Trastuzumab Beyond Progression for HER2 Positive Metastatic Breast Cancer: Progression‐Free Survival on First‐Line Therapy Predicts Overall Survival Impact

Trastuzumab beyond first progression in the metastatic setting has been adopted based on limited data suggesting improved outcomes compared to second‐line chemotherapy alone although predictive factors for preferential benefit remain elusive. We conducted a retrospective review of all patients receiving trastuzumab for HER2 + metastatic disease between Jan 1, 1999–June 15, 2011. Univariate and time to event analyses described treatment and survival patterns. Median duration of each line of therapy and overall survival times for covariates, including treatment era (pre versus post Jan 1, 2005), lines of trastuzumab‐based therapy (1 versus 2 versus 3 + ), first‐line chemotherapy partner (docetaxel/paclitaxel versus other) and median exposure to first‐line trastuzumab‐based therapy (=/> versus < cohort median) were estimated. A total of 119 patients received a median of two lines of trastuzumab‐based therapy (range 1–8). Median overall survival was 21.8 months (95% CI = 14.5–27.1 m), by era was 15.6 m (95% CI = 9.7–24.8 m) versus 26.1 m (95% CI = 20.0–39.3 m; p = 0.11) and by lines of trastuzumab‐based therapy received was 10.6 m (95% CI = 5.3–17.4 m) versus 13.9 m (95% CI = 9.5–27.6 m) versus 32.5 m (95% CI = 25–49.4 m) (p = 0.0014). Median overall survival was significantly longer for those receiving taxanes with trastuzumab compared to other first line partners (26.1 m, 95% CI = 17.8–31.4 m versus 14.5 m, 95% CI = 9.4–21.9 m, p = 0.02). Median overall survival with duration of first‐line trastuzumab‐based therapy =/> cohort median was 31.9 m (95% CI = 26.2–52.2 m) versus 10.3 m for shorter durations (95% CI = 6.9–15.6 m; p < 0.0001). Our observations support progression‐free survival on first‐line trastuzumab‐based therapy as a clinically relevant predictive factor for overall survival benefit with the adoption of a trastuzumab beyond progression treatment strategy.     

Effect of Ki‐67 on Immunohistochemical Classification of Luminal A to Luminal B Subtypes of Breast Carcinoma

It has recently been proposed to include an immunohistochemical marker of cell proliferation, Ki‐67, as an element with which to classify the molecular subtypes of breast cancer. The objective of this study was to evaluate the effect of the introduction of the Ki‐67 marker on the molecular classification of breast cancer by immunohistochemistry. This study was performed on 234 cases of invasive ductal carcinoma of the breast submitted to two immunohistochemical classification panels, one including Ki‐67 and the other not. The data obtained with the two classifications were correlated with well‐established prognostic factors such as histologic grade, the number of lymph nodes affected and tumor size. The molecular classification without Ki‐67 identified: 136 cases of luminal A (58.1%), 19 cases of luminal B (8.1%), 27 cases of human epidermal growth‐factor receptor 2 overexpressing (11.5%), 27 cases of basal‐like (11.5%), and 25 cases of nonbasal‐like triple‐negative tumors (10.7%). When Ki‐67 was included, this situation changed significantly, with the following cases being identified: 72 cases of luminal A (30.8%) and 83 cases of luminal B tumors (35.5%), resulting in a Kappa score of 0.216. Evaluation of correlations between the luminal A and luminal B tumor subtypes and the selected prognostic factors showed a statistically significant difference only when Ki‐67 was included and only with respect to histologic grade (p < 0.001). The new classification with Ki‐67 significantly altered the prevalence of the luminal A and luminal B subtypes and improved correlation with the histologic grade.     

Bone marrow mesenchymal stem cells undergo nemosis and induce keratinocyte wound healing utilizing the HGF/c-Met/PI3K pathway

We previously showed cell–cell contacts of human dermal fibroblasts to induce expression of the hepatocyte growth factor/scatter factor (HGF) in a process designated as nemosis. Now we report on nemosis initiation in bone marrow mesenchymal stem cells (BMSCs). Because BMSCs are being used increasingly in cell transplantation therapy we aimed to demonstrate a functional effect and benefit of BMSC nemosis for wound healing. Nemotic and monolayer cells were used to stimulate HaCaT keratinocyte migration in a scratch-wound healing assay. Both indicators of nemosis, HGF production and cyclooxygenase-2 expression, were induced in BMSC spheroids. When compared with a similar amount of cells as monolayer, nemotic cells induced keratinocyte in vitro scratch-wound healing in a concentration-dependent manner. The HGF receptor, c-Met, was rapidly phosphorylated in the nemosis-stimulated keratinocytes. Nemosis-induced in vitro scratch-wound healing was inhibited by an HGF-neutralizing antibody as well as the small molecule c-Met inhibitor, SU11274. HGF-induced in vitro scratch-wound healing was inhibited by PI3K inhibitors, wortmannin and LY294002, while LY303511, an inactive structural analogue of LY294002, had no effect. Inhibitors of the mitogen-activated protein kinases MEK/ERK1/2 (PD98059 and U0126), and p38 (SB203580) attenuated HGF-induced keratinocyte in vitro scratch-wound healing. We conclude that nemosis of BMSCs can induce keratinocyte in vitro scratch-wound healing, and that in this effect signaling via HGF/c-Met is involved.     

