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Background/aim: The oral bacteria involved in the development of periodontitis alter the tissue conditions and modify immune responses in a way that may also influence tumor development. We investigated the prevalence of R gingipain (Rgp), a key virulence factor of the oral pathobiont Porphyromonas gingivalis, and the tissue-destructive enzymes matrix metalloproteinase 8 (MMP-8) and 9 (MMP-9) in 202 unselected consecutive oropharyngeal squamous cell carcinoma (OPSCC) samples. We further investigated the relationships between these factors and human papillomavirus (HPV) status, Treponema denticola chymotrypsin-like proteinase (Td-CTLP) immunoexpression, clinical parameters, and patient outcome., Patients and Methods: Clinicopathological data were derived from university hospital records. Rgp, MMP-8, and MMP-9 immunoexpression was evaluated by immunohistochemistry; the immunohistochemistry of Td-CTLP and HPV has been described earlier for this patient series. Cox regression analysis including death by causes other than OPSCC as a competing risk served to assess sub distribution hazard ratios., Results: In multivariable survival analysis, positive tumoral MMP-9 immunoexpression predicted poor prognosis among all patients [sub distribution hazard ratio (SHR)=2.4; confidence interval (CI)=1.2-4.4, p=0.008], and especially among those with HPV-negative OPSCC (SHR=3.5; CI=1.7-7.3, p=0.001). Positive immunoexpression of Rgp in inflammatory cells was associated with favorable outcome among all patients (SHR=0.5, CI=0.2-0.9, p=0.021) and among those with HPV-negative disease (SHR=0.4, CI=0.2-0.9, p=0.022)., Conclusion: Our results suggest that tumoral MMP-9 may be related to poor outcome in OPSCC, especially in HPV-negative disease, while Rgp immunoexpression in inflammatory cells is associated here with better disease-specific survival (DSS)., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Distinguishing between pancreatic cancer and chronic pancreatitis (CP) is often difficult. Certain (5-6%) CP cases are autoimmune in nature, and these patients respond to corticosteroid treatment, making surgery avoidable. Our aim was to evaluate the incidence of autoimmune pancreatitis (AIP) among patients operated on for a pancreatic mass with a final histology of CP., Patients and Methods: A total of 33 patients were operated on at the Tampere or Helsinki University Hospital for suspicion of cancer, but with final histopathological diagnosis of CP. The median age was 58 (31-81) years; 26 patients (79%) were male. There were 28 pancreaticoduodenectomes and five left pancreatic resections. Surgical specimens were re-evaluated by experienced pathologists, with representative samples chosen for immunohistochemistry Each sample was scored as positive or negative for immunoglobulin G4 (IgG4) independently by two pathologists. Honolulu consensus criteria served for AIP sub-typing., Results: Out of the 33 specimens, 10 (30%) were positive for IgG4. Histopathological re-evaluation of these revealed all to be type 1 AIP., Conclusion: The proportion of AIP, according to IgG4-positive immunohistochemistry and histological re-evaluation, was much higher than expected. This suggests that by focusing on diagnosis of AIP preoperatively, certain patients might be treated with corticosteroids and possibly avoid unnecessary surgery., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Expression of novel stem cell-associated marker human embryonic stem cell 77 (HES77) was studied in rectal neuroendocrine tumors (NETs), which comprise 10 to 15% of gastroenteropancreatic NETs, some with metastatic potential., Materials and Methods: WHO 2010 classification was applied, and immunohistochemical positivity for HES77 was assessed in 72 primary tumors and 6 metastases. Correlations were calculated between HES77 expression, metastasis and patient survival., Results: Expression of HES77 strongly positively correlated with metastatic potential and poorer prognosis. The proliferative index determined in the metastasis did not correlate with patient survival., Conclusion: Novel stem cell-associated marker HES77 has a strong prognostic value in patients with rectal NETs and may be useful in selecting those who are at-risk for developing metastatic disease, and who may benefit from intensive adjuvant therapy. Proliferative index in the metastasis did not predict for outcome. Characterization of the HES77 epitope would certainly enhance the interest in the antibody., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: We sought to clarify whether the expression of toll-like receptors (TLR) in Merkel cell carcinoma (MCC) is linked to tumor and patient characteristics, especially the presence of Merkel cell polyoma virus (MCV)., Materials and Methods: The study comprised of 128 patients with data on Merkel cell polyomavirus (MCV) status and clinical features were included in the study. Immunohistochemistry for TLR expression was performed on tissue microarray (TMA) slides., Results: TLR 2, 4, 5, 7 and 9 expression was noted in most of the tumor specimens. Decreased expression of TLR 9 correlated strongly with MCV positivity. Cytoplasmic TLR 2 expression correlated with small tumor size, while nuclear TLR 2 and TLR 5 expressions with larger tumors. Increased nuclear TLR 4 expression and decreased TLR 7 expression were associated with older age., Conclusion: TLR 2, 4, 5, 7 and 9 appear to reflect certain clinicopathological variables and prognostic markers of MCC tumors., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Carcinoembryogenic antigen (CEA) is useful in the evaluation of chemotherapy response of metastatic colorectal cancer (CRC). We studied weekly CEA during one fluorouracil-based chemotherapy cycle, correlated with long-term (8-12 week interval) computed tomography (CT) and CEA responses., Patients and Methods: CEA, liver function tests and inflammatory parameters were measured prospectively at baseline, day 7, day 14, and after the cycle (day 21/28), in 60 patients with metastatic CRC., Results: CEA non-significantly decreased at day 7 and was increased on day 14. In progressive disease, CEA increased significantly during the evaluation cycle (55.4 μg/l vs. 148.2 μg/l; p=0.024), but the level was stable in patients with disease control (10.6 μg/l vs. 17.8 μg/l; p=0.58). CEA fluctuation correlated neither with liver function test nor with inflammatory parameters. Correlation of long-term response was most evident in progressive disease., Conclusion: CEA should not be measured during 5-fluorouracil-based oral chemotherapy nor within two weeks from intravenous chemotherapy administration.

