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Researchers Uncover New Mechanism of Resistance to Melanoma Drug
Researchers have discovered a new way that melanoma cells may become resistant to treatment with vemurafenib (Zelboraf), a targeted therapy that has produced dramatic, if transitory, results for some patients with advanced disease. In some cases, the drug has caused tumors to shrink and even disappear, but the treatment invariably stops working. Read more > >
Survey of Oncologists Suggests Lack of Progress in Cancer Pain ManagementResults show room for improvement in education, attitudes, and beliefs on cancer pain
Trial Confirms Efficacy of HPV Vaccine, Shows Cross-ProtectionCervarix protects against infections by HPV-16, -18, and four other strains
Genetic Study Yields Clues to Neuroendocrine Prostate CancerResearchers identify potential therapy for this aggressive disease
A Conversation With Dr. Mason Bond on Improving the Treatment of Patients with Ewing Sarcoma
Dr. Mason Bond of the University of British Columbia in Vancouver discusses the addition of a novel drug combination to standard therapy in patients younger than 50.
Study Raises Concerns about Using Cancer Cell Lines to Test Drug ResistanceAuthors say new models are needed for studying resistance to cancer drugs
Unexpected Complications: Treating Cancer during PregnancyLimited research suggests most children prenatally exposed to chemotherapy are healthy
Interpreting Risk: Direct-to-Consumer Genetic TestingHow accurately do lay consumers interpret genetic test results?
Featured Clinical Trial: Novel Combination Chemotherapy for Localized Ewing SarcomaWill additional chemotherapy improve survival of children and young adults with Ewing sarcoma?
FDA Update
- FDA Commissioner Revokes Approval of Bevacizumab for Metastatic Breast Cancer
- New Form of Asparaginase Approved to Treat Acute Lymphoblastic Leukemia
- Ruxolitinib Approved to Treat the Bone Marrow Disease Myelofibrosis
- National Cancer Advisory Board Will Meet Next Week
- Proposals Sought for Use of PLCO Data and Biospecimens
- Cyber-Seminar Will Address Systems Thinking to Solve Public Health Problems
- NCI Guide on Communicating Data to Lay Audiences Now Available
- Major League Baseball Limits Players' Use of Tobacco
- President Obama Encourages Smokers to Quit
Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.
The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.
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Featured Article
Researchers Uncover New Mechanism of Resistance to Melanoma Drug
Researchers have discovered a new way that melanoma cells may become resistant to treatment with vemurafenib (Zelboraf), a targeted therapy that has produced dramatic, if transitory, results for some patients with advanced disease. In some cases, the drug has caused tumors to shrink and even disappear, but the treatment invariably stops working.
By exposing melanoma cells in the laboratory to the drug for extended periods, Dr. David Solit of Memorial Sloan-Kettering Cancer Center and his colleagues have learned that some resistant cells produce a shortened version of the mutant BRAF protein that vemurafenib targets. The shortened protein—which is missing its middle section—is active even in the drug's presence, the researchers reported online November 23 in Nature.
"This is a common mechanism whereby the melanoma tumors overcome the effects of the drug," said Dr. Solit, noting that 6 of 19 patients with resistant tumors had a form of the protein that had been shortened in this way. "We hope that this discovery will lead to more effective treatments."
Vemurafenib blocks growth-promoting signals activated by a mutation in the BRAF gene known as V600E. In August, the Food and Drug Administration (FDA) approved the treatment for patients with unresectable or metastatic melanoma whose tumors have this mutation, which is found in about 60 percent of melanomas.
In their study, Dr. Solit and his colleagues found that the shortened forms of the BRAF V600E protein represent splicing variants—that is, they arose through a change in the processing of the RNA that was transcribed from the gene.
"This is an important study because it identifies the first resistance mechanism to BRAF inhibitors that involves a structural change in BRAF itself," said Dr. Ravi Amaravadi of the Perelman School of Medicine at the University of Pennsylvania, who treats patients with melanoma and was not involved in the study.
It will be important to determine how widespread this resistance mechanism is compared to other proposed resistance mechanisms, Dr. Amaravadi added.
So far, the investigators have found this form of the BRAF V600E protein only in vemurafenib-resistant tumors. They believe that the splicing alteration is specific to BRAF and does not affect splicing in general, suggesting that it could have arisen from a mutation or an epigenetic change.
"Conceptually, we have found a novel form of resistance for any drug," said Dr. Solit. "As happens with other targeted therapies, the drug stops working—but the mechanism is different."
—Dr. Ravi Amaravadi
With drugs such as imatinib (Gleevec) or erlotinib (Tarceva), for example, resistance often occurs when tumors acquire new genetic mutations that prevent a drug from binding to its molecular target. As these resistance mechanisms have been discovered, the knowledge has been used to develop second-generation drugs, such as dasatinib (Sprycel), which can bind to mutant forms of the BCR-ABL kinase to which imatinib cannot bind.
With vemurafenib, the shortened BRAF protein forms complexes within cells that promote growth signals in the presence of the drug. To overcome the resistance, researchers could try to develop more potent drugs and find ways to disrupt the complexes, the authors noted.
Another strategy involves combining drugs that target different proteins, an approach that is already being tried. In June, for example, researchers reported positive preliminary results from an early-phase study testing a BRAF inhibitor in combination with a drug that inhibits a second kinase, MEK, which is part of the same signaling pathway as BRAF. Consequently, the use of a MEK inhibitor could prevent or delay development of a drug-resistant form of BRAF.
"Based on the results of our study, we hypothesize that the combination of the BRAF inhibitor and the MEK inhibitor will be more effective and less toxic than either drug alone," said Dr. Solit. "But we need a randomized study to test this idea."
Studies are also needed to fully characterize the molecular basis for the altered RNA processing that leads to resistance to vemurafenib, as well as to identify additional mechanisms that lead to vemurafenib resistance. If drugs were developed to address the altered RNA processing, these agents could be administered with vemurafenib, Dr. Solit noted.
Dr. Amaravadi agreed. The development of new drugs directed against the molecular changes caused by the BRAF splice variant could "significantly prolong the clinical benefit of BRAF inhibitors," he predicted.
"This study identifies RNA processing as a potentially common resistance mechanism," said co-author Dr. Tom Misteli of NCI's Center for Cancer Research. The findings add to research suggesting the importance of alternative splicing as a mechanism of disease, he added.
"The number of splicing diseases is growing, yet our efforts to target RNA processing as a therapeutic strategy are minimal at the moment," Dr. Misteli said. "RNA therapy offers a largely unexplored, powerful therapeutic strategy."
Cancer Research Highlights
Survey of Oncologists Suggests Lack of Progress in Cancer Pain Management
Results of a national survey show that U.S. medical oncologists receive inadequate training in cancer pain management and perceive numerous barriers to managing pain optimally in their patients. The results of the survey, conducted by Dr. Brenda Breuer and her colleagues at Beth Israel Medical Center in New York, were published online November 15 in the Journal of Clinical Oncology (JCO).
The survey, which was modeled in part after a 1990 survey conducted by the Eastern Cooperative Oncology Group (ECOG), "demonstrated disturbingly little progress" in attitudes and practices related to pain management among medical oncologists over the last 20 years, according to an accompanying editorial. Yet during this time, guidelines for managing cancer pain have been developed and disseminated, continuing medical education on the subject has become common, and access to pain specialists has increased, the study authors noted.
Dr. Breuer and her colleagues mailed the anonymous survey to a randomly selected, geographically representative sample of 2,000 medical oncologists, and 610 usable surveys (32 percent) were returned.
In the survey, oncologists gave their medical specialty good marks (a median rating of 7 on a scale of 0 to 10) for relieving cancer pain but rated their peers as more conservative than themselves in prescribing opioid drugs to manage pain. And although most respondents agreed with the basic principles of pain management, their responses to two challenging clinical scenarios presented in the survey suggest that a majority of oncologists are deficient in knowledge about opioids, the study authors reported.
As in the 1990 survey, "oncologists continue to perceive that the most significant barriers to adequate pain management are poor pain assessment, patient reluctance to report pain, and patient reluctance to take analgesics," Dr. Breuer and her co-authors wrote. Furthermore, "poor ratings of pain management training [during medical school and residency] have barely changed" in the two decades since the 1990 ECOG survey.
"There is a worldwide outcry for adequate cancer pain management, yet the skills of many oncologists remain inadequate in this domain," commented the authors of the editorial, Dr. Jamie H. Von Roenn of Northwestern University, who was also the lead author of the ECOG survey, and Dr. Charles von Gunten of the Institute of Palliative Medicine at San Diego Hospice. "If we are to provide patients the care they deserve, we must not just integrate training in pain management into every fellowship program, we must expect oncologists to practice what they learn."
(For more information, listen to this JCO podcast, in which Dr. Eduardo Bruera, chair of the Department of Palliative Care and Rehabilitation Medicine at the University of Texas M. D. Anderson Cancer Center, discusses the survey's findings and offers recommendations on addressing some of the problems identified by the survey.)
