Month: October, 2011

Breast-Cancer Adjuvant Therapy with Zoledronic Acid

29 October, 2011 (18:19) | Cancer | By: Health news

Metastasis is a complex process that is dependent on both the biologic features of the primary tumor and cellular interactions within host tissues. In the bone microenvironment, cancer cells stimulate osteoblasts to release receptor activator of nuclear factor κB ligand (RANKL), which binds to its receptor, RANK, on both precursor and mature osteoclasts. The resulting increase in osteoclastic bone resorption leads to the release of bone-derived growth factors that may provide a fertile environment for survival and growth of adjacent cancer cells. Thus, targeting bone-cell function provides a potential additional approach to preventing bone metastases as a component of standard adjuvant therapy. In many in vivo models, bisphosphonates prevent or delay metastasis. In addition, synergistic interactions between aminobisphosphonates and cytotoxic drugs have been shown in preclinical models.

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In patients with early-stage breast cancer, several clinical trials have suggested that the adjuvant use of bisphosphonates reduces rates of recurrence and death.6-8 In addition, despite a lack of regulatory approval in most health care systems, the inclusion of a bisphosphonate as part of adjuvant therapy has become increasingly widespread. In this randomized, controlled, open-label phase 3 study, called the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, we evaluated the adjuvant use of zoledronic acid in a broad population of patients with stage II or III early-stage breast cancer.


Study Patients

The research protocol and statistical analysis plan are available with the full text of this article at To be eligible for the study, all the patients had to be at least 18 years of age, have a Karnofsky performance status of at least 80, and have a histologically confirmed breast cancer with axillary lymph-node metastasis (N1) or a T3–T4 primary tumor. Complete primary tumor resection was mandated or intended after neoadjuvant therapy. In addition, patients who were eligible for completion surgery (margin excision, mastectomy, or axillary lymph-node dissection) after completion of adjuvant chemotherapy could be included.

Patients were not eligible if there was clinical or imaging evidence of distant metastases or if complete treatment of the primary breast tumor and regional lymph nodes was not possible. Other exclusion criteria included a cancer diagnosis within the preceding 5 years, use of bisphosphonates during the previous year, or a diagnosis of osteoporosis or other bone disease likely to require bone-targeted treatment. The serum creatinine level had to be less than 1.5 times the upper limit of the normal range. In 2005, after case reports of osteonecrosis of the jaw associated with bisphosphonates,9 an amendment was adopted to exclude patients with clinically significant, active dental problems or planned jaw surgery.

Randomization and Treatment

After providing written informed consent, patients were randomly assigned in a 1:1 ratio to receive standard adjuvant systemic therapy (control group) or standard adjuvant systemic therapy along with zoledronic acid. The zoledronic acid was administered immediately after each cycle of adjuvant chemotherapy in a 4-mg dose by intravenous infusion every 3 to 4 weeks for 6 cycles and then every 3 months for 8 doses, followed by 5 cycles on a 6-month schedule for a total of 5 years. Dose adjustments for renal-function abnormalities were recommended in accordance with the product license. Daily oral supplements containing calcium (400 to 1000 mg) and vitamin D (200 to 500 IU) were recommended for all patients during the first 6 months and were continued thereafter at the discretion of the treating physician.

External-beam radiotherapy to the breast and chest wall, with or without irradiation of regional lymph nodes, and adjuvant cytotoxic and endocrine treatments were given in accordance with standard protocols at each participating institution. After regulatory approval of trastuzumab for adjuvant use, the drug was allowed in patients with HER2-positive tumors.

Cardiomyopathy of Overload. Part 2

27 October, 2011 (21:34) | Heart Diseases | By: Health news

The systemic responses to impaired cardiac performance that generally predominate in this condition include salt and water retention, vasoconstriction, and sympathetic stimulation.

These responses probably represent the long-term effects of adaptive mechanisms, which by augmenting preload, maintaining blood pressure, and increasing the heart rate compensate for short-term reductions in cardiac output. When sustained in heart failure, however, these responses become deleterious.

Because these compensatory responses to low cardiac output lead to the most prominent symptoms of heart failure, until recently the major goal of therapy for this condition has been to rid the body of excess salt and water and to correct vasomotor abnormalities in the peripheral circulation. The use of diuretics to manage salt and water retention and vasodilators to overcome inappropriate vasoconstriction, however, fails to address directly the primary cardiac abnormalities in these patients. The cardiac glycosides have been the traditional agents used for inotropic therapy. Although Osler recognized almost a century ago that “degeneration and weakening” of the overloaded heart contribute to the clinical deterioration in congestive heart failure, only recently have clinical strategies for the care of these patients begun to address important and progressive abnormalities in the structure and function of the cells of the failing heart.

What Is Heart Failure?
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Since this article focuses on the state of the failing myocardium, rather than on alterations elsewhere in the body that result from impaired cardiac performance, heart failure is defined in terms of myocardial abnormalities. Thus, no effort is made to define this condition in terms of the clinical syndromes of heart failure, which — as already pointed out — are dominated by the circulatory consequences rather than the myocardial causes of the condition.