Relationship between medication errors and adverse drug events

OBJECTIVE: To evaluate the frequency of medication errors using a multidisciplinary approach, to classify these errors by type, and to determine how often medication errors are associated with adverse drug events (ADEs) and potential ADEs. DESIGN: Medication errors were detected using self-report by pharmacists, nurse review of all patient charts, and review of all medication sheets. Incidents that were thought to represent ADEs or potential ADEs were identified through spontaneous reporting from nursing or pharmacy personnel, solicited reporting from nurses, and daily chart review by the study nurse. Incidents were subsequently classified by two independent reviewers as ADEs or potential ADEs. SETTING: Three medical units at an urban tertiary care hospital. PATIENTS: A cohort of 379 consecutive admissions during a 51-day period (1,704 patient-days). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Over the study period, 10,070 medication orders were written, and 530 medications errors were identified (5.3 errors/100 orders), for a mean of 0.3 medication errors per patient-day, or 1.4 per admission. Of the medication errors, 53% involved at least one missing dose of a medication; 15% involved other dose errors, 8% frequency errors, and 5% route errors. During the same period, 25 ADEs and 35 potential ADEs were found. Of the 25 ADEs, five (20%) were associated with medication errors; all were judged preventable. Thus, five of 530 medication errors (0.9%) resulted in ADEs. Physician computer order entry could have prevented 84% of non-missing dose medication errors, 86% of potential ADEs, and 60% of preventable ADEs. CONCLUSIONS: Medication errors are common, although relatively few result in ADEs. However, those that do are preventable, many through physician computer order entry. Received/mm the Division of General Medicine, Departments of Medicine and Pharmacy, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. Supported in part by the Risk Management Foundation. Dr. Bates is the recipient of National Resource Service Award 1 F32 HS00040-01 from the Agency for Health Care Policy and Research.     

Right Ventricular Diastolic Function in Children With Pulmonary Regurgitation After Repair of Tetralogy of Fallot: Volumetric Evaluation by Magnetic Resonance Velocity Mapping

Objectives. We sought to assess right ventricular diastolic function in young patients with corrected tetralogy of Fallot and pulmonary regurgitation.

Background. Pulmonary regurgitation is an important problem in repair of tetralogy of Fallot. Its effects on right ventricular diastolic function in children are unknown.

Methods. Nineteen children with repair of tetralogy of Fallot (mean age [±SD] 12 ± 3 years, mean age at operation 1.5 ± 1) and 12 healthy children were studied. Summation of magnetic resonance velocity mapping pulmonary and tricuspid volume flow curves provided right ventricular time–volume curves. Ventricular size was assessed with tomographic magnetic resonance imaging (MRI). Graded exercise testing was performed.

Results. Systematic and random differences (mean ± SD) of velocity mapping and Doppler tricuspid time to peak velocities (peak E: 1 ± 26 ms, r = 0.43; peak A: 2 ± 11 ms, r = 0.76), E/A ratios (0.04 ± 0.5, r = 0.63) and duration of pulmonary regurgitation (20 ± 35 ms, r = 0.74) were satisfactory. In 6 patients (group I), late diastolic forward pulmonary artery flow was absent; in 13 patients (group II), this flow contributed 1% to 14% to right ventricular stroke volume. Significant differences were increased deceleration time (315 ± 91 vs. 168 ± 28 ms, p < 0.001), decreased filling fraction (44 ± 11 vs. 55 ± 16%, p = 0.02) and increased peak early filling rate (378 ± 124 vs. 286 ± 112 ml/s, p = 0.018) between control subjects and group I, and increased deceleration time (230 ± 40, p = 0.03) between control subjects and group II. Pulmonary regurgitation, ventricular size and ejection fraction did not differ significantly between patient groups. Exercise function was diminished with restrictive right ventricular physiology (p < 0.001, group II vs. control subjects).

Conclusions. Impaired relaxation and restriction to filling affect diastolic right ventricular function in children with repair of tetralogy of Fallot and pulmonary regurgitation. Restrictive right ventricular physiology is associated with decreased exercise function.

