Nuclear morphometry and DNA flow cytometry as prognostic factors in female breast cancer.

OBJECTIVE--To evaluate the predictive value of traditional prognostic factors, nuclear morphometry, and flow cytometric data in invasive breast cancer. DESIGN--Open study. SETTING--One university hospital in Finland. SUBJECTS--248 women with invasive breast cancer followed up for more than 11 years. MAIN OUTCOME MEASURES--Univariate and multivariate analysis of factors thought to indicate prognosis. RESULTS--Diameter of the tumour, lymph node status, S phase fraction. DNA index, the age of the patient, and the SD of nuclear perimeter were significant independent predictors in the whole series in a multivariate analysis. In node negative patients the SED of the nuclear perimeter and diameter of the tumour had independent prognostic value, whereas in node positive patients diameter of the tumour and the S phase fraction were independently related to survival. CONCLUSIONS--Diameter of the tumour is an important prognostic factor in breast carcinomas. Histoquantitative methods are superior to conventional histological techniques for the prediction of outcome in women with breast cancer.     

Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival

Hyaluronan (HA) is an extracellular matrix polysaccharide that promotes cell migration through its cell surface receptors and by effecting changes in the physical environment. HA expression is frequently increased in malignant tumors, whereas its association with the invasive potential and patient outcome in breast cancer has not been reported. The localization and signal intensity of HA was analyzed in 143 paraffin-embedded tumor samples of human breast carcinoma using a biotinylated HA-specific probe. In the immediate peritumoral stroma, HA signal was moderately or strongly increased in 39% and 56% of the cases, respectively. Normal ductal epithelium showed no HA, whereas in 57% of the tumors at least some of the carcinoma cells were HA positive. The intensity of the stromal HA signal and the presence of cell-associated HA were both significantly related to poor differentiation of the tumors, axillary lymph node positivity, and short overall survival of the patients. In Cox's multivariate analysis, both the intensity of stromal HA signal alone and that combined with the HA positivity in tumor cells were independent prognostic factors for overall survival. These results suggest that HA is directly involved in the spreading of breast cancer and may offer a potential target for new therapies.     

Normal and homogeneous red blood cell populations over a wide range of hyper-iso-hypotonic media. III. Corrected volumes in Coulter Counter measurements

The volumes of human erythrocytes after rapid and gradual swelling in hypotonic NaCl media were measured using a Coulter Counter ZB at temperatures of +4 degrees C and +20 degrees C together with potassium leakage, the degree of hemolysis and the 'returning volume', i.e., the volume in an isotonic solution to which the cells will return from that in a hypotonic solution. The methodological and systematic errors in the volume measurements were corrected by taking into account the shape dependence of the Coulter Counter and the change in cell population during hemolysis, whereafter the measured cell volume values and the comparison between them become more reliable. The curves for cell volume as an inverse function of osmotic pressure appeared to be non-linear. The slopes were small at first but showed a rapid increase as the cells approached their maximal volume. The critical hemolytic volume was approx. 8% higher at +20 degrees C after both rapid and gradual swelling than at +4 degrees C and approx. 4% higher after a gradual swelling as compared with a rapid swelling both at +4 degrees C and +20 degrees C. A decrease in temperature resulted in an increase in the critical osmotic pressure both in rapid and gradual hemolysis, but did not greatly affect the amount of prelytic K+ leakage. The critical osmotic pressure was smaller in gradual hemolysis than in rapid hemolysis and the prelytic K+ leakage was doubled at both +4 degrees C and +20 degrees C. The shifts in osmotic fragility as a function of temperature may be due to differences in the visco-elastic properties of the cell membrane, but the shifts in osmotic fragility as a function of swelling rate may be connected with differences in potassium leakage and membrane stretch.     

Results of metal-on-metal hip resurfacing in patients 40 years old and younger

The prevalence of total hip arthroplasty in young patients is small but increasing. We analyzed the results of metal-on-metal hip resurfacing (MMHR) in patients aged 40 years or less. In total 74 operations were performed on 64 patients. Mean age at operation was 33.2 years. HHS averaged 92.3 points at latest follow-up, mean UCLA activity was 8.2. Patients with comorbidity evinced lower scores in HHS, in UCLA activity and in quality of life than patients without comorbidities. Eight revisions (10.8 %) were performed, of which seven due to adverse reaction to metal debris. Seven-year survival was 90.5 %. The functional outcome of hip resurfacing in this cohort was excellent, but overall survival was unsatisfactory. Further analysis is required to verify the role of hip resurfacing among young and active patients.     