MacKenzie’s definition of heart failure as “exhaustion of the reserve force of the heart muscle” highlights the importance of myocardial abnormalities in patients with this condition. Of course, MacKenzie’s “reserve force” and the mechanism by which it might be “exhausted” in the failing heart could not be understood in terms of the knowledge of cardiac muscle that existed at the beginning of the century. It was not until the late 1960s, when myocardial contractility came to be appreciated as a manifestation of complex biochemical and biophysical processes in the myocardium, that our modern understanding of the pathophysiology of heart failure in terms of disordered myocardial-cell function became possible.

Cardiomyopathy of Overload

26 October, 2011 (16:33) | Heart Diseases | By: Health news

MORE than 80 years ago, Sir James MacKenzie noted: “The more I study the symptoms of heart failure, and the more I reflect on the part played by the heart muscle, the more convinced I am that… heart failure is due to the exhaustion of the reserve force of the heart muscle.” Except for the cardiac glycosides, however, therapy for congestive heart failure generally has focused on the systemic signs and symptoms that appear when the failing heart becomes unable to meet the hemodynamic demands of the body, rather than on abnormalities in the heart muscle itself, which both cause and exacerbate the clinical disability.

A new understanding of the pathophysiology of congestive heart failure has led to the identification of important cellular and molecular alterations in the failing heart. Although often masked by prominent systemic compensations for depressed cardiac performance, notably salt and water retention and vasoconstriction, the heart-muscle disorders play a major part in determining the poor prognosis in this condition, which a few years ago had a five-year mortality of approximately 50 percent. Stimulated by a growing realization that medical therapy can alter this grim outlook, applications of new knowledge of the pathophysiology of the heart in congestive heart failure are increasingly affecting strategies for the clinical care of patients with the condition.
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Although myocardial hypertrophy, one of the most important responses of the failing heart, is an adaptive process that enables the heart to compensate for overloading, the cells of the hypertrophied, failing heart are not normal. This review of the cellular abnormalities in the failing myocardium describes a cardiomyopathy of overload that appears to be among the chief causes of deterioration and death in patients with congestive heart failure.

Clinical Syndromes in Heart Failure

The hemodynamic abnormalities that result from heart failure are conceptually simple because, as a pump, the heart has but two ways to fail: through inadequate emptying of the venous reservoirs (backward failure) and through reduced ejection of blood under pressure into the aorta and pulmonary artery (forward failure). However, the response of the body to these abnormalities is complex and varies from person to person. Furthermore, because blood flows in a circle, forward failure and backward failure generally coexist, although the highly variable circulatory adjustments in response to impaired pump performance may cause one or the other to dominate the clinical picture in any given patient.

In patients with left ventricular dysfunction, by far the most common cause of heart failure, an increase in left atrial pressure (backward failure) leads to dyspnea, to pulmonary congestion, and when severe, to pulmonary edema. Reduced cardiac output (forward failure) causes poor tissue perfusion and fatigue; since the body tends to protect blood pressure at the expense of cardiac output (because of vasoconstriction), hypotension is uncommon in chronic heart failure, usually appearing only in the very late stages when pump function has become severely impaired.

Alterations in Myosin

20 October, 2011 (11:53) | Heart Diseases | By: Health news

Molecular changes in the proteins synthesized by the myocardium play a major part in the adaptation of the hypertrophied heart to chronic overload and may influence the long-term prognosis in patients with congestive heart failure. However, as noted more than a decade ago, the extent to which most changes induced by chronic overload contribute to or compensate for the deterioration of the heart is still poorly-understood.

Alterations in Myosin

The synthesis of the myosin heavy chains, which determine myosin ATPase activity (a measure of the rate of energy liberation by myosin in vitro) and muscle-shortening velocity (a measure of the rate of energy use by myosin in vivo), is altered by chronic hemodynamic overloading and heart failure. The functional consequences of the expression of different members of the family of genes that encode the myosin heavy chain have been studied in depth in the rat ventricle: the expression of a VI (α) myosin heavy chain leads to high myosin ATPase activity and rapid shortening velocity, and the expression of a V3 (β) myosin heavy chain leads to low myosin ATPase activity and slow shortening velocity. In response to overload, the preferential synthesis of the V3 heavy chain causes “slow” myosin to replace “fast” myosin, which by decreasing the rate of cross-bridge cycling reduces myocardial contractility. At the same time, however, the tension generated during each systole is increased, which facilitates ejection by the overloaded heart. Furthermore, although the slowing of cross-bridge cycling has a negative inotropic effect, it also improves mechanical efficiency and so is sparing of energy. online pharmacy viagra

A change in the myosin-gene expression has also been observed in overloaded human hearts. Although the human ventricle synthesizes only a slow-myosin isoform, changes similar to those just described for the rat ventricle have been seen in human atria, in which a decrease in the proportion of fast (α) atrial myosin heavy chains parallels the pathologic elevation of left atrial pressure and the extent of left atrial enlargement. Overload has also been found to alter the expression of myosin light chains in the human heart; however, in this case the new gene product is a ventricular isoform of the myosin subunit.