Trial Confirms Efficacy of HPV Vaccine, Shows Cross-Protection
End-of-trial results from a trial testing Cervarix, a vaccine against human papillomavirus (HPV) types 16 and 18, showed that the vaccine continued to provide substantial protection against cervical precancers 4 years after vaccination. Cervarix provided almost complete protection in young women who had no evidence of exposure to HPV at the time of vaccination. The vaccine provided less protection for the total vaccinated cohort and was less effective with increasing age at vaccination. These findings reflect the vaccine's lack of effectiveness against infections acquired before vaccination.
The vaccine also partially protected women against four types of HPV that are not targeted by the vaccine. (Although HPV-16 and -18 cause about 70 percent of cervical cancers worldwide, as many as 15 HPV types can cause cancer.) These results from the PATRICIA trial (Papilloma Trial against Cancer in Young Adults) were published online November 9 in Lancet Oncology in two separate papers, available here and here.
The PATRICIA trial enrolled 18,644 young women between the ages of 15 and 25 from 14 countries. The participants were randomly assigned to receive either three doses of Cervarix or three doses of a hepatitis A vaccine as a control. Results from the interim analysis, published in July 2009, showed that the vaccine greatly reduced the risk of grade 2 cervical intraepithelial neoplasias and higher (CIN2+).
The new analysis shows that, 4 years after vaccination, Cervarix provided complete protection against grade 3 cervical intraepithelial neoplasias or higher (CIN3+) associated with HPV-16 and -18 among women who had no evidence of exposure to HPV. The vaccine provided strong protection against CIN3+ caused by other HPV types in this same group of women. Among the total cohort of women who received at least one dose of Cervarix, some of whom may have had prior exposure to HPV, the vaccine provided some protection. (See the table below.)
Cervarix Vaccine Efficacy among Women Who Received at Least One Dose of Cervarix
|Women with no evidence of HPV exposure at baseline
|Women who may have had prior exposure to HPV
|Against CIN3+ associated with HPV-16 and -18
|100 percent
|45.7 percent
|Against all CIN3+, regardless of HPV type
|93.2 percent
|45.6 percent
|Against all adenocarcinoma in situ
|100 percent
|76.9 percent
The vaccine provided cross-protection against HPV-33, HPV-31, HPV-45, and HPV-51, all cancer-causing types of the virus. The researchers speculate that the observed cross-protection may be due either to the vaccine adjuvant (a substance that stimulates the immune system) or to similarities among proteins found on the surfaces of different HPV types.
In an accompanying editorial, Drs. Mark Schiffman and Sholom Wacholder of NCI's Division of Cancer Epidemiology and Genetics, who were involved with the NCI Costa Rica HPV vaccine trial, noted the importance of the PATRICIA trial results. They also stated that "the practical aspects of vaccine uptake are now the most important issue in HPV vaccine research from a public health perspective." To increase vaccine uptake in the developing world, where 90 percent of cervical cancer cases occur, next-generation HPV vaccines will need to be less expensive, provide protection in a single dose, and/or be stable without refrigeration, they explained.
Further reading: "Second Cervical Cancer Vaccine Protects against Additional HPV Types" and "Use and Acceptance of HPV Vaccine Still a Work in Progress"
Genetic Study Yields Clues to Neuroendocrine Prostate Cancer
Researchers have identified a signaling pathway that may play an important role in neuroendocrine prostate cancer (NEPC), a very rare but aggressive form of the disease. Based on this discovery, the researchers tested a drug that inhibits the pathway and observed anticancer effects in two model systems. The findings appear in the November issue of Cancer Discovery.
Most cases of NEPC, which accounts for a small percentage of prostate cancers, arise following hormone therapy for prostate adenocarcinoma. To better understand the origins of the disease, Dr. Himisha Beltran of Weill Cornell Cancer Center and her colleagues profiled the gene-expression patterns of 7 NEPC tumors, 30 prostate adenocarcinomas, and 5 benign prostate tissue samples.
When they compared NEPCs and prostate adenocarcinomas, the authors found "dramatic differences" in the expression of certain genes, as well as differences in the number of copies of some genes. Two genes emerged as particularly interesting suspects in the disease—the AURKA gene, which encodes a protein called aurora kinase A and has been implicated in other cancers, and MYCN, another cancer-associated gene.
The researchers confirmed the association of AURKA expression with NEPC by analyzing benign prostate tissue and prostate tumors from a separate, larger cohort of patients. They concluded that the protein products of AURKA and MYCN may work together to induce characteristics of NEPC in prostate cancer cells.
Aurora kinase inhibitors are being evaluated in clinical trials, and the researchers tested one of these drugs against prostate adenocarcinoma and NEPC cells grown in laboratory culture as well as in mice bearing xenograft tumors derived from these cells. In the laboratory experiments, NEPC but not prostate adenocarcinoma cells were sensitive to the inhibitors; in the mice, the inhibitors caused tumor shrinkage of NEPC but not prostate adenocarcinoma xenograft tumors. In addition, drug treatment suppressed the expression of markers of neuroendocrine cells.
"The next step is to initiate a clinical trial," said Dr. Beltran, who noted that there are no standard therapies for NEPC and that most patients die within a year of diagnosis. A small percentage of patients with prostate adenocarcinomas also show increased expression of the AURKA and MYCN genes, and these patients could be candidates for aurora kinase inhibitors as well, Dr. Beltran explained.
Previous studies have indicated that NEPCs and prostate adenocarcinomas may share the same cell of origin. It is known, for instance, that a genetic rearrangement often found in prostate adenocarcinomas is present at roughly the same rate in NEPCs. The precise number of cases of NEPC is unknown, however, in part because patients with advancing prostate cancer do not always have a biopsy, which is how NEPC is diagnosed.
The study authors cited evidence that long-term androgen deprivation therapy may promote the transformation of prostate cancer cells into NEPC. This suggests that "with the recent introduction of new highly potent androgen deprivation therapies into the clinical arena, the incidence of NEPC may escalate," they noted.
"The current study is a stepping stone toward identifying neuroendocrine prostate cancer that is usually missed using regular screening modalities," commented Dr. Sudhir Srivastava, who heads NCI's Early Detection Research Network. "Understanding the biology of neuroendocrine prostate cancer will lead to better clinical management of this rare form of the disease."
A Conversation With
A Conversation with Dr. Mason Bond on Improving the Treatment of Patients with Ewing Sarcoma
Dr. Mason Bond of the Department of Pediatrics at the University of British Columbia in Vancouver serves as the principal investigator of a Children's Oncology Group (COG) clinical trial. The phase III trial, which is still recruiting patients, is testing the addition of a novel drug combination to standard therapy in patients younger than 50 years who have localized Ewing sarcoma.
How is your treatment trial different from earlier trials?
The basic structure of the trial is similar to that of past trials, but we are testing the addition of vincristine, cyclophosphamide, and topotecan to the standard drug combinations for first-line treatment. In phase II studies, patients with metastatic and relapsed disease showed better responses to this combination than to any other combination recently tested. Since the topoisomerase I inhibitors, like topotecan, are not part of the current standard combinations, we hope that adding a combination that works in a slightly different way can improve progression-free survival. Patients can also receive this experimental combination as an outpatient therapy, which makes it easier for patients to get treated.
We have also modified the definitions of surgical margins, for example, to clarify how far a lesion can be from a margin, and we've incorporated up-to-date radiation oncology techniques. We are looking at other prognostic factors and studying whether PET imaging might help predict either tumor response or patient outcome.
Is this trial only for pediatric patients?
No, this is the first COG trial to enroll young adults through the Clinical Trials Support Unit. Nearly 20 percent of the people in the trial are 18 years or older, but all of them have been enrolled through pediatric centers.
I would like more young adults to participate in this trial. One goal of the pediatric oncology cooperative groups is to encourage older adolescents and young adults to get into clinical trials in any way we can. We have seen with pediatrics how participation in clinical trials leads to improvements in outcomes; young adult participation in clinical trials is the best and fastest way to make improvements for this age group.
How have treatments for Ewing sarcoma been changing?
The treatment changes, in general, have been a little slow. We were quite excited when a trial published in 2009 showed that treatment given every 2 weeks yielded better results than treatment given every 3 weeks, because other ways of intensifying treatment that we tested had not produced better results. The last time there was a big step forward like this was in 2003, with the addition of ifosfamide and etoposide.
Since then, we have been looking for new agents to add to first-line treatment that would improve progression-free survival. There has been a lot of effort looking for new biologic agents, but we have not been able to identify one to test in Ewing sarcoma just yet. The best chemotherapy combination for which there is quite a lot of information in phase II trials, and in patients with relapsed, refractory, and metastatic disease, was cyclophosphamide and topotecan. That is why we decided to test that combination in our study.
