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Breast Cancer Screening (PDQ®):
Patient version
Health professional version
U.S. Preventive Services Task Force Recommendations on screening for breast cancer
Some young patients with forms of acute lymphoblastic leukemia (ALL) that do not respond to current treatments may have new options, according to two clinical trials published online October 5 in the Journal of Clinical Oncology. Both trials were led by the NCI-supported Children's Oncology Group (COG), and each yielded impressive results for patients with difficult-to-treat cancers. Read more > >
by Dr. James H. Doroshow
The FDA's recent approval of the new agent pralatrexate (Folotyn) for the treatment of peripheral T-cell lymphoma (PTCL) was especially satisfying news for those of us at NCI who have been involved with this drug. Of course, we are always pleased to see a new, effective cancer treatment reach the clinic, especially one for patients with this rare form of lymphoma who have relapsed after or failed to respond to their initial treatment. Read more > >
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Some young patients with forms of acute lymphoblastic leukemia (ALL) that do not respond to current treatments may have new options, according to two clinical trials published online October 5 in the Journal of Clinical Oncology. Both trials were led by the NCI-supported Children's Oncology Group (COG), and each yielded impressive results for patients with difficult-to-treat cancers.
In the first study, children and young adults with an uncommon type of ALL linked to a genetic mutation known as the Philadelphia chromosome (Ph chromosome) lived longer without their disease coming back when the drug imatinib (Gleevec) was added to conventional intensive chemotherapy. The Ph chromosome causes leukemia cells to produce a fusion protein called Bcr-Abl, which is blocked by imatinib, a type of drug called a tyrosine kinase inhibitor (TKI). While less than 5 percent of childhood ALL cases are linked to the Ph chromosome, only about 40 percent of patients with this form of the disease are cured by conventional therapy.
COG researchers led by Dr. Kirk Schultz of British Columbia Children's Hospital in Vancouver, Canada, treated 92 patients aged 1 to 21 with Ph-chromosome-positive ALL in five cohorts, with each successive cohort receiving a longer period of imatinib therapy. They compared patient outcomes with those for similar patients treated with standard chemotherapy in previous COG trials. Among patients who received the most imatinib (280 continuous days), 80.5 percent were alive and had not had a relapse after 3 years. Only about 35 percent of patients who received standard therapy in previous trials achieved this outcome.
"The remarkable improvement Dr. Schultz and his colleagues saw in early outcomes for children receiving imatinib plus chemotherapy provides strong evidence that children with Ph-chromosome-positive ALL should receive treatment that includes a TKI such as imatinib," commented Dr. Malcolm Smith, a pediatric cancer specialist in NCI's Cancer Therapy Evaluation Program.
Longer follow-up is needed to ensure that this outcome is sustained, and the results should be confirmed in a larger group of patients, said Dr. Smith. Further research is needed, he added, to determine whether imatinib or a "second generation" TKI, such as dasatinib, is more effective when added to chemotherapy for children with Ph-chromosome-positive ALL.
Dr. Crystal Mackall, chief of NCI's Pediatric Oncology Branch, noted that "of five dosing cohorts in this study, only patients receiving the highest exposure to imatinib experienced a benefit––yet, remarkably, this was not associated with any detectable increase in toxicity. It is an unusual occurrence in oncology to see benefit with no increase in toxicity, but this is exactly the type of outcome that is to be expected when effective targeted therapies are incorporated into treatment regimens."
In the second study, adolescents and young adults aged 16 to 21 with ALL who were treated with an intensive multi-drug pediatric chemotherapy regimen lived longer and remained cancer-free longer than patients treated with adult therapies. Patients in this age group tend to have poorer outcomes than younger children with ALL.
Dr. James B. Nachman of the University of Chicago Children's Hospital and his COG colleagues randomly assigned 164 adolescents and young adults with ALL who responded rapidly to induction therapy to receive a further course of either standard or intensified chemotherapy with multiple drugs, including vincristine, pegylated asparaginase, and intravenous methotrexate.
Among rapid responders to induction therapy who went on to receive intensified chemotherapy, 83 percent were alive after 5 years and 82 percent had not had a relapse. Among rapid responders treated with standard-intensity chemotherapy, 76 percent were alive after 5 years and 67 percent had not had a relapse.
These findings add to data from previous studies showing that relapse-free survival is 20 percent to 30 percent better for young adults with ALL who are treated using pediatric regimens rather than adult regimens, the authors wrote. The reason for this difference is unknown. Potential explanations include the distinctive way in which pediatric-type regimens combine specific types of leukemia agents, said Dr. Smith. An ongoing trial in which young adult patients with ALL are being treated with this COG pediatric-type regimen by medical oncologists may shed further light on this question.
Dr. Nachman and colleagues further noted that when a pediatric-type regimen is used for this patient population, routine use of stem-cell transplantation in first remission seems unwarranted.
This study, Dr. Smith said, offers convincing evidence that patients in the 16 to 21 year age range with ALL should be treated with a pediatric-type ALL regimen. "Several studies from across the world comparing outcomes for patients in this age group who are treated with adult versus pediatric regimens have uniformly shown that the pediatric ALL regimens perform better," he added.
—Eleanor Mayfield
Minimally invasive surgeries to remove the prostate in men with prostate cancer, including procedures performed with a surgical robot, are superior to standard "open" prostate removal surgeries by some measures but fall short on several other important outcomes, including risk of incontinence and erectile dysfunction. The study was published October 14 in the Journal of the American Medical Association.
From 2003 to 2007, the number of minimally invasive radical prostatectomy (MIRP) procedures increased from 1 percent to more than 40 percent of all prostatectomies, an increase that the researchers believe has been largely driven by the rapid proliferation of robotic surgery. Currently, robotic prostatectomy accounts for 70 percent of all MIRP procedures, said the study's lead author Dr. Jim C. Hu of Brigham and Women's Hospital in Boston.
The study was not a randomized clinical trial. Rather, the researchers used billing and diagnostic data from NCI's SEER Medicare database, identifying 1,938 men who underwent MIRP and 6,899 men who underwent open surgery. After accounting for differences in physician and patient characteristics in men receiving MIRP versus open procedures, the researchers found that men who underwent MIRP had shorter hospital stays (2 days versus 3 days), far fewer blood transfusions, and a lower risk of respiratory and other surgical complications. But they also had more than twice the risk of genitourinary complications, a 30 percent increased risk of incontinence, and a 40 percent increased risk of erectile dysfunction 18 months after the procedure.
The need for additional cancer therapies was roughly equivalent between the groups, Dr. Hu explained, suggesting that neither procedure is superior in terms of cancer control. The study also revealed several disparities related to MIRP, including less frequent use by African American and Hispanic men.
Given the available data on standard open surgery compared to MIRP, said Dr. Hu, open surgery should remain the "gold standard" for men who opt for surgery to treat localized prostate cancer.
A small RNA molecule in liver tumors could be a biological marker for assessing a patient's prognosis and might also be used to select candidates for treatment with the biological therapy interferon, according to a study in the October 8 New England Journal of Medicine. The molecule is one of approximately 1,000 microRNAs in the human genome. Each microRNA is thought to regulate the activitiy of several hundred genes.
The researchers found that patients whose tumors had reduced levels of a microRNA called miR-26 tended to have a poor prognosis but were more likely to benefit from interferon than other patients. MicroRNAs are thought to regulate the activity of hundreds of genes, and some have been linked to cancer.
"We think this microRNA could be quite useful for helping clinicians determine how aggressive a tumor will be and also to identify patients who will benefit from interferon to prevent relapse," said lead investigator Dr. Xin Wei Wang, head of NCI's Liver Carcinogenesis Section. The study was done with investigators at Fudan University, Shanghai; the University of Hong Kong in China; and Ohio State University.
The study's original aim was to see whether differences in microRNA levels, or expression, could help explain the different outcomes seen in males and females with a form of liver cancer called hepatocellular carcinoma. The analysis found clear differences in the expression of miR-26 between males and females and also between patients with more or less aggressive tumors.
Overall, both male and female patients with low levels of miR-26 did not live as long as patients with higher levels of the microRNA. The difference in survival was about 4 years between the groups. But while patients with low levels of miR-26 had a poor prognosis, these patients were more likely to benefit from interferon as an adjuvant therapy. This group survived at least 7.7 years longer than patients with low tumor levels of miR-26 who did not receive interferon therapy. Patients with normal levels of miR-26 in their tumors did not benefit from interferon.
The association between miR-26 and prognosis or treatment response does not imply cause and effect, but a recent study in mice provided evidence that miR-26 may act as a tumor suppressor, noted Dr. Wang. Future studies will assess the microRNA in additional populations and explore its potential use as a therapeutic target in the disease, he added.
Rhabdomyosarcoma (RMS), an aggressive childhood cancer caused by mutations in genes that control the development of skeletal muscle tissue, has often spread (metastasized) by the time it is diagnosed in children, leading to poor survival rates. Researchers have now identified mutations in the fibroblast growth factor receptor 4 (FGFR4) gene that are associated with metastasis and poor outcomes in patients with RMS. The FGFR4 protein belongs to a family of proteins known as receptor tyrosine kinases, which are involved in cellular signaling processes that help regulate cell growth, maturation, and survival. The gene, the researchers believe, may provide a target for therapy. The results appeared online October 5 in the Journal of Clinical Investigation.
Researchers from NCI; the National Heart, Lung, and Blood Institute; The Children's Hospital at Westmead, Australia; and the Nationwide Children's Hospital in Columbus, OH, were involved in the project. Their previous research, and that of others, has shown that FGFR4 is highly expressed in RMS. Because the gene is active during muscle development and not in mature muscle, the team investigated whether expression of FGFR4 might contribute to RMS. Using mouse models, the researchers showed that the growth and spread of human RMS cells to the lungs was inhibited by suppressing FGFR4 expression. After sequencing the FGFR4 gene in human RMS tumor samples, they found that more than 7 percent of the tumors had mutations in the tyrosine kinase portion of the protein. Some of these mutations caused the protein to become overly active. Mutations that increase receptor tyrosine kinase activity have been found in other cancers, but the researchers note that this is the first time that mutations in a receptor tyrosine kinase have been found in RMS.
With a series of lab and animal studies, they confirmed that two of the FGFR4 mutations caused increased tumor growth, reduced RMS cell death, and enhanced the ability of RMS cells to metastasize.
The mutations, which were found in both types of RMS, alveolar and embryonal, appeared to act via the STAT3 pathway. Mouse RMS cells harboring these mutations were also more sensitive to treatment with drugs that inhibit FGFR4, which has "direct implications for personalized therapy and for patients with metastatic RMS, for whom long-term prognosis remains poor," said lead author Dr. Javed Khan of NCI's Pediatric Oncology Branch.
Using next-generation DNA sequencing technology, researchers in Canada have compared the genetic changes in two breast tumors collected from the same patient 9 years apart. The secondary tumor (metastasis) included genetic changes not present in the tumor sample collected at diagnosis, suggesting that "significant evolution can occur with disease progression," the researchers reported in the October 8 Nature.
