Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer.

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC â†’ T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC â†’ T (α = 0.05, ß = 80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC â†’ T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P = 0.02). Further evaluation of NOV-002 in a randomized study is warranted.

Early noninvasive detection of failed epicardial reperfusion after fibrinolytic therapy.

Available noninvasive techniques for identifying patients with failed epicardial reperfusion after fibrinolytic therapy are limited by poor accuracy. It is unknown whether combining multiple noninvasive predictors would improve diagnostic accuracy and facilitate identification of candidates for rescue percutaneous coronary intervention. In the Thrombolysis In Myocardial Infarction (TIMI) 14 trial, we evaluated the ability of ST-segment resolution (n = 606), chest pain resolution (n = 859), and the ratio of 60-minute/baseline serum myoglobin (n = 308) to identify patients with angiographic evidence of failed reperfusion 90 minutes after fibrinolysis. Three criteria were prospectively defined: <50% ST resolution at 90 minutes, presence of chest pain at the time of angiography, and myoglobin ratio <4. Patients who met any individual criterion were more likely to have less than TIMI 3 flow and an occluded infarct-related artery (TIMI 0/1 flow) than those who did not meet the criterion (p <0.005 for each). When the 3 criteria were used together (n = 169), patients who satisfied 0 (n = 29), 1 (n = 68), 2 (n = 51), or 3 (n = 21) of the criteria had a 17%, 24%, 35%, and 76% probability of failing to achieve TIMI 3 flow (p <0.0001 for trend), a 0%, 6%, 18%, and 57% probability of an occluded infarct-related artery (p <0.0001 for trend), and a 0%, 1.5%, 2.0%, and 9.5% rate of 30-day mortality (p = 0.05 for trend), respectively. Use of the criteria in combination increased positive predictive values without decreasing negative predictive values. In conclusion, ST-segment resolution, chest pain resolution, and early washout of serum myoglobin can be used in combination to aid in the early noninvasive identification of candidates for rescue percutaneous coronary intervention.

Abciximab and early adjunctive percutaneous coronary intervention are associated with improved ST-segment resolution after thrombolysis: Observations from the TIMI 14 Trial.

BACKGROUND: Percutaneous coronary intervention (PCI) improves clinical outcomes in selected patients with failed thrombolysis but has not been proven to benefit patients who achieve a patent infarct-related artery. Even after successful epicardial reperfusion, myocardial perfusion may be inadequate. We sought to evaluate whether a strategy that uses a reperfusion regimen containing abciximab and a reduced-dose thrombolytic agent (combination therapy), followed by early adjunctive PCI, would result in improved myocardial perfusion, as assessed by ST-segment resolution. METHODS: ST resolution from 90 to 180 minutes after therapy was calculated for all 410 patients from the TIMI 14 trial who had evaluable electrocardiograms at both time points and who were treated with alteplase or reteplase. Patients were grouped according to whether they were treated with combination therapy or full-dose thrombolytic agent alone and whether they underwent PCI between the 90- and 180-minute electrocardiographic measurements. RESULTS: Among 105 patients who underwent adjunctive PCI between 90 and 180 minutes, mean ST resolution from 90 to 180 minutes was significantly greater in those who had received combination therapy versus those who had received full-dose thrombolytic alone (54% vs 8%; P =.002). Among 241 patients with TIMI grade 3 flow in the infarct-related artery at 90 minutes, adjunctive PCI significantly improved mean ST resolution in patients who had been treated with combination therapy (57% [PCI] vs 24% [no PCI]; P =.006), but PCI did not have this effect in patients who had received thrombolytic therapy alone (1% [PCI] vs 10% [no PCI]; P =.70). In a multivariate model controlling for factors that would be expected to independently influence 90- to 180-minute ST resolution, abciximab treatment remained significantly associated with greater ST resolution (P =.008). CONCLUSIONS: A strategy that uses a combination reperfusion regimen that includes abciximab, followed by early adjunctive PCI, is associated with greater ST-segment resolution, which may reflect enhanced tissue level and microvascular perfusion. Future studies should evaluate prospectively the clinical efficacy of this strategy.

Heart-type fatty acid binding protein as a marker of reperfusion after thrombolytic therapy.

Accurate, rapid, and simple noninvasive measures of infarct-related artery (IRA) patency are needed to identify patients with failed coronary reperfusion for rescue percutaneous coronary intervention (PCI). Heart-type Fatty Acid Binding Protein (H-FABP) is a small, cytosolic protein found in high concentrations in the myocardium. We evaluated the efficacy of H-FABP as a marker for successful reperfusion after thrombolysis. Fifty-eight subjects from the TIMI 14 trial had H-FABP and myoglobin concentrations measured at baseline (immediately prior to thrombolysis) and 60, 90, and 180 min after thrombolysis. All patients underwent coronary angiography at 90 min. By 60 min after thrombolysis, median concentrations of H-FABP and myoglobin were significantly higher in patients with a patent IRA than in those with an occluded IRA (P<0.01 for each). Similarly, the 60 and 90 min/baseline H-FABP and myoglobin ratios were significantly higher among patients with a patent IRA (P<0.01 for each). There were no significant differences in marker concentrations or ratios between patients with TIMI grade 2 and TIMI grade 3 flow. The area under the ROC curve tended to be greater for the 60 and 90 min/baseline myoglobin ratios than for similar ratios of H-FABP (0.71 and 0.73 vs. 0.64 and 0.62; P=ns). In conclusion, successful reperfusion can be detected within the first 60 min after thrombolysis with either H-FABP or myoglobin. Despite a favorable kinetic profile, however, H-FABP does not appear to represent a significant advance over myoglobin in the noninvasive detection of reperfusion after thrombolysis.

Repair of elastase-digested elastic fibers in acellular matrices by replating with neonatal rat-lung lipid interstitial fibroblasts or other elastogenic cell types.

Disruption of elastic fibers is a major factor in the pathogenesis of pulmonary emphysema. Elastic fibers in culture, injured by exposure to elastase, undergo repair in the presence of elastogenic cells that restores the fibers toward normal as determined by biochemical and ultrastructural methods. The repair appears to be the result of both salvage and de novo repair mechanisms. The evidence for salvage repair is that hot-alkali resistance, lost as a result of elastase treatment, is restored to previously radiolabeled elastic fibers. This repair mechanism has been shown in aortic smooth muscle cell cultures. In order to determine the potential relevance of this mechanism for elastic fiber repair in the lungs, experiments were carried out using neonatal rat lung lipid interstitial fibroblasts (LIF). Treatment of the LIF cultures with elastase, in the absence of serum, caused solubilization of 12% of elastin; however, 81% of the elastin protein and 80% of the elastin-associated radioactivity (EAR) were solubilized by subsequent hot-alkali treatment, indicating that most of the elastin was retained in the matrix but was damaged. Ultrastructurally, the elastic fibers were frayed. After 6 additional wk in culture, hot-alkali resistant elastin protein and EAR were restored to 88 and 62% of control values, respectively, and the ultrastructural appearance of elastic fibers was restored to normal. We calculate that about 42% of the restored elastin represented salvage repair; the remainder was new elastin. No repair occurred in matrices rendered acellular by azide treatment; however, when acellular matrices were replated with LIF, repair was complete at 6 wk. No repair was seen when acellular matrices were replated with a transformed mouse macrophage cell line. We conclude that lung LIF are capable of mounting a robust repair process after elastolytic injury of elastin and that the repair is the result of both salvage and de novo repair mechanisms.