Background: Updated National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. Methods: Published reports relevant to use of tumor markers for 4 cancer sites—liver, bladder, cervical, and gastric—were critically reviewed. Results: α-Fetoprotein (AFP) may be used in conjunction with abdominal ultrasound for early detection of hepatocellular carcinoma (HCC) in patients with chronic hepatitis or cirrhosis associated with hepatitis B or C virus infection. AFP concentrations >200 μg/L in cirrhotic patients with typical hypervascular lesions >2 cm in size are consistent with HCC. After a diagnosis of HCC, posttreatment monitoring with AFP is recommended as an adjunct to imaging, especially in the absence of measurable disease. Although several urine markers have been proposed for bladder cancer, none at present can replace routine cystoscopy and cytology in the management of patients with this malignancy. Some may, however, be used as complementary adjuncts to direct more effective use of clinical procedures. Although carcinoembryonic antigen and CA 19-9 have been proposed for use gastric cancer and squamous cell carcinoma antigen for use in cervical cancer, none of these markers can currently be recommended for routine clinical use. Conclusions: Implementation of these recommendations should encourage optimal use of tumor markers for patients with liver, bladder, cervical, or gastric cancers.

Background: Cyclooxygenase-2 (COX-2) overexpression is related to poor outcome in several cancers. COX-2 is upregulated in 42-90% of pancreatic ductal adenocarcinomas and is a potential target for chemotherapy. Earlier studies have not shown the expression of COX-2 to be a prognostic factor in pancreatic cancer. Objective: To evaluate the prognostic value of COX-2 in a series of patients with pancreatic adenocarcinoma. Methods: 128 patients operated on for pancreatic adenocarcinoma at Helsinki University Central Hospital between 1974 and 1998 provided sections from primary tumours which were immunohistochemically stained with a COX-2-antihuman monoclonal antibody. Results: Cytoplasmic COX-2 reactivity (.5%) occurred in 46 specimens (36%), correlating neither with age, sex, stage, size, tumour stage, nodal metastases, nor grade. Lack of COX-2 expression correlated with distant metastases (p = 0.026). In univariate survival analysis, COX-2 expression (p = 0.0114), stage (p = 0.0002), grade (p = 0.0001), and age (p = 0.042) had prognostic significance. One, two, and five year survival rates were 51%, 32%, and 8% in the COX-2 negative groups compared with 34%, 5%, and 5% in the COX-2 positive groups (p = 0.011). Prognostic significance was especially high for patients operated on with curative intent (p = 0.004). In multivariate analysis, COX-2 was an independent prognostic factor (hazard ratio = 1.6 (95% confidence interval, 1.1 to 2.3)). Conclusions: Expression of COX-2 was associated with poor outcome from pancreatic ductal adenocarcinoma and was independent of tumour stage, grade, or age in multivariate analysis.

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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) CEA; CA 242; hCG␤; colorectal cancer; prognosis; survival; tumour marker Colorectal cancer is the most common gastrointestinal cancer in the Western world and it is an important cause of cancer-related death. Tumour stage is generally considered to be the strongest prognostic factor in colorectal cancer. 1 With the development of more effective chemo-and radiotherapies, additional prognostic factors, such as tumour markers, could have an important role in identifying patients who would benefit the most from pre-or postoperative adjuvant therapies. In colorectal cancer, the most widely applied marker in follow-up of the disease is carcinoembryonic antigen (CEA), and its preoperative serum level has been shown to predict adverse prognosis. 1-3 Elevated levels of cancer associated antigens CA 19-9, CA 242 and CA 72-4 have also been reported to be associated with poor prognosis. 4 -7 Human chorionic gonadotropin (hCG) is a glycoprotein hormone produced at high concentrations by the placenta during pregnancy. It is also a very sensitive marker for trophoblastic tumours. HCG consists of an ␣ and a ␤ subunit, and the free ␤ subunit (hCG␤) has been shown to be expressed in many nontrophoblastic cancers, including gastrointestinal ones. 8 -10 We have previously shown in another patient material that CA 242, specific tissue polypeptide antigen (TPS) and hCG␤ have independent prognostic significance in colorectal cancer. 6,11 In our current study, we investigated the preoperative serum concentrations of CEA, CA 19-9, CA 242, CA 72-4 and hCG␤ and their relationship with prognosis in colorectal cancer patients., Key words: MATERIAL AND METHODS PatientsFrom January 1990 to June 1995, 354 patients with histologically verified primary colorectal cancer were operated on at the Department of Surgery of the Meilahti Hospital, Helsinki University Central Hospital. Preoperative serum samples (taken within 30 days prior to surgery) were available from 243 patients. Of these, 38 were excluded because they had had another cancer previously or during the follow-up period, and 1 patient because of lack of follow-up and survival data. Clinical characteristics of the 204 patients included are shown in Table I. Stage of the tumours was determined according to the modified Dukes' classification. 12 Clinical data was obtained from patient records, survival data until August 2001 from the Population Register Centre of Finland and cause of death data from the Statistics Finland. The minimum follow-up period was 6 years or until death; median follow-up time was 4.66 years (range 0.02-11.18 years).The ethics committee of the hospital approved our study. AssaysSerum samples were stored at Ϫ20°C before assays. The serum levels of CEA, CA 19-9, CA 242 and CA 72-4 were measured with comme...

Background: Although papillary thyroid cancer (PTC) is among the most curable cancer types, it can be a distressing disease for those patients suffering from frequent recurrences or even distant metastases leading to death. Age over 45 years is the most important indicator of poor prognosis. Our aim was to evaluate markers which might predict the outcome of an individual patient better than does TNM classification alone. Materials and Methods: Of 601 consecutive patients who underwent surgery for PTC, retrospectively we selected 36 patient pairs in which one recovered completely after primary surgery, and the other suffered from aggressive disease. Formalin-fixed, paraffin-embedded tumor samples from these 72 patients were analyzed by immunohistochemistry for COX-2, MMP-2, VEGF-C, Bcl-2, Ki-67, and p21 expression. Results and Conclusions: None of the markers we studied showed a superiority over TNM classification in selecting patients likely to progress to aggressive disease. However, the expression of COX-2 and VEGF-C seemed to be increased in patients over 45, which could explain the more aggressive behavior of these tumors. Moreover, we found that age over 45, tumor size over 4 cm, extrathyroidal extension of tumor, nodal metastases, distant metastases, and stage IV had an unfavorable effect on survival.

Background and Aims Severe acute pancreatitis is characterized by acinar cell death and inflammation. Necroptosis is an aggressive and pro-inflammatory mode of cell death that can be prevented by necrostatin-1 administration or RIP3 deletion. Methods Mouse pancreatic acinar cells were incubated with supramaximally stimulating concentrations of caerulein or sub-micellar concentrations of TLCS and necroptosis was inhibited by either addition of necrostatin or by RIP3 deletion. Cell death was quantitated using either LDH leakage from acini or PI staining of nuclei. Necrosome formation was tracked and quantitated using cell fractionation or immunoprecipitation. Pancreatitis was induced in mice by retrograde intraductal infusion of TLCS or by repetitive supramaximal stimulation with caerulein. Results Necroptosis was found to be the most prevalent mode of acinar cell in vitro death and little or no apoptosis was observed. Acinar cell death was associated with necrosome formation and prevented by either necrostatin administration or RIP3 deletion. Both of these interventions reduced the severity of TLCS- or caerulein-induced pancreatitis. Delaying necrostatin administration until after pancreatitis had already been established could still reduce the severity of TLCS-induced pancreatitis. Conclusions Necroptosis is the predominant mode of acinar cell death in severe experimental mouse pancreatitis. The severity of pancreatitis can be reduced by administration of necrostatin and that necrostatin can still reduce the cell injury of pancreatitis even if it is administered after the disease has already been established. Inhibition of necroptosis may be an effective strategy for the treatment of severe clinical pancreatitis.

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.

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.