"The cancer evolved significantly in terms of its genome content, but moreover, the primary cancer was heterogeneous from the start," said lead investigator Dr. Samuel Aparicio of the BC Cancer Research Center in Vancouver. "We've known that cancer cells must be heterogeneous for many decades, but now we're seeing it up close."
The researchers found 32 genetic mutations in the secondary tumor, 19 of which were not in the primary tumor. (It was not known whether these 19 mutations were a consequence of radiation therapy or of innate tumor progression.) Knowing which alterations are present in a primary tumor prior to therapy and to metastasis could make it easier to uncover the genetic factors responsible for the initial cancer, the researchers said.
When asked about the findings, Dr. Joan Massagué of Memorial Sloan-Kettering Cancer Center said that because cancers essentially happen by accident and evolve in the body any way they can, one would expect to see many different paths of evolution. Studies like the current one show how tumor evolution "may happen in one situation or another," but he cautioned against drawing broader conclusions from any particular report.
Dr. Massagué made his comments at a recent press briefing on metastasis hosted by the American Association for Cancer Research.
Much remains unknown about the process tumors undergo to evade attack by the immune system. Now a team including researchers from NCI's Center for Cancer Research and the Fred Hutchinson Cancer Research Center has shown that tumor-specific immune cells that have migrated to the mouse prostate tumor microenvironment can switch from their normal antitumor activity to an immune suppressor function. Their report appeared in the October 15 Journal of Immunology.
The researchers found that, once within the microenvironment of mouse prostate tumors, tumor-specific CD8+ T cells actually began to block the normal immune response: a call for nonspecific T cells to multiply and attack the tumor.
This immune-suppressive activity appeared to be caused, in part, by substances secreted by the CD8+ T cells in the tumor microenvironment. One of these substances, TGF-β, is a protein that controls cell proliferation and differentiation and plays a role in cancer and other diseases. When the researchers used an antibody to block TGF-β, the CD8+ cells were prevented from switching to a suppressor role.
While it's not clear whether TGF-β is required for this process, the researchers did note that CD8+ T cells only suppressed other immune cells after they had infiltrated the tumor microenvironment. In contrast, CD8+ T cells isolated from elsewhere (in this case from the lymph nodes of the same mice) were unable to suppress the growth of nonspecific T cells. The research team also found that they could disrupt suppressive immune signaling within the tumor microenvironment by introducing CD4+ T cells into the region. When CD4+ T cells were added, CD8+ T cells isolated from the prostate tumors no longer suppressed the proliferation of other T cells, and they produced less TGF-β.
With these findings, the authors concluded that "new approaches to block these pathways will enhance our ability to generate more sustained and effective antitumor T cell responses."
The FDA's recent approval of the new agent pralatrexate (Folotyn) for the treatment of peripheral T-cell lymphoma (PTCL) was especially satisfying news for those of us at NCI who have been involved with this drug. Of course, we are always pleased to see a new, effective cancer treatment reach the clinic, especially one for patients with this rare form of lymphoma who have relapsed after or failed to respond to their initial treatment.
NCI has a particular interest in this drug because it is the first agent from NCI's Rapid Access to Intervention Development (RAID) program to receive FDA approval for a cancer indication. For a program that was in existence for a decade, the fact that this is the first approval demonstrates how difficult it can be to bring a new treatment to patients. Now that RAID has been incorporated into NCI's Experimental Therapeutics (NExT) program, we believe that efficiencies and improvements in NCI's drug development efforts are achievable and real.
There is a great deal of excitement about NExT, which is a collaboration between NCI's Division of Cancer Treatment and Diagnosis and Center for Cancer Research (CCR). The program's goal is to speed up the drug development process by getting promising drugs—particularly those for pediatric and rare cancers—into human trials more quickly and to prune agents from the development pipeline that are unlikely to be effective, saving valuable resources.
NExT was designed to bring NCI's diverse drug development efforts into a single pipeline and to follow a formalized, business-like approach to the development of potentially promising therapeutics. At the same time, the broad array of services and resources such as toxicology testing and drug manufacturing that was available to researchers via RAID is still available with NExT.
Where RAID was more focused on aiding researchers with highly specific tasks, drugs accepted into NExT can provide a more comprehensive approach to advancing agents through the development pipeline, including established milestones that drive "go/no-go" decisions about whether to continue NCI's role in the development of a given agent. The objective is to move drug candidates through preclinical work into first-in-human studies, including phase 0 trials in which nontoxic doses of the agent are tested in a small number of patients. Using advanced imaging and other techniques, in these trials we can determine in a matter of months whether the drug is reaching its intended target and having the intended biologic effects. This will give us more confidence in the decision to move the agent further along in human trials and help to shave at least a year off of the time it typically takes to develop a drug, while also limiting the resources spent developing treatments that will likely never benefit patients.
A number of agents are already in the NExT pipeline, including agents being investigated by researchers from CCR, large academic medical centers, and private industry. (See the box below.) And we've already seen an example of how NExT will function. NCI worked with Abbott Laboratories in the early clinical development of its PARP inhibitor, ABT-888, and in testing it in the first-ever phase 0 trial of only 13 patients. The trial demonstrated that the drug, which interferes with a cell's ability to repair DNA damage, was in fact hitting its biologic target. Now we are working with Abbott to test this agent in phase I and II clinical trials in patients with a variety of tumors.
Although many of the agents in NExT will be supported from preclinical testing through first-in-human studies, the program is open for applicants to enter and exit at any stage in the process. There may be cases, for example, where a research team or private company is already testing an agent in early stage trials in adults, but they may be interested in using NExT to develop the agent for use in a pediatric population, an area in which NCI has unique expertise and resources.
So whether it is serving as a bridge at critical points in the development path, as was the case for pralatrexate, or as a more comprehensive driver of an agent's development from the earliest stages of preclinical research, we are confident that with NExT we can have many more successes in the coming decade.
Dr. James H. Doroshow
Director, NCI Division of Cancer Treatment and Diagnosis
Dr. Yves Pommier, chief of CCR's Laboratory of Molecular Pharmacology, has two compounds in the NExT program on the verge of being tested in phase I trials. In both laboratory tests and animal model studies, the two compounds, known as indenoisoquinolines, or indenos, have demonstrated an impressive ability to kill cancer cells with little evidence of toxicity.
Like a class of compounds known as camptothecins, the indenos target topoisomerase 1, which plays a critical role in DNA replication during cell division. But the indenos have some advantages over camptothecins, Dr. Pommier said, including more chemical stability and the ability to remain active in the blood for longer periods.
"It takes time to realize that you have something worthy of pursuing in human trials," Dr. Pommier stressed. The compounds have been under development for more than a decade, he noted, so the researchers involvement in NExT is a bridging step before likely working with industry to conduct large-scale human trials.
At Ohio State University (OSU) Medical Center, Dr. Michael Grever and his colleagues, Drs. Doug Kinghorn and David Lucas, are pursuing the development of an agent called silvestrol, a natural product derived from a plant found in Sarawak, on the island of Borneo. Their research is focused on developing new treatments for chronic lymphocytic leukemia and acute lymphoblastic leukemia, both of which involve the overproduction of malignant B cells.
In very low concentrations, silvestrol induced selective killing of leukemic cells taken from patients. And in an animal model of a highly aggressive leukemia, treatment with silvestrol appeared to completely eradicate the disease in some cases. The compound causes little if any apparent damage to normal immune system cells, Dr. Grever said—a common problem with current treatments for these cancers.
As part of its involvement in NExT, silvestrol is undergoing intensive safety analyses at NCI, and the OSU researchers are working in close collaboration with scientists in Sarawak. His goal with NExT, Dr. Grever said, is to help move silvestrol into phase I clinical trials.
For more than a decade, researchers at NCI and their collaborators have collected DNA from seven families with an inherited form of chordoma, a type of bone cancer. The researchers have now identified a genetic change that may lead to the disease in four of the families.
The change was not a mutation in the DNA sequence of a gene, as the researchers had expected, but rather the duplication of an entire gene. In each family, an extra copy of the gene was created by a large structural change in the genome—a rearrangement—that occurred once and was passed down to future generations.
While the type of the genetic change was perhaps unexpected, the identity of the gene was not. As the researchers reported online in Nature Genetics on October 4, the gene is active in the chordoma tumor cells of people with the noninherited form of the disease. The gene is called T, or brachyury (for the protein it encodes).
"We have found the gene for a subset of families with an inherited predisposition to chordoma," said lead investigator Dr. Rose Yang of NCI's Division of Cancer Epidemiology and Genetics (DCEG). "We had thought this gene may be important in predisposing to the disease, and for the first time we have direct evidence from a study of high-risk families."
Broader Implications
About 300 cases of the noninherited form of chordoma are diagnosed in the United States each year. The disease causes a tumor to develop anywhere along the spinal column, from the base of the skull to the tailbone, and the tumor can be fatal. Researchers believe the tumors arise from remnants of the notochord, an embryonic precursor to the spinal cord.
The discovery provides a new clue to the biology of chordoma and could have broader implications. It suggests an alternate strategy for finding susceptibility genes when traditional methods fail, the researchers said. In this case, genetic mapping studies had linked a region of chromosome 6 to the disease, but sequencing DNA in the region, including the T gene, revealed no suspicious changes.
"Sequencing DNA doesn't find everything, and it won't tell you if a whole gene is deleted or duplicated," said co-author Dr. David Ng of the National Human Genome Research Institute (NHGRI). "So if a gene appears to play a role in a disease but you don't find any mutations by sequencing, looking for genomic rearrangements, including duplications or deletions in the gene, is a reasonable next step."
To survey the structural changes in the genome, the researchers used a technique called array comparative genomic hybridization (CGH), which revealed a different genomic rearrangement in each of the four families. Yet nearly all of the affected family members had tumors in the same area (the base of the skull).
Counting Copies
Most human DNA is present in two copies per cell (one from each parent), yet in each cell, certain regions are deleted or present in multiple copies—what are known as copy number variations, or CNVs. These changes are usually harmless, but certain types of rearrangements can lead to cancer and other diseases.
In the largest survey to date of frequent CNVs in the human genome, reported this month in Nature, researchers said that any two human genomes differ by more than 1,000 CNVs (about 0.8 percent of a person's DNA sequence). The study authors predicted that genomic rearrangements are likely to play a role in rare as well as common diseases.
