Johanna Louhimo

Serum HCGβ, CA 72-4 and CEA are independent prognostic factors in colorectal cancer

In colorectal cancer, stage is considered to be the strongest prognostic factor, but also serum tumour markers have been reported to be of prognostic value. The aim of our study was to investigate the prognostic value of serum carcinoembryonic antigen (CEA), CA 19‐9, CA 242, CA 72‐4 and free β subunit of human chorionic gonadotropin (hCGβ) in colorectal cancer. Preoperative serum samples were obtained from 204 colorectal cancer patients, including 31 patients with Dukes A, 70 with Dukes B, 49 with Dukes C and 54 with Dukes D cancer. The serum levels of CEA, CA 19‐9, CA 242 and CA 72‐4 were measured with commercial kits with cut‐off values of 5 μg/L for CEA, 37 kU/L for CA 19‐9, 20 kU/L for CA 242 and 6 kU/L for CA 72‐4. The serum hCGβ was quantitated by an immunofluorometric assay (IFMA) with 2 pmol/L as a cut‐off value. Survival analyses were performed with Kaplan‐Meier life tables, log‐rank test and Cox proportional hazards model. The sensitivity was 44% for CEA, 26% for CA 19‐9, 36% for CA 242, 27% for CA 72‐4 and 16% for hCGβ. The overall 5‐year survival was 55%, and in Dukes A, B, C and D cancers the survival was 89%, 77%, 52% and 3%, respectively. Elevated serum values of all markers correlated with worse survival (p < 0.001). In Cox multivariate analysis, the strongest prognostic factor was Dukes stage (p < 0.001), followed by tumour location (p = 0.002) and preoperative serum markers hCGβ (p = 0.002), CA 72‐4 (p = 0.003) and CEA (p = 0.005). In conclusion, elevated CEA, CA 19‐9, CA 242, CA 72‐4 and hCGβ relate to poor outcome in colorectal cancer. In multivariate analysis, independent prognostic significance was observed with hCGβ, CA 72‐4 and CEA.

MMP-7 as a prognostic marker in colorectal cancer

Matrix metalloproteinase-7 is capable of degrading many extracellular matrix proteins and cellular adhesions. In many malignancies, it is overexpressed, and it plays a role in cancer progression by enhancing tumor invasion and thereby metastatic potential. The purpose of this study was to evaluate the association between MMP-7 tissue expression and prognosis in colorectal cancer. From 623 patients who underwent surgery for colorectal cancer, surgical specimens were collected into tissue array blocks and stained by immunohistochemistry for MMP-7. Specimens from 545 patients were suitable for analysis. In specimens from 105 patients (19.3%), MMP-7 scored as high; in 103 (18.9%), as moderate; and in 134 (24.9%), as mild. In 203 cases (37.2%), immunoreactivity was negative. A significant correlation appeared between MMP-7 immunoexpression and tumor differentiation. High MMP-7 positivity associated with poor prognosis during a 5-year follow-up. During longer follow-up, the differences in survival between groups disappeared. MMP-7 is a potential target for tumor therapy, which should be evaluated in clinical trials.

Preoperative hCGβ and CA 72‐4 are prognostic factors in gastric cancer

In gastric cancer, the role of tumour markers in assessment of prognosis is unconfirmed. In our study, we evaluated the prognostic significance of serum tumour markers carcinoembryonic antigen (CEA), CA 19‐9, CA 72‐4, CA 242 and free β subunit of human chorionic gonadotropin (hCGβ) in gastric cancer. Preoperative serum samples were obtained from 146 patients with gastric cancer, including 29 with stage I, 11 with stage II, 42 with stage III and 64 patients with stage IV cancer. Quantitation of CEA, CA 19‐9, CA 72‐4 and CA 242 in serum was performed with commercial assays. HCGβ was measured with an in‐house immunofluorometric assay based on monoclonal antibodies specific for the free β‐subunit of hCG. Survival analysis was performed with Kaplan‐Meier life‐tables and log‐rank test, and with multivariate Cox regression analysis. Disease‐specific cumulative 2‐year survival rate was 40%. Serum levels of CEA, CA 72‐4, CA 242 and hCGβ showed significant correlation with stage (p<0.027); for CA 19‐9 the association was of borderline significance (p=0.056). Of the studied markers, CA 19‐9, CA 72‐4, CA 242 and hCGβ were found to be prognostic factors in univariate analysis (p< 0.022). In multivariate analysis, stage had the statistically most significant association with prognosis followed by hCGβ, tumour histology according to the Laurén classification and by CA 72‐4. In gastric cancer, tumour markers hCGβ and CA 72‐4 are independent prognostic factors in addition to stage and histological type of the tumour.

