New ASCO/CAP guideline recommendations for HER2 testing increase the proportion of reflex in situ hybridization tests and of HER2 positive breast cancers.

Accurate determination of tumour human epidermal growth factor receptor type 2 (HER2) status is critical for optimal treatment of breast cancer. In October 2013, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) issued joint updated guideline recommendations for HER2 testing in breast cancer, with a revised algorithm for interpretation of immunohistochemistry (IHC) and in situ hybridisation (ISH) results. This study investigates the impact on HER2 IHC categorisation, implication for reflex ISH testing and potential for identification of false negative IHC. HER2 IHC preparations on 251 invasive breast tumours, originally reported according to 2007 guidelines, were re-scored using 2013 guidelines and the diagnostic categories compared. The results of ISH testing on a separate cohort of 32 breast tumours reported as HER2 IHC 2+ following the introduction of the 2013 guidelines, that would have been designated 1+ according to 2007, were reviewed. Application of 2013 guidelines resulted in a decrease in tumours classified as HER2 negative (83/251 vs 144/251) and a comparable increase in those classified as equivocal (2+) (139/251 vs 80/251). Relatively few tumours were re-classified as positive (29/251 vs 27/251). Furthermore, 3/32 breast cancer cases (HER2 IHC 2+ as per 2013 guidelines, 1+ using 2007 guidelines) were HER2 ISH positive. Application of the 2013 guidelines increases the HER2 IHC equivocal (2+) category and requirement for reflex ISH testing. The reduced threshold for ISH testing identifies some patients with HER2 positive breast cancer whose tumours would have been categorised as HER2 negative according to the 2007 guidelines.

Impact of chronic oral H2-antagonist therapy on left ventricular systolic function and exercise capacity.

It has been suggested that H2-antagonists may adversely affect left ventricular systolic function. To assess the effects of cimetidine, famotidine, and ranitidine on exercise capacity and left ventricular systolic function, the authors conducted a randomized, double-blind, four-way crossover study in 15 healthy male volunteers with placebo control. Each subject underwent a maximal upright treadmill exercise test, aerobic metabolic assessment, and two-dimensional stress echocardiography on six separate occasions. The initial two treadmill exercise tests with aerobic metabolic assessment and stress echocardiography were performed to minimize the learning effect. In the final four evaluations, subjects were randomized to receive 7 days of oral treatment with cimetidine 400 mg twice daily, famotidine 40 mg daily, ranitidine 150 mg twice daily, and placebo. A comparison of exercise tests, aerobic metabolic assessment, and stress echocardiography results found no significant differences between any of the H2-antagonists and placebo. In addition, there were no significant differences in test results between cimetidine, famotidine, and ranitidine. Specifically, exercise treadmill time, maximal oxygen consumption, respiratory quotient, maximal exercise systolic and diastolic blood pressure, maximal exercise heart rate, left ventricular end-diastolic dimension, left ventricular end-systolic dimension, and ejection fraction were not different between treatments. The authors conclude that 7 days of oral treatment with cimetidine, famotidine, or ranitidine has no deleterious effect on exercise capacity or left ventricular systolic function in healthy subjects.

Localization of type X collagen in canine growth plate and adult canine articular cartilage.

