Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer.

PURPOSE: The objective of this study was to determine whether the addition of trastuzumab to chemotherapy in the neoadjuvant setting could increase pathologic complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2) -positive disease. PATIENTS AND METHODS: Forty-two patients with HER2-positive disease with operable breast cancer were randomly assigned to either four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. The primary objective was to demonstrate a 20% improvement in pCR (assumed 21% to 41%) with the addition of trastuzumab to chemotherapy. The planned sample size was 164 patients. RESULTS: Prognostic factors were similar in the two groups. After 34 patients had completed therapy, the trial's Data Monitoring Committee stopped the trial because of superiority of trastuzumab plus chemotherapy. pCR rates were 25% and 66.7% for chemotherapy (n = 16) and trastuzumab plus chemotherapy (n = 18), respectively (P = .02). The decision was based on the calculation that, if study continued to 164 patients, there was a 95% probability that trastuzumab plus chemotherapy would be superior. Of the 42 randomized patients, 26% in the chemotherapy arm achieved pCR compared with 65.2% in the trastuzumab plus chemotherapy arm (P = .016). The safety of this approach is not established, although no clinical congestive heart failure was observed. A more than 10% decrease in the cardiac ejection fraction was observed in five and seven patients in the chemotherapy and trastuzumab plus chemotherapy arms, respectively. CONCLUSION: Despite the small sample size, these data indicate that adding trastuzumab to chemotherapy, as used in this trial, significantly increased pCR without clinical congestive heart failure.     

Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia

Ectopic Mer expression promotes pro-survival signaling and contributes to leukemogenesis and chemoresistance in childhood acute lymphoblastic leukemia (ALL). Consequently, Mer kinase inhibitors may promote leukemic cell death and further act as chemosensitizers increasing efficacy and reducing toxicities of current ALL regimens. We have applied a structure-based design approach to discover novel small molecule Mer kinase inhibitors. Several pyrazolopyrimidine derivatives effectively inhibit Mer kinase activity at sub-nanomolar concentrations. Furthermore, the lead compound shows a promising selectivity profile against a panel of 72 kinases and has excellent pharmacokinetic properties. We also describe the crystal structure of the complex between the lead compound and Mer, opening new opportunities for further optimization and new template design.     

Too Big to Fail: Successful Resection of a Large Hepatocellular Carcinoma with Portal Tumor Thrombus

Digestive Diseases and Sciences -     

Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model

Decreased amplitude and slower kinetics of cardiomyocyte intracellular calcium (Ca(i)(2+)) transients may underlie the diminished cardiac function observed in heart failure. These alterations occur in humans and animals with heart failure, including the TNF1.6 mouse model, in which heart failure arises from cardiac-specific overexpression of tumor necrosis factor alpha (TNF alpha). OBJECTIVE: Since ablation of phospholamban expression (PLBKO) removes inhibition of the sarcoplasmic reticulum (SR) Ca(2+) pump, enhances SR Ca(2+) uptake and increases contractility, we assessed whether ablation of phospholamban expression could improve cardiac function, limit remodeling, and improve survival in the TNF1.6 model of heart failure. METHODS: We bred PLBKO with TNF1.6 mice and characterized the progeny for survival, cardiac function (echocardiography), cardiac remodeling (hypertrophy, dilation, fibrosis), and Ca(2+)(i) transients and contractile function of isolated cardiomyocytes. RESULTS: PLB ablation did not improve survival, cardiac function, or limit cardiac chamber dilation and hypertrophy in TNF1.6 mice (TKO mice). However, contractile function and Ca(2+)(i) transients (amplitude and kinetics) of isolated TKO cardiomyocytes were markedly enhanced. This discordance between unimproved cardiac function, and enhanced Ca(2+)(i) cycling and cardiomyocyte contractile parameters may arise from a continued overexpression of collagen and decreased expression of gap junction proteins (connexin 43) in response to chronic TNF alpha stimulation. CONCLUSIONS: Enhancement of intrinsic cardiomyocyte Ca(2+)(i) cycling and contractile function may not be sufficient to overcome several parallel pathophysiologic processes present in the failing heart.     