Syndecan-1 Expression – A Novel Prognostic Marker in Pancreatic Cancer

Objective: Syndecan-1 is a transmembrane receptor that participates in cell-cell and cell-matrix interactions, cell proliferation and cell migration. Expression of syndecan-1 is downregulated in many cancers, but in pancreatic ductal adenocarcinoma it is upregulated. Method: We studied the immunohistochemical expression of syndecan-1 in 144 pancreatic adenocarcinomas and evaluated the prognostic value of syndecan-1 expression. Formalin-fixed, paraffin-embedded specimens were stained with mouse monoclonal antibody B-B4 against human syndecan-1. The epithelial and stromal staining was separately evaluated and compared with patient survival, clinical stage and histological grade. Result: Epithelial immunoreactivity was observed in most of the pancreatic carcinoma samples: in 70 (49%) of the samples the epithelial staining was weak, in 48 (33%) moderate, in 18 (12%)strong and in only 8 (6%) of the samples the epithelial staining was negative. Stromal staining was weak in 24 (17%), moderate in 31 (22%), strong in 11 (8%) and negative in 78 (54%) of the pancreatic carcinoma samples. Lack of stromal expression predicted a better prognosis (p = 0.002; HR 1.7) and it was independent of stage (p = 0.01; HR = 1.5) and grade (p = 0.0004; HR 2.1) in multivariate analysis. Epithelial expression predicted better prognosis for patients that underwent surgery for cure (n = 94, p = 0.03). Conclusion: Stromal syndecan-1 expression is an independent prognostic marker in pancreatic cancer, whereas epithelial syndecan-1 expression predicts better prognosis only in resectable disease.

Anaplastic and Poorly Differentiated Thyroid Carcinoma: Therapeutic Strategies and Treatment Outcome of 52 Consecutive Patients

Anaplastic thyroid carcinoma (ATC) is one of the most lethal malignancies; poorly differentiated thyroid carcinoma (PDTC) is a new diagnosis for rare aggressive thyroid tumours. Surgery is often considered the only chance for survival, but the benefit of surgery and subsequent multimodal therapy is unclear. We retrospectively analyzed the outcome of 44 ATC and 8 PDTC consecutive patients treated at Helsinki University Central Hospital between 1990 and 2008. All ATC and PDTC cases were re-examined and reclassified histologically. Median survival was only 3.1 months for ATC, but 3.7 years for PDTC. Most patients in both groups eventually died of cancer. ATC patients were older than PDTC patients (74 vs. 66 years). Nodal and distant metastases had a negative impact on survival (ATC; p = 0.038, p = 0.008). Long-term survivors in both groups were stage N0M0 at presentation. Multimodal therapy was successful for 9 (20%) ATC patients, and their median survival was the longest (11.6 months) among treatment groups. Most PDTC patients (88%) underwent total thyroidectomy followed by radioiodine ablation; the only 2 who received chemotherapy survived longest. Although ATC and PDTC are both aggressive thyroid carcinomas, multimodal therapy for both can provide a chance of prolonged survival in patients with locoregional disease.

Expression of COX-2 is increased with age in papillary thyroid cancer

Aims:u2002 To study cyclooxygenase‐2 (COX‐2) and matrix metalloproteinase‐2 (MMP‐2) expression in papillary thyroid cancer (PTC). Expression of COX‐2 is elevated in various human tumours and it has an important role in carcinogenesis. MMP‐2 is also an important component of the metastatic potential of tumours. In PTC the most important factor affecting survival is age, but it is poorly understood why older PTC patients have a worse prognosis.

Clinical outcome after D1 vs D2-3 gastrectomy for treatment of gastric cancer.

Background: Clinical benefit from extended lymphadenectomy for gastric cancer remains controversial as a considerable variation exists between results of different studies. Methods: 562 patients were treated at HUCH between 1987–2003, whereof 223 underwent gastrectomy with curative intent. Of these, 114 patients underwent subtotal/total gastrectomy with D1 (standard) lymphadenectomy and 109 patients had D2–3 (extended) lymph node dissection. The clinical outcome of these patients was analysed retrospectively. Results: The incidence of surgical complications was 33.0% in D2–3 and 16.8% in D1 lymphadenectomy groups (p = 0.008). Abscess was the most common complication (11.0%) among D2–3 operated patients and haemorrhage (4.4%) in D1 group. Hospital mortality was 3.7% in D2–3 and 1.8% in D1 group (p = 0.438). The only statistically significant factor influencing the rate of complications was D2–3 lymphadenectomy (OR 2.620, 95% C.I. 1.375 to 4.991). D2–3 was associated with a longer postoperative hospital stay and operation time, greater blood loss and increased need for blood transfusions compared to D1. The 5-year survival was not statistically different between lymphadenectomy groups. Conclusion: It is justified to perform a D2–3 gastrectomy in Europe with a acceptable postoperative mortality but with a significant morbidity. Further studies are needed to assess the value of extended lymphadenectomy in gastric cancer

Expression and prognostic value of transcription factor PROX1 in colorectal cancer.

Background:PROX1 is a specific target of the β-catenin/TCF pathway in the intestinal epithelium. It acts as a regulator of progression from a benign to a highly dysplastic phenotype in colorectal tumours. However, the clinical significance of PROX1 expression is not known.Methods:We studied the prognostic value of immunohistochemical expression of PROX1 in a series of 517 patients with colorectal cancer (CRC).Results:The majority of the tumour samples expressed PROX1 (91%, 471 out of 517). High PROX1 expression was associated with a poor grade of tumour differentiation (P<0.0001). In the subgroup of patients with colon cancer, high PROX1 expression was associated with unfavourable colorectal cancer-specific survival (CCSS) as compared with low PROX1 expression (CCSS 47% vs 62%; P=0.045; RR 1.47). The association between high PROX1 and poor outcome was further strengthened in female colon cancer patients (CCSS 38% vs 63%; P=0.007; RR 2.02). Nonetheless, in multivariate survival analysis PROX1 expression was not retained as an independent prognostic factor.Conclusion:High PROX1 expression is associated with a poor grade of tumour differentiation, and, in colon cancer patients, also with less favourable patient outcome. Our results strengthen the previous preclinical observations that PROX1 has a role in tumour progression in CRC.

Epithelial MMP-2 expression correlates with worse prognosis in pancreatic cancer.

Objective: Matrix metalloproteinases (MMPs) degrade extracellular matrix and are involved in tumor invasion and metastasis in various cancers. In pancreatic cancer, MMP-2 expression is upregulated and correlates with tumor recurrence. The aim of this study was to evaluate the prognostic significance of MMP-2 in pancreatic ductal adenocarcinoma. Methods: MMP-2 expression was assessed by immunohistochemistry in 127 patients operated on at Helsinki University Hospital from 1974 to 1998, with expression interpreted separately in epithelial and stromal samples. Results: Epithelial MMP-2 expression was strong in 5%, moderate in 20%, weak in 25% and negative in 50% of the tumors, with high epithelial MMP-2 expression significantly associated in univariate survival analysis with advanced stage, poor grade and poor survival. Stromal MMP-2 expression was strong in 0%, moderate in 14%, weak in 70% and negative in 16% of the cases, and did not significantly correlate with patient survival. Conclusion: Epithelial MMP-2 correlates with advanced tumor stage and grade, but is not an independent predictor of survival.

The novel WHO 2010 classification for gastrointestinal neuroendocrine tumours correlates well with the metastatic potential of rectal neuroendocrine tumours.

Background: Approximately 10–15% of gastroenteropancreatic neuroendocrine tumours (NETs, carcinoids) occur in the rectum, some of which are potentially able to metastasize. The new WHO 2010 classification of NETs applies to all gastroenteropancreatic NETs, but no reports have studied its correlation with the prognosis of rectal NETs. Patients and Methods: We retrospectively classified 73 rectal NETs according to the novel WHO 2010 and the previous WHO 2000 classifications. The aim was to assess the validity of the classifications in distinguishing indolent rectal NETs from metastasising tumours. Results: Using the WHO 2010 criteria, we identified 61 G1 tumours, none of which had metastasised during follow-up. Of 11 G2 tumours, 9 had shown distant metastases. The only G3 neuroendocrine carcinoma that occurred had been disseminated at initial presentation. Conclusion: Our results show that rectal NETs classified as G1 according to the WHO 2010 classification have an indolent clinical course, whereas G2 NETs often metastasise. The WHO 2010 classification of NETs predicts the metastatic potential of rectal NETs better than the WHO 2000 classification.