Long-term tiapamil treatment of patients with angina pectoris

The effects of a 12-week oral treatment with tiapamil (200 mg t.i.d.) were compared to those of placebo treatment in a group of 20 men with coronary heart disease. There was a slight reduction of anginal symptoms (p < 0.05) and a tendency to less nitroglycerin consumption (p < 0.07). There were no statistically significant differences between the treatments in blood pressure, exercise tolerance during repeated exercise tests, ECG conduction intervals, or routine laboratory tests. No adverse side-effects were encountered. It seems that tiapamil may be beneficial in preventing angina pectoris, but a higher oral dose must be used.     

Downregulation of CPPED1 Expression Improves Glucose Metabolism In Vitro in Adipocytes

We have previously demonstrated that the expression of calcineurin-like phosphoesterase domain containing 1 (CPPED1) decreases in adipose tissue (AT) after weight reduction. However, the function of CPPED1 in AT is unknown. Therefore, we investigated whether the change in CPPED1 expression is connected to changes in adipocyte glucose metabolism. First, we confirmed that the expression of CPPED1 decreased after weight loss in subcutaneous AT. Second, the expression of CPPED1 did not change during adipocyte differentiation. Third, CPPED1 knockdown with small interfering RNA increased expression of genes involved in glucose metabolism (adiponectin, adiponectin receptor 1, and GLUT4) and improved insulin-stimulated glucose uptake. To conclude, CPPED1 is a novel molecule involved in AT biology, and CPPED1 is involved in glucose uptake in adipocytes.Lifestyle modification improves glucose metabolism and results in a substantial reduction in the risk of type 2 diabetes in the long-term (1). In searching new putative genes related to obesity and type 2 diabetes, we have previously demonstrated a multitude of changes in adipose tissue (AT) gene expression in response to weight reduction in individuals with metabolic syndrome (2,3). Among the downregulated genes was calcineurin-like phosphoesterase domain containing 1 (CPPED1) (2); its function in AT is completely unknown.Therefore, we continued to study the role of CPPED1 in AT in more detail. Interestingly, the experiment using a Simpson-Golabi-Behmel syndrome (SGBS) cell strain demonstrated an impact of CPPED1 small interfering RNA (siRNA) on insulin-stimulated glucose uptake in mature adipocytes. Overall, the results demonstrate that CPPED1 is a novel molecule expressed in AT and is related to adipocyte function.     

Predictors of mortality following primary hip and knee replacement in the aged: A single-center analysis of 1,998 primary hip and knee replacements for primary osteoarthritis

Background and purpose High age is associated with increased postoperative mortality, but the factors that predict mortality in older hip and knee replacement recipients are not known.

Methods Preoperative clinical and operative data on 1,998 primary total hip and knee replacements performed for osteoarthritis in patients aged ≥ 75 years in a single institution were collected from a joint replacement database and compoared with mortality data. Average follow-up was 4.2 (2.2–7.6) years for the patients who survived. Factors associated with mortality were analyzed using Cox regression analysis, with adjustment for age, sex, operated joint, laterality, and anesthesiological risk score.

Results Mortality was 0.15% at 30 days, 0.35% at 90 days, 1.60% at 1 year, 7.6% at 3 years, and 16% at 5 years, and was similar following hip and knee replacement. Higher age, male sex, American Society of Anesthesiologists risk score of > 2, use of walking aids, preoperative walking restriction (inability to walk or ability to walk indoors only, compared to ability to walk > 1 km), poor clinical condition preoperatively (based on clinical hip and knee scores or clinical severity of osteoarthritis), preoperative anemia, severe renal insufficiency, and use of blood transfusions were associated with higher mortality. High body mass index had a protective effect in patients after hip replacement.

Interpretation Postoperative mortality is low in healthy old joint replacement recipients. Comorbidities and functional limitations preoperatively are associated with higher mortality and warrant careful consideration before proceeding with joint replacement surgery.     

Repeated metal ion measurements in patients with high risk metal-on-metal hip replacement

Purpose

Conventional follow-up methods are not sufficient to identify adverse soft tissue reactions in patients with metal-on-metal hip replacements. The national guidelines regarding metal ion measurements are debatable. The aims of our study were to investigate (1) if there is a clinically significant change in whole blood (WB) cobalt (Co) or chrome (Cr) levels in repeated WB assessment in patients operated on with ASR hip replacements, and (2) what proportion of patients has WB Co or Cr level below the previously established safe upper limits (SUL) in the repeated WB metal ion assessment.

Methods

We identified all patients (n = 254) with unilateral ASR implants who had second blood sample taken eight to 16 months after the first.

Results

WB Co and Cr levels remained below SUL and within their initial values during a mean one-year measurement interval in the majority of patients with a high risk HR device. In contrast to this, 50 % of patients with THRs had metal ion levels exceeding the SUL in the first measurement. WB Co values significantly increased over the measurement interval in the THR group.

