Activity and regulation by growth factors of calmodulin-dependent protein kinase III (elongation factor 2-kinase) in human breast cancer.

Calmodulin-dependent protein kinase III (CaM kinase III, elongation factor-2 kinase) is a unique member of the Ca2+/CaM-dependent protein kinase family. Activation of CaM kinase III leads to the selective phosphorylation of elongation factor 2 (eEF-2) and transient inhibition of protein synthesis. Recent cloning and sequencing of CaM kinase III revealed that this enzyme represents a new superfamily of protein kinases. The activity of CaM kinase III is selectively activated in proliferating cells; inhibition of the kinase blocked cells in G0/G1-S and decreased viability. To determine the significance of CaM kinase III in breast cancer, we measured the activity of the kinase in human breast cancer cell lines as well as in fresh surgical specimens. The specific activity of CaM kinase III in human breast cancer cell lines was equal to or greater than that seen in a variety of cell lines with similar rates of proliferation. The specific activity of CaM kinase III was markedly increased in human breast tumour specimens compared with that of normal adjacent breast tissue. The activity of this enzyme was regulated by breast cancer mitogens. In serum-deprived MDA-MB-231 cells, the combination of insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) stimulated cell proliferation and activated CaM kinase III to activities observed in the presence of 10% serum. Inhibition of enzyme activity blocked cell proliferation induced by growth factors. In MCF-7 cells separated by fluorescence-activated cell sorting. CaM kinase III was increased in S-phase over that of other phases of the cell cycle. In summary, the activity of Ca2+/CaM-dependent protein kinase III is controlled by breast cancer mitogens and appears to be constitutively activated in human breast cancer. These results suggest that CaM kinase III may contribute an important link between growth factor/receptor interactions, protein synthesis and the induction of cellular proliferation in human breast cancer.

The effect of surgical ICU triage patterns on differing severity adjusted outcomes in France and the United States.

INTRODUCTION: Surgical patients treated in French intensive care units (ICU's) appear to have higher mortality rates than patients in the United States. We hypothesized that this may be due to the French practice of not transferring dying patients from the ICU. We wished to determine if the different mortality rates could be explained by transfer practices for dying patients or other factors such as severity of illness. METHODS: Flowsheet data for 6,787 consecutive surgical ICU (SICU) patients from our institution over a 31 month period was entered into an ICU Clinical Information System which calculated the Day 1 Simplified Acute Physiology Score (SAPS) for each patient upon admission to the SICU. SICU and overall hospital mortality data were matched with severity data and the complete data set was analyzed against results for 2,604 surgical patients in French ICU's. Since terminally ill patients in France are not transferred to floor care, we also compared the French ICU mortality rate with both our SICU mortality rate and combined SICU and surgical floor mortality rates. RESULTS: Our overall SICU mortality was 1.7% and our combined SICU and hospital mortality was 4.2%, while the French ICU mortality was 14.1%. The French ICU's had more patients with higher severity of illness as measured by SAPS. When the effects of ICU transfer practices and severity of illness were considered, there were no mortality differences seen among patients admitted to the different units after elective surgery. Significant differences in mortality were seen when patients admitted emergently were studied. CONCLUSIONS: The differences in severity adjusted ICU mortality between French ICU's and our SICU are explained by different triage practices for terminally ill patients following elective ICU admission. These triage differences do not fully explain the mortality differences seen among patients emergently admitted to the ICU. Other factors such as the presence of trauma, ICU staffing practices, patient mix or other unidentified factors may be responsible for the severity adjusted differences in mortality among emergency surgical ICU patients.

Pulmonary artery rupture associated with the Swan-Ganz catheter.