The chordoma study certainly supports this idea. It also underscores just how important advances in technology and persistence are in the search for susceptibility genes.
"We almost gave up hope of finding the gene on several occasions," said Dr. Dilys Parry of DCEG, who launched the project in 1996 after identifying a chordoma family that now has 10 affected members spanning several generations. "But in the last 13 years, the technology has changed enormously, and we've been able to take advantage of the advances at every step along the way."
This was perhaps most evident 2 years ago, when the team used new markers and tools to locate the region of chromosome 6 with the T gene. After negative results from DNA sequencing, the researchers used the array-CGH technology to screen 13 members of the 7 families (including 11 with chordoma) for genomic rearrangements.
New Beginning
The result made sense immediately to the researchers because the T gene is active in some chordoma tumor cells and it regulates the development of the notochord. However, they do not yet understand how the gene might cause chordoma, according to co-author Dr. Michael Kelley of Duke University Medical Center and a former NCI investigator.
Another question is what caused the disease in the three families without the T gene duplication. The researchers predict that mutations in other genes or an as-yet-unknown mechanism involving the T gene will eventually provide the answer. They are actively enrolling chordoma families to participate in an ongoing study to identify the other genes.
In some rare inherited cancers, there are not enough families—or the families are too small—to use traditional linkage studies to locate chromosome regions of interest. But in some of these cases, noted Dr. Yang, testing for genomic rearrangements may be informative.
"This study really highlights what we can do with new genomic technologies," said Dr. Joan Bailey-Wilson, who studies the genetics of inherited diseases at NHGRI and was not involved in the research. "CNVs are another item in our tool box for locating genetic susceptibility variants, and most of us are excited about any new tool we can get."
The discovery of a susceptibility gene always leads to important questions about biological processes that can take many years to answer, Dr. Bailey-Wilson added. "Once we find a gene that we believe is responsible for a linkage signal, we have to realize that the true work is only starting," she said.
—Edward R. Winstead
The argument for screening women for breast cancer with mammography sounds simple: Mammography can detect cancers before they begin to cause symptoms. Clinical trials have shown that fewer women die of breast cancer when they are screened with mammography than when they are not.
But what if some of the very early stage breast cancers found by mammography are not destined to grow and become potentially lethal? Although the idea of a harmless cancer may seem counterintuitive, such cancers do exist.
Some cancers never grow, or they grow so slowly that they never become clinically detectable. Autopsy studies have found breast tumors in women between age 40 and 70 who died of unrelated causes. And a 2008 study made the provocative suggestion that some very early stage invasive breast tumors may regress spontaneously.
The identification of tumors that would never have become a clinical problem in the patient's lifetime is known as overdiagnosis.
"With overdiagnosis, we often end up 'curing' cancers that didn't need to be cured in the first place," said Dr. Barry Kramer, director of the NIH Office of Disease Prevention and an expert on cancer screening.
Because doctors can't distinguish breast cancers that will progress from those that will not, these "overdiagnosed" tumors will in most cases lead to surgery, possibly with radiation, chemotherapy, or hormone therapy. Some people, therefore, are receiving unnecessary treatment that is of no benefit to them, can be toxic, and often comes with significant side effects.
Studies strongly suggest that overdiagnosis occurs with screening for several cancers, including prostate and lung cancer, as well as breast cancer, said Dr. Kramer.
The precise extent of breast cancer overdiagnosis is unclear. In a paper published in July in the British Medical Journal, Danish researchers estimated that one out of every three tumors detected by screening mammography was overdiagnosed. Their estimate was based on an analysis of breast cancer rates before and after the implementation of government-run mammography screening programs in Australia, Canada, Norway, Sweden, and the United Kingdom.
Breast Cancer Screening (PDQ®):
Patient version
Health professional version
U.S. Preventive Services Task Force Recommendations on screening for breast cancer
A 2006 study that was based on 25 years of follow-up with women who were screened with mammography in Sweden concluded that one in six breast cancers was overdiagnosed. Other estimates of overdiagnosis have ranged from 5 percent to 32 percent.
"Pulling Cases Out of the Future"
Several factors can lead to varying estimates of breast cancer overdiagnosis. One is whether researchers count both early stage invasive tumors and ductal carcinoma in situ (DCIS) detected by mammography, or only invasive tumors. "If you count only invasive cancers, estimates will be lower. If you also count DCIS, they will generally be higher," said Dr. Kramer.
Another factor is what assumptions researchers make about time trends in cancer rates. "In the absence of overdiagnosis, [mammography] should be pulling cases out of the future into the present," said Dr. Kramer. In other words, every breast cancer detected early by mammography should equal one less cancer detected later on.
This is what the Danish researchers assumed would happen, explained Dr. Kathleen Cronin of NCI's Statistical Research and Applications Branch. "They assumed that the number of new breast cancer cases diagnosed each year after mammography screening began would have followed the same trend seen before mammography was introduced," she said.
But in fact, from the 1980s through 2001, a span of time roughly corresponding to the period during which mammography screening programs became established, the number of newly diagnosed breast cancer cases increased year by year. And, as noted in this week's Journal of the American Medical Association, the incidence of aggressive or later-stage disease has not decreased at a rate that would be explained by an increase in earlier diagnoses.
Changes in breast cancer risk factors––more women delaying childbirth or using postmenopausal hormone therapy, for example––may have contributed to the increase in breast cancer cases, said Dr. Kramer. Overdiagnosis may have, too.
Molecular Features
The bottom line? Many other researchers think the Danish investigators may have overestimated the level of breast cancer overdiagnosis. Most agree, however, that mammography does diagnose some breast cancers that would never have needed to be treated.
Recognizing that current estimates of the extent of the problem are unsatisfactory, researchers are striving to develop more accurate ways of estimating just how much overdiagnosis of breast cancer results from mammography in the hopes of sparing some women from unnecessary and often toxic treatments. Dr. Cronin is scientific coordinator for an NCI-supported consortium of researchers who are working to better understand how mammography, among other factors, influences breast cancer rates.
Overdiagnosis can be identified at a population level by comparing cancer rates in groups of people over time. Relevant data are provided by the Breast Cancer Surveillance Consortium (BCSC) and NCI's Medicare SEER database. Longitudinal data are a critical aspect of these efforts. Over its 15-year existence, the BCSC has collected information on 2,017,869 women, including 86,700 with cancer.
Researchers agree that one solution to the problem of breast cancer overdiagnosis may ultimately emerge from advances in molecular medicine that will enable doctors to distinguish mammography-detected tumors likely to progress from those unlikely to do so.
"If we can identify tumors that are not destined to become a problem, we can avoid treating patients unnecessarily," said Dr. Sudhir Srivastava, chief of NCI's Cancer Biomarkers Research Group. "And differentiating progressive and nonprogressive tumors on the basis of molecular features is currently an active area of research within the NCI-supported Early Detection Research Network," he explained.
In the meantime, for women aged 40 and over who may be wondering if they should continue having regular mammograms, Dr. Stephen Taplin, a breast cancer screening specialist with NCI's Applied Research Program, offered this advice:
"Today, regardless of age, women are less likely to die of breast cancer than they were 20 years ago because of improvements in treatment and wider use of screening. There is no simple way for a woman to measure the benefit of mammography to her as an individual, but research is under way to improve our ability to estimate a woman's risk. What we do know is that, on average, for women aged 50 to 75, mammography reduces the likelihood of dying from breast cancer by about 20 percent. For women aged 40 to 49, the reduction in mortality is smaller, although still real, and the balance of benefits versus harms may be more uncertain.
"The balance of benefits and harms is something that is best done by each woman with her health care provider," Dr. Taplin continued. "Think about what is important to you. Think about how you would feel if you had an abnormal mammogram. Then make the decision that is right for you."
—Eleanor Mayfield
Name of the Trial
Phase II Study of Satraplatin and Prednisone in Patients with Progressive, Metastatic Androgen-Independent Prostate Cancer (NCI-08-C-0074). See the protocol summary.
Principal Investigator
Dr. William Dahut, NCI Center for Cancer Research
Why This Trial Is Important
Men with metastatic prostate cancer that does not respond to hormone therapy (androgen-independent prostate cancer) have very few treatment options available. Chemotherapy with docetaxel or other drugs is often used to alleviate symptoms and delay disease progression, but most men continue to get worse despite this treatment.
Satraplatin is a third-generation, orally administered platinum drug that may delay disease progression in men with androgen-independent prostate cancer. Previous preclinical and clinical research has shown that satraplatin is active against androgen-independent prostate cancer and that it may overcome the resistance to platinum drugs commonly seen in advanced disease.
In this trial, men with androgen-independent metastatic prostate cancer that has progressed after first-line chemotherapy will be treated with satraplatin and prednisone. The researchers want to see if this regimen can delay disease progression and if alterations in the ERCC1 gene are associated with improved progression-free survival. ERCC1 is an important DNA repair gene that may contribute to resistance to platinum drugs. The researchers believe that DNA variations in ERCC1 may be related to satraplatin's observed ability to overcome this resistance.
"A phase III study of satraplatin and prednisone in patients with metastatic androgen-independent prostate cancer has demonstrated that satraplatin can significantly improve progression-free survival and help alleviate cancer-related pain, although patients receiving satraplatin in this study did not live longer overall than those receiving a placebo," said Dr. Dahut.
"Our trial is unique because it aims to determine whether the presence of ERCC1 gene polymorphisms may be associated with an impact on the progression-free survival of patients with metastatic prostate cancer," he said. "This trial will provide critical information about patient selection for satraplatin therapy."
For More Information
See the lists of entry criteria and trial contact information or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.
Director: Dr. Michelle M. Le Beau • 5841 South Maryland Avenue, MC1140, Chicago, IL 60637
Phone: 773-702-6180 • Web site: http://uccrc.uchicago.edu
Founded in 1973, the University of Chicago Cancer Research Center (UCCRC) is one of two NCI-designated comprehensive cancer centers in Illinois. The University of Chicago has been a leader in cancer research for many decades. Its scientists have made groundbreaking discoveries that have led to advances in chemotherapy, hormonal therapy, gene therapy, and bone marrow transplantation.
In 1943, the University of Chicago's Dr. Leon Jacobson performed the first successful cancer treatment using chemotherapy and demonstrated the potential of bone marrow transplantation. In FY 2009, UCCRC's pediatric and adult bone marrow transplant programs performed 180 bone marrow transplants.
Nobel Prize recipient Dr. Charles Huggins discovered in 1966 that cells were not autonomous and self perpetuating, as previously believed, but were dependent on chemical signals, such as hormones, to grow and survive. His discoveries offered researchers new perspectives on the behavior of hormone-responsive cancers and redefined treatment of metastatic cancers.