Quantitative evaluation of liver-specific promoters from retroviral vectors after in vivo transduction of hepatocytes

Hepatic gene therapy could be used to treat a number of inherited blood diseases such as hemophilia or thrombophilia. Although liver-directed retroviral transduction can result in long-term gene expression in vivo, the low level of protein production has limited its clinical application. We reasoned that the insertion of liver-specific promoters into retroviral vectors would increase gene expression in vivo. The 347- bp human alpha 1-antitrypsin (hAAT), the 810-bp murine albumin (mAIb), the 490-bp rat phosphoenolpyruvate carboxykinase (rPECK), and the 596- bp rat liver fatty acid binding protein promoters were inserted into a Moloney murine leukemia retroviral backbone containing the hAAT reporter gene. Vectors that produced appropriately sized RNA and hAAT protein in vitro were tested in vivo by transducing regenerating rat livers. Long-term serum expression of the hAAT reporter gene was normalized to retroviral transduction efficiency as determined by using a polymerase chain reaction-based assay of genomic DNA from transduced rat livers. The hAAT, mAIb, and rPEPCK promoters were, respectively, 35- , 8-, and 0.02-fold as strong as the previously studied constitutive Pol-II promoter. We conclude that the hAAT promoter resulted in the highest expression from a retroviral vector and may result in therapeutically significant expression of other clinically significant blood proteins.     

HIV Sexual Risk and Syndemics among Women in Three Urban Areas in the United States: Analysis from HVTN 906

Limited data are available on the longitudinal occurrence of syndemic factors among women at risk for HIV infection in the USA and how these factors relate to sexual risk over time. HVTN 906 was a longitudinal study enrolling 799 HIV-uninfected women in three cities. Assessments were done at baseline, 6, 12, and 18 months to assess syndemic factors (low education, low income, unemployment, lack of health insurance, housing instability, substance use, heavy alcohol use, partner violence, incarceration) and sexual risk outcomes. For each sexual risk outcome, a GEE model was fit with syndemic factors or syndemic score (defined as sum of binary syndemics, ranging from 0 to 9), visit, study site, age and race/ethnicity as predictors to examine the multivariable association between syndemic factors and outcomes over time. Odds of unprotected sex while drunk or high were significantly higher when women reported lack of health insurance, substance and heavy alcohol use and partner violence. Housing instability, substance and heavy alcohol use, partner violence and recent incarceration were associated with higher odds of having multiple sexual partners. Odds of sex exchange were significantly higher in the presence of unemployment, housing instability, low education, lack of health insurance, substance and heavy alcohol use, partner violence and incarceration. Housing instability, substance and heavy alcohol use, and partner violence were significantly associated with higher odds of unprotected anal sex. Odds of having a recent STI were significantly higher when women reported housing instability and partner violence. There were significantly higher odds of the reporting of any risk outcomes during follow-up with higher syndemic score. This study highlights a group of women experiencing multiple poor social and health outcomes who need to be the focus of comprehensive interventions.     

Long-term follow-up of patients undergoing closed transventricular mitral commissurotomy: a useful surrogate for percutaneous balloon mitral valvuloplasty?