Aim: The purpose of this study was to assess if the addition of a panel of tumor markers to established clinicopathological factors could improve the accuracy of 5-year outcome prediction in gastric cancer. The studied markers were chosen to represent different aspects of tumor biology., Patients and Methods: The expression of syndecan-1, tenascin-C, tumor-associated trypsin inhibitor (TATI), p53, p21 and bcl-2 was analyzed by immunohistochemistry informalin-fixed, paraffin-embedded specimens from 337 patients with gastric cancer. In addition, the DNA ploidy and S-phase fraction (SPF) were assessed by flow cytometry., Results: The loss of epithelial syndecan-1, strong stromal syndecan-1, the loss of stromal tenascin-C, the loss of tumor tissue TATI, high p53 and high p21 expression, aneuploidy and high (> or =7.6%) SPF were all associated with an unfavorable prognosis in univariate survival analysis. In multivariate survival analysis, p53 (hazard ratio (HR) 1.58; confidence interval (CI) 95% 1.16-2.16), p21 (HR 1.67; CI 95% 1.09-2.56) and DNA ploidy (HR 1.50; CI 95% 1.10-2.05) were independent prognostic factors, in addition to penetration depth (pT), lymph node status (pN), age at diagnosis and estimated radicality of surgery. The difference in prognostic accuracy between a base model with pT, pN, age and radicality of surgery (area under the curve (AUC) 0.898; CI 95% 0.86-0.94) and an extended model including p53, p21 and DNA ploidy (AUC 0.900; CI 95% 0.86-0.94) was not statistically significant (p=0.85)., Conclusion: In gastric cancer, p53 and p21 expression, as well as DNA ploidy, are independent prognostic factors in addition to standard clinicopathological factors. However, the established indicators of the extent of disease show an impressively high accuracy in 5-year outcome prediction and adding the examined tumor markers to the base model does not significantly improve the prognostic accuracy.

