SAN ANTONIO, TX – Researchers suggested that women with breast cancer experienced fewer skeletal adverse events if they are treated with the monoclonal antibody denosumab instead of zoledronic acid.
Up to 75% of patients with advanced breast cancer develop bone metastases, which in turn lead to osteoclast-related bone destruction, said Alison Stopeck, MD, associate professor of medicine at the University of Arizona, Tucson.
That can lead to fractures, need for radiation therapy and/or surgery, spinal compression, and pain. Intravenous bisphosphonates, predominantly zoledronic acid, are frequently used to delay or prevent these events. Denosumab inhibits Receptor Activator for Nuclear Factor κ B Ligand, the primary mediator of osteoclast formation, function and survival.
She reported the results at the 32nd San Antonio Breast Cancer Symposium.
Based on Phase 2 trials that demonstrated lowered bone turnover markers and reduced skeletal-related events with denosumab, an international, randomized, double-blind phase 3 trial was conducted among 2046 adults with advanced breast cancer and confirmed bone metastases.
Every 4 weeks, the patients received either denosumab 120 mg in a subcutaneous injection and placebo intravenously or subcutaneous placebo and intravenous zoledronic acid 4mg. Patients were encouraged to take supplemental calcium and vitamin D.
At the primary analysis cutoff date after 34 months, 45% of patients remained on study. About 17% of the patients died; another 17% exhibited disease progression; about 12% withdrew consent.
Time to first on-study skeletal-related event was reduced a significant 18% (P=0.01), at a median of 26.5 months for zoledronic acid and with median not reached for denosumab.
Curves began to separate as early as 6 months, Dr. Stopeck noted. After a median time on study of 17 months, events were experienced in 36.5% of zoledronic acid patients and in 30.7% of the denosumab patients.
Time to first on-study skeletal-related event or hypercalcemia of malignancy also favored denosumab (P=0.007) at a median of 25.2 months for zoledronic acid and median not reached for denosumab.
Dr. Stopeck explained that hypercalcemia of malignancy is typically a direct consequence of bone metastases and often has particularly dire clinical consequences.
Also, time to first-and-subsequent on-study skeletal-related events favored denosumab as did time to first radiation to bone and time to experiencing moderate or severe pain.
Overall disease progression was similar for both treatments.
While adverse events were experienced at similar rates between groups, acute phase reactions of pyrexia, bone pain, chills, arthralgia, influenza-like illness, myalgia, and flushing occurred in about 27.3% of patients on zoledronic acid compared with 10.4% of patients on denosumab.
“Denosumab was more efficacious than zoledronic acid,” Dr. Stopeck said. “Denosumab administered as a monthly subcutaneous injection represents a novel treatment option for the management of bone metastases without the need for renal monitoring.”
When asked in the question and answer period if she would use the agent if it is approved, she replied, “I would incorporate it rather quickly because it shows better efficacy, the subcutaneous injection is easier to give, I don’t have to monitor the creatinine and it has less toxicity—assuming the price isn’t exorbitant.”
BETHESDA, MD - The National Heart, Lung, and Blood Institute, part of the National Institutes of Health, has awarded four contracts totaling $23.6 million to begin preclinical testing of devices to help children born with congenital heart defects or those who develop heart failure. The four-year program is called Pumps for Kids, Infants, and Neonates.
Each year in the United States, nearly 1,800 infants die as a result of congenital heart defects and another 350 develop heart disease, which leads to heart failure for many. Approximately 60 infants and children under 5 years old who are placed on the heart transplant waiting list die each year before receiving one. Mechanically assisted circulatory support could be used to sustain these young patients as they seek to recover or wait to receive a heart transplant.
“This research seeks to develop technologies to expand life-saving options for infants and children born with congenital heart defects or those who develop heart failure,” said National Heart, Lung, and Blood Institute Acting Director Susan B. Shurin, M.D., a pediatrician. “The National Heart, Lung, and Blood Institute is committed to saving the lives of our youngest patients. Well-designed circulatory support devices are expected to substantially improve the outcomes of the infants and young children who need them as they seek to recover or wait to receive a heart transplant.”
The options for chronic circulatory support devices for infants and young children are limited, and all have substantial risks for serious adverse events such as infection, stroke, and device failure. With this in mind, the National Heart, Lung, and Blood Institute launched the Pediatric Circulatory Support Program in 2004 by funding the development of five novel circulatory support devices for infants and young children with congenital and acquired cardiovascular disease.
