Proteomic Serum Biomarkers and Their Potential Application in Cancer Screening Programs

Early diagnosis of cancer is of pivotal importance to reduce disease-related mortality. There is great need for non-invasive screening methods, yet current screening protocols have limited sensitivity and specificity. The use of serum biomarkers to discriminate cancer patients from healthy persons might be a tool to improve screening programs. Mass spectrometry based proteomics is widely applied as a technology for mapping and identifying peptides and proteins in body fluids. One commonly used approach in proteomics is peptide and protein profiling. Here, we present an overview of profiling methods that have the potential for implementation in a clinical setting and in national screening programs

Quality Improvement of Pancreatic Surgery by Centralization in the Western Part of the Netherlands

BACKGROUND: Centralization of pancreatic surgery in high-volume hospitals is under debate in many countries. In the western part of the Netherlands, the professional network of surgical oncologists agreed to centralize all pancreatic surgery from 2006 in two high-volume hospitals. Our aim is to evaluate whether centralization of pancreatic surgery has improved clinical outcomes and has changed referral patterns. MATERIALS AND METHODS: Data of the Comprehensive Cancer Centre West (CCCW) of all 249 patients who had a resection for suspected pancreatic cancer between 1996 and 2008 in the western part of the Netherlands were analyzed. Multivariable modeling was used to evaluate survival for 3 time periods; 1996–2000, 2001–2005 (introduction of quality standards), and 2006–2008 (after centralization). In addition, the differences in referral pattern were analyzed. RESULTS: From 2006, all pancreatic surgery was centralized in 2 hospitals. The 2-year survival rate increased after centralization from 39% to 55% (P = .09) for all patients who had a pancreatic resection for pancreatic cancer. After adjustment for age, tumor location, stage, histology, and adjuvant treatment, the latter period was significantly associated with improved survival (hazard ratio [HR] 0.50; 95% confidence interval [95% CI] 0.34–0.73). CONCLUSIONS: Centralization of pancreatic surgery was successful and has resulted in improved clinical outcomes in the western part of the Netherlands, demonstrating the effectiveness of centralization

Serum N-Glycosylation RPLC-FD-MS Assay to Assess Colorectal Cancer Surgical Interventions.

A newly developed analytical strategy was applied to profile the total serum N-glycome of 64 colorectal cancer (CRC) patients before and after surgical intervention. In this cohort, it was previously found that serum N-glycome alterations in CRC were associated with patient survival. Here, fluorescent labeling of serum N-glycans was applied using procainamide and followed by sialic acid derivatization specific for α2,6- and α2,3-linkage types via ethyl esterification and amidation, respectively. This strategy allowed efficient separation of specific positional isomers on reversed-phase liquid chromatography-fluorescence detection-mass spectrometry (RPLC-FD-MS) and complemented the previous glycomics data based on matrix-assisted laser desorption/ionization (MALDI)-MS that did not include such separations. The results from comparing pre-operative CRC to post-operative samples were in agreement with studies that identified a decrease in di-antennary structures with core fucosylation and an increase in sialylated tri- and tetra-antennary N-glycans in CRC patient sera. Pre-operative abundances of N-glycans showed good performance for the classification of adenocarcinoma and led to the revisit of the previous MALDI-MS dataset with regard to histological and clinical data. This strategy has the potential to monitor patient profiles before, during, and after clinical events such as treatment, therapy, or surgery and should also be further explored. </p

Clinical impact of different detection methods for disseminated tumor cells in bone marrow of patients undergoing surgical resection of colorectal liver metastases: a prospective follow-up study

<p>Abstract</p> <p>Background</p> <p>Large number of patients with colorectal liver metastasis show recurrent disease after curative surgical resection. Identification of these high-risk patients may guide therapeutic strategies. The aim of this study was to evaluate whether the presence of disseminated tumor cells in bone marrow from patients undergoing surgical resection of colorectal liver metastases can predict clinical outcome.</p> <p>Methods</p> <p>Sixty patients with colorectal liver metastases were planned for a curative resection between 2001 and 2007. All patients underwent bone marrow aspiration before surgery. Detection of tumor cells was performed using immunocytochemical staining for cytokeratin (CK-ICC) combined with automated microscopy or indirectly using reverse transcription-polymerase chain reaction (RT-PCR).</p> <p>Results</p> <p>Disseminated tumor cells were found in 15 of the 46 patients (33%) using CK-ICC and in 9 of 44 of the patients (20%) using RT-PCR. Patients with negative results for RT-PCR had a significant better disease-free survival after resection of their liver metastases (p = 0.02). This group also showed significant better overall survival (p = 0.002). CK-ICC did not predict a worse clinical outcome.</p> <p>Conclusions</p> <p>The presence of disseminated tumor cells in bone marrow detected using RT-PCR did predict a worse clinical outcome. The presence of cells detected with CK-ICC did not correlate with poor prognosis.</p

Standardization of the tumor-stroma ratio scoring method for breast cancer research

Purpose: The tumor-stroma ratio (TSR) has repeatedly proven to be correlated with patient outcomes in breast cancer using large retrospective cohorts. However, studies validating the TSR often show variability in methodology, thereby hampering comparisons and uniform outcomes. Method: This paper provides a detailed description of a simple and uniform TSR scoring method using Hematoxylin and Eosin (H&E)-stained core biopsies and resection tissue, specifically focused on breast cancer. Possible histological challenges that can be encountered during scoring including suggestions to overcome them are reported. Moreover, the procedure for TSR estimation in lymph nodes, scoring on digital images and the automatic assessment of the TSR using artificial intelligence are described. Conclusion: Digitized scoring of tumor biopsies and resection material offers interesting future perspectives to determine patient prognosis and response to therapy. The fact that the TSR method is relatively easy, quick, and cheap, offers great potential for its implementation in routine diagnostics, but this requires high quality validation studies

Модификации арефлюксного холедохоеюноанастомоза с восстановлением пассажа желчи в двенадцатиперстную кишку

Разработаны модификации формирования холедохоеюноанастомоза, способствующие восстановлению желчетока с пассажем желчи в двенадцатиперстную кишку, что предупреждает развитие в ней пептической язвы. Предложена специальная методика мобилизации отключенного по Ру сегмента тощей кишки, обеспечивающая его полноценную моторику.Modifications of forming choledochoanastomosis promoting restoration of bile passage to the duodenum, which prevented development of peptic ulcer, were worked out. A special technique for mobilization of the switched off segment of the jejunum according to Roux promoting an adequate motility was suggested

The intra-tumoral stroma in patients with breast cancer increases with age

Purpose The tumor microenvironment in older patients is subject to changes. The tumor-stroma ratio (TSR) was evaluated in order to estimate the amount of intra-tumoral stroma and to evaluate the prognostic value of the TSR in older patients with breast cancer (≥70 years). Methods Two retrospective cohorts, the FOCUS study (N = 619) and the Nottingham Breast Cancer series (N = 1793), were used for assessment of the TSR on hematoxylin and eosin stained tissue slides. Results The intra-tumoral stroma increases with age in the FOCUS study and the Nottingham Breast Cancer series (B 0.031, 95% CI 0.006-0.057, P = 0.016 and B 0.034, 95% CI 0.015-0.054, P ≤ 0.001, respectively). Fifty-one percent of the patients from the Nottingham Breast Cancer series ≤40 years had a stroma-high tumor compared to 73% of the patients of ≥90 years from the FOCUS study. The TSR did not validate as an independent prognostic parameter in patients ≥70 years. Conclusions The intra-tumoral stroma increases with age. This might be the result of an activated tumor microenvironment. The TSR did not validate as an independent prognostic parameter in patients ≥70 years in contrast to young women with breast cancer as published previously

Longitudinal Serum Protein Analysis of Women with a High Risk of Developing Breast Cancer Reveals Large Interpatient Versus Small Intrapatient Variations:First Results from the TESTBREAST Study

The prospective, multicenter TESTBREAST study was initiated with the aim of identifying a novel panel of blood-based protein biomarkers to enable early breast cancer detection for moderate-to-high-risk women. Serum samples were collected every (half) year up until diagnosis. Protein levels were longitudinally measured to determine intrapatient and interpatient variabilities. To this end, protein cluster patterns were evaluated to form a conceptual basis for further clinical analyses. Using a mass spectrometry-based bottom-up proteomics strategy, the protein abundance of 30 samples was analyzed: five sequential serum samples from six high-risk women; three who developed a breast malignancy (cases) and three who did not (controls). Serum samples were chromatographically fractionated and an in-depth serum proteome was acquired. Cluster analyses were applied to indicate differences between and within protein levels in serum samples of individuals. Statistical analyses were performed using ANOVA to select proteins with a high level of clustering. Cluster analyses on 30 serum samples revealed unique patterns of protein clustering for each patient, indicating a greater interpatient than intrapatient variability in protein levels of the longitudinally acquired samples. Moreover, the most distinctive proteins in the cluster analysis were identified. Strong clustering patterns within longitudinal intrapatient samples have demonstrated the importance of identifying small changes in protein levels for individuals over time. This underlines the significance of longitudinal serum measurements, that patients can serve as their own controls, and the relevance of the current study set-up for early detection. The TESTBREAST study will continue its pursuit toward establishing a protein panel for early breast cancer detection

The prognostic value of the tumor–stroma ratio is most discriminative in patients with grade III or triple‐negative breast cancer

The tumor-stroma ratio (TSR) was evaluated as a promising parameter for breast cancer prognostication in clinically relevant subgroups of patients. The TSR was assessed on hematoxylin and eosin stained tissue slides of 1794 breast cancer patients from the Nottingham City Hospital. An independent second cohort of 737 patients from the Netherlands Cancer Institute to Antoni van Leeuwenhoek was used for evaluation. In the Nottingham Breast Cancer series, the TSR was an independent prognostic parameter for recurrence-free survival (RFS) (HR 1.35, 95% CI 1.10 to 1.66, p = 0.004). The interaction term was statistically significant for grade and triple-negative status. Multivariate Cox regression analysis showed a more pronounced effect of the TSR for RFS in grade III tumors (HR 1.89, 95% CI 1.43 to 2.51, p < 0.001) and triple-negative tumors (HR 1.86, 95% CI 1.10 to 3.14, p = 0.020). Comparable hazard ratios and confidence intervals were observed for grade and triple-negative status in the ONCOPOOL study. The prognostic value of TSR was not modified by age, tumor size, histology, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status or lymph node status. In conclusion, patients with a stroma-high tumor had a worse prognosis compared to patients with a stroma- low tumor. The prognostic value of the TSR is most discriminative in grade III tumors and triple-negative tumors. The TSR was not modified by other clinically relevant parameters making it a potential factor to be included for improved risk stratification