Background: The aim of this study was to examine the expression of vascular endothelial growth factor receptor-2 (VEGFR-2) in Merkel cell carcinoma (MCC) and to correlate the expression with tumour growth and the development of metastasis., Patients and Methods: The study included 21 patients treated for MCC at Helsinki University Hospital, Helsinki, Finland between 1987 and 2003. The VEGFR-2 expression was studied by immunohistochemistry. The correlations between the quantitative expression of VEGFR-2 and tumour size and metastatic dissemination were analyzed statistically., Results: VEGFR-2 was expressed in 91% of the large (> or =2 cm) and 70% of the small (<2 cm) tumours. There was a stronger positive correlation between expression of VEGFR-2 and tumour size than between VEGFR-2 and metastatic potential., Conclusion: A correlation between the expression of pro-angiogenic marker and tumour size was established. Our results indicate that inhibiting angiogenesis could be a treatment option for MCC. The role of neovascularization in the metastatic process in MCC remains to be determined.

Background: The aim of this study was to examine the expression of endostatin in Merkel cell carcinoma (MCC) and to correlate the expression with tumour growth and the development of metastasis., Patients and Methods: The study comprised 19 patients treated for MCC at the Helsinki University Hospital, Helsinki, Finland between 1987 and 2003. Endostatin expression was studied by immunohistochemistry. The correlations between the quantitative expression of endostatin and tumour parameters were analysed statistically., Results: The expression of endostatin was documented in only 40% of the samples. Endostatin correlated negatively with tumour size, and was expressed in 30% of the large and 56% of the small tumours. There was no difference in expression between tumours expanding to metastases and tumours with more indolent behaviour. The simultaneous expression of vascular endothelial growth factor receptor-2 and endostatin was distinguished in small-sized tumours., Conclusion: This study showed a correlation between endostatin expression and small tumour size in Merkel cell carcinoma. This finding was further confirmed by the finding that tumours positive for VEGFR-2, but not for endostatin, seemed to be larger than tumours that showed simultaneous expression of VEGFR-2 and endostatin.

Merkel cell carcinoma (MCC) is an aggressive dermal tumour of neuroendocrine origin with poor prognosis. The role of cell cycle-regulatory proteins (p53/p21/p27) in MCC pathogenesis and their prognostic importance were evaluated. Twenty-four primary MCC specimens with corresponding clinical data were analysed by immunohistochemistry for p21, p27 and p53 antibodies. The stainings were evaluated semi-quantitatively and the results analysed statistically. p53 was negative in 80% and p21 in 71% of the samples. Positive staining for p27 was evident in 92% of the samples. However, the expression of these antibodies did not correlate with the outcome of the patient. The proportion of p53- and p21-negative samples seems to indicate that correction processes after DNA damage are not activated during MCC pathogenesis, a supposition that is supported by the aggressive nature of this tumour. Therefore, the expressions of the three studied cell cycle regulators cannot serve as prognostic markers for survival.

Background: Cyclooxygenase-2 (Cox-2) is expressed by several types of epithelial malignancies, i.e., carcinomas, and inhibition of Cox-2 may have a therapeutic role in chemoprevention and treatment of cancer. The role of Cox-2 in non-epithelial malignancies, however, is unclear., Materials and Methods: We investigated, by immuno- histochemistry, the expression of Cox-2 in 103 human soft-tissue sarcomas., Results: All 10 biphasic synovial sarcomas were positive for Cox-2, but positivity was observable only in the epithelial component of these tumours. Excluding sarcomas with epithelial differentation, uniform staining of the tumour was observed in only 2 samples. In addition, positivity for Cox-2 appeared in tumour cells in only 18 samples around necrotic areas., Conclusion: In human soft-tissue sarcomas, Cox-2 expression seems to be associated with epithelial differentation and, in some types of sarcomas, to be expressed in otherwise negative tumours at sites of necrosis.