Dr. Janet Rowley's discoveries of recurring chromosomal abnormalities in leukemias and lymphomas revolutionized the understanding and treatment of cancer. President Barack Obama honored Dr. Rowley with the Medal of Freedom, the nation's highest civilian award, earlier this year.
Building on this tradition of excellence, the UCCRC laboratory research programs have made fundamental discoveries in the molecular genetics of cancers, cancer immunology, hormonal therapy, bone marrow transplantation, cell signaling, and advanced imaging techniques. Clinical researchers have made critical breakthroughs in the investigation of breast, head and neck, lung, kidney, and prostate cancers, leukemia, mesothelioma, and cancer genetics.
Prevention and control research at the UCCRC emphasizes identifying genetic risk factors for cancer, investigating potential chemoprevention agents, and studying early detection, health disparities, and quality-of-life issues. UCCRC members are world-renowned experts in advanced imaging, radiation treatment, the development of novel anticancer drugs, and pharmacogenomics.
Active UCCRC research programs include a Specialized Program of Research Excellence (SPORE) in breast cancer, participation in a SPORE in prostate cancer (with Lurie Comprehensive Cancer Center of Northwestern University), the Pharmacogenetics of Anticancer Agents Research Consortium (U01), a Specialized Center of Research (SCOR) in hematological malignancies, the Ludwig Center for Metastasis Research, a National Center for Complementary and Alternative Medicine Center of Excellence in Research, and the Chicago Center for Systems Biology.
Patient Care
UCCRC offers the full range of specialty and primary care services for adults and children. The center had 25,300 admissions in FY 2009 and 150,000 patient days annually. Cancer patients make up a large portion of the patient base, with almost 5,000 new cancer patients annually. Cancer patients account for over 61,500 outpatient visits.
Advanced cancer care will be a priority of the 1.2 million-square-foot New Hospital Pavilion (NHP) that is currently under construction.
Translational Research
The NHP will be adjacent to two new research facilities. The 400,000-square-foot Ellen and Melvin Gordon Center for Integrative Science (GCIS), the university's largest science building, opened in 2005. The GCIS is the home of the Ben May Department for Cancer Research. The Gordon Center brings scientists from the biological and physical sciences together under one roof, enabling new research collaborations.
The 330,000-square-foot Gwen and Jules Knapp Center for Biomedical Discovery (KCBD), which is the home of the UCCRC, opened in 2009. This facility houses 22,000 square feet of wet lab space for UCCRC investigators, as well as the D.K. Ludwig Center for Metastasis Research and the Institute for Genomics and Systems Biology. The proximity of the GCIS, KCBD, and NHP will encourage and facilitate interdisciplinary and translational research. The three facilities represent the continuum of research that transforms fundamental discoveries into advanced cancer care.
On October 7, a panel of cancer survivors, advocates, and researchers testified before the U.S. House of Representatives Committee on Energy and Commerce, Subcommittee on Health, at a hearing on the Eliminating Disparities in Breast Cancer Treatment Act of 2009. Panel members included Dr. Stephen Taplin, chief of NCI's Applied Cancer Screening Research Branch; Dr. Otis Brawley, chief medical officer of the American Cancer Society; Jenny Luray, president of the Susan G. Komen for the Cure Advocacy Alliance; Debra L. Ness, president of the National Partnership for Women and Families; Fran Visco, president of the National Breast Cancer Coalition; and Dr. Marisa C. Weiss, president and founder of Breastcancer.org.
The legislators and panelists called for greater emphasis on tailoring prevention and treatment to an individual's risk, improved early detection methods, and increased access to health care that covers the entire screening and treatment process. Dr. Taplin stressed the need for additional research to improve the accuracy of breast cancer screening to avoid overtreatment, and he discussed the importance of addressing screening as a multi-step process.
Rep. Debbie Wasserman Schultz (D-FL) is working on a new version of the EARLY Act, which drew concerns from many in the medical and scientific community when it was first introduced in March 2009. The revised bill will designate the CDC to lead the development of the educational messages required by the legislation, and those messages will focus on evidence-based actions that affect breast health over a woman's lifetime.
More information on the hearing, including witness statements, can be found on the Committee Web site.For more information about this and other NCI congressional activity, visit the NCI Office of Government and Congressional Relations Web site.
Fifteen members of Congress and 16 congressional staffers gathered at the NIH Clinical Center on October 6 to learn about NIH ventures, successes, challenges, and future directions. Rep. Ron Klein (D-FL), who requested and organized the visit, opened with congratulatory remarks to Dr. Francis Collins on his appointment as NIH director. In subsequent presentations, Dr. Collins provided an overview of NIH, introducing issues ranging from NIH's contemporary role in medicine to evolving public health challenges. NIH Deputy Director Dr. Raynard Kington spoke about the impact of stimulus funding.
NCI Director Dr. John E. Niederhuber opened the presentation on cancer research at NIH and introduced Drs. Lee Helman, acting clinical director of NCI's Center for Cancer Research, and Steven Rosenberg, chief of NCI's Surgery Branch, who discussed new avenues in cancer research, focusing particularly on personalized medicine, targeted therapy, and immunotherapy. The congressional delegation also heard a presentation on the H1N1 virus by NIAID Director Dr. Anthony Fauci.
This was the largest congressional delegation to visit the NIH campus to date, and it provided NCI the opportunity to demonstrate how appropriated funds are being used.
The FDA has approved a second vaccine to prevent cervical cancer and cervical precancers, the vaccine's manufacturer, GlaxoSmithKline (GSK), announced last week. The approval is based on data from a large clinical trial showing that the vaccine, Cervarix, prevented precancerous lesions in 93 percent of those who received the full vaccine sequence of three injections over 6 months.
Cervarix is a bivalent vaccine, meaning it is specifically designed to protect against two human papillomavirus (HPV) types, HPV 16 and 18, which together are responsible for three-quarters of cervical cancers in North America. Clinical trial data also indicate that Cervarix offers more modest protection against precancerous lesions associated with HPV 31, GSK explained in a statement, as well as other tumor-causing (or oncogenic) HPV types. The company expects the vaccine to be available in the United States by the end of the year.
The FDA last week also approved the HPV vaccine Gardasil for the prevention of genital warts in boys. Gardasil is already approved and is being actively used in girls and young women for the prevention of cervical cancer. Gardasil is a quadrivalent vaccine that is designed to specifically protect against infections with four HPV types: 16, 18, 6, and 11. HPV types 6 and 11, which are not considered to be oncogenic, cause genital warts.
The agency's approval of Gardasil for boys aged 9 to 26 is based on data from a randomized clinical trial of more than 4,000 males aged 16 to 26, which demonstrated 90 percent protection against HPV 6- and 11-related genital warts. In a press statement announcing the approval, the FDA explained that for boys aged 9 to 15, studies have been conducted to measure their immune response to the vaccine, and "the results showed that the immune response was as good as that found in the 16- to 26- year-old age group, indicating that the vaccine should have similar effectiveness."
A number of studies have now linked infection with HPV 16 to certain types of head and neck cancers, in particular oropharyngeal cancer (the tonsils and base of the tongue), the rates of which have been increasing over the last decade. So there is a chance, some researchers believe, that widespread HPV vaccination of both males and females could have a broader cancer prevention effect.
"There is every reason to be optimistic that vaccination may help us to reduce the current trends of HPV-related tonsillar cancer," said Dr. Maura Gillison, a researcher at Ohio State University who was among the first to identify the link between HPV and head and neck cancer. Dr. Gillison said she is hopeful that a clinical trial can be launched in the near future to assess whether vaccination can prevent oral HPV 16 infections.
The CDC's Advisory Committee on Immunization Practices, which makes recommendations on the administration of FDA-approved vaccines to the medical community, will decide later this week whether to recommend that males be vaccinated against HPV to prevent genital warts.
There are now six agents available for the treatment of advanced kidney cancer, with the FDA's approval yesterday of pazopanib (Votrient). The approval is based on the results of an international phase III clinical trial that showed an improvement in progression-free survival (PFS)—survival in the absence of tumor growth—compared with patients who received a placebo. The trial found no improvement in overall survival with the drug.
Earlier this month, the agency's Oncologic Drugs Advisory Committee voted 10-0 in favor of approving pazopanib. This came despite concerns raised by the agency's own review staff about some of the side effects associated with pazopanib in the trial, including three deaths caused by severe liver injury. The side effects call into question "the benefit-to-risk ratio of pazopanib in the intended population of patients," particularly considering the availability of other effective therapies, FDA reviewers wrote in a briefing document.
In the trial, the results of which were presented earlier this year at the American Society of Clinical Oncology annual meeting, PFS more than doubled in patients given pazopanib compared with those who received placebo, 9.2 months versus 4.2 months. The PFS improvement was the strongest in patients who had not been previously treated, 11.1 months versus 2.8 months. The most common side effects associated with pazopanib in the trial were diarrhea and hypertension, as well as an elevation in the ALT liver enzyme, a common indicator of liver injury.
An industry-sponsored phase III trial comparing pazopanib against sunitinib (Sutent) is currently enrolling patients.
NIH employees and members of the scientific community mourned the loss of former NIH Deputy Director Dr. Ruth Kirschstein, who passed away on October 6 at the NIH Clinical Center in Bethesda, MD, after a long illness.
Dr. Kirschstein and her husband, NCI Deputy Director Dr. Alan Rabson, came to NIH in the 1950s to work as pathology researchers. While at NIH's biologics division, later part of the FDA, Dr. Kirschstein investigated a disease-causing batch of polio vaccine and helped choose the Sabin vaccine for world-wide use. In 1974, she became the first woman to direct an NIH institute, the National Institute of General Medical Sciences. During her 19 years there she promoted cell and molecular biology and pushed to support young investigators and diversity in science.
Dr. Kirschstein later served as NIH deputy director for 6 years when NIH Director Dr. Harold Varmus became director in 1993. She also served twice as acting NIH director, including 29 months before Dr. Elias Zerhouni became director in 2002 and made her a senior adviser. In 2002, Congress renamed NIH's graduate student fellowship program after Dr. Kirschstein.
"Ruth embodied the spirit of the NIH. She was an icon," wrote current NIH Director Dr. Francis Collins in a memo to staff. "She was loved and admired by so many at the NIH, across the medical research community, among hundreds of members of Congress, and around the world."
The NCI Cancer Bulletin was honored today with a 2009 NIH Merit Award for "outstanding contribution to cancer research communications" at the NCI Director's Awards Ceremony. Now in its 6th year of publication, the newsletter currently maintains a circulation to over 48,000 researchers, physicians, nurses, survivors and their family members, and others. Many of the Bulletin's editorial and technical staff were on hand to receive the award.
The Institute for Palliative Medicine at San Diego Hospice launched the International Palliative Care Resource Center, IPCRC.net, on October 1. The Web site provides online access to global information and education resources on palliative care, including comfort, supportive, hospice, end-of-life, and bereavement care. IPCRC.net is designed to be constantly updated with contributions from physicians, nurses, patients, families, caregivers, and other site users. Offering easy access over high- and low-speed communication links, IPCRC.net can be accessed in developed and resource-limited nations, promoting worldwide information exchange and collaboration. NCI's Office of International Affairs helped fund the site's development.


