigated the CRC innate inflammatory infiltrate in over 1,600 CRC using two independent tissue microarrays and immunohistochemistry. Survival time was assessed using the Kaplan-Meier method and Cox proportional hazards regression analysis in a multivariable setting. Spearman's rank correlation tested the association between macrophage and lymphocyte infiltration. The Basel study included over 1,400 CRCs. The level of CD16+ cell infiltration correlated with that of CD3+ and CD8+ lymphocytes but not with NK cell infiltration. Patients with high CD16+ cell infiltration (score 2) survived longer than patients with low (score 1) infiltration (p = 0.008), while no survival difference between patients with score 1 or 2 for CD56+ (p = 0.264) or CD57+ cell (p = 0.583) infiltration was detected. CD16+ infiltrate was associated with improved survival even after adjusting for known prognostic factors including pT, pN, grade, vascular invasion, tumor growth and age [(p = 0.001: HR (95% CI) = 0.71 (0.6-0.9)]. These effects were independent from CD8+ lymphocyte infiltration [(p = 0.036: HR (95% CI) = 0.81 (0.7-0.9)] and presence of metastases [(p = 0.002: HR (95% CI) = 0.43 (0.3-0.7)]. Phenotypic studies identified CD16+ as CD45+CD33+CD11b+CD11c+ but CD64- HLA-DR-myeloid cells. Beneficial effects of CD16+ cell infiltration were independently validated by a study carried out at the University of Athens confirming that patients with CD16 score 2 survived longer than patients with score 1 CRCs (p = 0.011). Thus, CD16+ cell infiltration represents a novel favorable prognostic factor in CRC., (Copyright © 2010 UICC.)

Fetal bovine serum (FBS) and fibroblast growth factor (FGF)-2 are key supplements for the culture of stromal vascular fraction (SVF) cells from adipose tissue, both for typical monolayer (2D) expansion and for streamlined generation of osteogenic-vasculogenic grafts in 3D perfusion culture. The present study investigates whether factors present in human platelet lysate (PL) could substitute for FBS and FGF-2 in 2D and 3D culture models of SVF cells from human lipoaspirates. SVF cells were grown in medium supplemented with 10% FBS+FGF-2 or with 5% PL. In 2D cultures, PL initially supported SVF cell proliferation, but resulted in growth arrest shortly after the first passage. Freshly isolated SVF cells cultured with both media under perfusion for 5 days within 3D ceramic scaffolds induced bone formation after subcutaneous implantation in nude mice. However, blood vessels of donor origin were generated only using FBS+FGF-2-cultured cells. This was unexpected, because the proportion of CD34+/CD31+ endothelial lineage cells was significantly higher with PL than that of FBS+FGF-2 (33% vs. 3%, respectively). These results support the use of PL as a substitute of FBS+FGF-2 for short-term culture of human SVF cells, and indicate that more specific serum-free formulations are required to maintain a functionally vasculogenic fraction of SVF cells expanded under 3D perfusion.

Background: The ilioinguinal approach by Letournel has fundamentally contributed to the successful treatment of acetabular fractures. Since most of the present complications arise from soft tissue structures in the inguinal part, it would be desirable to avoid the surgical dissection of this region. We have therefore developed a less invasive anterior intrapelvic approach consisting of a suprapubic access combined with the lateral window of the ilioinguinal approach., Methods: Between January 2000 and October 2002, 14 patients with acetabular fractures and 6 patients with pelvic ring injuries were consecutively operated using our technique. The patients were prospectively followed up clinically and by standard X-rays for 1 year., Results: In 19 patients the technique was successful and only one patient was converted to an ilioinguinal approach due to difficulties in reducing the fracture. Our access allowed good visibility but reduction manoeuvres were sometimes difficult and the development of a new reduction forceps became necessary. Anatomical and satisfactory reduction was achieved in 13 acetabular fractures and 4 pelvic ring injuries. One cutaneous femoris neurapraxy and one superficial infection occurred related to the approach and both resolved with conservative treatment. Clinical outcome at one year was good to excellent in 17 patients (modified Merle d'Aubigné/Postel score). In 3 patients the result was fair to poor for reasons unrelated to the approach., Conclusions: Our approach permits visualisation of the entire anterior column and pelvic ring without the necessity to dissect the inguinal neurovascular structures. Our preliminary results demonstrate that safe reduction and stable fixation of selected acetabular- and pelvic ring fractures are possible.