Type X collagen was extracted from ends of canine growth plates by pepsin digestion after 4 M guanidine hydrochloride extraction, purified by stepwise salt precipitation (2.0 M NaCl in 0.5 M acetic acid), and chromatographed on a Bio-Gel A1.5 M column in 1.0 M CaCl2. Without reduction on sodium dodecyl sulfate (SDS) polyacrylamide gels, the preparation yielded a single, high-molecular-weight (mol wt) band; after reduction, a single band of relative mol wt 5.0 x 10(4) was found. Polyclonal sera were raised against the purified collagen and used in the immunolocalization of canine type X collagen. As expected, indirect immunoperoxidase (IP) or indirect immunofluorescent staining with the polyclonal sera demonstrated that most of the immunoreactivity was localized in the zone of provisional calcification of the growth plate and in cartilage remnants in the metaphyseal region of the physis. A progressive decrease in staining toward the diaphysis of the fetal canine long bone was apparent as the trabecular structures were remodeled to bone. Unexpectedly, type X collagen was also detected in the zone of calcified, mature articular cartilage. It was concentrated in the pericellular matrix of the chondrocytes, appeared at or just above the tidemark, and was expressed immediately before mineralization. Identification of type X collagen in both the canine growth plate and the zone of calcified articular cartilage suggests that cells in the deep layer of cartilage and in the zone of calcified cartilage in the adult animal retain some characteristics of a growth plate and may be involved in regulation of mineralization at this critical interface. The expression of growth plate-like properties would allow the deep chondrocytes of mature articular cartilage to play a role in remodeling of the joint with age and in the pathogenesis of osteoarthritis.

Delivery on the hands and knees. A case study approach.

This article uses a case study approach to describe two deliveries on the hands and knees. This alternative birthing position is suggested as a means of preserving the perineal floor at the time of delivery. Explicit instruction in the conduct of a hands and knees delivery position is offered. Both advantages and disadvantages of this birth position are outlined. The primary advantage of preserving the perineum may come at the expense of the vulvar structures. Further study is urged on the use of alternative birthing positions and their effect on the birthing process.

Reducing time delays in the administration of thrombolytic therapy to patients with acute myocardial infarction.

The extent of myocardial damage occurring during acute myocardial infarction is time dependent. Current approaches designed to reduce the time between symptom onset and the initiation of thrombolytic therapy have focused on increasing public awareness of the need to seek prompt medical attention, prehospital administration of thrombolytic agents, and reducing inhospital delays in initiation of therapy. Results from short-term, public awareness campaigns suggest that patient delays in seeking medical assistance can be reduced in some communities; however, these campaigns do not influence overall patient use of emergency rooms and emergency transport services. In addition, the long-term benefit of media campaigns has not been demonstrated. Prehospital thrombolytic therapy appears to be feasible and safe in certain communities, but definite therapeutic benefit of the small time savings realized in studies to date has not been seen. Even if prehospital thrombolysis is proven to benefit selected patients, it will not affect the large number of patients who choose not to use emergency medical transport services. Adherence to established protocols designed to facilitate rapid institution of thrombolytic therapy can reduce inhospital delays. Initiating thrombolytic therapy within 30 minutes of patient arrival in the emergency department is a goal that should be readily achievable in today's healthcare environment.

Efficacy and safety of early versus late initiation of warfarin during heparin therapy in acute thromboembolism.

There is no universally accepted approach to the initiation of systemic anticoagulant therapy. In an open, randomized study, two anticoagulant regimens that differed only in the timing of warfarin therapy after the start of heparin were compared. We randomized 119 patients with acute thromboembolic events to receive warfarin either within 48 hours of the start of heparin (early group, n = 63) or 96 hours or later after the start of heparin (late group, n = 56). Heparin was given as a 5000 IU bolus as a constant infusion titrated to maintain the activated partial thromboplastin time at 1.5 to 2 times control values. Warfarin was started at 10 mg daily for 3 days and the dose was titrated to maintain the prothrombin time at 1.2 to 1.5 times control values. There were no significant differences between the early and late warfarin groups with regard to age, sex, indication for anticoagulation, heparin dose, mean activated partial thromboplastin time during heparin, warfarin dose at discharge, length of warfarin therapy before discharge, bleeding, recurrent thromboembolic events, or mortality rates. Time to the start of warfarin after heparin was 31 hours and 108 hours in the early and late groups, respectively. Length of hospitalization, hospital costs, and the incidence of heparin-induced infusion phlebitis and thrombocytopenia were significantly less in the early group compared with the late group. Early initiation of warfarin after heparin is safer, less expensive, and as effective as the late initiation of warfarin.