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FO: More 3×1 Garter Rib Socks
Pattern: A simple 64-st 3×1 garter rib sock with an 8-st decrease over 8 rows for calf shaping
Yarn: ShibuiKnits Sock in Bark
Needles: US 1 1/2
Since I've needed mindless socks to work on to get through some dense reading lately, I worked up a second pair of garter rib socks. I changed needles for the calf shaping for the last pair but I didn't have smaller needles on me when I reached the shaping on these so I used decreases.
I'm a bit ambivalent about which method is better. I think I prefer changing needle sizes but it's hard to talk myself into using anything smaller when I'm desperate to get to the heel.
The yarn was a little disappointing, given the promise of no pooling. It did not pool with 56 sts on size 1 needles but there was plenty of pooling at the ribbing (64 sts), the heel turn and the toe. While it looks like Koigu or CTH, as Christy warned me at the time I bought it, Shibui Sock is a bit thinner than it looks (along the lines of Lorna's Shepherd Sock). Nevertheless, that's one more pair of socks for the rotation and two more skeins of sock yarn gone!
I cast on a pair of Latvian Socks from Folk Socks by Nancy Bush with some J. Knits, thinking that this lace pattern would be easy to do while reading. As it turns out, it's not exactly mindless knitting so I might cast on some stockinette socks. I do love how the pattern works up, however. Isn't the picot lovely?
More on these next week!
Finally, I must thank Tiennie, Laura and Stella for tagging me for the Make My Day meme! I'm so flattered! I feel conflicted about choosing only a few people to tag because there are so many of you! Needless to say, my blog roll makes my day. I love seeing the beautiful garments you all create and I look forward to reading your posts about them so you're all tagged! Have a wonderful weekend!
31 comments so far
That seems to be a common tale with shibui, unfortunately. I'm currently coming up with non-sock ideas for my two skeins that I bought on impulse last fall…
That Latvian sock is looking gorgeous. I'm not normally a big pink fan but that shade is really quite lovely.
Oh the new socks are very lovely!
I think you got lucky with the ShiBui… I've seen some HIDEOUS pooling with that stuff. It looks fantastic in the hank, but boy… it knits up strangely!
Love those garter rib socks, it's such a great mindless pattern. Bummer about pooling, but I'm not so sure how Shubui can promise no pooling, since that's pretty much impossible to control. Oh well, they still look nice :)
And those pink socks are absolutely gorgeous! I think I have a thing for pink picot edges, even though I'm a boy ;)
Love those socks… both varieties. The brown ones are really quite lovely though and I really like the extra length… great job!
I've been having the *same* frustrating problem with pooling and Shibui. Bummer. Oh well… your socks look lovely, though.
And the new ones are a lovely shade of pink!
love your socks, especially the pink one. I always love the picot edge.
I love both those socks, but I can see why you'd be a bit narked by the shibui. The colours and shades of brown are lovely though, so at least it has pooled attractively.
The Latvian socks – gorgeous :) I wasn't all that enamoured when I saw them in the book, but in that pink they look great! You've inspired me to try them :D
that is definitely a lovely picot hem :) i like your decreases on that sock. i think that each method has its pros and cons. it's good that you got to try them both!
I don't think that the pooling is that bad–at least the tones are pretty similar! Love the picot edge–I want to picot everything lately, even though I hate sewing up the edge and haven't had much luck knitting the edge up.
Oh my, those pink socks are just stunning. I love the picot, the pattern, the yarn, everything.
I had total pooling with shibui too. Still the socks look great!
The socks look great, pooling or no! Now I'm curious about the shibui I have… The Latvian socks are stunning!
Love the picot edge on the pink socks. Am with you on changing to smaller needles….Am usually yearning to just get it done by then. Enjoy your socks!
Lovely socks! The picot edge looks so cute – I've never tried it, maybe I should?
Beautiful socks! Girl, I've tried to read and knit, and I think that's just a combo that my brain can't grasp. It would increase my knitting time tenfold if I could do both, though.
Gorgeous new socks! And the socks in progress are just too adorable. Can't wait to see them finished!
Grr! Shibiui! *Shakes fist*
If they ust wouldn't advertise it as a semisolid, it wouldn't irritate me so much, you know?
Love the Latvian socks.
I have heard good things about the Shibui, but good to know it's a bit thin…I love the decreases – I think it adds a nice little design element to the sock!
I knit a pair of plain stockinette socks on US1s with Shibui and it produced a really good fabric, some would call it thick, I think. But I tend to be a pretty tight knitter. I love the simple socks in Bark. I am also thinking a picot edge is worth a go too, it's terribly cute.
Wonderful finished socks! I love all Nancy Bush patterns, though they're usually not completely mindless. I find them the perfect mix of interesting yet easy enough to memorize that I don't need to haul the book around. I can't wait to see the finished object!
Oooh, I love those Latvian socks! I'm looking forward to seeing the finished product.
Both socks are lovely. I do agree that sometimes we need to knit a simple sock – for me, it's relaxing & gives me a break from reading patterns.
Oooh, I love that shade of brown. You are a sock knitting machine! I'm jealous. So much yarn, so little time…
Lovely socks, I especially love the colour and the picot edging of the Latvian ones!
Bad news about the Shibui, but I think your socks came out fantastic anyway. And you Latvian sock is looking wonderful!
Wonderful color for the Latvian socks! Those are really beautiful.
Too bad about the Shibui yarn. I have used it only once for gift socks. I hope they are wearing well.
Those orchid socks are just lovely. I like the lacy look!
[...] yarn is lovely to work with, but, as others have noted, it pools. In obvious ways. Always. A lot. You can see in the photo above where [...]
What's up it's me Fiona, I am also visiting this siteon a regular basis, this site is really pleasant and the users are really sharing pleasant thoughts.