Researchers are still hoping to identify more specific agents for Ewing sarcoma, such as new agents that target signaling pathways. It just takes a long time for agents to be tested in pediatric populations and for agents with an adult indication to be identified for use in pediatric patients. I think the identification of new and effective agents to test in [early-phase] trials is the key to moving treatment forward.
Are there certain patients who still have a poorer prognosis?
People who have metastatic disease at the time of diagnosis have poor outcomes. Trying to find an effective treatment for them, and even trials for them, has been challenging, but they are also the people who are more likely to be part of clinical trials testing new agents at an earlier stage.
In general, older adolescents and young adults also have a poorer prognosis than younger people, and one of the challenges has been enrolling young adults in trials. It is important to capture older adolescents and young adults in these kinds of trials, because enrolling them in trials could improve progression-free survival in that age group in a way that has not really happened in recent years.
Special Report
Study Raises Concerns about Using Cancer Cell Lines to Test Drug Resistance
Cancer cells grown in culture and stored for use in laboratory studies—known as cell lines—are the workhorses of basic cancer research. A new study from NIH and NCI researchers suggests, however, that established cancer cell lines may have important limitations when used to investigate resistance to chemotherapy drugs. The findings indicate the need for better in vitro models of cancer that more accurately represent how tumors behave in the body, they said.
In the study, published November 15 in the Proceedings of the National Academy of Sciences, Dr. Michael Gottesman, NIH deputy director for Intramural Research, and his colleagues showed that, in various cancer types, the expression of a specific set of genes associated with drug resistance was very different in cell lines than it was in tumor samples representing the same cancer types.
The study included cell lines from NCI's Human Tumor Cell Line Screen, commonly called the NCI-60 panel, a collection of 60 cancer cell lines derived from 9 common tumor types. Cancer cell lines from the NCI-60 panel and other sources are used for many types of studies, such as testing experimental drugs for anticancer effects or investigating how specific genes influence tumor development.
The researchers focused on 380 genes associated with drug resistance. They compared the activity of these genes in cancer cell lines representing six tumor types with the activity of the same genes in clinical samples of the same six tumor types. There was "no correlation between clinical samples and established cancer cell lines," the researchers found.
In addition, when the researchers profiled the activity of these genes associated with drug resistance across all the cell lines of the NCI-60 panel, they made "the striking observation that all of the cell lines…bear more resemblance to each other, regardless of the tissue of origin, than to the clinical samples that they are supposed to model," the researchers wrote.
"We thought we might see some similarities among the cancer cell lines," said the study's lead author, Dr. Jean-Pierre Gillet of the Laboratory of Cell Biology in NCI's Center for Cancer Research. But the extent of the differences in the activity of these drug-resistance genes between the cell lines and tumor samples was "impressive" and "definitely surprising," Dr. Gillet added.
In cell lines, the researchers found changes in gene expression that may be the result of "selection pressure and culture conditions" that the cells acquired during extended growth in culture so they can thrive in an artificial environment. These same genes are also involved in drug resistance. "In other words, the cancer cell lines are highly selected during their establishment for expression of genes associated with [multidrug resistance]," the researchers wrote.
The research team initially focused on ovarian cancer. They compared the gene expression profile of the drug-resistance genes for 15 ovarian cancer cell lines—including five from the NCI-60 panel and 10 other commonly used lines—with the profiles of 80 tumor samples obtained from patients before treatment began. Not only were the cell line and tumor sample profiles "strikingly different," the researchers reported, but the ovarian cancer cell line profiles were similar.
The research team also found that the drug-resistance profiles of the other cell lines in the NCI-60 panel were very similar to those of the ovarian cancer cell lines. Moreover, the profiles of the cell lines for five other cancer types were also different from those of the tumor types they are meant to model.
These findings should be interpreted with caution, noted Dr. Cyril Benes, director of the Center for Molecular Therapeutics at Massachusetts General Hospital. "The functional significance" of the similar gene expression profiles, or clustering, "is unclear," Dr. Benes wrote in an e-mail. "The transcriptional profile is different, but does that translate into an important biological outcome in terms of drug response?"
No one believes that cancer cell lines are perfect, said Dr. Edward Sausville, associate director for clinical research at the University of Maryland Greenebaum Cancer Center. Other studies have hinted at these types of issues with cell lines, and it's not surprising that cells grown in a plastic dish and stored for long periods evolve to handle the stress of the conditions, he continued.
"Whether it's a set of cell lines or other models, they're not one size fits all," Dr. Sausville said. "They are good for some things and not good for others."
Studies like this one, that molecularly characterize the NCI-60 panel and other commonly used cell lines, are welcome and needed, said Dr. Susan Holbeck of NCI's Developmental Therapeutics Program, the program through which the NCI-60 panel is managed. But even with their shortcomings, she stressed, cancer cell lines are still highly valuable tools.
For example, some of the early suggestions that the targeted therapies vemurafenib (Zelboraf) and crizotinib (Xalkori)—both of which were recently approved by the Food and Drug Administration—may be highly effective in patients with mutations in the BRAF and ALK genes, respectively, came from studies of cell lines with those mutations, she noted.
"Each cell line can be seen as a bag full of molecular targets," Dr. Holbeck continued. "They're excellent tools for generating hypotheses that can then be tested in other models," such as genetically engineered mouse models that more closely mimic how tumors develop and progress in humans.
Studies like this "are certainly valuable," Dr. Benes said, in part because they demonstrate that the entire undertaking of modeling human cancer "is a learning process…. Understanding what predicts translation from results in models to patients is also an important part of it, as well as making different, possibly better models."
Unexpected Complications: Treating Cancer during Pregnancy
Trina Pockett of Fortuna, CA, was 23, the mother of a 2-year-old, and pregnant with her second child when she noticed a lump under her collar bone. The lump wasn't painful, so for a while she ignored it. When the lump didn't go away, she showed it to her doctor, who ordered an emergency biopsy.
The diagnosis was devastating. She had Hodgkin lymphoma, an immune-system cancer that is one of the most commonly diagnosed cancers in young adults. Because the cancer had already spread to her neck, chest, and stomach, her doctors advised starting chemotherapy immediately.
Pockett suddenly found herself a member of an extremely small club: the estimated 3,500 women in the United States who each year receive a diagnosis of cancer during pregnancy. For each woman and her doctors, the diagnosis creates an exquisite dilemma: delaying treatment may risk her life, but proceeding with therapy may risk harming her unborn child.
No Rigorous Studies
Cancer—most commonly breast cancer, cervical cancer, lymphoma, and melanoma—occurs in about one pregnancy in a thousand. Because cancer during pregnancy is a rare event, most doctors have encountered few if any cases, and the medical literature offers few rigorous studies to provide guidance.
"It's extraordinarily difficult to do meaningful research in patients with cancer who are pregnant," said Dr. Clifford Hudis, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center, who estimates that in more than two decades of practice he has seen one pregnant patient with breast cancer "every year or 2."
In addition to the rarity of cancer in pregnancy, concerns about the risks of chemotherapy to the fetus pose a significant barrier to conducting clinical research in pregnant women with cancer, explained Dr. Ted Trimble, former head of gynecological cancer therapeutics with NCI's Cancer Therapy Evaluation Program.
"Most trial sponsors are not comfortable encouraging pregnant women to participate in a trial of any agent whose mechanism of action might cause birth defects or fetal death," Dr. Trimble said.
As more women delay childbearing until their 30s or 40s—ages at which cancer risk, while still low, begins to creep up—some researchers predict that cancer diagnoses during pregnancy will increase. Swedish researchers have estimated that the incidence of breast cancer diagnosed during pregnancy or within 2 years of delivery more than doubled between 1963 and 2002.
Toxic to DNA
Chemotherapy agents are known to cause malformations in laboratory animals. The risk of birth defects is highest during the first trimester of pregnancy when organs are forming.
"Chemotherapy agents are meant to interfere with rapidly dividing cells; they are supposed to be toxic to DNA," explained Dr. John J. Mulvihill, a specialist in cancer genetics at the University of Oklahoma Health Sciences Center.
—Dr. Elyce Cardonick
Since 1984, Dr. Mulvihill has maintained the Registry of Pregnancies Exposed to Chemotherapeutic Agents, which has accumulated data from the medical literature since 1950 on the outcomes of 845 pregnancies in women treated for cancer. "It's not great population-based data," he said. "It's more a collection of rare clinical experience.
"We do see an excess of malformations, 19 percent, with first-trimester exposure to chemotherapy," Dr. Mulvihill continued. "Exposure in the second and third trimesters seems to have no increased adverse effects except when therapy is given very late in pregnancy, when it can cause transient effects like low white-blood-cell counts."
Given the obstacles to conducting clinical trials in pregnant women, studies based on data from registries—with all their limitations—provide the best evidence available about outcomes for children prenatally exposed to chemotherapy, according to Dr. Trimble.