Background: The aim of this study was to examine the level of neuroendocrine differentiation to determine its association with clinicopathological parameters., Patients and Methods: Twenty-five primary MCC samples were evaluated for neuroendocrine differentiation profiles by immunohistochemistry using antibodies to chromogranin-A, microtubule associated protein-2 and synaptophysin. The data were compared with clinical parameters to find out whether their expression correlates with prognosis., Results: In general, MCC shows a high degree of neuroendocrine differentiation. A higher expression of chromogranin-A and synaptophysin associated with benign behaviour. Chromogranin-A appeared to be the most important one in predicting the course of disease., Conclusion: Low levels of neuroendocrine differentiation in MCC associates with poor prognosis. Chromogranin-A could be used to identify patients who might benefit from oncological treatments.

Background: Tenascin-C (Tn-C) is an extracellular matrix protein with growth-, invasion- and angiogenesis-promoting activities. It is up-regulated in tumorigenesis and has been suggested to correlate with prognosis in various carcinomas, but its significance in squamous cell carcinoma of the head and neck remains unknown. The purpose of this study was to examine the prognostic significance of Tn-C expression in oral and pharyngeal squamous cell carcinomas., Patients and Methods: Tn-C expression was determined by immunohistochemistry in 65 consecutive tumors from patients with primary oral and pharyngeal squamous cell carcinoma. Based on staining intensity, both the stroma and invasion border were separately classified into two groups and the results correlated with overall survival (OS) and disease-free survival (DFS)., Results: The tumor stroma showed strong Tn-C expression in 56 (86%) samples, and weak Tn-C expression in 9 (14%). At the invasion border, Tn-C expression was strong in 38 (58%) samples and weak in 27 (42%). Tn-C expression was not a statistically significant predictor of survival and there was no correlation between Tn-C expression and tumor or patient characteristics., Conclusion: Tn-C protein was overexpressed in the majority of our oral and pharyngeal squamous cell carcinoma samples. The presence of TnC did not appear to predict for OS or DFS.

Background: CEA, CA 19-9, CA 242 and CA 72-4 are commonly used tumour markers for gastrointestinal malignancies. The advantage of the concomitant use of these markers is under debate., Materials and Methods: Serum concentrations of the markers were measured at the time of diagnosis in 161 patients with benign and 125 with malignant gastrointestinal diseases. Concomitant use of the markers was evaluated in a logistic regression model., Results: CA 19-9, CA 242 or CA 72-4 showed similar sensitivity of 44% for gastric cancer, whereas CEA was elevated in 25% of the cases. In patients with colorectal cancer, CEA was most frequently elevated (54%), followed by CA 242 (46%), CA 19-9 (36%) and CA 72-4 (25%). High CA 19-9 and CA 242 serum levels were frequent in patients with cholangiocarcinoma (86% and 68%, respectively) and pancreatic cancer (80% and 63%, respectively). In the benign disease group, serum CA 19-9 was most frequently elevated, i.e. in 24%, 25% and 38% of patients with pancreatic, biliary and liver disorders, respectively. The overall accuracy of CEA, CA 19-9, CA 242 and CA 72-4 was 66%, 71%, 71% and 66%, respectively (p > 0.18). When combined in a logistic regression model, CA 72-4, CA 19-9 and CEA provided independent diagnostic information, whereas CA 242 contributed with independent diagnostic information only on excluding CA 19-9. The probability of cancer for each patient, calculated with the model, was applied as a diagnostic test and was compared with the single markers by ROC-curve analysis. The AUC value of the probability index was significantly higher than the values of the different tumour markers., Conclusion: An algorithm based on the combination of CEA, CA 19-9 and CA 72-4 improved the diagnostic accuracy in gastrointestinal tract malignancies compared with these markers alone.