subset: commoncrawl


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Colm Toibin
News about Colm Toibin, including commentary and archival articles published in The New York Times.
Chronology of Coverage
Nov. 24, 2013
Charles Isherwood reviews audiobook The Testament of Mary by Colm Toibin, read by Meryl Streep. MORE
Apr. 23, 2013
Ben Brantley reviews Colm Toibin play The Testament of Mary, directed by Deborah Warner and starring Fiona Shaw at the Walter Kerr Theater. MORE
Apr. 23, 2013
Ben Brantley reviews Colm Toibin play The Testament of Mary, directed by Deborah Warner and starring Fiona Shaw at the Walter Kerr Theater. MORE
Mar. 3, 2013
Maureen Dowd Op-Ed column relates discussion she had with author Colm Toibin about his book The Testament of Mary, which has been turned into play and will appear on Broadway, and about his views on Catholic Church. MORE
Nov. 11, 2012
Mary Gordon reviews book The Testament of Mary by Colm Toibin. MORE
Jun. 12, 2012
Dwight Garner reviews book New Ways to Kill Your Mother: Writers and Their Families by Colm Toibin. MORE
There are no additional abstracts to display.
Highlights From the Archives
One by One, Narratives Reflecting Life's Mosaic
The two most haunting stories in the volume — "Lélé" by Edwidge Danticat and "Donal Webster" by Colm Toibin — unfold, like elaborate origami flowers, into complex portraits with the emotional density and historical depth of field of a novel.January 8, 2008 booksReview
The Passion of Henry James
For a while, during the Gay Nineties of their respective centuries, the American writer Henry James and the Irish writer Colm Toibin -- whose remarkable new novel is about James -- were faced with the same embarrassing problem. It was a problem that touched both their personal and professional lives; to both writers, it seemed to be a problem that fiction alone could solve.June 20, 2004 artsReview
A Writer's Ambiguous Love Affair With New York
How he seemed to hate New York. A ''terrible town,'' Henry James called it in ''The American Scene.'' For Colm Toibin, author of ''The Master,'' the acclaimed biographical novel about James published last year, James's anger at the city reflects his sexual ambivalence, and perhaps offers a clue to the nature of ''the obscure hurt'' that James claimed he suffered in his youth, which kept him out of the Civil War, but may also have paralyzed him emotionally.November 25, 2005 artsNews
A Little Nearer Redemption
Set in Dublin and rural County Wexford, Colm Toibin's new novel summons three generations of an Irish family and lets them have at one another -- a clash of country versus city, conservative versus liberal, old ways versus new.September 10, 2000 artsReview
Memories of a Catholic Boyhood
Mr. Toibin, an Irish novelist who also works as a journalist, has written a memoir about his own relation to faith in the Irish context, augmented by a correspondent's reports of Holy Week visits over the years to the new Eastern Europe, Spain, the Balkans and Rome.September 17, 1995 artsReview
Big City Book Club Discusses 'Brooklyn'
The Big City Book Club talks about Colm Toibin's acclaimed 2009 novel, the story of a young Irishwoman who leaves a fragile mother behind to find herself in Dodgerland in the early 1950s.
May 19, 2014, Monday
MORE ON COLM TOIBIN AND: Toibin, Colm , Brooklyn (NYC) , Immigration and Emigration , Book Clubs
Big City Book Club
When the Big City Book Club convenes next, we'll be reading Colm Toibin's acclaimed 2009 novel, "Brooklyn." The online discussion will take place on Monday, May 19, starting at 6:30 p.m.
May 11, 2014, Sunday
MORE ON COLM TOIBIN AND: Book Clubs , Toibin, Colm Brooklyn (NYC) , Book Clubs , Toibin, Colm
PEN World Voices Festival Opens 'On the Edge'
The Syrian poet Adonis, Salman Rushdie, Judith Butler and others spoke at Cooper Union on Monday night.
April 29, 2014, Tuesday
MORE ON COLM TOIBIN AND: Adonis , Rushdie, Salman , Toibin, Colm , Butler, Judith , Chomsky, Noam , Cooper Union for the Advancement of Science and Art , Writing and Writers , Books and Literature
Colm Toibin Named Chairman of PEN World Voices Festival
Mr. Toibin will take over the duties from Salman Rushdie beginning in 2015.
April 17, 2014, Thursday
MORE ON COLM TOIBIN AND: Rushdie, Salman , Toibin, Colm , PEN American Center , Writing and Writers , Books and Literature
New York Public Library to Offer Lunch-Hour Readings
The library's series will include readings by P.J. O'Rourke, Joyce Carol Oates, Colm Toibin and Michael Cunningham.
March 3, 2014, Monday
MORE ON COLM TOIBIN AND: Oates, Joyce Carol , Toibin, Colm , Cunningham, Michael , New York Public Library , Books and Literature
To Hear Her Tell It
Meryl Streep gives voice to the Mother of Jesus in Colm Toibin's "The Testament of Mary."
November 24, 2013, Sunday
MORE ON COLM TOIBIN AND: Audiobooks , Toibin, Colm , Streep, Meryl , Books and Literature
Shortlist for Man Booker Prize for Fiction Announced
The winner of the prize — which is open to writers from Britain, Ireland or one of the Commonwealth nations — will be named at a ceremony in London on Oct. 15.
September 10, 2013, Tuesday
MORE ON COLM TOIBIN AND: Toibin, Colm , Lahiri, Jhumpa , Ozeki, Ruth L , Catton, Eleanor , Crace, Jim , Bulawayo, NoViolet , Great Britain , Man Booker Prize , Books and Literature
The Testament of Toibin: A Tony Nod, and a Closing Notice
The writer Colm Toibin reflects on his first experience as a Broadway playwright with "The Testament of Mary," which was nominated for a top award and announced its closing on the same day.
May 1, 2013, Wednesday
MORE ON COLM TOIBIN AND: Rudin, Scott , Warner, Deborah , Shaw, Fiona , Toibin, Colm , Writing and Writers , Tony Awards (Theater Awards) , Theater
With a Vulture but No Angels
A great actress and a fine, trenchant script are struggling to assert themselves at the Walter Kerr Theater, where Colm Toibin's "Testament of Mary" opened on Monday night.
April 23, 2013, Tuesday
MORE ON COLM TOIBIN AND: Shaw, Fiona , Theater , Toibin, Colm , Warner, Deborah
With a Vulture but No Angels
A great actress and a fine, trenchant script are struggling to assert themselves at the Walter Kerr Theater, where Colm Toibin's "Testament of Mary" opened on Monday night.
April 23, 2013, Tuesday
MORE ON COLM TOIBIN AND: Theater , Toibin, Colm , Shaw, Fiona , Warner, Deborah
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Receive My Alerts e-mails on topics covered on this page.More Alerts >>


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Trials Fusion 'Riders of the Rustlands' DLC is out now, has ten new tracks
The first of six planned Trials Fusion DLC packs is now available in the form of 'Riders of the Rustlands', which moves away from the shiny futuristic theme of the core game and out into the apocalyptic wastelands. That's according to creative director Antti Ilvessuo, who says the new theme will feature "groups of scraggly bikers who are not fit for the city" keeping themselves busy by "scavenging for motorcycle parts and pulling off amazing Trials tricks." So Trials does Mad Max, then?