A recent report that the abnormal gene responsible for hypertrophic cardiomyopathy is located on chromosome 14, where both α and β cardiac myosin heavy chains also map, may provide a clue about the pathogenesis of this abnormal hypertrophic response of the myocardium.

Follow-up and Assessment of Outcome. Part 4

12 October, 2011 (13:06) | Hypertension | By: Health news

The current results of this trial indicate that medical therapy as delivered in this trial is superior to PTAS with the Wingspan stent system, which is associated with a high risk of periprocedural stroke or death in this population. Although not all the components of the aggressive medical regimen used in this trial may be easy to duplicate in clinical practice, essential elements can readily be adopted, including adding clopidogrel to aspirin for the first 90 days and following the trial’s protocol with respect to lowering blood pressure and LDL cholesterol in order to achieve target levels that are based on national guidelines. cheap canadian cialis

Supported by a research grant (U01 NS058728) from the National Institute of Neurological Disorders and Stroke (NINDS). In addition, the following institutions received Clinical and Translational Science Awards, funded by the National Institutes of Health, that provided local support for the evaluation of patients in the trial: Medical University of South Carolina (UL1RR029882), University of Florida (UL1RR029889), University of Cincinnati (UL1RR029890), and University of California, San Francisco (UL1RR024131). This research is also supported by the Investigator-Sponsored Study Program of AstraZeneca, which donates rosuvastatin (Crestor) to study patients. Stryker Neurovascular (formerly Boston Scientific Neurovascular) provided study devices and supplemental funding for third-party distribution of devices and continues to provide funding for site monitoring and study auditing, and Nationwide Better Health–INTERVENT provides the lifestyle modification program to the study at a discounted rate. The Regulatory and Clinical Research Institute (Minneapolis) provided assistance in designing the site monitoring processes and performs the site monitoring visits. The Cooperative Studies Program Clinical Research Pharmacy Coordinating Center of the Department of Veterans Affairs (Albuquerque, NM) handles the procurement, labeling, distribution, and inventory management of the study devices and rosuvastatin. Walgreens pharmacies provide study medications, except rosuvastatin, to patients at a discounted price (paid for by the study). The Physician-based Assessment and Counseling for Exercise (PACE) self-assessment forms for physical activity and smoking cessation were provided by the San Diego Center for Health Interventions.

Follow-up and Assessment of Outcome. Part 3

11 October, 2011 (20:03) | Hypertension | By: Health news

The rate of stroke in the medical-management group was much lower than expected. Patients in the WASID trial with the same entry criteria who were treated with aspirin or warfarin and standard management of risk factors had a 30-day rate of stroke or death of 10.7% and a 1-year rate of the primary end point of 25%. In contrast, the corresponding rates in the medical-management group in this trial were 5.8% and 12.2%. Although we expected the rate of stroke to be reduced with intensive management of risk factors — on the basis of post hoc analyses from the WASID trial that suggested that lowering LDL cholesterol and systolic blood pressure could reduce the risk of stroke — we were surprised at the extent and rapidity of the reduction. It is also possible that the combination of aspirin and clopidogrel played an important role in lowering the early risk of stroke. This is supported by the results of a study of transcranial Doppler ultrasonography involving patients with recently symptomatic intracranial stenosis, which showed that aspirin and clopidogrel, as compared with aspirin alone, reduced the frequency of ipsilateral distal microemboli. The effect of the lifestyle modification program on the outcome can be determined only at the end of the follow-up period, but it is unlikely that it contributed to a reduction in the risk of stroke in the medical-management group within 30 days after enrollment.

The difference between the treatment groups in the rate of the primary end point is driven by the early events, since the rates of the primary end point beyond 30 days are currently similar in the two groups. However, fewer than half the patients have been followed for longer than 1 year. Therefore, continued follow-up of the patients who are currently enrolled will be important to determine the long-term outcome in the two groups. Among patients who are receiving medical management only, progression of stenosis may occur over time that could result in a stroke from a distal embolism or hypoperfusion. Among patients in whom a stent has been placed, restenosis occurs in 25 to 30% within 6 months after intracranial PTAS and could also lead to later stroke.

Patients with symptoms that occurred more than 30 days before enrollment or with stenosis of 50 to 69% of an intracranial artery were excluded from this trial because their risk of stroke while receiving standard medical care is relatively low (approximately 3 to 9% at 1 year8,21), making it unlikely that they would benefit from PTAS. These patients could have an even lower risk of stroke if they received aggressive medical therapy. This trial did not evaluate angioplasty alone or other devices (e.g., balloon-mounted stents) that are used off-label to treat patients with intracranial stenosis. Although these devices may have benefits over the Wingspan system (e.g., single-step delivery and deployment of the stent and less residual stenosis after the procedure), none have been compared with medical management.