OBJECTIVES: This study was designed to determine the incidence rate, define risk factors, and suggest proper management protocols for pulmonary artery (PA) rupture associated with Swan-Ganz catheters. DESIGN: This is a retrospective chart-review study. SETTING: This study involved 32,442 inpatients requiring hemodynamic monitoring with Swan-Ganz catheters in the operating rooms and ICUs at a large, private teaching hospital over a 17-year period (1975 to 1991). RESULTS: Ten patients sustained PA rupture, yielding an observed rupture rate of 0.031% of catheter insertions. All ten patients had hemoptysis and five (50%) had pulmonary hypertension. Two patients (20%) had undergone anticoagulation at the time of rupture. Four of the six surgical patients were still in surgery at the first sign of rupture. A thoracotomy was performed in five patients. We noted a trend toward survival with thoracotomy, but it was not statistically significant. The overall mortality rate was 70%. When data from our 10 patients were combined with 65 patients from the literature, we found that thoracotomy was essential for survival in patients with hemothorax. There were no survivors among seven patients with hemothorax simply observed, compared with eight (50%) survivors in 16 patients undergoing thoracotomy (p = 0.026). Thirty-nine (75%) of 52 patients without hemothorax survived, whether or not a thoracotomy was performed. CONCLUSIONS: Our study suggested that the incidence of Swan-Ganz catheter-associated PA rupture is 0.031% and that an urgent thoracotomy should be performed if hemothorax is present at any point.

Effect of reexcision on the success of breast-conserving surgery.

BACKGROUND: The success of lumpectomy and radiotherapy is dependent on minimizing the residual tumor burden in the breast. Histologic margin status is one measure of the extent of residual tumor. This study was undertaken to determine the success rate of a single conservative lumpectomy in obtaining negative margins and to evaluate the incidence of residual tumor after biopsies with positive or unknown margins. METHODS: This is a retrospective study covering a 5-year period (June 1988-June 1993). RESULTS: Three hundred sixteen women had lumpectomies. In 239, lumpectomy was the initial operation after a positive fine-needle aspiration or as a diagnostic procedure. Thirteen cases had positive margins. Reexcision was performed in 90 cases. The indication for reexcision was a positive margin in 42 cases (4 with gross tumor) and unknown margin status in 48. Nineteen of the reexcisions for positive margins and 20 of the reexcisions for unknown margins contained residual tumor. Eighty-six (96%) of the 90 reexcised patients underwent breast preserving surgery. Patient age, menopausal status, histologic tumor type, tumor size, and clinical presentation were not predictive of residual tumor. CONCLUSIONS: The need for reexcision does not preclude breast preservation. Because single-stage lumpectomy is successful in achieving negative margins in 95% of patients, diagnostic biopsy without margin evaluation should be abandoned to avoid routine reexcision.

Trauma in the elderly: an analysis of outcomes based on age.

This study evaluated the comparative outcomes of elderly trauma patients admitted to a tertiary Surgical Intensive Care Unit (SICU) over a 5-year period (4/1/87-3/31/92). A total of 289 trauma patients 65 or older (mean age 76.3 +/- 0.4 years) were compared with 1,877 trauma patients under age 65 (mean age 31.4 +/- 0.3). The Simplified Acute Physiology Score (SAPS) severity of illness on admission for elderly trauma patients was 12.2 +/- 0.3, significantly higher than the SAPS of the younger patient group, 7.9 +/- 0.1 (P < 0.0005). Elderly survivors had higher than the SAPS of admission than their younger cohorts, 11.0 +/- 0.3 versus 7.3 +/- 0.1 (P < 0.0005), but there was no significant difference in SAPS for non-survivors. The Injury Severity Score (ISS) of elderly patients, 14.2 +/- 1.0, was not significantly higher than the ISS of younger patients, 12.3 +/- 0.3 (P = 0.06). Thirty-three elderly trauma patients (11.4%) died in the SICU, compared with 90 (4.8%) deaths in younger patients (P < 0.00005). However, when patients were stratified by admission SAPS, SICU mortality was nearly equivalent between the older and younger patient groups. An additional 14 elderly patients (4.8%) died in the hospital after SICU discharge, compared with 9 additional deaths (0.5%) in the younger patient group (P < 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)

Automated severity scoring in level I trauma patients.