(J Am Coll Cardiol 1996;28:1827–35)>     

Clinical outcome 10 years after attempted percutaneous transluminal coronary angioplasty in 856 patients

Objectives. This study reports the 10-year outcome of 856 consecutive patients who underwent attempted coronary angioplasty at the Thoraxcenter during the years 1980 to 1985.

Background. Coronary balloon angioplasty was first performed in 1977, and this procedure was introduced into clinical practice at the Thoraxcenter in 1980. Although advances have been made, extending our knowledge of the long-term outcome in terms of survival and major cardiac events remains of interest and a valuable guide in the treatment of patients with coronary artery disease.

Methods. Details of survival, cardiac events, symptoms and medication were retrospectively obtained from the Dutch civil registry, medical records or by letter or telephone or from the patient's physician and entered into a dedicated data base. Patient survival curves were constructed, and factors influencing survival and cardiac events were identified.

Results. The procedural clinical success rate was 82%. Follow-up information was obtained in 837 patients (97.8%). Six hundred forty-one patients (77%) were alive, of whom 334 (53%) were symptom free, and 254 (40%) were taking no antianginal medication. The overall 5- and 10-year survival rates were 90% (95% confidence interval [CI] 87.6% to 92.4%) and 78% (95% CI 75.0% to 81.0%), respectively, and the respective freedom from significant cardiac events (death, myocardial infarction, coronary artery bypass surgery and repeat angioplasty) was 57% (95% CI 53.4% to 60.6%) and 36% (95% CI 32.4% to 39.6%). Factors that were found to adversely influence 10-year survival were age ≥60 years (≥60 years [67%], 50 to 59 years [82%], <50 years [88%]), multivessel disease (multivessel disease [69%], single-vessel disease [82%]), impaired left ventricular function (ejection fraction <50% [57%], ≥50% [80%]) and a history of previous myocardial infarction (previous myocardial infarction [72%], no previous infarction [83%]). These factors were also found to be independent predictors of death during the follow-up period by a multivariate stepwise logistic regression analysis. Other factors tested, with no influence on survival, were gender, procedural success and stability of angina at the time of intervention.

Conclusion. The long-term prognosis of patients after coronary angioplasty is good, particularly in those <60 years old with single-vessel disease and normal left ventricular function. The majority of patients are likely to experience a further cardiac event in the 10 years after their first angioplasty procedure.     

A Reappraisal of Exercise Electrocardiographic Indexes of the Severity of Ischemic Heart Disease: Angiographic and Scintigraphic Correlates

Objectives. We explored how the exercise electrocardiographic (ECG) indexes generally presumed to signify severe ischemic heart disease (IHD) correlate with coronary angiographic and scintigraphic myocardial perfusion findings.

Background. In exercise testing, it is generally assumed that the early onset of ST segment depression and its occurrence at a low rate–pressure product (ischemic threshold); the amount of maximal ST segment depression; and a horizontal or downsloping ST segment and its prolonged recovery after exercise signify more severe IHD. However, the relation of these indexes to coronary angiographic and exercise myocardial perfusion findings in patients with IHD is unclear.

Methods. We prospectively carried out a symptom-limited 12-lead Bruce protocol thallium-201 single-photon emission computed tomographic (SPECT) exercise test in 66 consecutive subjects with stable angina, ≥70% stenosis of at least one coronary artery, normal rest ECG and left ventricular wall motion and a prior positive exercise ECG. The above ECG indexes, vessel disease (VD), a VD score and the quantitative thallium-SPECT measures of the extent, maximal deficit and redistribution gradient of the perfusion abnormality were characterized.

Results. Maximal ST segment depression could not differentiate the number of diseased vessels; was not related to VD score, maximal thallium deficit or redistribution gradient; but was related to the extent of perfusion abnormality (r = 0.29, 95% confidence interval [CI] 0.08 to 0.52, p = 0.02). Time of onset of ST segment depression correlated inversely only with VD (r = −0.22, 95% CI −0.44 to −0.05, p < 0.05), whereas the ischemic threshold had low inverse correlation only with VD score (r = −0.25, 95% CI −0.47 to −0.01, p < 0.05) and the redistribution gradient (r = −0.33, 95% CI −0.53 to −0.10, p < 0.01). A horizontal or downsloping compared with an upsloping ST segment did not demonstrate more severe angiographic and scintigraphic disease. Recovery time did not correlate with angiographic and scintigraphic findings, and correlations between angiographic and scintigraphic findings were also low or absent.

Conclusions. In this homogeneous study group, the exercise ECG indexes did not necessarily signify more severe IHD by angiographic and scintigraphic criteria. Lack of concordance between the exercise ECG, angiography and myocardial scintigraphy suggests that these diagnostic modalities examine different facets of myocardial ischemia, underscoring the need for caution in the interpretation of their results.

(J Am Coll Cardiol 1997;29:1497–504)