Reason for Optimism
"After the first trimester, the concern is less about birth defects and more about potential for impaired organ or brain function, since the brain continues to develop throughout pregnancy, " said Dr. Elyce Cardonick, a maternal-fetal medicine specialist at Cooper University Hospital in Camden, NJ.
Dr. Cardonick maintains the Pregnancy & Cancer Registry, which since 1997 has compiled information on nearly 300 pregnancies in women with cancer, and is following 247 mothers and children over the long term. Findings from her studies and others offer some reason for optimism: In general, children prenatally exposed to chemotherapy do not appear to have higher rates of birth defects or developmental abnormalities than other children.
Mexican researchers closely followed 84 children whose mothers received chemotherapy for hematologic cancers during pregnancy, including 38 who were treated during the first trimester, for a median of 18 years. All the children were normal, physically and neurologically, and performed normally at school. Some gave birth to their own children, adding 12 second-generation offspring to the study cohort.
Premature birth is more likely than chemotherapy to impair the cognitive development of children prenatally exposed to chemotherapy, an international research group reported in September at a European oncology meeting. Of the 70 children they studied, who ranged in age from 18 months to 18 years, 47 were born prematurely. Although most of the children were normal, most of those with cognitive development problems were born early.
Lead researcher Dr. Frederic Amant, of University Hospitals Leuven in Belgium, said it was not clear whether chemotherapy caused the early deliveries, but in many cases preterm delivery was induced. "Our results suggest [inducement of early delivery] should be avoided," he said.
At the 2011 American Society of Clinical Oncology annual meeting, Dr. Jennifer Litton, a medical oncologist specializing in breast cancer at the University of Texas M. D. Anderson Cancer Center, reported on 41 children born to women who were treated during the second or third trimester with a standardized multidrug chemotherapy regimen in a prospective registry trial.
Overall, the children, now ages 1 to 21, are doing well, she said. Three to four percent have birth defects, equivalent to the national average for children not prenatally exposed to chemotherapy. The cohort has now increased in size to nearly 90 children, whom Dr. Litton and her colleagues are still following.
The M. D. Anderson study has enrolled 81 pregnant women with breast cancer since 1989 and has used the same chemotherapy regimen of 5-fluorouracil, doxorubicin, and cyclophosphamide since its inception. Pregnant patients are generally treated with older anticancer agents because of a lack of safety data for newer therapies, according to Dr. Trimble.
Don't Ignore a Lump
Data from the Pregnancy & Cancer Registry indicate that in about one in five cases doctors recommended terminating the pregnancy before starting cancer treatment, according to Dr. Cardonick. Anecdotally, she has heard of pregnant women who didn't tell their doctors about a lump or other abnormality because they feared they would be advised to terminate the pregnancy.
"Women and oncologists need to know it's possible to successfully treat cancer while continuing with a pregnancy," she said. "Women should not be afraid to bring a breast mass or mole to their doctor's attention.
"Most oncologists want to treat the patient as if she's not pregnant, and, for the most part, in the second and third trimester, they can," she continued. "But they need to make some adjustments. For example, you should not give chemo after the 34th week of pregnancy because, if the patient goes into labor while her white blood cell counts are low, the baby could be born with neutropenia."
Trina Pockett's doctor suggested she consider termination but supported her decision to continue with the pregnancy. She underwent four cycles of chemotherapy before her daughter, Kate, was born 6 weeks prematurely. After the birth she completed chemotherapy, followed by radiation treatment.
She has been cancer-free since 2001. Kate, who spent nearly 4 weeks in neonatal intensive care, is now a healthy 11-year-old who aspires to be a veterinarian. Pockett gave birth to a third child, Noah, in 2004.
In 2009, she achieved a personal goal when she competed in a half-marathon in San Diego. "To run in the same city where I had chemotherapy was very special," she said.
Cancer and Pregnancy Resources
Collection of Outcomes Data for Pregnant Patients with Cancer
An observational study that is collecting data on disease characterization, treatment, and outcomes for 200 pregnant patients with cancer.
Consortium of Cancer in Pregnancy Evidence
A compendium of evidence-based information on the diagnosis, management, prognosis, and fetal outcome of cancer in pregnancy.
Hope for Two—The Pregnant with Cancer Network
A peer support network for women diagnosed with cancer during pregnancy. To the extent possible, each woman is paired with a woman who received a similar cancer diagnosis during her pregnancy.
Pregnancy & Cancer Registry
A confidential registry for women diagnosed with cancer during pregnancy and their children, who are followed annually with their consent and the cooperation of their doctors.
Primary Breast Cancer Occurring Concomitant with Pregnancy
A prospective registry study evaluating a standardized multidrug chemotherapy regimen for breast cancer in women diagnosed with the disease during pregnancy. Study participants are followed up to evaluate the outcome of labor and delivery and the long-term health outcomes of children prenatally exposed to chemotherapy.
Registry of Pregnancies Exposed to Chemotherapeutic Agents
A database of literature reports (1950 to the present) and physician-referred cases of chemotherapy during pregnancy, maintained at the University of Oklahoma College of Medicine. Contact: email@example.com
A Closer Look
Interpreting Risk: Direct-to-Consumer Genetic Testing
In the winter of 2009, Shannon Behrman ordered a genetic test online because she was curious to know whether she had inherited her family's increased risk for melanoma. The direct-to-consumer (DTC) genetic test revealed an increased risk for melanoma, as well as for autoimmune disorders, but average risk for breast cancer, Parkinson disease, and most other diseases.
She received the test results without ever speaking with a doctor or a genetic counselor. Unlike most customers, however, Dr. Behrman has a Ph.D. in molecular biology and is a health communications fellow in NCI's Office of Cancer Genomics.
DTC genetic tests are DNA tests that are marketed and sold directly to the customer without a doctor's order or a consultation with a genetic counselor. In recent years, the tests have become more accessible as many new genetic testing companies have emerged. Moreover, prices for DTC genetic tests have continued to drop, increasing their availability to the general public.
With greater public access to DTC genetic tests, researchers are examining whether members of the public will be able to accurately interpret their test results without the aid of genetic counselors.
Public Perspective
A recent study in Public Health Genomics reported that although members of the general public are likely to think that DTC genetic test results are easy to understand, they may not interpret them correctly. The authors also found that the general public thinks DTC genetic test results are more helpful in making decisions about medical care than genetic counselors think they are.
For the study, the researchers asked members of the general public—in this case, the Facebook friends of the lead researcher—and members of the National Society of Genetic Counselors to interpret mock DTC genetic test results. The Facebook friends of the principal investigator were not a representative sample of the public, however. On the whole, the subjects were young, white, female, highly educated, and mostly employed in the health care field. Because this is a skewed population, the results of the study may underemphasize the challenges the general public may face when interpreting DTC genetic test results.
Although most subjects correctly interpreted whether the test results meant more or less risk, overall, they did less well than the genetic counselors. Members of the general public also trusted the test results more than the genetic counselors did.
The researchers note that if members of the general public misunderstand the meaning of their DTC genetic test results they may experience unnecessary anxiety or feel falsely reassured about their health. Both outcomes could ultimately cause harm if, for example, they led to unwarranted changes in screening behavior.
A Third Possibility
The study findings did not surprise Dr. Jean Claude Zenklusen of NCI's Office of Cancer Genomics. In his experience, most people hear what they want to hear. "If you tell them their risk is lower, but not zero, they think 'OK, I'm great!'" he explained. He added that many people don't pay attention to a test result that shows they have increased risk, but those who do can become overly concerned.
Dr. Gillian Hooker of the Johns Hopkins Bloomberg School of Public Health/National Human Genome Research Institute (NHGRI) Genetic Counseling Training Program noted a third possible outcome: A finding of an increased risk on a DTC test could cause the person to change his or her behavior. For instance, she said, if someone received a test result that showed higher risk for a disease, and if evidence-based interventions were available to reduce that risk, that person could choose to change his or her behavior to reduce the risk of that particular disease.
For Dr. Behrman, the DTC genetic test results didn't reveal new information. "[My increased melanoma risk] is in line with my family history," she said. She has yet to make health changes or seek a genetic counselor for interpretation. "I just try to be healthy and slather on the sunscreen," she said.
—Dr. Jean Claude Zenklusen
A major obstacle in interpreting DTC genetic test results is numeracy. Numeracy, analogous to literacy, is a person's ability to correctly read and interpret numbers. Dr. Hooker noted the challenges of numeracy. "It's really hard to imagine what a difference of 1 or 2 percent means for your health," she said. "There's a fair amount of data in the risk communication literature that says that people translate risk much as the paper described."
Dr. Behrman noted a similar issue in her DTC genetic test results. "If I look at the results for my melanoma risk, it shows I have a twofold elevated risk of 2.4 percent. For the average person, when they see these numbers, they may just think, 'that's a twofold risk!'" But people receiving such a result should note that even though the risk may be double the average person's risk, it is still, at 2.4 percent, a fairly small risk.
