Mārcis Leja

Tumor-associated autoantibody signature for the early detection of gastric cancer

Autoantibodies against tumor‐associated antigens are very attractive biomarkers for the development of noninvasive serological tests for the early detection of cancer because of their specificity and stability in the sera. In our study, we applied T7 phage display‐based serological analysis of recombinant cDNA expression libraries technique to identify a representative set of antigens eliciting humoral responses in patients with gastric cancer (GC), produced phage–antigen microarrays and exploited them for the survey of autoantibody repertoire in patients with GC and inflammatory diseases. We developed procedures for data normalization and cutoff determination to define sero‐positive signals and ranked them by the signal intensity and frequency of reactivity. To identify autoantibodies with the highest diagnostic value, a 1,150‐feature microarray was tested with sera from 100 patients with GC and 100 cancer‐free controls, and then the top‐ranked 86 antigens were used for the production of focused array that was tested with an independent validation set comprising serum samples from 235 patients with GC, 154 patients with peptic ulcer and gastritis and 213 healthy controls. The receiver operating characteristic curve analysis showed that 45‐autoantibody signature could discriminate GC and healthy controls with area under the curve (AUC) of 0.79 (59% sensitivity and 90% specificity), GC and peptic ulcer with AUC of 0.76 and GC and gastritis with AUC of 0.64. Moreover, it could detect early GC with equal sensitivity than advanced GC. Interestingly, the autoantibody production did not correlate with histological type, H. pylori status, grade, localization and size of the primary tumor, whereas it appeared to be associated with the metastatic disease.

Sperm-associated antigens as targets for cancer immunotherapy: expression pattern and humoral immune response in cancer patients.

The identification of novel cancer-related and immunogenic proteins is still a challenge to be faced to improve antigen-specific tumor immunotherapy. The category of so-called cancer-testis (CT) antigens is one of the most perspective groups of proteins for anticancer immune response activation as normally they are expressed in immunoprivileged tissues and are immunogenic if aberrantly generated in tumors. The heterogeneous group of proteins called sperm-associated antigens (SPAG) might encompass novel CT antigens owing to their common expression in male germ cells, their ability to elicit immune response underlying infertility, and lately proposed oncogenic properties. We carried out a comprehensive analysis of the expression pattern in various normal and cancerous tissues and assessed the frequency of spontaneous humoral immune response against members of the SPAG group in cancer patients using phage-displayed antigen microarrays. Our results show that out of 15 analyzed SPAG genes only SPAG1, SPAG6, SPAG8, SPAG15, and SPAG17 are predominantly expressed in testis, whereas the others are ubiquitously expressed with only a testis-associated alternative splice variant of SPAG16. mRNA expression of SPAG1, SPAG6, and alternative splice variants of SPAG8, SPAG16, and SPAG17 was elevated in various tumors with frequencies ranging from approximately 10% to 70%. The upregulation of SPAG6 in lung and breast cancer was confirmed by immunohistochemical analysis of tumor and normal tissue microarrays. Cancer-associated spontaneous humoral immune response was detected against SPAG1, SPAG6, SPAG8, and a novel testis-specific splice variant of SPAG17 and ascribe these as novel CT antigens that potentially are applicable as immunotherapeutic targets and serologic biomarkers.

Prevalence of Helicobacter pylori infection and atrophic gastritis in Latvia.

Objectives Helicobacter pylori infection and atrophic gastritis are related to an increased risk for gastric cancer. There is a decrease in global H. pylori prevalence. We analyzed the prevalence of H. pylori infection in Latvia by the plasma IgG test and the presence of atrophy by means of pepsinogen testing. Methods This subanalysis was carried out on a randomly selected cross-sectional sample of a general population of adults to access cardiovascular risk factors. Plasma samples were screened for H. pylori IgG (cutoff value 24 U/ml), and pepsinogens (Pg) I and II. Pg cutoff values of PgI/PgII⩽3 and PgI⩽70 ng/ml were used to assess the prevalence of atrophy of any grade and PgI/PgII⩽2 and PgI⩽30 ng/ml for advanced atrophy. Results Altogether, 3564 serum samples were available for the study (2346 women, 1218 men; median age 54 years). Of the tested individuals, 79.21% were H. pylori positive, with no difference between sexes. The prevalence increased with age (P<0.001). Atrophy of any grade was identified in 1444 individuals (40.52%) and advanced atrophy in 475 individuals (13.33%). Linear association with age was present in both response types (P<0.001). The prevalence of atrophy of any grade was higher in women (41.73%) than in men (38.18%; P=0.04); this difference was lost for advanced atrophy (women 13.98%, men 12.07%; P=0.1). Conclusion The prevalence of H. pylori infection or atrophy remains high in Latvia. Determining the right cutoff value is critically important for pepsinogen-based atrophy detection in Europe in order to objectively stratify gastric cancer risk.

The accuracy of flexible spectral imaging colour enhancement for the diagnosis of gastric intestinal metaplasia: do we still need histology to select individuals at risk for adenocarcinoma?