The authors evaluated the sensitivity and specificity of a computerized Simplified Acute Physiology Score (SAPS) for outcome prediction in Level I trauma patients admitted to a Surgical ICU (SICU). SAPS was compared with the combined Trauma Score (TS) and Injury Severity Score (ISS). 1434 consecutive trauma patients admitted to the SICU over a 3-year period were studied. All patients had the SAPS automatically calculated on the first SICU day. Patient data was extracted from an electronic flowsheet, and the most abnormal values for the previous 24 hours were used to calculate the SAPS. TS and ISS were calculated by a trained nurse. The relationship among the severity scores, ICU length of stay (LOS), and survival was evaluated. A logistic regression equation was calculated for SAPS alone and for TS combined with ISS. The predictive power of the severity methods was compared using Receiver Operating Characteristic (ROC) curve analysis. Scores for survivors and non-survivors were compared with Student's t-tests. 1085 patients had complete data available. There were 995 survivors and 90 non-survivors. The mean (+/- standard error of the mean) ISS was 12.7 (+/- 3.2) with 36 per cent of the patients having an ISS > or = 15. The mean SAPS was 8.1 (+/- 2.5). Survivors had a significantly lower SAPS than non-survivors, 7.0 versus 20.2 (P < 0.0005) and a shorter LOS, 2.5 versus 4.9 days (P < 0.002). ROC curve analysis revealed no statistically significant difference in the areas under the two curves, indicating that the SAPS was equivalent to TS combined with ISS in outcome prediction (P > 0.70).(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor aneuploidy in young patients with colorectal cancer.

BACKGROUND: Colorectal cancer in young patients (40 years of age or younger) often is considered to have a worse prognosis than in older patients. The authors studied tumor DNA status and stage of disease to determine whether tumors in younger patients behaved differently from tumors in older patients. METHODS: This retrospective study identified 33 young patients with colorectal cancer treated surgically between 1979 and 1989. The DNA content of the tumors was analyzed by DNA flow cytometry. Results were compared with 75 cases of colon cancer in patients older than 40 years of age. RESULTS: Six of the 33 young patients had inadequate tissue for study. Four patients with ulcerative colitis were excluded. Tumor aneuploidy was present in 14 of 23 young patients (61%; mean age, 35 years) and 46 of 75 older patients (61%; mean age, 71 years). When Dukes staging was performed for the young patients, one had Stage A (4%), nine had Stage B (39%), eight had Stage C (35%), and five had Stage D (22%) disease. The control group had similar staging. The distribution of aneuploid tumors within each Dukes stage was also similar. Twenty-one young patients were available for follow-up. Four (31%) of 13 patients with aneuploid tumors died, whereas none of 8 patients with diploid tumors died. This trend was not statistically significant (P < 0.10). CONCLUSIONS: The frequency of tumor aneuploidy, stage of disease at presentation, and distribution of tumor aneuploidy within each stage was similar when young and old patients with colorectal cancer were compared. There is a trend toward tumor aneuploidy being associated with a poorer prognosis in young patients.

Coagulopathy and catecholamines in severe head injury.

The prospective study reported here evaluated the relationship between coagulopathy, catecholamines, and outcome in severe head trauma. Thirty-six trauma patients (10 with penetrating injuries, 26 with blunt injuries, 50% overall mortality) were evaluated. These patients had severe head trauma (Glasgow Coma Scale score less than 9). Blood was analyzed for platelet count, prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen, D-dimer, antithrombin III, protein C, and protein S levels. A 24-hour urine sample was collected for vanillylmandelic acid (VMA), normetanephrine, and metanephrine determinations. A control group of five patients undergoing elective neurosurgery was also studied. Statistically significant differences between head injury survivors and nonsurvivors were present for platelet count, PT, and fibrinogen activity. There were no differences in the results of the other coagulation tests or in urinary catecholamine levels. The trauma patients differed from the elective neurosurgery patients with regard to D-dimer levels, PT, PTT, protein C levels, and urinary normetanephrine concentrations. Head trauma patients have a coagulopathy that is absent in patients following elective neurosurgical procedures. The coagulopathy may correlate with poor survival in head trauma and may be related to a catecholamine surge.