Communication scientists recognize that the way risk information is reported influences how it is perceived. Indicating that "2 in every 1,000" people with a genetic predisposition for a disease will develop it, compared to "1 in every 1,000" people in the general population, provides more complete information than saying that an individual is "twice as likely" than the average person to contract a disease. The former presentation is referred to as absolute risk, the latter as relative risk. Most risk communication experts argue for using absolute risk estimates when communicating risk information to patients to provide greater context and more meaningful information.
Medical Paternalism
Given the challenges in interpreting genetic results and the serious possible consequences of misunderstanding, some companies are offering testing only through a doctor or genetic counselor. "I understand how [a result indicating higher risk] could be alarming to people who aren't familiar with biology or statistics," explained Dr. Behrman. "If all you see is elevated risk, you panic." She added that ordering her DTC genetic test through a doctor would not have been a significant barrier.
Some argue that going through a doctor could be a barrier to accessing one's own genetic information. "There is some concern about medical paternalism," said Dr. Hooker, referring to the philosophy that certain health decisions are best left to health care providers. "It's something I struggle with myself. To what extent do people have the right to access DTC genetic testing directly, or is allowing the consumer that access irresponsible?"
Dr. Zenklusen also takes a moderate path. "Your genome is yours," he said. "You should have full access to your genome, but companies bear a responsibility to report [genetic test results] in a responsible way." He added that the method of returning results should not be "over-reassuring or over-scaring."
The Public Health Genomics study suggests that research must be continued in several areas: risk communication, the best formats for communicating genetic information to patients, the connections between SNPs and disease, algorithms to find causative mutations, calculations to interpret genetic data, and other modifiers of our genomes.
—Emma J. Spaulding
More information: Cancer Genetics Risk Assessment and Counseling (PDQ)
Featured Clinical Trial
Novel Combination Chemotherapy for Localized Ewing Sarcoma
Name of the Trial
Phase III Randomized Study of Adding Vincristine Sulfate, Topotecan Hydrochloride, and Cyclophosphamide to Standard Chemotherapy in Patients with Non-Metastatic Extracranial Ewing Sarcoma (COG-AEWS1031). See the protocol summary.
Principal Investigator
Dr. Mason Bond, Children's Oncology Group (COG)
Why This Trial Is Important
Ewing sarcoma is a rare cancer of the bone or soft tissue that occurs primarily in adolescents and young adults. In fact, it is the second most common malignant bone tumor diagnosed in patients younger than 20 years of age. Most Ewing sarcomas have a characteristic chromosomal alteration that results in the expression of a fusion protein (EWS-FLI1) that inappropriately turns on cell-growth-promoting genes. Thus, these tumors tend to grow rapidly and often metastasize to the lung, bone, or bone marrow. The presence of metastases at diagnosis and being diagnosed at an older age are associated with a poorer prognosis.
Treatment for patients with Ewing sarcoma includes surgery, radiotherapy, or both, along with systemic chemotherapy. Until the introduction of combination chemotherapy, the 3- to 5-year survival rate for patients with Ewing sarcoma was less than 10 percent. However, results from several clinical trials have demonstrated improved survival for patients without metastases who were treated with a chemotherapy combination called VDC-IE, in which administration of the drugs vincristine, doxorubicin, and cyclophosphamide (VDC) is alternated with administration of the drugs ifosfamide and etoposide (IE), and by reducing the interval between cycles of VDC-IE.
In this clinical trial, which is being conducted in the United States, Canada, and Australia, researchers will test whether the addition of the drug combination vincristine, topotecan, and cyclophosphamide (VTC) to VDC-IE improves overall survival and event-free survival (survival without cancer progression or recurrence) in newly diagnosed patients with non-metastatic Ewing sarcoma of the bone or soft tissue (excluding the soft tissue of the skull). Eligible patients will be randomly assigned to receive six cycles of VDC-IE or VTC-IE-VDC followed by surgery, radiation therapy, or both and 11 more cycles of the initial chemotherapy.
"Because topotecan and cyclophosphamide are active in patients when Ewing sarcoma recurs or relapses, our thinking is that the combination may contribute to improving survival or preventing relapse in newly diagnosed patients," said Dr. Leo Mascarenhas, vice chair of the trial.
"This trial is unique in that it is the first COG trial available through NCI's Cancer Trials Support Unit (CTSU) that will enroll both adolescents and young adults," added Dr. Mascarenhas. "It provides broader access to patients who may not be treated at a pediatric center, which is the case for a significant number of patients with Ewing sarcoma."
Secondary aims of the trial include assessing the importance of initial tumor volume, tumor histology, and response to treatment as measured by PET scans as prognostic factors for localized Ewing tumors. Additionally, the effect of the type of local therapy (surgery, radiotherapy, or both) on associated complications and survival will be evaluated. "There are a lot of issues we hope to address in this trial to help us understand this disease better to improve the outcome of patients," said Dr. Mascarenhas.
For More Information
See the lists of entry criteria and trial contact information or call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.
FDA Update
FDA Commissioner Revokes Approval of Bevacizumab for Metastatic Breast Cancer
On November 18, Food and Drug Administration (FDA) Commissioner Dr. Margaret Hamburg announced her decision to revoke the agency's approval of the drug bevacizumab (Avastin) for the treatment of metastatic breast cancer. The FDA Center for Drug Evaluation and Research (CDER) granted bevacizumab accelerated approval for this indication in February 2008 with the condition that Genentech, the drug's manufacturer, perform two confirmatory clinical trials.
"Unfortunately, the additional studies failed to confirm Avastin's initial promise," said Dr. Hamburg at a press briefing explaining the revocation. The two trials showed that bevacizumab delayed tumor growth slightly but did not improve survival or patients' quality of life.
Based on these findings, CDER's Oncologic Drugs Advisory Committee (ODAC) voted 12 to 1 in July 2010 to recommend that the FDA withdraw its accelerated approval for metastatic breast cancer. Following an appeal from Genentech in July of this year, ODAC upheld its recommendation to withdraw approval for the indication.
"Sometimes, despite the hopes of investigators, patients, industry, and even the FDA itself, the results of rigorous testing can be disappointing," said Dr. Hamburg at the press briefing. "This is the case with Avastin when used for the treatment of metastatic breast cancer." In light of the potentially severe side effects of bevacizumab, including heart attack or heart failure, severe high blood pressure, and bleeding or hemorrhaging, "it is clear there is no proof of a benefit in breast cancer patients that would justify those risks," Dr. Hamburg explained.
Bevacizumab is still approved for the treatment of metastatic colorectal cancer and kidney cancer, advanced non-small cell lung cancer, and glioblastoma. Dr. Hamburg stressed that the "FDA doesn't regulate the practice of medicine," so a final decision on whether to use bevacizumab for metastatic breast cancer will be up to a patient and her doctors. "I urge women who are currently taking the drug for breast cancer to discuss the risks and benefits…with their oncologist," she added.
Future studies may identify subsets of patients with metastatic breast cancer who would benefit from bevacizumab. "I would really be very pleased to see Genentech pursue those studies, and we would of course be very open to the submission of a new application that would include additional data, including support for the notion of a subset of responders to the use of Avastin," Dr. Hamburg concluded.
Further Reading: "Progression-free Survival: Patient Benefit or Lower Standard?"
New Form of Asparaginase Approved to Treat Acute Lymphoblastic Leukemia
On November 18, the Food and Drug Administration (FDA) approved Erwinaze, an alternate form of asparaginase that is derived from the bacterium Erwinia chrysanthemi, to treat acute lymphoblastic leukemia (ALL) in patients who have become allergic (hypersensitive) to other forms of asparaginase derived from the bacterium Escherichia coli.
Asparaginase kills leukemia cells by breaking down the amino acid asparagine in the plasma. Asparagine depletion is selectively toxic to leukemia cells, which, unlike normal cells, cannot synthesize asparagine. The level of asparaginase activity is known to correlate with leukemia control and survival.
The FDA approval was based on the results of a single-arm trial involving 58 patients between the ages of 2 and 18 and a safety analysis of 574 patients between the ages of 1 and 66 who participated in a program to expand access to the drug. Patients in both studies had developed allergic reactions to asparaginase and pegaspargase, another modified form of asparaginase, both of which are derived from E. coli.
In the single-arm trial, the main outcome measure was the proportion of patients in whom a prespecified threshold level of asparaginase activity was maintained at 48 or 72 hours after dosing. All evaluable patients in the trial achieved this outcome.
Erwinaze is given as an injection three times per week. Side effects associated with Erwinaze treatment include serious allergic reactions, inflammation of the pancreas, high blood levels of liver enzymes, blood clotting, bleeding, nausea, vomiting, and high blood sugar.
Erwinaze has been designated as an orphan drug, a designation given to drugs for the treatment of diseases affecting fewer than 200,000 people in the United States.
Ruxolitinib Approved to Treat the Bone Marrow Disease Myelofibrosis
On November 16, the Food and Drug Administration (FDA) approved ruxolitinib (Jakafi) for patients with intermediate- or high-risk myelofibrosis. Ruxolitinib is the first drug approved specifically to treat patients with this bone marrow disease.
In patients with myelofibrosis, fibrous tissue replaces the bone marrow, causing blood cells to be made in organs such as the liver and the spleen. This disease is marked by an enlarged spleen, anemia, and decreased numbers of white blood cells and platelets. Symptoms include fatigue, abdominal discomfort, pain under the ribs, feelings of fullness, muscle and bone pain, itching, and night sweats.
Myelofibrosis and other myeloproliferative disorders are associated with the increased activity of tyrosine kinase enzymes called JAK 1 and 2, which play key roles in a signaling pathway that is involved in cell proliferation and growth, hematopoiesis, and the immune response. Ruxolitinib, a pill taken twice daily, binds to and inhibits JAK 1 and 2, which may lead to reduced inflammation and cell proliferation.
The safety and effectiveness of ruxolitinib were evaluated in two clinical trials with a total of 528 patients. Patients in both trials had myelofibrosis that was resistant or refractory to available myelofibrosis therapy or ineligible for allogeneic bone marrow transplantation. All patients had enlarged spleens and needed treatment for disease-related symptoms. Patients in one study received ruxolitinib or the best available therapy; in the other study patients received ruxolitinib or a placebo. The primary endpoint in both trials was the proportion of patients whose spleen size was reduced by at least 35 percent.
In both studies, a significantly higher proportion of patients taking ruxolitinib saw their spleen shrink by 35 percent or more—29 percent of patients receiving ruxolitinib compared with zero percent of those receiving the best available therapy, and 42 percent of patients taking the drug compared with 1 percent of those taking the placebo. In the placebo-controlled study, a greater proportion of patients receiving ruxolitinib than receiving the placebo had their myelofibrosis-related symptoms reduced by 50 percent.
The most serious side effects seen in patients treated with ruxolitinib include low blood platelet levels, anemia, fatigue, diarrhea, shortness of breath, headache, dizziness, and nausea.
Ruxolitinib was reviewed under FDA's priority review program, an expedited 6-month review of drugs that may offer significant advances in treatment over available therapy or that provide a treatment when no adequate therapy exists.
The treatment has been designated an orphan drug, a designation given to drugs for the treatment of diseases affecting fewer than 200,000 people in the United States.
National Cancer Advisory Board Will Meet Next Week
The National Cancer Advisory Board (NCAB) will meet December 5–6 in Building 31 on the NIH main campus in Bethesda, MD.
The agenda is now available, and the proceedings will be broadcast live online. An archived videocast will be available a few days after the meeting.
Videocasts of past meetings are available here.
Proposals Sought for Use of PLCO Data and Biospecimens
Data and biospecimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial are available to qualified researchers through a peer-review process. The Etiology and Early Marker Studies (EEMS) program accepts proposals for access to PLCO biospecimens twice a year, with the current cycle ending on January 16, 2012, at 5:00 p.m. ET.
By collecting biologic materials and risk factor information from trial participants before the diagnosis of disease, EEMS—a component of the PLCO—provides a resource for cancer researchers who are studying cancer etiology and early detection. Etiologic studies investigate the environmental, biochemical, and genetic risk factors for cancer. Early detection studies aim to develop reproducible, reliable biomarkers of early disease.
Proposals will be accepted for the next EEMS review cycle starting December 1. Details of the review process and application materials are available online. Questions may be directed to email@example.com or 240-314-2313. Proposals for the next cycle will be accepted in June or July 2012.
Cyber-Seminar Will Address Systems Thinking to Solve Public Health Problems
The December 14 NCI Research to Reality (R2R) cyber-seminar will feature an overview by Dr. Allan Best on systems thinking and practical tools to help solve complex population health issues.
Addressing these health issues often requires intervention and engagement with key stakeholders and organizations across many levels, ranging from local entities (schools, churches, and work environments), to regional systems (health departments and hospital networks), to entire countries (national agencies). This multilevel, multiparticipant view is at the heart of systems thinking, a process of understanding how parts influence one another within a whole.
Drs. Ross Brownson and Ken McLeroy will provide real-world examples of how systems models can be applied in a variety of settings. Dr. Brownson will highlight the use of concept mapping and discuss the different levels that should be considered when implementing evidence-based programs within organizations or developing public health policies. Dr. McLeroy's presentation will focus on the use of social network analysis as a tool to analyze community capacity and ensure that organizations and communities are working together to develop, implement, evaluate, and sustain effective programs.
For more information and to register for this event, visit the R2R website, where you can watch presentations and join discussions. This cyber-seminar will be available on the R2R website approximately 1 week after the presentation.
If you missed any of the past cyber-seminars, you can view them in the R2R archive.
NCI Guide on Communicating Data to Lay Audiences Now Available
Making Data Talk: A Workbook helps public health practitioners, scientists, health educators, clinicians, researchers, students, and statisticians effectively communicate data to lay audiences.
The workbook, based on the book Making Data Talk: Communicating Public Health Data to the Public, Policy Makers, and the Press, by Drs. David E. Nelson, Bradford W. Hesse, and Robert T. Croyle of NCI's Division of Cancer Control and Population Sciences, provides key information, practical suggestions, and examples on how to successfully communicate health-related scientific data.
The workbook also offers recommendations about selecting and presenting data and introduces the OPT-IN (organize, plan, test, integrate) framework, which guides public health practitioners on how to present health data to lay audiences. Many chapters also include practice exercises that use real-world examples to reinforce and apply key concepts.
Making Data Talk: A Workbook is available in print and electronic formats. Visit NCI's website to order a copy or download the workbook.
Major League Baseball Limits Players' Use of Tobacco
Major League Baseball (MLB) and the MLB Players Association announced a 5-year collective bargaining agreement on November 22 that includes limits on smokeless tobacco use.
The agreement prohibits players, managers, and coaches from using smokeless tobacco during televised interviews, club appearances, or other events where fans are permitted. In addition, players, managers, and coaches may not carry tobacco packages or tins when fans are in the ballpark. Individuals who violate the policy will be subject to discipline.
The agreement also expands tobacco education programs for players and calls for a program of education and public outreach on the dangers of smokeless tobacco.
The effort to promote "tobacco-free baseball" is supported by numerous national health and medical organizations, including the American Cancer Society, the American Medical Association, and the American Academy of Pediatrics, as well as many youth organizations, researchers, public health organizations and others. More information about the effort can be found online.
Further reading: "House Committee Convenes Hearing on Smokeless Tobacco"
President Obama Encourages Smokers to Quit
You must have flash installed and enabled to view the video.
November 17 marked the American Cancer Society's 36th annual Great American Smokeout, a day set aside every year to encourage smokers to make a plan to quit smoking for good and to remind nonsmokers not to start.
President Barack Obama congratulated those participating in the Great American Smokeout in a short video message.
Visit NCI's smoking home page to see the video and for information and resources on quitting smoking.


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A Grosse Pointe Woods mother of three, JoAnn Romain, was found dead in the Detroit River nearly four years ago. Police say she died by suicide, but her family firmly believes she was murdered. "I know that she was victim. I know this was homicide. I know that the police did not properly investigate this," says Michelle Romain, Joann's daughter. Michelle has spent two hundred thousand dollars of her own money hiring attorneys, experts and private investigators who obtained police reports and interviewed countless witnesses to help prove it.On January 12, 2010 Grosse Point Farms police said the 55-year-old mother of three attended a short mass at St. Paul Catholic Church then died by suicide after walking across the street into the icy waters of lake St. Clair. Around 9:30 that night, only two hours after church let out, police showed up at the family's house but no one had reported JoAnne missing.Fox 2's Taryn Asher gets clarification from Michelle: "Police came to you and told you she was missing, that her car was abandoned, before you reported her missing? "Correct. And she was actually driving my car that was registered to me," Michelle says. VIDEO: Click on the video player above to hear more from Michelle in a report from Taryn AsherJoAnne's Lexus was found in the church parking lot but Michelle says, according to witnesses who were interviewed, it had been moved. Witnesses also remember the panic alarm going off. That's what led Michelle to believe her mother was abducted and eventually dumped somewhere else.Although an autopsy shows no sign of foul play Michelle believes nothing added up. JoAnne wasn't depressed; she was seen on surveillance video filling up her car with gas right before church. Also, that night there was no current. If JoAnne would have drowned in the shallow waters across the street from the church Michelle believes her body would have been found sooner than nearly two months later, and not 60 miles away in the Detroit river near Ontario.Michelle believes her mother was abducted from church and murdered for a vendetta. A personal vendetta, she claims, against a close family member possibly tied to his money troubles. Why police refused to go along with this theory and investigate, Michelle says will be revealed in a press conference Wednesday morning, January 8, 2014.The family has recently hired private investigator Scott Lewis, who is asking the Michigan State Police to reopen this case.
205 N. Michigan AvenueGround FloorChicago, IL 60601Station Operator: (312) 565-5532Newsroom: (312)565-5533

subset: commoncrawl


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G.17 Industrial Production and Capacity Utilization
This release began in 1990, resulting from a merging of Capacity Utilization, Manufacturing, Mining, Utilities and Industrial Materials (G.3) and Industrial Production (G.12.3).
Releases are available on the website of the Board of Governors of the Federal Reserve System for 1998 – present.
1990 to 1997
Industrial Production: Market Groups
Download this page from:
Download this page in groups:
March 1990 and First Quarter 1990 Preliminary-November 1994 Preliminary and Third Quarter 1994 Revised (50.2M)
December 1994 and Fourth Quarter 1994 Preliminary-November 1997 Preliminary and Third Quarter 1997 Revised (27.5M)


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Singer-guitarist St. Vincent (real name Annie Clark) began her career with Polyphonic Spree and spe...
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hi everyone,
my son nathan was born on thursday, 3/10/11 due to my blood pressure and severe headaches. i was kept overnight from wednesday to get a 24 hour urine collection, but on thursday my headache was so severe they put me on magnesium and started pitocin to start an induction. after several hours i had not had a single contraction, in fact i slept most of that time. the doctor decided we needed to do a c-section right away and by 6:30pm my son was born. he was 2 lbs 15 oz and i was able to see him for just a minute before they took him to the NICU.
i was not able to see him for over a day after that because of the magnesium, i was not allowed out of bed for ANYTHING. i came home from the hospital on tuesday and they are not sure how long nathan will be in the NICU. he is breathing on his own and tolerating feedings well. he had lost a few ounces but is now up to 3 lbs 1 oz. he has to be at least 4 lbs, breathing on his own, gaining weight steadily and has to be able to keep himself warm before he is allowed to come home.
i am having a bit of a hard time in that i don't feel like a mother yet...when i visit him he doesn't feel like MY baby, it feels like i'm visiting someone else's baby. i've only been allowed to hold him once. it's hard to only be able to watch him through the isolette and when he gets upset i have to watch a nurse comfort him. i just don't feel like a mom at all. i've had a few people tell me that they had the same problem and i'm not alone, which helps. i've been feeling terribly guilty about it. i mean, i LOVE him very much and i worry about him, he just doesn't feel like he's MINE.
anyway...that's my story. i'm glad to see this forum here where people understand what it's like having early babies in the NICU. i am sending positive thoughts to all of you and your babies in hopes that they all progress quickly and are able to come home. hugs to you all!


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"Customer service is priority #1 at Rocky Mountain ATV/MC. We value our customers and strive to be the best shopping experience- when you buy from us, you are buying lifetime service."
-Dan Thomas, CEO and Founder
We take pride in offering no hassle returns. In the event of a return, please call, email or chat with us to receive a solution to the problem. For apparel that doesn't fit quite right, Click here to see our Fit Guaranteed Program.
We will stand behind all products we sell with regards to manufacturing defects in workmanship and material. Most products are limited to the manufacturer's warranty. However, we will do everything in our power to take care of the problem.
Live chat: Click here
(Leave email if after hours)
Call us: 1 800 336-5437
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Each review submitted enters you into a $100 gift card monthly drawing, and a $500 gift card quarterly drawing!
Comments On Oct 31, 2013:they were cheap enough but u cant tell by looking at them
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Comments On May 12, 2013:can't beat the price and they've held up well so far
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Comments On Nov 27, 2012:I bought these to use with my Oniel boots. There is no way I can use them with boots as they are too long. I gave them away since shipping them back to RockyMountain would have cost what I paid for them. The kid I gave them to uses them for skateboarding. He seems to like them.
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Comments On Nov 16, 2012:Not bad for the price. But if you take a fall on some hard ground you will be bruised through these things, just ask my wife! we have upgraded to some thicker knee pads now... I like these for more casual riding though, and are MUCH better than nothing!
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Comments On Mar 16, 2012:Bought these for my son and he did not have any complaints. They fit good and easy to adjust.
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Sequin Midi Skirt
AVAILABILITY: Unavailable for immediate shipment.
Give your cocktail dresses a night off with this bebe skirt, featuring allover sequins and a lengthier cut that sculpts an elegant silhouette. Try it with a silk button up, a statement necklace and a pair of glossy black heels for a classic look.
As seen in our October 2012 mailer.
- 100% nylon.
- Center back to hem: 28" (71 cm).
- Hand wash.
- Made in USA.
- Model is 5'9" and is wearing a US size S.


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See and share Beautiful Nature Photos and amazing photos of interesting places
Oldest of five brothers, I was the one who got away with everything. Spent thirty years as a Navy Reservist. People say I'm a little crazy. Thank God, normal people lead mundane lives. My greatest love is kids and I spend weekends working with abused kids with psychiatric problems almost always created by adult animals. I like music, mostly country and early rock. Married for forty years (my wife will be given the Medal of Honor) and have four kids, a 36 and 35 year old and two 23 year olds. The twins are a boy and girl. Including me, my wife has five. Got 5 grand kids. I'm big on amusement parks and would work for Mickey and Donald any day. I've seen a lot of the world (14 countries) and definitely miss the travelling with the Navy. I'm a firm believer in the power of prayer. I love this planet, so I'm going to stay awhile. I do believe war could be a necessity only in defense of your country and not as an excuse to prospect for oil. I believe that if there is any honesty or integrity in Washington, the guy is in the wrong city. People I most admire include Jimmy Carter, JFK and Billly Graham. I'm pro-life and anti- political correctness. I think the problem with political jokes is that most of them get elected.
ps_2012-01-08 12.42.18.jpg


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An expert says making you kids clean their entire plate could give them an eating disorder later in life.
The nutritionist says there have been sever studies that found making kids eat their entire plate is bad for them.
One that found kids who are allowed to eat as much as they want were less likely to have eating disorder as young adults
Kids grow up not knowing what being full means.
I got the story at dailymail.co.uk


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It is impossible to be a sportswriter and not mention Curt Flood on Labor Day.
Anyone who doesn't is selfish, lazy or ignorant.
[Photo: Flood in court, ca. 1971, via Wikimedia Commons]
Of course, Flood himself was accused of all those things as he stood up to battle baseball's reserve clause.
Flood had already spent 12 years in the majors, won seven Gold Gloves and two World Series. He was an accomplished center fielder for the St. Louis Cardinals when he and a number of teammates were traded to the terrible Philadelphia Phillies. Rather than play on a moribund team in a dilapidated stadium for [what he believed to be] racist fans, Flood felt he had earned some say in where he and his career went. He refused to report and sat out the 1970 season as he petitioned Commissioner Bowie Kuhn to become a "free agent."
[Photo: Flood as a Cincinnati Redleg in 1957, via Wikimedia Commons]
Even a lot of sports fans remember the story wrong. They forget he started in Cincinnati. They remember that Flood filed suit against the commissioner but don't realize he lost. It was a later ruling -- the Seitz decision -- that struck down the reserve clause. Flood did return to baseball in 1971, albeit for only 13 games, with the incarnation of the Washington Senators that became later the Texas Rangers. Flood is not remembered enough for his greatness on the field, nor is he reviled enough for his dreadful lack of business acumen that included bankruptcy and severe tax turmoil that led to an exile in Majorca for a few years. Scant sports fans ever knew he was a gifted painter.
So when you lament how much professional -- and occasional "amateur" athletes [Johnny Manziel] -- get paid, think back to Curt Flood. He struck the first blow to break the bonds of what was basically indentured servitude to owners who made even greater riches off players than they do now. When you complain about greedy unions grandstanding for greedier players, think back to Curt Flood. He gave a voice to an entire class of workers who never had one before. When you have a choice in your own life -- of where to work, for whom or for how much -- think back to Curt Flood.
Happy Labor Day.
[Photo: Flood's letter to Kuhn, ca. Dec. 1969, via Wikimedia Commons]


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The HSUS recommends that you do not transport your pet by air unless absolutely necessary. According to the Airline Transportation Association, more than 5,000 animals are killed, injured, or lost on commercial flights each year. Our beloved pets face risks including excessively hot or cold temperatures, poor ventilation, scarcity of oxygen, and rough handling.
The airline industry treats live animals as mere baggage, transporting them in cargo holds not truly designed for life support. In the past, airlines have neither responded appropriately to reports of animal injuries, nor provided accurate information to the flying public.
In response to the problems associated with pet air travel, Congress passed the Safe Air Travel for Animals Act in April 2000. The Humane Society lobbied extensively for this law. Although the U.S. Department of Transportation has yet to adopt regulations to implement the law, many airlines responded to the law's passage by announcing restrictions on accepting pets as cargo.