Background Targeting biopsies on the basis of visual recognition of mucosal changes in the stomach instead of the currently accepted random biopsy sampling may be attractive. Aim The aim of this study was to evaluate the accuracy of endoscopic findings using flexible spectral imaging colour enhancement (FICE) for intestinal metaplasia (IM) in the gastric mucosa. Methods A consecutive cohort of 126 individuals aged over 50 years (27% men) was subjected to upper endoscopy using FICE. Histological assessment (per patient and per biopsy) was considered the gold standard to accuracy estimates. Results Histological assessment revealed IM in 50% of the individuals [OLGIM (operative link on gastric intestinal metaplasia assessment) stages I–IV]. Overall, endoscopy presented sensitivities, specificities, positive likelihood ratio, negative likelihood ratio and accuracies per patient of 60% [95% confidence interval (95% CI) 48–72], 87% (95% CI 79–95), 4.7 (95% CI 2.4–93), 0.45 (95% CI 0.33–0.62) and 74% (95% CI 0.66–0.82), respectively, for IM diagnosis and 71% (95% CI 37–100), 87% (95% CI 79–95), 5.6 (95% CI 2.5–12.5), 0.32 (95% CI 0.10–1.0) and 86% (95% CI 77–94), respectively, for selecting individuals with OLGIM (III–IV). The proportions of agreement (and &kgr; values) for IM in the antrum and the corpus were 75% (0.37) and 81% (0.19), respectively. Conclusion FICE endoscopy yielded favourable results in the endoscopic diagnosis of IM of the gastric mucosa, and this is a very practical and easy method to use in daily clinical practice for unselected patients. Our study demonstrated a good specificity for FICE endoscopy to detect IM in the stomach. Further improvement in disseminating and training of this assessment is required to improve the reliability.

Implementation of gastric cancer screening – The global experience

Gastric cancer (GC) is still an important global healthcare problem, and in absolute figures it is going to remain at the present level in foreseeable future. In general, survival of patients with GC is poor mainly due to advanced-stage diagnosis. Early-stage GC can be cured by endoscopic resection or less invasive surgical treatment. Unfortunately, there is no appropriate screening strategy available for global application. This article provides a description of established national and regional GC screening programs and the screening modalities used. This review also summarizes current approaches to develop cancer-screening biomarkers. Although candidates with initial promising results have been suggested, moving discovery into clinical practice is still a major challenge. Well-designed biomarker studies, with systematic validation steps, are needed to decrease the burden of this fatal disease.

Epidemiology and Surgical Treatment of Gastric Cancer in Latvia

Epidemiology and Surgical Treatment of Gastric Cancer in Latvia The aim of the study was to evaluate short- and long-term results of surgical treatment of gastric cancer performed in Latvia Oncology Centre. Retrospectively data was collected from 461 patients who underwent gastrectomy with curative intent in the Latvia Oncology Centre from January 2001 to December 2005. The data was subjected to statistical analysis. On average, 92.2 (range 81-102) R0-R1 gastrectomies were performed each year. Post-operative complications occurred in 75 patients (16.3%); in-hospital mortality was 3.3%. The overall 5-year survival was 50.8%. In 444 cases (96.3%) there was histopathologic confirmation of R0-resection with a 5-year survival of 52.5% (P < 0.001). Considering pT category, 5-year survival (median) was 88.6% (not reached) for pT1 patients, 65% (not reached) for pT2, 42.3% (35.7 months) for pT3 and 27% (14.2 months) for pT4 (P < 0.001). Considering the pN category, 5-year survival (median) was 67% (not reached) for pN0 patients, 30% (22.1 months) for pN1 and 29% (14.2 months) for pN2-3 (P < 0.001). Short- as well as long-term results are comparable with Western experiences, but not for pN+ patients where no difference between pN1 and pN2 cases was observed. Kuņga Vēža Epidemiologija Un Ķirurgiskā Ārstēšana Latvijā Lai gan mirstība no kuņga vēža Rietumeiropā un Amerikas Savienotajās valstīs samazinās, Austrumeiropā tā joprojām ir augsta. Šī pētījuma nolūks bija novērtēt Latvijas Onkologijas centrā veiktās kuņga vēža kirurgiskās ārstēšanas īstermiņa un ilgtermiņa rezultātus. Statistiskajai analīzei tika izmantota retrospektīvi apkopota informācija par 461 pacientu, kam, laika posmā no 2001. gada janvāra līdz 2005. gada decembrim, Latvijas Onkologijas centrā ārstnieciskos nolūkos tika veikta gastrektomija. Katru gadu tika veiktas vidēji 92,2 (81-102) R0-R1 gastrektomijas. Pēcoperācijas komplikācijas tika novērotas 75 pacientiem (16,3%), bet stacionārā mirstība bija 3,3%. Piecu gadu izdzīvošana bija 50,8%. 444 gadījumos (96,3%) bija R0 rezekcijas histopatologijas apstiprinājums un piecu gadu izdzīvošana 52,5% (P < 0,001). Ņemot vērā pT kategorijas, piecu gadu izdzīvošana pT1 pacientiem bija 88,6%, pT2 - 65%, pT3 - 42,3% (35,7 mēneši) un pT4 - 27% (14,2 mēneši). Ņemot vērā pN kategorijas, piecu gadu izdzīvošana pN0 pacientiem bija 67%, pN1 - 30% (22,1 mēnesis) un pN2-3 - 29% (14,2 mēneši) (P < 0,001). Klīniski patologiskais pacientu raksturojums, kuriem ārstnieciskos nolūkos veikta rezekcija, ir salīdzināms ar Rietumu pieredzi. Arī īstermiņa un ilgtermiņa rezultāti ir līdzīgi, izņemot pN+ pacientus, kuriem netika novērota atšķirība starp pN1 un pN2 gadījumiem.