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How to tame an ocelot
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Bangladeshi labours and relatives wait to enter a garment factory that was destroyed in a fire the day before in Savar, about 30 kilometres north of Dhaka on November 26, 2012. Garment workers staged mass protests to demand the end to "deathtrap" labour conditions after Bangladesh's worst-ever textile factory fire, as a new blaze sparked fresh panic and terror. Ahead of the first of a series of mass funerals for the 110 victims, survivors of Saturday night's blaze joined several thousand colleagues to block a highway and march in the manufacturing hub of Ashulia. AFP PHOTO/ STR (Photo credit should read STR/AFP/Getty Images)
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Members of the public interested in attending the George Zimmerman trial can enter a lottery for one of 24 seats in the courtroom, the Eighteenth Judicial Circuit said.The court will accept applications for a random drawing from 2 to 4 p.m. through Monday through Friday at the Supervisor of Elections office, 1500 E. Airport Blvd., Sanford.The first drawing will be held Friday for the first day of jury selection Monday.Anyone interested in a seat must submit their name and phone number at the elections office a day before the court date on which they want to attend. Those selected will be notified by phone and given instructions for picking up their visitor pass at the courthouse the next morning. Photo identification will be required.The Zimmerman trial will be held at the Seminole County Criminal Justice Center at 101 Bush Blvd., Sanford. For more information, go to the Eighteenth Judicial Circuit website at www.flcourts18.org.
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Baby Onesies & Shirts
Baby onesies, lap tees and rompers. From celebrities to silly little squirrels, we've got a onesie or shirt for every one-of-a-kind baby. Choose from several colors of 100% cotton American Apparel onesies and lap tees to create your perfect shirt! Check out our hilarious "That's What She Said" and other funny baby shirts by checking out our Funny Theme!
The Elizabeth Taylor Marigold Tender Wondersuit
Regular Price: $48.00
Special Price: $36.00


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DOOM 3: Resurrection of Evil Announced
This press release announces the development of Resurrection of Evil, the first expansion pack for DOOM 3. Co-developed by Nerve Software and id Software, the expansion comes with a new singleplayer campaign as well as new multiplayer maps with support for up to 8 players.
Following the events of DOOM 3 and featuring new locations, characters and weapons, including the return of the double-barreled shotgun, DOOM 3: Resurrection of Evil expands the terrifying action that fans and critics have been raving aboutAs you would expect from an id Software game, no release date is mentioned.
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San Francisco Opera
Buy tickets now to the exciting 92nd season! From new productions of Norma and La Bohème to Berlioz's thrilling The Trojans, an epic season awaits you!
See directions, parking options, hotels and restaurants, and other attractions near the Opera House.
Watch season announcements, interviews, and opera excerpts.
Watch San Francisco Opera productions in HD at your local movie theaters.
Listen to San Francisco Opera from the comfort of your own home.
Browse our performance archive from 1923 to present by title, conductor, cast and more.
Browse Archives
For Adults
Lectures, workshops, and more.
For Teachers
Classroom materials for teaching opera to your students.
For Students
School programs, conservatory, and student dress rehearsals.
For Families
Family workshops and more.
Making a gift online is fast, easy, and secure. Use our online form and add your contribution to your shopping cart.
David Gockley
General Director
Nicola Luisotti
Music Director
Download resources for the media, such as press releases and high resolution images.
Go to Press Room
San Francisco Opera
301 Van Ness Avenue
San Francisco, CA 94102
(415) 861-4008
All contact info
We are thrilled to be kicking off our official Backstage at San Francisco blog. This first blog post comes from Christopher Theofanidis—the composer of Heart of a Soldier, our world premiere commission based on the book of the same name by James B. Stewart. Heart of a Soldier will have its premiere on September 10, 2011—the eve of the tenth anniversary of the September 11 terrorist attacks. While the opera may be new to all of us, there are many who have been working on it for years now. Read on to gain insight into some of the musical challenges Christopher worked through early in his composing process.
San Francisco Opera


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Billowing black smoke blanketed the skyline around Charlottesville Monday afternoon as firefighters battled a blaze at the indoor practice facility at the University of Virginia.
The building in the 300 block of Massie Road off Emmett Street, which was still under construction, caught on fire around 12:30 p.m. It took every fire truck in the city to put the blaze out. Crews spent more than an hour putting the fire out, but continued to put out hotspots through the afternoon. About 20 percent of the roof burned. No one was injured.
UVA interim spokesperson McGregor McCance says the preliminary report revealed that a cutting torch used in construction ignited the insulation in the roof, which caused the rubber membrane of the roof to burn. That rubber membrane is what caused the massive amounts of black smoke. The insulation and membrane are part of the lightning protection systems for the building.
According to a UVA projects report, the contractor of the new practice facility is Barton Malow. The building, which will be named for former UVA Football Coach George Welsh, is part of a $13 million project. It was supposed to be complete by next August. A representative with the company referred all questions about Monday's incident to UVA.
As of 5:00 Monday afternoon, there is no estimate on damage cost.
Press ReleaseCharlottesville Fire Department
Today at approximately 12:35 pm, CFD responded to a reported fire at the outdoor UVA Football Practice Facility which is now under construction. Firefighters were confronted with a number of challenges. First, the fire was on the roof of a facility which posed a high access problem. Second, the construction site had very limited access to the facility which made access by our aerial ladder units extremely difficult. Both of these contributing factors along with wind, made application of water directly onto the fire extremely difficult. The fire, which mainly involved insulation and the rubber roof membrane, became so hot that the rubber liquefied and was spilling from the roof and on fire as it dripped to below. There was concern that the burning liquid rubber may flow over onto the adjacent UVA Field Hockey field. Nearby watering sprinklers were used to provide protection to the field. Finally, after placement pieces of wood shoring on very uneven and soft ground, CFD was able to set the outriggers and safely reposition the aerial ladder on the south side of the facility. This allowed us to use a solid bore nozzle which provided a pressurized and solid stream of water onto the facility roof directly and penetrate the decking and extinguish the seat of the fire.For several hours following, CFD worked with roofing contractors to perform a roof trench cut around the entire burnt area to ensure that the fire was out and that it could not spread.Fortunately the wind was blowing in a direction away from other buildings and toward the end of the facility's roof. This prevented the situation from getting much more serious. Our hope is that the largest portion of the roof that was undamaged can be salvaged.


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Clean property with friendly service. Free coffee in lobby. Located within 3 miles of US-69. ... read more...
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Free local calls, microwave and fridge available. 3.93 miles from Lake El Reno. ... read more...
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Located near area attractions such as the Riverwind Casino and the Lloyd Noble Center, this Motel 6 features interior ... read more...
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The Comfort Inn hotel is conveniently located with easy access to Interstate 69 and Interstate 62. Amenities include a ... read more...
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Located within walking distance of downtown Pawhuska, this beautiful Osage owned 3,520 sq ft house was built in 1925. ... read more...
Email: email@example.com


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As earlier promised by Aamir Khan, interesting posters of the upcoming film 'PK' keep coming out. Recently the third motion poster of 'PK' was released. But before the release there was a little mix-up by none other than 'Mr. Perfectionist' himself. On Twitter, Aamir posted in Bhojpuri, "Ei
Aamir & Juhi watch QSQT on 25th anniversary
Aamir Khan News
During the last two seasons the Aamir Khan hosted social issue based reality show 'Satyamev Jayate' has become one of the most talked about shows in the country. Now a third season will be hitting the air waves soon. The promos are also ready for release. The makers and the channel that airs the
Perfectionist Aamir Khan who is gearing up for his new season of 'Satyamev Jayate' said if he is offered a nomination to the Rajya Sabha, he would "think" about it. When asked about Rajya Sabha member, former cricketer Sachin Tendulkar and actress Rekha, Aamir said, "I won't comment on wha


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Rufus Giuseppe
Publication: theday.com
I've been remiss when it comes to updating my blog lately, but here's why: I've been really busy. Seriously. I started a new pet therapy job in September and I love it, though I do need a good nap when I get home.
It's not easy being adored.
Like many choice gigs, I got mine because of a referral from someone I know. I met Karen at a Labor Day cookout, and she just couldn't get enough of my deep, soulful eyes and gentle ways. She suggested I talk to the folks where she works, L+M Hospital in New London, about working as a therapy dog with the patients there.
So my people called her people, and after a couple of interviews and some blood tests, we were good to go. I can't thank her enough for suggesting this line of work. Apparently, I'm well suited to it.
And, of course, this is in addition to all the unofficial pet therapy work I do with family, friends, the woman's coworkers, and Grampy, one of my biggest fans.
In a typical work day at the hospital, I start at the Community Cancer Center where folks come weekly for chemotherapy and other treatments. I enjoy seeing the familiar faces every week, especially my pal R., who tells me he loves me and kisses me. I like to drape myself across his lap while he showers me with affection. I could stay there all morning, but there are many floors to go before I sleep.
I stop and say hi to Karen in her office and usually can't make it down a hallway without being stopped several times along the way by staff and families. Now I know how Bieber feels.
I take an elevator to the sixth floor and stop at the nurse's desk, where they know me by name. Then they suggest animal-loving patients I should visit or say just knock and see who needs a little furry love. We work our way down the floors of the hospital, room to room, nurses station to nurses station.
I get patted and rubbed and kissed and fed treats to my heart's delight; and I like to think I leave 'em wanting more. You even could say I work like a dog, and you'd be right.
Day Photo Staff | On Assignment
David Collins | Today, in The Day
Karen Florin | On The Docket
Day staff | Taste Buds (Dining)
Jenna Cho | Salt to Taste
Jill Blanchette | Healthy Cooking
Kristina Dorsey | Reel Life
Marisa Nadolny | Pop Blog
Rick Koster | Aging Rock Dude
Sunday Night TV | Mad Men Monday
Just Listen | The Day's music writers share their playlists
Steve Fagin | The Great Outdoors
Vickie Fulkerson | High School Sports
Richard Cooke | Yawkey Way
Ned Griffen | High School Football
Gavin Keefe | UConn Men's Hoops
Clint L. Bramlett | The Real Mister Fantasy


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Personalized Miniature Gold Chair Box Set of 12 Style 15008GD
Final sale. This item cannot be exchanged or returned.
This item is available online only. *
Shining moments, like your wedding, deserve the warm, elegant ambience that only gold can give! These classically designed, miniature chairs with a stunning, gold finish silently beckon your guests to their seats with a stylish place card and a sweet surprise.
Some assembly required.
A delicate, sheer fabric, often layered or worn over another fabric because of its transparent quality.
Used in various widths, lengths and fabrics, ribbons and bows are popular additions to bridal and special occasion fashions.
customers bought with this dress
*Color & Style representation may vary by monitor. Not responsible for typographical or pictorial errors. Product availability varies by store and online. Some in-store purchases require special order and markdown styles cannot be special ordered. Contact your local store for details.