The Pumps for Kids, Infants, and Neonates program is the next phase of National Heart, Lung, and Blood Institute support for the development and clinical realization of these devices. The program’s goal is to complete the needed animal studies and other tests in artificial environments for the most promising devices in order to gain approval from the FDA to begin clinical testing.
Devices in the program will provide suitable circulatory support for newborns, older infants, and children less than 55 pounds who experience heart failure due to congenital and acquired cardiovascular disease. They are designed to supply adequate blood flow to prevent organ damage while minimizing the risk of blood vessel damage, infection, breakdown of red blood cells, excessive bleeding, brain damage, and dangerous blood clots. The devices are intended to support circulation in pediatric patients for one to six months, be sufficiently small and reasonably portable, and be able to be routinely positioned and functioning in less than one hour, among other specifications.
“Similar devices are used in adults,” Shurin noted. “As an adult, your heart is normally about the size of your fist; devices for small children require radically different designs from adult devices to adapt to the differences in the size of the patients.”
The program will test ventricular assist devices and advanced extracorporeal membrane oxygenator devices. The ventricular assist devices in the Pumps for Kids, Infants, and Neonates program are very small rotary pumps which are implanted to provide circulatory support for extended periods of use. They work by drawing blood from the heart and pumping it to the body. Extracorporeal membrane oxygenator devices circulate and supply oxygen to the blood, and are commonly used for patients who need both heart and lung support. For extracorporeal membrane oxygenator devices, tubes connecting the patient to the device are placed directly into large blood vessels near the base of the neck. Blood is drawn from the right side of the heart, pumped through the oxygenator, and then returned to the body on the left side of the heart so the oxygen-rich blood can be delivered throughout the body.
CHICAGO, IL — In a study was presented at the Society for Maternal-Fetal Medicine’s annual meeting, The Pregnancy Meeting, in Chicago, researchers will show the use of haplotype tagging single-nucleotide polymorphisms to study the relationship between genetic predispositions, an environmental factor - bacterial vaginosis, and preterm birth.
Studies previously demonstrated that genetic variation within genes that regulate the maternal inflammatory response are associated with an increased risk of spontaneous preterm delivery. The new study sought to determine if an environmental exposure associated with maternal inflammation, bacterial vaginosis, modifies these genetic susceptibilities.
The March of Dimes notes that babies born before 37 completed weeks of pregnancy are called premature, and in the United States, about 12.8 percent of babies (more than half a million a year) are born prematurely.
The study that was conducted was a prospective cohort study in which maternal DNA samples were collected from 744 women, and demographics and outcomes data were recorded. Vaginal smears for Gram-staining were obtained from subjects at 26-28 wk gestation. It studied haplotype tagging single-nucleotide polymorphisms in 5 BioCarta and KEGG pathways in which >3 single-nucleotide polymorphisms were strongly associated (P<0.01) with spontaneous preterm delivery at <37 weeks (Illumina GoldenGate 1,536-single-nucleotide polymorphism custom chip panel). Associations between genotype distributions and spontaneous preterm delivery were examined using Fisher’s exact tests.
In the cohort, 68 women experienced spontaneous preterm delivery at <37 wk, while 676 women delivered at term (9.1% spontaneous preterm delivery rate). 306 women had asymptomatic bacterial vaginosis (Nugent score *7) at 26-28 wk, and bacterial vaginosis was not associated with an increased risk of spontaneous preterm delivery (P=0.30). 20 haplotype tagging single-nucleotide polymorphisms were associated with an increased risk of spontaneous preterm delivery (P<0.05) in the bacterial vaginosis+ group. For 9 single-nucleotide polymorphisms in 3 genes (FLT1, PRKCA, and IL6), the OR of spontaneous preterm delivery ranged from 2.0-7.0 among bacterial vaginosis+ women who were carriers of the rare allele, and the OR for spontaneous preterm delivery were 2.0-5.0 times greater among bacterial vaginosis+ women than among bacterial vaginosis- women (P<0.05 for test of homogeneity between ORs).
“The result is that chip assays for haplotype tagging single-nucleotide polymorphisms provide a powerful tool for studying genes related to preterm birth and increase our potential to find groups of single-nucleotide polymorphisms in biologically relevant pathways that might cause preterm birth,” said Dr. Samuel Parry, the study’s author of the University of Pennsylvania in Philadelphia. “It is unlikely that any single single-nucleotide polymorphism is related with a large percentage of preterm births.”