Background: Earlier studies suggest that the free beta-subunit of human chorionic gonadotropin (hCGbeta) may be a useful tumour marker for gastrointestinal cancers. Our aim was to investigate hCGbeta in serum in gastrointestinal diseases in comparison with CA 19-9 and carcinoembryonic antigen (CEA)., Patients and Methods: The serum concentrations of hCGbeta, CA 19-9 and CEA were measured from 142 patients with malignant and 178 with benign gastrointestinal diseases. The diagnostic accuracies of the markers were compared and a diagnostic algorithm was established with logistic regression (LR) analysis., Results: The hCGbeta serum level was elevated most frequently in bile duct (56%), pancreatic (45%) and gastric cancer (41%). In benign diseases, hCGbeta concentration was elevated in 10% of the patients. In an LR model each marker provided independent diagnostic information and the probability of cancer was calculated. It was applied as a diagnostic algorithm providing better accuracy than the markers alone. In receiver operating characteristic (ROC) curve analysis the area under the curve (AUC) value of the algorithm was significantly higher than the AUC values of CA 19-9, CEA, or hCGbeta (p=0.009-0.049)., Conclusion: Serum hCGbeta, CA 19-9 and CEA provide additive diagnostic information in gastrointestinal malignancies and the use of an algorithm established by LR analysis improves diagnostic accuracy.

Background: Production of the glycoprotein hormone hCG beta has been associated with aggressive behavior in nontrophoblastic tumors. In this study the prognostic value of serum level and tissue expression of hCG beta were compared in 232 patients with colorectal cancer., Materials and Methods: Serum levels were measured with a hCG beta specific immunofluorometric assay. Tissue specimens were stained with the same monoclonal antibody as in the serum assay., Results: The proportion of patients with a positive immunohistochemical expression of hCG beta was higher (22%) than the proportion with elevated serum levels (17%). The correlation between serum and tissue expression was moderate (kappa 0.298). Both serum and tissue expression of hCG beta were independent prognostic factors. hCG beta serum level was a stronger prognostic factor than tissue expression both in uni- and in multivariate analysis. The accuracy when predicting 5-year survival status of the patients was highest (63%) when using the combined results of serum and tissue expression., Conclusions: There is a moderate correlation between hCG beta expression in serum and in tissue. The predictive accuracy of serum hCG beta was higher than the predictive accuracy of tissue expression, and the prognostic accuracy was further slightly increased when using a combination of tissue and serum expression.

Background: Syndecan-1, a cell surface heparan sulphate proteoglycan, has a role in cell adhesion, maturation and proliferation. Syndecan-1 has been reported to be a promising prognostic marker in various cancer forms., Materials and Methods: We analysed tumour specimens from 296 gastric cancer patients. Syndecan-1 expression was studied by immunohistochemistry., Results: Syndecan-1 immunoreactivity was observed in 234 (79%) patients. The expression of syndecan-1 did not correlate significantly with the presence of lymph node metastases, distant metastases, peritoneal spreading, penetration depth, tumour size, tumour location, Borrmann's classification, Laurén's classification, age or gender. Syndecan-1 immunoreactivity correlated significantly with survival in the whole patient series (p = 0.0499) and also in the subgroup of patients with stage I cancer (p = 0.0417), but not in patients with stage II, III or IV disease. In multivariate survival analysis, stage of disease and tumour size emerged as the only independent prognostic factors., Conclusions: In conclusion, immunohistochemical expression of syndecan-1 is a potential prognostic factor in gastric cancer, especially in patients with stage I disease.

