ABSTRACT
Based on data from a large multicenter phase III trial (ToGA study) trastuzumab has very recently been approved by the EMEA for metastatic gastric cancer and adenocarcinoma of the gastro-esophageal junction. Only patients with tumors which over express Her2 as defined by IHC2+ and a confirmatory FISH+ result, or IHC 3+, determined by an accurate and validated assay are eligible for trastuzumab therapy. However, testing of Her2 status by immunohistochemistry (IHC) differs from breast cancer in core aspects: 1. IHC2+/3+ is scored even though membranous staining is incomplete if membrane staining is clearly detectable even at low magnification (2.5x/5x, 3+) or medium magnification (10x/20x, 2+). 2. Additionally, membrane staining at the appropriate intensity found in at least 10% of tumor cells is restricted to resection specimens. Evaluation of Her2 in situ hybridization (ISH) is similar to breast cancer with ratio values of > or =2.0 indicating Her2 gene amplification. Taking these modifications into account and defining the HER2 positive subgroup as IHC 3+ and IHC2+/FISH+, approximately 16% of gastric cancers are considered Her2 positive, affecting mainly tumor regions with intestinal (gland forming) type carcinoma. In contrast to breast cancer, up to one-third of gastric cancers show a heterogeneous Her2 status both at IHC and ISH levels which favors bright field ISH over FISH.
Subject(s)
Breast Neoplasms/genetics , Receptor, ErbB-2/genetics , Stomach Neoplasms/genetics , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Algorithms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Female , Gene Amplification , Humans , In Situ Hybridization , In Situ Hybridization, Fluorescence , Neoplasm Metastasis , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathologyABSTRACT
Determining ErbB2/Her-2/neu status has become an essential part of breast cancer diagnosis and a prerequisite before considering a patient's eligibility for treatment with trastuzumab. Currently the most common techniques to assess ErbB2 status in routine practice are the identification of receptor overexpression by means of immunohistochemistry (IHC) and the analysis of gene amplification by means of dual color fluorescence in situ hybridisation (FISH). According to recent recommendations ("ASCO/CAP Guidelines" and German S3 guidelines for breast cancer) the choice of primary test procedure--IHC or ISH - is left to the individual institution. Both techniques are of equal predictive value provided that strict quality precautions have been taken: internal test validation by comparing IHC and (F)ISH, carrying out controls, and annual participation in round-robin tests. Equivocal IHC (score 2+) has to be checked by ISH for amplification. Borderline ISH (ratio 1.8-2.2 or gene copy number 4.0-6.0) should be retested by counting additional cells or performing IHC. In approximately 5% of cases these criteria give conflicting results and the gene copy number alone generates over 90% of the equivocal ISH cases, mostly due to chromosome 17 polysomy. These cases need to be tested by IHC since over-expression is very exceptional and only these tumors have the potential to be trastuzumab responders.
Subject(s)
Breast Neoplasms/genetics , Receptor, ErbB-2/genetics , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Female , Genes, erbB-2 , Humans , Immunohistochemistry , In Situ Hybridization , In Situ Hybridization, Fluorescence , Reproducibility of ResultsABSTRACT
There is a need for predictive biomarkers that identify non-small-cell lung cancer (NSCLC) patients most likely to respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. There are numerous potential candidates, although none has been proven in prospective clinical trials. The EGFR gene copy number evaluated by fluorescence in situ hybridisation (FISH) has been highlighted as one of the most effective markers for sensitivity to EGFR TKIs in large phase III, randomised placebo-controlled trials and has been used in clinical settings to assist physicians in defining the therapeutic regimen. The EGFR FISH assay has technical challenges and it is critical that detailed guidelines are provided to help clinical laboratories in performing and interpreting the test. Excellent assay reproducibility and portability rates among laboratories are crucial to guarantee that accurate clinical decisions can be made for patients with NSCLC. This article discusses the consensus outcomes of a global workshop convened to discuss key technical issues and standardise reading strategies for the EGFR FISH assay of NSCLC tumour tissue.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/diagnosis , ErbB Receptors/metabolism , Lung Neoplasms/diagnosis , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Clinical Trials, Phase III as Topic , ErbB Receptors/antagonists & inhibitors , Humans , In Situ Hybridization, Fluorescence/methods , Lung Neoplasms/drug therapy , Neoplasm Proteins/metabolism , Practice Guidelines as Topic , Protein Kinase Inhibitors/therapeutic useABSTRACT
Intracranial vascular malformations are rare but tend to appear more frequently than usual in patients with type I neurofibromatosis (NFI). Aneurysms of the basilar artery have been described four times so far. We report two cases of 51- and 62-year-old patients with type I neurofibromatosis who showed long fusiform dilation of the basilar artery. Clinically both patients presented with locked-in syndrome and died 15 and 11 days after admission. The diagnosis was confirmed by autopsy. These are the first published cases of locked-in syndrome following thrombosis of a megadolichobasilar artery in association with neurofibromatosis I. Our results show that cerebral vascular malformations are found more frequently than random chance would predict in patients with NF I.
Subject(s)
Intracranial Aneurysm/diagnosis , Neurofibromatosis 1/diagnosis , Vertebrobasilar Insufficiency/diagnosis , Basilar Artery/pathology , Brain Stem Infarctions/diagnosis , Brain Stem Infarctions/genetics , Cerebral Angiography , Chromosome Aberrations , Fatal Outcome , Humans , Intracranial Aneurysm/genetics , Magnetic Resonance Angiography , Male , Middle Aged , Neurofibromatosis 1/genetics , Neurologic Examination , Pons/pathology , Tomography, X-Ray Computed , Vertebrobasilar Insufficiency/geneticsABSTRACT
Most frequently, chronic granulomatous meningitis (CGM) is caused by infectious agents. However, in some cases the cause of CGM remains undetermined. It is unclear whether antimicrobial agents, including antituberculous drugs, are helpful in such cases. We describe a 61-year-old man who had multiple cranial nerve lesions, epilepsy, sinus thrombosis, stroke, and hydrocephalus attributable to CGM. Repeated extensive search for a causative agent in the cerebrospinal fluid (CSF) and the meninges remained negative. Only a single culture of the sputum revealed growth of Mycobacterium tuberculosis, which prompted antituberculous therapy with isoniazid, rifampicin, and ethambutol. After 6 months of therapy, neurologic abnormalities were slightly improved. We conclude that antimicrobial/ antituberculous agents have only a minor short-term effect in long-lasting CGM of undetermined cause.