CHICAGO, IL — In a study presented at the Society for Maternal-Fetal Medicine’s annual meeting, The Pregnancy Meeting, in Chicago, researchers will present findings that there were less complications for women, after having a cesarean delivery, if sutures were used instead of staples to close the wound.
When Suzanne Basha, M.D. began her career as an obstetrician/gynecologist, she was surprised to find nothing in the literature that provided evidence about which method was better to close a wound after a cesarean.
“It seemed to me that I was seeing more patients return with complications after a cesarean birth when staples were used instead of sutures but I couldn’t find any studies that supported a recommendation for the use of either method,” Basha said.
Basha and her colleagues at the Lehigh Valley Health Network in Allentown, Pa., conducted a study of 425 patients who were randomized. Women undergoing cesarean delivery in labor as well as scheduled cesarean delivery were eligible. Surgical and postpartum care was otherwise at the discretion of the provider. Wound complication data was complete for 98% of subjects (219 suture and 197 staples) and included wound separation, wound infection, antibiotic use, need for a wound-related physician visit, and readmission. Data were collected via telephone interview two to four weeks postoperatively by a single investigator.
Maternal demographic data was similar in both groups. Use of staples resulted in a higher wound separation rate (16.8 v. 4.6%, p< 0.001), higher composite wound complication rate (21.8 v. 9.1%, p< 0.001), and increased post-operative physician visits (36.0 v. 10.6%, p< 0.001); these associations persisted after adjusted analysis. Staple closure was associated with a more than four-fold increased risk of wound separation (adjusted OR 4.66, 95%CI 2.07, 10.52, p< 0.001). Median operative time was eight minutes shorter in the staple group (49 vs. 57 min p< 0.0001).
The study demonstrates that the use of staples for cesarean delivery closure is associated with an increased risk of wound complications and post-operative physician visits. Subcuticular suture may therefore be the preferred method of skin closure for cesarean delivery.
SAN FRANCISCO, CA - Most of us probably think of sperm as rather active little cells, swimming with quick movements of their “tail” or flagella. But actually sperm’s motility is in fact short lived. When in the male reproductive tract they have to rest easy, lest they wear themselves out prematurely and give up any chance of ever finding an egg.
Scientists have long known that sperm’s activity level depends on their internal pH. And now — after many years of looking – researchers reporting in a recent issue of the journal Cell, a Cell Press publication, have finally found the channel that allows the tiny cells to rid themselves of protons. Once in the female reproductive tract, that proton release changes their internal environment from acidic to alkaline and begins their race to the finish line.
The findings offer new insight into a critical event in human fertilization and may lead to new ways of controlling male fertility, according to the researchers.
“The concentration of protons inside the [sperm] cell is 1,000 times higher than outside,” said Yuriy Kirichok of the University of California, San Francisco. “If you just open a pore, protons will go outside. We identify the molecule that lets them out.”
Kirichok likens the quiescent sperm cells to balloons inflated with protons instead of air. If you open a hole in the sperm, protons will readily flow out. In fact, each sperm’s flagellum is covered in many so-called Hv1 proton channels, they show. When the channels are activated by external cues, the flood gates open and protons escape from many pores at once.
Kirichok said there are many conditions that open up the Hv1 pore, including alkaline conditions and the removal of zinc outside the cell. They also open when exposed to the endocannabinoid known as anandamide, a substance that is present in both the male and female reproductive tracts and that may be at particularly high levels in the vicinity of the egg.
That raises an interesting possibility, Kirichok said. Endocannabinoids are natural lipids that influence the activity of neurons. They are so named because they act on the same receptors that the active component of marijuana does. It remains to be shown, but that connection might explain why marijuana has been linked to impaired male fertility.
“Marijuana likely activates sperm prematurely, leaving them burnt out in a matter of hours,” Kirichok said.
Perhaps most importantly, the newly discovered Hv1 channel may allow for new ways to modify the activity of sperm in either direction, Kirichok said. In fact, many key biochemical reactions in sperm depend on intracellular pH levels, including its initial activation, hyperactivation once near the fallopian tubes and the acrosome reaction, in which enzymes are released to penetrate the egg.
“All of these events are essential to fertilization,” Kirichok said. “You can imagine now that we know the molecule responsible we could block it to prevent activation and fertilization as a kind of male contraception.” On the other hand, you might also give some sperm the extra boost they need.
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