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Ari Ristimäki

HER-2 in gastroesophageal carcinomas

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Amplification of human epidermal growth factor receptor-2 (HER-2 also known as ErbB2 and Neu) leads to overexpression of HER-2 oncoprotein and is present in several human carcinomas, including breast and gastroesophageal adenocarcinomas. It was recently shown that HER-2 targeted therapy with anti-HER-2 antibody trastuzumab led to significantly improved overall survival among patients with HER-2 positive metastatic gastroesophageal adenocarcinoma (the ToGA trial). The rate of HER-2 immunopositivity ranges widely (10-40%) in different studies on gastroesophageal adenocarcinomas, which is partially dependent on technical issues and on the nature of the clinical material, i.e. proportion of esophageal versus gastric cancers and histological distribution of the gastric adenocarcinomas. In clinical setting, HER-2 overexpression is most often initially analyzed by immunohistochemistry. Fluorescence in situ hybridization is most commonly used to verify moderate immunostaining results, and HER-2/Cep17 ratio ≥2.0 is considered positive.  Scoring algorithm for the immunopositivity differs somewhat between breast and gastroesophageal cancers, most prominent features being for the latter cancer type acceptance of incomplete (basolateral or so called U-shaped) membrane staining and also more frequently found heterogeneous or even very focal staining pattern. It is important to recognize that some of the tumors that are scored as positive in the gastroesophageal location would remain negative in the breast. It should, however be recognized that even the most commonly used HER-2 antibodies show occasional cytoplasmic and nuclear background immunopositivity. It is important to recognize these specific immunohistochemical features and shortcomings, in order to provide HER-2 targeted treatment to those patients, who are most likely to benefit from it.

Mismatch repair proteins

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Microsatellite instability (MSI) is present in approximately 15% of colorectal cancers (CRC), and it associates with certain clinicopathological features, such as prognosis and histological subtypes. Most often MSI is caused by sporadic epigenetic silencing (i.e. promoter hypermethylation) of MLH1 gene, while Lynch syndrome (LS; hereditary non-polyposis colorectal cancer) is caused by germline mutations of one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2). LS accounts for 2-5% of CRC and is characterized by young onset and an increased risk for other cancers, including endometrial cancer. Family history, presence of synchronous or metachronous syndrome-associated tumors and certain histological features of CRC are included to the Revised Bethesda Guidelines. In addition to clinicopathological parameters, identification of LS involves a complex diagnostic workflow that includes combination of immunohistochemical and genetic tests. Most often initial testing of the tumor is based on immunohistochemistry of the four MMR proteins and/or PCR-based MSI analysis. In case a positive result is obtained, genetic counseling is recommended that is followed by germline testing for mutations in the MMR genes. If a germline mutation is identified, surveillance of the patient and testing of the family members are offered. Routine molecular screening of patients with CRC for LS using immunohistochemistry or MSI has in some studies shown better sensitivity for detecting mutation carriers than using the clinicopathological guidelines. Role of distinct genetic features, such as BRAF V600E mutations and testing for MLH1 promoter methylation, which are often found in sporadic MSI but not in LS, may improve test algorithms in the future. In addition, screening for LS in the CRC patient population may yield cost effective long-term health benefits.

CV

Current positions in Helsinki, Finland (1.8. 2010 onwards):
Professor of Clinical (Surgical/Histological) Pathology, Haartman Institute, University of Helsinki.
Head of Gastrointestinal Pathology and Coordinator of Molecular Pathology, Meilahti Pathology Laboratories, Division of Pathology and Genetics, HUSLAB and Helsinki University Central Hospital.
Principal Investigator, Genome-Scale Biology, Research Programs Unit, University of Helsinki.

Education:
1990:   Licentiate of Medicine (MD), University of Helsinki, Helsinki, Finland.
1991:   Doctor of Medicine (MD/PhD), University of Helsinki, Helsinki, Finland.
1992-5:   Postdoctoral Fellow, Department of Molecular Biology, Holland Laboratory, American Red Cross,  MD, USA (Fogarty Fellow), 1992-5.
1997:   Docent of Cell Biology, University of Helsinki, Helsinki, Finland.
2005:   Specialist in surgical pathology, University of Helsinki, Helsinki, Finland.

Previous professional appointments in (surgical/histological) pathology:
1.1.2009-31.7.2010: Professor of (Surgical/Histological) Pathology, University of Oulu, Oulu, Finland. Chief pathologist (ylilääkäri), University Hospital of Oulu, Oulu, Finland.

1.1.2007-31.12.2009: Chief pathologist (vs. ylilääkäri) 50%, Division of Pathology and Genetics, HUSLAB and Helsinki University Central Hospital, Helsinki, Finland. Academy of Finland senior researcher 50%, Genome-Scale Biology, Research Programs Unit and Haartman Institute, University of Helsinki, Helsinki, Finland.

1.9.2006-30.11.2006: Department chief pathologist (vs. osastonylilääkäri), Division of Pathology and Genetics, HUSLAB and Helsinki University Central Hospital, Helsinki, Finland.
1.6.2005-31.8.2006: Specialist in pathology (vs. osaston- tai erikoislääkäri), Division of Pathology and Genetics, HUSLAB and Helsinki University Central Hospital, Helsinki, Finland.

Research experience:
Group leader, Genome-Scale Biology, Research Programs Unit and Haartman Institute, University of Helsinki, Helsinki, Finland, 2007 onwards.
Group leader, Molecular Cancer Biology, Research Programs Unit and Haartman Institute, University of Helsinki, Helsinki, Finland, 2000-6.
Senior Scientist, Cancer Institute of Finland, Department of Bacteriology Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland, 1999-2000.
Independent (Junior) Scientist, Academy of Finland, Research laboratory of the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland, 1995-8.

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