ABSTRACT
AIMS: Currently, testing for mismatch repair deficiency in colorectal cancers is initiated by performing immunohistochemistry with four antibodies (MLH1, PMS2, MSH2 and MSH6). If any one of these stains is negative the tumour is considered microsatellite unstable and, if clinical circumstances warrant it, the patient is offered genetic testing for Lynch's syndrome. Due to the binding properties of the mismatch repair heterodimer complexes, gene mutation and loss of MLH1 and MSH2 invariably result in the degradation of PMS2 and MSH6, respectively, but the converse is not true. We propose that staining for PMS2 and MSH6 alone will be sufficient to detect all cases of mismatch repair deficiency and should replace routine screening with all four antibodies. METHODS: The electronic database of the department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia, was searched for all colorectal carcinomas on which a four panel immunohistochemical microsatellite instability screen was performed. An audit of the slides for concordant loss of MLH1-PMS2 and MSH2-MSH6 was then undertaken. Unusual or discordant cases were reviewed and, in some cases, re-stained to confirm the staining pattern. RESULTS: Of 344 cases of colorectal cancer which underwent four antibody immunohistochemistry, 104 displayed loss of at least one mismatch repair protein. Of these, 100 showed concordant mismatch repair loss (i.e., loss of MLH1 and PMS2 or loss of MSH2 and MSH6). The four discordant cases comprised two single negative cases (1 MSH6 negative/MSH2 positive case, 1 PMS2 negative/MLH1 positive) and two triple negative (both MLH1/PMS2/MSH6 negative). The microsatellite instability (MSI) group showed a relatively high median age (69.3 years) due to the departmental policy of testing all cases with possible MSI morphology regardless of age. CONCLUSIONS: The sensitivity and specificity of a two panel test comprised of PMS2 and MSH6, compared to a four panel test, is 100%. No false negatives or positives were identified. We conclude that the two panel test should replace a four panel protocol for immunohistochemical screening for mismatch repair deficiency.
Subject(s)
Adenocarcinoma/metabolism , Adenosine Triphosphatases/metabolism , Colorectal Neoplasms/metabolism , DNA Repair Enzymes/metabolism , DNA-Binding Proteins/metabolism , MutS Homolog 2 Protein/metabolism , Adenocarcinoma/genetics , Adenosine Triphosphatases/immunology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Colorectal Neoplasms/genetics , DNA Mismatch Repair/genetics , DNA Repair Enzymes/deficiency , DNA Repair Enzymes/genetics , DNA Repair Enzymes/immunology , DNA-Binding Proteins/immunology , Female , Humans , Immunoenzyme Techniques , Male , Middle Aged , Mismatch Repair Endonuclease PMS2 , MutS Homolog 2 Protein/immunology , Predictive Value of Tests , Young AdultABSTRACT
BACKGROUND: Critically ill postsurgical patients fare better with intensive control of blood glucose level. The link between glucose control and outcome is less well studied for medical intensive care patients. Whether intensive glucose control requires additional staffing is unclear. OBJECTIVES: To compare intensive glucose control with modified conventional control in the medical intensive care unit and to assess compliance with glucose targets, incidence of hypoglycemia, and staffing adequacy. METHODS: Medical intensive care patients who had been receiving mechanical ventilation for less than 24 hours were randomized to intensive or modified conventional protocols for glucose control. Nurses were trained before participating in the study and were interviewed after its completion. RESULTS: Five subjects were randomized to each protocol. Mean blood glucose levels were 5.8 (SD 1.5) mmol/L (105.3 [SD 26.3] mg/dL) for the intensive group and 9.8 (SD 2.5) mmol/L (177.4 [SD 45.5] mg/dL) for the modified conventional group (P < .001). Fifty percent of glucose levels met target values in the intensive group, and 72% of glucose levels met target values in the modified conventional group (P < .001). Severe hypoglycemia (glucose <2.2 mmol/L [<40 mg/dL]) occurred rarely and without complication. Nurses suggested protocols might be improved by using smaller steps in adjusting insulin dosage and reported that simultaneously caring for more than 1 study subject was taxing. CONCLUSIONS: Target levels for blood glucose were achieved with both protocols. Severe hypoglycemia was rare and uncomplicated regardless of type of glucose control. Additional staffing may be needed for intensive glucose control.