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Vacuum Cleaner Belts
Did you know that proper maintenance can extend the life of your vacuum cleaner? One of the most basic maintenance items is belt maintenance. It is crucial part in your cleaning system that connects your motor to the brush roll. To check this, you need to remove the bottom plate and place a finger under the best to feel if it is taut. If you find that it's not, and it is showing signs of wear, it is time to replace it. While it is recommended you change vacuum belts once or twice a year, the frequency will actually depend on how often you use your vacuum cleaner. Frequent use makes it prone to cracks, sagging and other forms of damage. The motor is unable to turn a belt that does not have good traction on the brush roll. As a result, your vacuum does not clean up to its potential.
Looking for belts for your vacuum cleaning system? At GoVacuum, we recommend customers reduce the risk for vacuum repairs in the long-term by regularly checking the internal parts including belt, bag and hose regularly. While our advice represents general care and maintenance, we also stock a wide range of vacuum cleaner accessories including belts for a wide range of cleaners and ensure that your vacuum cleaner performs according to your needs!
Euro-Pro Shark Belts and Lightbulbs for Uprights Part XSLB72.Euro-Pro Shark upright replacement belts and lightbuls. Each package contains 4 light bulbs, and 4 drive belts. The belts are maked; WK-11/06. These belts and light bulbs will fit Euro-Pro Shark models; EP825, FM310, FM310K, FM718, UV180, UV204, UV208, Learn More
2 Generic Shark Roadster UV208 Upright Vacuum Cleaner Belts Designed to fit Shark Europro Part XSLB72. 2pk.2 Replacement Drive Belts for Shark UV208 Roadster Upright Vacuum Cleaners, Generic. Fits Shark Part Number XSLB72. Learn More
Results 1 - 2 of 2


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Men's adidas
mi Nastyquick Mid Custom Cleats
Product Information
Set your gridiron game apart with shoes that shed defenders and show your spirit. Choose from a huge range of colors and personalization options to create a unique look no one will forget.
- Go bold or stay subtle with a huge range of color options to set your look apart
- A broad selection of school colors lets you put your pride on display, all the way down to your shoes
- Customize your identity with personalized name and number options
- Imported
Welded SPRINTWEB provides lightweight support and breathability.
Single layer upper material to achieve a truly lightweight soccer cleat for an intense ball feeling.


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commandlinefu.com is the place to record those command-line gems that you return to again and again.
Delete that bloated snippets file you've been using and share your personal repository with the world. That way others can gain from your CLI wisdom and you from theirs too. All commands can be commented on, discussed and voted up or down.
If you have a new feature suggestion or find a bug, please get in touch via http://commandlinefu.uservoice.com/
You can sign-in using OpenID credentials, or register a traditional username and password.
First-time OpenID users will be automatically assigned a username which can be changed after signing in.
Every new command is wrapped in a tweet and posted to Twitter. Following the stream is a great way of staying abreast of the latest commands. For the more discerning, there are Twitter accounts for commands that get a minimum of 3 and 10 votes - that way only the great commands get tweeted.
» http://twitter.com/commandlinefu
» http://twitter.com/commandlinefu3
» http://twitter.com/commandlinefu10
Use your favourite RSS aggregator to stay in touch with the latest commands. There are feeds mirroring the 3 Twitter streams as well as for virtually every other subset (users, tags, functions,…):
Subscribe to the feed for:
Site by David Winterbottom (user root).
Remove annoying improperly packaged files that untar into the incorrect directory.
Example, When you untar and it extracts hundreds of files into the current directory.... bleh.
this bzips a folder and transfers it over the network to "host" at 777k bit/s.
cstream can do a lot more, have a look http://www.cons.org/cracauer/cstream.html#usage
for example:
echo w00t, i'm 733+ | cstream -b1 -t2
hehe :)
You can flexibly change file pattern(*.tar.gz) and uncompress command to other job!
Example, remove all files :
for i in *.tar.gz; do rm $i; done
(Just for example, because if you really want to remove file, simply use wildcard like this rm *.tar.gz)
Very simple and useful, you need to change the word "directory" for your directory
Leave it to a proprietary software vendor to turn a cheap and easy parlor trick into a selling point. "Hey guys, why don't we turn our _collection of multiple files_ into a *collection of multiple files*!!" Extract the ^above with this:
cat pics.tar.gz.??? | tar xzv
^extract on any Unix - no need to install junkware!
(If you must make proprietary software, at least make it do something *new*)
if [ -e windows ]; then use 7-Zip
create an archive of files with access time older than 5 days, and remove original files.
This will update the tarball, adding files that have changed since the last update.
This assumes that the tarball is in the same directory as the files being archived.
N.B. This command can't be used on compressed tarballs.
N.B. This will add the updated files to the tarball, so that the tarball will have two versions of each file. This will make the tarball larger, but doesn't have any other significant effect.
Where foodir is the directory you want to zip up.
PRIVATEKEY - Of course the full path to the private key \n
HOST - The host where to get the backup \n
SOURCE - The directory you wish to backup \n
DESTINATION - The destination for the backup on your local machine
gpg's compression is as suitable as gzip's however your backups can now be encrypted.
to extract use:
gpg < folder.tpg | tar -xf -
An easy one but nice to keep in mind.
Clone a partion with tar.
creates a tar.gz with a name like:
of a given directory.
this file was made 10 April 2009 at 5:30:53pm
see date's man page to customize the timestamp format
This command will copy files and directories from a remote machine to the local one.
Ensure you are in the local directory you want to populate with the remote files before running the command.
To copy a directory and it's contents, you could:
ssh user@host "(cd /path/to/a/directory ; tar cvf - ./targetdir)" | tar xvf -
This is especially useful on *nix'es that don't have 'scp' installed by default.
This is useful for sending data between 2 computers that you have shell access to. Uses tar compression during transfer. Files are compressed & uncompressed automatically. Note the trailing dash on the listening side that makes netcat listen to stdin for data.
on the listening side:
sudo nc -lp 2022 | sudo tar -xvf -
explanation: open netcat to -l listen on -p port 2022, take the data stream and pipe to tar -x extract, -v verbose, -f using file filename - means "stdin"
on the sending side:
tar -cvzf - ./*| nc -w 3 name_of_listening_host 2022
explanation: compress all files in current dir using tar -c create, -v verbose, -f using file, - filename - here means "stdout" because we're tar -c instead of tar -x, -w3 wait 3 seconds on stream termination and then end the connection to the listening host name_of_listening_host, on port 2022
I recently found myself with a filesystem I couldn't write to and a bunch of files I had to get the hell out of dodge, preferably not one at a time. This command makes it possible to pack a bunch of files into a single archive and write it to a remote server.
Create backup (.tar.gz) for all first-level directory from current dir.
create tar.bz2 package from files "-type f" modificated today "-mtime -1" in ~/project
Add z to the flags to enable compression.


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DESPERATE HOUSEWIVES - "In Buddy's Eyes" - Bree and Orson at the Founders Day Ball, on Desperate Housewives," SUNDAY, APRIL 20 (9:00-10:02 p.m., ET) on the ABC Television Network. (ABC/RON TOM) MARCIA CROSS, KYLE MACLACHLAN
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As the mercury seems permanently stuck in the negative degree department, some farmers may be concerned about the effect on their alfalfa winter survival. While the alfalfa plant will die if exposed to cold enough temperatures, Dr. Dan Undersander, Forage Agronomist says there are several reasons the crop generally survives.
- Alfalfa can survive temps down to 10 to 15°F
- That is the temperature of the crown and not the topgrowth
- As little as 4 inches of loose snow will insulate up to 16°F of air temperature.
- The crown is also insulated by soil, so the crucial temperature is at 2-4 inches below the soil surface.
The soil temperature of bare ground at 4 inches on January 8th is generally in the single digits above 0°F for the Midwest at this time of year. The snow cover has kept the soil temperature above the air temperature for the past few days. If you go down to the 2-4 inch level, the temperature is ranging from 28-30°F; well above critical levels. Doesn't mean I'm not excited about the 30's this weekend!
Portions of this post taken from the UW Extension newsletter, with permission.


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Employees have the option to copy and paste the following text into their Out of Office Assistant in Outlook for upcoming holidays.
I will be out of the office on __________ in observance of the _____________ holiday. I apologize for any inconvenience and will respond to your message when our offices reopen _____________.
Optional Addition:
If you have an urgent matter, please contact ____________ at______________.
2014 Holiday Closure Posters
All 2014 posters are in English and Spanish. To print the 11" x 17" Holiday posters for your agency, please click the links below: