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

Total vs partial fundoplication in the treatment of gastroesophageal reflux disease: a meta-analysis

Objective: To perform a meta-analysis of randomized trials comparing partial fundoplication (PF) with total (Nissen) fundoplication (TF) for gastroesophageal reflux disease in terms of morbidity, efficacy, and long-term symptomatology. Data Sources: A structured Medline search for published studies. Study Selection: The available literature from 1975 until June 2007 was searched using the Medical Subject Headings of the National Library of Medicine term fundoplication and the free-text terms fundoplication, surgery, and reflux. Data were analyzed using Review Manager software (Cochrane Collaboration, Oxford, England). Data Extraction: Eleven trials were identified comparing TF with PF in 991 patients. Data Synthesis: Total fundoplication resulted in a significantly higher incidence of postoperative dysphagia (odds ratio [OR], 1.82-3.93; P<.001), bloating (OR, 1.07-2.56; P=.02), and flatulence (OR, 1.66-3.96; P<.001). No significant differences were noted in the incidence of esophagitis (OR, 0.72-2.7; P=.33), heartburn (OR, 0.48-1.52; P=.58), or persisting acid reflux (OR, 0.77-1.79; P=.45). The reoperation rate was significantly higher after TF compared with PF (OR, 1.13-3.95; P=.02). No significant differences were present in the proportion of patients experiencing a good or excellent long-term outcome (OR, 0.54-1.38; P=.53) or in the proportion of patients with a Visick I or II score (OR, 0.62-1.59; P=.99). Conclusions: Partial fundoplication is a safe and effective alternative to TF, resulting in significantly fewer reoperations and a better functional outcome. The poor quality of the included trials warrants caution in the interpretation of the results of this meta-analysis

Ultrahigh resolution profiles lead to more detailed serum peptidome signatures of pancreatic cancer

Mass spectrometry-based (clinical) proteomics has been widely applied as a technology to find and validate disease-specific protein signatures. MALDI-based peptidome profiles provide a suitable platform for classification of body fluids or tissues, albeit at the cost of being unable to observe low abundant species. Here we show that a fully automated one-step solid-phase extraction serum sample cleanup in combination with fast MALDI acquisition and ultrahigh precision 15 T FTICR readout provides a powerful, fast and robust approach for obtaining biomarker signatures. This is exemplified for a cohort of pancreatic cancer patients. Specific “early cancer” symptoms such as pain, jaundice or weight loss are often not experienced, thus delaying diagnosis of the disease. Novel markers for early diagnosis of pancreatic cancer are therefore urgently needed. A total of 273 serum samples, distributed over a calibration and validation set, were processed and mass analyzed within a time frame of 24 h. In both sets sensitivity and selectivity values were well above 85%. In these “next-generation” MALDI peptidome profiles all species up to 9 kDa were isotopically resolved. Finally, it is noted that the low ppm mass accuracy of peptides and proteins observed between 1 and 9 kDa in the FTICR profiles facilitates sequence identifications

Serum peptide signatures for pancreatic cancer based on mass spectrometry : a comparison to CA19-9 levels and routine imaging techniques

Purpose The detection of pancreatic tumors lacks a sensitive and specific diagnostic tool. Mass spectrometry (MS)based profiling of serum proteins is a promising approach for discovery of new clinical biomarkers or biomarker signatures. Methods Serum samples from pancreatic cancer (PC) patients and control individuals were collected and processed using a standardized protocol. Samples were divided in a calibration set (n = 49 PC and 110 controls) and a validation set (n = 39 PC and 75 controls). Peptide profiles were obtained using a combination of automated solid-phase extraction with reversed-phase C18 paramagnetic beads and matrix-assisted laser desorption ionization time-of-flight MS. Results Linear discriminant analysis with double cross-validation resulted in a discriminating peptide signature for PC in the calibration set with a sensitivity of 78 % and a specificity of 91 % [ area under the curve (AUC) of 92 %]. Classification was validated with a sensitivity of 93 % and a specificity of 100 % (AUC of 98 %), and the results were compared with carbohydrate antigen 19-9 levels and currently available clinical imaging techniques. The ten most discriminating peptide peaks were identified as fragments of proteins involved in the clotting cascade, acute phase response and immunologic response. Conclusions In this study, it is shown that MS-based serum peptide profiles can discriminate between PC and control samples. The approach has great potential for highthroughput analysis in surveillance programs and appears to be most promising for patients with an inherited risk for PC, who benefit from more frequent screening

Serum peptide signatures for pancreatic cancer based on mass spectrometry : a comparison to CA19-9 levels and routine imaging techniques

Purpose The detection of pancreatic tumors lacks a sensitive and specific diagnostic tool. Mass spectrometry (MS)based profiling of serum proteins is a promising approach for discovery of new clinical biomarkers or biomarker signatures. Methods Serum samples from pancreatic cancer (PC) patients and control individuals were collected and processed using a standardized protocol. Samples were divided in a calibration set (n = 49 PC and 110 controls) and a validation set (n = 39 PC and 75 controls). Peptide profiles were obtained using a combination of automated solid-phase extraction with reversed-phase C18 paramagnetic beads and matrix-assisted laser desorption ionization time-of-flight MS. Results Linear discriminant analysis with double cross-validation resulted in a discriminating peptide signature for PC in the calibration set with a sensitivity of 78 % and a specificity of 91 % [ area under the curve (AUC) of 92 %]. Classification was validated with a sensitivity of 93 % and a specificity of 100 % (AUC of 98 %), and the results were compared with carbohydrate antigen 19-9 levels and currently available clinical imaging techniques. The ten most discriminating peptide peaks were identified as fragments of proteins involved in the clotting cascade, acute phase response and immunologic response. Conclusions In this study, it is shown that MS-based serum peptide profiles can discriminate between PC and control samples. The approach has great potential for highthroughput analysis in surveillance programs and appears to be most promising for patients with an inherited risk for PC, who benefit from more frequent screening

Recommendations for the Optimal Radiation Dose in Patients With Primary Cutaneous Anaplastic Large Cell Lymphoma: A Report of the Dutch Cutaneous Lymphoma Group

Purpose: To determine the optimal radiation dose for treatment of primary cutaneous anaplastic large cell lymphoma (C-ALCL) with solitary or localized, multifocal or recurrent skin lesions. Methods and Materials: In this multicenter study, patients with C-ALCL who had been treated with radiation therapy(RT) between 1984 and 2016 were retrieved from the Dutch registry of cutaneous lymphomas. Distinction was made between patients first presenting with solitary or localized lesions (n=63), with multifocal skin lesions (n=6), and patients with a skin relapse (n=22). Radiation doses, treatment response, and follow-up were evaluated. Radiation doses were categorized as low-dose (≤20 Gy), intermediate-dose (21-39 Gy), and high-dose (≥40 Gy) RT. Results: Of 63 patients presenting with solitary or localized skin lesions, 61 (97%) showed a complete response (CR). There were no differences in CR between low-dose (16 of 17), intermediate-dose (15 of 15), and high-dose RT (30 of 31). After a median follow-up of 46 months, 30 of 63 patients (48%) had a relapse, but in-field relapses were never observed. Six of 6 patients (100%) initially presenting with multifocal skin lesions showed a CR (3 of 3 low-dose, 2 of 2 intermediate-dose, 1 of 1 high-dose RT). After a median follow-up of 27 months, 3 of 6 patients had a relapse. Treatment of 33 skin relapses in 22 patients showed no differences in CR between low-dose (18 of 19), intermediate-dose (6 of 6), and high-dose RT (8 of 8). In the last 10 years there has been a decrease in radiation dose used in the treatment of C-ALCL. Treatment of multifocal and recurrent lesions with a dose of 8 Gy (2 × 4 Gy) resulted in CR of 17 of 18 lesions. Conclusions: Our results show that a radiation dose of 20 Gy (8 x 2.5 Gy) is effective in patients presenting with solitary or localized skin lesions. For patients with multifocal skin lesions and patients with a skin relapse, a dose of 8 Gy (2 x 4 Gy) may be sufficient