Background: In the intact stomach, Helicobacter pylori associated gastritis is considered to be a risk factor for cancer. After partial gastrectomy increased mucosal cell proliferation associated with chronic bile reflux has been claimed to increase the risk for cancer in the gastric stump, whereas the influence of H. pylori infection is not so clear., Material and Methods: The study was a retrospective study with 130 patients, who had undergone partial gastrectomy for peptic ulcer. The cell proliferation rate was determined from immunohistochemical stainings of gastroscopy biopsies with Ki-67 antibodies from gastric remnants., Results: The mean labelling index (LI) was 30.8%. There was no clear association between H. pylori infection and proliferation rate. A significant difference in proliferation rate was seen between patients with a reconstruction type known to be associated with bile reflux and those with a reconstruction without bile reflux. The difference was small in H. pylori negative patients but strong in those with bile reflux and H. pylori infection. The LI increased with age. Smoking had no significant effect on proliferation whereas use of NSAIDs seemed to inhibit proliferation., Conclusions: Ki-67 is a convenient method for assessing the proliferation rate of the gastric epithelium. Bile reflux and H. pylori infection seem to have a synergistic effect on cell proliferation in the gastric remnant and may explain the increased risk of cancer after partial gastrectomy.

The prognostic value of the immunohistochemical expression of Ki-67 in paraffin embedded specimens was studied in 242 patients with gastric adenocarcinoma. The results were compared with ploidy and S-phase fraction (SPF) obtained by DNA flow cytometry. Both SPF and ploidy correlated with survival in univariate analysis. In multivariate survival analysis, stage of disease, DNA ploidy and presence of distant metastases emerged as independent prognostic parameters. There was no significant difference in survival between patients having tumours with high and low Ki-67 labelling, neither in univariatenor in multivariate survival analysis.

The prognostic value of Ki-67 expression, ploidy and s-phase fraction was evaluated in 133 patients with pancreatic cancer. Formalin-fixed paraffin-embedded surgical specimens of pancreatic ductal adenocarcinomas were stained with a polyclonal Ki-67 antibody. Ploidy and s-phase fraction was assessed by flow cytometry. The median percentage of Ki-67 positive nuclei was 26% (range 0-90%). The level of Ki-67 immunoreactivity was associated with TNM-stage, surgical resectability, tumour grade, ploidy and S-phase fraction. Ninetythree patients, with a nuclear expression of Ki-67 in < 50% of malignant cells, had a median survival of 12.8 months compared with 5.5 months for 25 patients with Ki-67 > or = 50% (p = 0.0008). Ploidy (p < 0.0001) and SPF (p = 0.002) were also significant prognostic factors in a univariate survival analysis. In a multivariate analysis, stage (or alternatively resectability), grade, ploidy and postoperative chemotherapy emerged as independent prognostic factors. When ploidy was excluded from the Cox multivariate model, S-phase fraction also predicted prognosis independently. Ploidy and S-phase fraction are independent prognostic factors in patients with pancreatic cancer. A high level of Ki-67 immunoreactivity is also an indicator of poor prognosis but seems to add little prognostic information to that provided by traditional parameters such as stage, resectability and grade.

The prognostic value of the novel tumour marker CA 242 was studied in 175 patients with pancreatic cancer and the results were compared with those of CA 19-9. Preoperative serum levels of CA 242 and CA 19-9 were determined by commercially available assays. Patients were classified according to UICC TNM-stage, and divided into three groups of resectable, non-resectable and advanced disease. The lowest cut-off levels that divided patients into groups with significant difference in survival were calculated. Patients with resectable disease and preoperative CA 242 below 25 U/ml had a significantly better prognosis than those with a higher level (p < 0.05). The corresponding cut-off values were 100 U/ml in non-resectable (p < 0.05) and 3500 U/ml in advanced disease (p < 0.05). It is noteworthy that the overall survival rate of patients who underwent resection for cure, but had a high preoperative CA 242 level, approached that of patients with non-resectable disease. In multivariate analysis, only resectability (p < 0.0001) and preoperative serum CA 242 level (p = 0.01) were independent prognostic factors. If TNM-stage was used instead of resectability, the results were similar (stage p < 0.0001, CA 242 p = 0.006). When CA 242 was excluded from the model, preoperative serum CA 19-9 level approached the borderline of significance as an independent prognostic factor (p = 0.07). In conclusion, the preoperative serum level of the novel tumour marker CA 242 is an independent prognostic factor in pancreatic cancer. CA 242 yielded more prognostic information than CA 19-9.