Conclusion

In patients with a high risk HR, repeated metal ion measurement did not provide useful information for clinical decision-making. In patients with a LD MoM THR repeated measurements revealed a large number of patients with metal ion levels exceeding SUL and might thus be clinically beneficial.     

Total Knee Arthroplasty with an Uncemented Trabecular Metal Tibial Component : A Registry-Based Analysis

Previous poor results have kept the appeal of uncemented total knee arthroplasties (TKAs) minimal. We analyzed the mid-term survivorship and reasons for failures of a contemporary uncemented porous tantalum monoblock tibial component nation-wide. During the study period (2003–2010), such tibial components were used in 1143 primary TKAs recorded in the Finnish Arthroplasty Registry. Seven-year survivorship of these TKAs was 100% (95% CI 99–100) with revision for aseptic loosening of the tibial component, and 97% (95% CI 96–98) with revision for any reason as the respective end points. The most common reasons for revisions were instability and prosthetic joint infections. In conclusion, TKAs using an uncemented porous tantalum monoblock tibial component showed excellent mid-term survivorship in a population-based setting.     

Comparison of extracapsular pseudotumors seen in magnetic resonance imaging and in revision surgery of 167 failed metal-on-metal hip replacements

Background and purpose

Magnetic resonance imaging (MRI) is important for detecting extracapsular pseudotumors, but there is little information on the accuracy of MRI and appropriate intervals for repeated imaging. We evaluated the sensitivity and specificity of MRI for detecting pseudotumors in 155 patients (167 hips) with metal-on-metal (MoM) hip arthroplasties that failed due to adverse reactions to metal debris (ARMD).

Methods

Preoperative MRIs were performed with two 1.5 T MRI scanners and graded by a senior musculoskeletal radiologist using a previously described MRI pseudotumor grading system. Revision findings were retrieved from surgical notes, and pseudotumors were retrospectively graded as fluid-filled, mixed-type, or solid.

Results

The sensitivity of MRI was 71% and the specificity was 87% for detecting extracapsular pseudotumors. The sensitivity was 88% (95% CI: 70–96) when MRI was performed less than 3 months before the revision surgery. Interestingly, when the time that elapsed between MRI and revision was more than 1 year, the sensitivity calculated was only 29% (95% CI: 14–56). Comparison between MRI and revision classifications gave moderate agreement (Cohen’s kappa = 0.4).

Interpretation

A recent MRI predicts the presence of a pseudotumor well, but there is more discrepancy when the MRI examination is over a year old, most likely due to the formation of new pseudotumors. 1 year could be a justifiable limit for considering a new MRI if development of ARMD is suspected. MRI images over a year old should not be used in decision making or in planning of revision surgery for MoM hips.Metal-on-metal (MoM) hip replacements have been widely used for the treatment of hip osteoarthritis, particularly in young and active patients (Bozic et al. 2009). During the last few years, an increased risk of developing soft tissue reactions linked to increased wear of MoM articulation has been reported (Pandit et al. 2008, Kwon et al. 2010, Langton et al. 2011). An umbrella term “adverse reaction to metal debris” (ARMD) has been used to describe these tissue reactions, which include metallosis, aseptic lymphocytic vasculitis-associated lesions, and the fluid-filled or solid extracapsular lesions often referred to as pseudotumors (Langton et al. 2011). Most patients have high blood metal ions and many experience pain in the groin and thigh region, but ARMD may also be found in patients presenting with no clinical symptoms and normal whole-blood metal ion levels (Hart et al. 2011, Wynn-Jones et al. 2011). Asymptomatic extracapsular pseudotumors have been reported to increase and decrease in size with occasional remission of small masses, and they may involve the abductor and iliopsoas muscles (Almousa et al. 2013). Revision surgeries because of pseudotumors have been reported to have significantly poorer outcome than hip revisions for other reasons (Grammatopolous et al. 2009). Imaging is therefore needed to identify these patients for closer follow-up or revision surgery. Preoperative magnetic resonance imaging (MRI) is also of importance for surgeons to visualize the location and dimensions of the pseudotumor for optimal resection (Liddle et al. 2013).MRI and ultrasonography are the main imaging modalities for assessment of ARMD lesions. Modern MRI techniques allow good visibility in the hip region, even though intracapsular lesions cannot be reliably assessed in some cases due to metal artifacts. To our knowledge, only 1 study has compared pseudotumors seen in MRI with those actually found in revision surgery (Liddle et al. 2013).The main aim of this study was to evaluate the ability of preoperative MRI to detect extracapsular pseudotumors encountered in revision surgery and to assess appropriate intervals for repeated imaging, when development/progression of soft tissue pathologies is suspected. A secondary aim was to ascertain whether pseudotumors fall into the same categories in both MRI and revision surgery classifications.