OBJECTIVE: The aim of this study was to determine the long-term outcome and multivariate predictors of late events in patients who underwent transventricular mitral commissurotomy at the Mayo Clinic in the early 1960s. BACKGROUND. Percutaneous balloon mitral valvuloplasty is an important new procedure for which long-term follow-up data are not yet available. However, such data do exist for patients who have undergone transventricular mitral commissurotomy, a similar but older and more invasive procedure. METHODS. Follow-up data (mean duration 13.9 years) for 207 women and 60 men who underwent transventricular mitral commissurotomy were obtained from medical records, referring physicians, questionnaires and telephone interviews. Survival and survival free of repeat commissurotomy or mitral valve surgery were estimated with the Kaplan-Meier method. Cox proportional hazards model was used to determine predictors of survival and repeat mitral valve surgery. RESULTS. Postoperatively, 92% of patients had symptomatic improvement, which was sustained for at least 3 to 4 years in 78%. At 10, 15 and 20 years postoperatively, 79%, 67% and 55%, respectively, of patients were alive and 57%, 36% and 24%, respectively, were alive and free of repeat mitral valve surgery. At 10 years, 90% of all patients were free of transient or fixed cerebrovascular events. In multivariate analyses, atrial fibrillation, age and male gender were independently associated with death, whereas mitral valve calcification, cardiomegaly and mitral regurgitation independently predicted repeat mitral valve surgery. CONCLUSIONS. Long-term results after transventricular mitral commissurotomy are excellent in selected patients with symptomatic mitral stenosis. Because of similarities in patient selection and mechanisms of mitral valve dilation, similar favorable long-term outcomes may be expected after percutaneous balloon mitral valvuloplasty.     

Trends in coronary revascularization 1989 to 1997: the Bypass Angioplasty Revascularization Investigation (BARI) survey of procedures.

Use of catheter-based and surgical coronary revascularization has steadily increased in North America. Introduction of catheter-based "new devices," including intracoronary stents, has expanded the range of patients who can be treated with percutaneous approaches. We sought to address trends in the practice of catheter-based and surgical coronary revascularization during 1989 to 1997. The 17 North American institutions participating in the NHLBI Bypass Angioplasty Revascularization Investigation (BARI) periodically completed a 5-working day survey of all surgical and catheter-based coronary revascularizations. Data collected included patient demographics, vessel disease, prior interventions, and use of new devices or minimally invasive surgical techniques. The proportion of all procedures that were catheter based (vs surgical) increased from 52.1% in 1989/1990 to 62.0% in 1997 (p <0.001). Among surgically treated patients, prevalence of prior bypass surgery decreased from 13.4% in 1989/1990 to 7.5% in 1997 (p <0.001). In 1997, 3% of surgical procedures used minimal incisions or were performed without cardiopulmonary bypass. Among patients undergoing catheter-based intervention, prevalence of left main disease increased from 2.2% to 5.7% (p <0.001), myocardial infarction within 24 hours increased from 2.4% to 9.7% (p <0.001), and prior bypass surgery increased from 16.2% to 20.8% (p = 0.056). Use of new devices increased from 11.6% of catheter-based procedures in 1990 to 67.0% in 1997 (p <0.001). Compared with the early 1990s, catheter-based revascularization is currently more commonly used for patients with acute myocardial infarction, prior bypass surgery, or severe left main narrowing. These trends are likely due to the proliferation of new devices, especially intracoronary stents, since the mid 1990s.     

Association of hormone replacement therapy with bronchial hyper-responsiveness

Postmenopausal hormone replacement therapy (HRT) has been linked to asthma in women, however, with inconsistent conclusions. This study examined the association of HRT with bronchial hyper-responsiveness (BHR). Eighty-five postmenopausal women completed a women-specific questionnaire and underwent methacholine challenge testing according to the protocol of the European community respiratory health survey. Associations of HRT use with BHR (based on a 20% fall in FEV1), mild BHR (10% fall in FEV1) or dichotomized dose-response slopes were analyzed by logistic regression, controlling for age, education, smoking and overweight. The 27 HRT users were less likely to show BHR compared to the 58 non-users (11% vs. 41%), multiply adjusted odds ratio (95% confidence interval) 0.12 (0.03, 0.55). Results for dose-response slopes were similar, while mild BHR showed no association with HRT use. These results point to a relaxing effect of estrogens on bronchial smooth muscle.