If you plan to travel with your pet by air, follow these suggestions from The HSUS:
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Persons with disabilities who need assistance with issues relating to the content of this station's public inspection file should contact Administrative Assistant Trista Truesdale at (815) 335-7856. Questions or concerns relating to the accessibility of the FCC's online public file system should be directed to the FCC at 888-225-5322, at 888-835-5322 (TTY) or at email@example.com.


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|Deviant Login
|Join deviantART for FREE
|Take the Tour
OR/AS Hype Art Contest + Giveaway!
Hi all! I'd like to celebrate the Pokemon Gen 3 remakes by going all-out with an art contest AND a giveaway. Both of these events will have 15 winners each! Prizes include plushies, free art, and multiple chances to win a copy of the upcoming Omega Ruby/Alpha Sapphire games. Keep reading to learn how to enter!
Available prizes:
Pokemon Omega Ruby/Alpha Sapphire game preorder (1 available)Adorable Treecko, Mudkip, or Torchic plushie (1 of each available)Super cool drawing by me (1 available - here are some examples of my work)Fancypants Kyogre & Groudon pendant keychain (5 available)Badass
Some art/webcomic adviceI got this really thoughtful question on my tumblr a week or two ago in regards to art/webcomics:
"Hello K-bo, I Have been aspiring to be a webcomic artist much like yourself for a long time. Viewing your artwork and your achievements inspire me to reach out for my dreams. I wasn't able to see you at Fan Expo this year so I wasn't able to ask you this in person. I feel like I'm at a point where I'm comfortable enough with my art and style to start a webcomic... but I have no idea where to start... Do you have any advice? Thank you!"
I wanted to share my answer with you guys since it might be relevant to your interests. I hope at least some of it is useful to you. Here goes...
"First off, that's awesome and I'm honored to have inspired you in any way. You should be very proud of yourself for being ready and willing to start this journey.
Now this is a pretty bro
520 points give away!i am give away 520 points for free
How can you get them? Here are the rules:
1. You need to be my watcher.
2. You need to fave this journal (You'll get a number, which I will use to determine the winner, via www.random.org/ )
3. You need to fave this photo:
That's all!!
The deadline for this giveaway is 10-2-2014 join and win!
I love u guys more!(WINNERS)Thnk u for all the support through this awesome years! n wow i didnt notice awhile ive got over 1700+ so u deserve something
;w; n now a r free raffle~
update* holly cheese duck ive got more watcher up to 1800+ guys thnk u so much im so happy n now i will given more winners!!
*there will be 6 winners~
get a lucky chance to get these prizes
-pixel icon
-pixel doll
-fullbody art
-custom design from my closed species
BUT one per person for each prices u may pick which u like to be
Thnk u for entering~NOW who the lucky winner?!
base on the random generator on ur no. of faves on this journal
SORTEO / 400 Points Giveaway (OPEN)This is my FIRST GIVEAWAY!
- 7 winners in total -
◊ 1st place:
200 points (one winner)
◊ 2nd place:
50 points (two winners)
◊ 3rd place:
25 points (four winners)
◘ This Journal and COMMENT • DON'T COMMENT 'faved' -.- you don't deserve to win and i don't deserve that comment
◘ +Watch Me ♥ StrongAsLion (why? Because i will post up more giveaways!, but it is NOT required) -it's not obligatory.-
Share this journal to your friends ♥ (not required) , maybe they need points (?
******************************it is NOT required to, give a llama, advertise, etc.
***************** I will post up more giveaways (SOON), so ,i need your help with some points, if you want, you can do it *u* ***********
600 Points giveaway!so im doing a giveaway again ^^
what you have to do to apply is: Be my watcher, fav this journal and comment below tagging 3 people!
this giveaway will last 2 weeks so it will end on 14th October!
there will be only one winner that the random number site will choose!
and the winner will be getting 600 points!
I am doing this events for my watchers and I will check every entry if they are watching me xD
When inspiration is far to be found...We all get these anoying times when we really want to make something cool, get inspired and work that magic. We see everyone around us (online) do it, but how come we are not?
So we look for ways to get inspired, we ask around, find these usual answers: go watch a film, listen to music.. take a walk...
But even when we do that, we still end up stuck most of the time.
Part of the solution is knowing WHY we get stuck and this is my theory.
ADT - Attention Deficit Trait.
'Experiencing an inner frenzy of distractability, impatience, difficulty in setting priorities, staying focused and managing time. Those are our biggest enemies as they all end up cluttering your head and keeping you from spending quality focused time on a singular topic.
Everything we do now a days is based around multitasking and it is giving us a constant overdose of information. Let me elaborate.
How many of you travel daily by public transport and don't look away
.this poem is drunk right now
this poem is a disappointment
this poem is a mess
this poem would be nothing without me
do you believe me? i will grow talons to tear
into and out of myself, there will be no need
for that knife, no need for gore
or for love,
there is nothing
and it will be gone
long before
it is something
(this is not a poem. do you believe me?)
.sometimes the cold holds my hands so tight
they start to burn, turn red and raw, i know it has
something to say but has no voice
so i must feel the chill instead, it knows
no other way, i know
no other way
to say
that i am thinking of the sun
(the tide comes in and licks her sandy lips, drinks in the moon and i am gone)
Quickie?Just dropping a line to the followers to let you all know i'm tattooing at Na8iv Ink Kenwick when they finish renovating it So if you wanna come visit here's our page!
You can also find me on instagram as hatefueled_tattoos
"Hey everyone we are currently seeking an apprentice to join our team. They will need to bring a portfolio with a variety of drawings to the shop. If you are interested or know of anyone who is interested please come down to the shop or ring 92092228 for enquiries.
Na8iv Ink Crew x"
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Keep in Touch!
A two-time Community Volunteer for the deviantART Related category, Anne is well-known as a positive, helpful force. She is the community's resident expert when it comes to CSS (Cascading Style Sheets), and her personal gallery offers a wide variety of tutorials for new and experienced coders alike. In addition, each winter she hosts a calendar project encouraging members to create Journal designs for all to use, bringing more creativity to the community.
It is with immense gratitude that we acknowledge Anne as the recipient of the Deviousness Award for October 2014. Read More
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From your first day of class to your walk across the graduation stage, the Office of the University Registrar supports you toward your educational goals and provides administrative services for students, faculty, and staff in alignment with Lesley's strategic mission.
The Office of the University Registrar oversees registration, maintains student academic records, and records grades, issues transcripts, handles degree audits, verifies enrollment, issues diplomas, assigns classrooms, supports online services such as WebReg and the class schedule, schedules final examinations, and provides VA administrative services to veterans.
In keeping with Lesley University's mission, the Office of the Registrar is dedicated to:
Quality Customer Service by providing professional, efficient, and courteous administrative services to all students, faculty, and staff;
Academic Support by administering fair and consistent execution of institutional policies, and, where possible and appropriate, assisting the faculty and administration in their academic endeavors; and
Record Integrity by maintaining and preserving the integrity of the student record data systems.
Downloadable Course Schedule PDFs
Lesley Intranet
Federal Educational Rights and Privacy Act
Financial Aid
Student Accounts
Registrar's Office Main Page
Forms for Students and Alumni
General Information for Students
Grading Scale
LOIS: How to Search for Courses
LOIS: WebReg Instructions [pdf]
How To Request a Transcript
Alumni Discount Information
Lesley Home
LOIS: Live Course Schedules
Courses Page: Static PDF Schedules
Academic Calendars
1.800.999.1959 extension 8740
Normal hours of operation9 am - 5 pm Mon - Thu10 am - 5 pm Fri
Mailing addressOffice of the University RegistrarLesley University29 Everett StreetCambridge, MA 02138-2790
Walk-in locationUniversity Hall (Cambridge)1815 Massachusetts Avenue, 3rd floorNear the Porter Square MBTA station
...And more!


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Regardless of your passion, we have the pants to keep you covered whether you are headed for the mountains, the yoga studio, the trailhead or just relaxing at home. We even have you covered for work. We specialize in casual men's and women's pants that fit your active lifestyle.
Our broadest category of pants is lifestyle and casual wear. Prana and Patagonia lead the casual category for men and women. Clean designs and 100% cotton fabrics set the standards for casual clothing. From the office to the backyard barbeque, these versatile pants are comfortable and ready for a full day of work and social engagements.
We break down the casual/lifecycle category further to include capris, jeans, and travel pants. Versatility and comfort are key design features when choosing the right clothing for travel. Royal Robbins and The North Face offer men's and women's pants designed with mobility and functionality in mind. Convertible or "zip-off" pants that transform into shorts ensure you are ready for a full day of adventure when on the road.
Comfort and freedom of movement are essential when looking for yoga wear and pants for running or climbing. Zobha, Prana and ALO lead the Yoga category with stretch fabrics that bend with your body and promote unrestricted movement for athletic pursuits
Brands like Carhartt and Mountain Khakis blur the line between workwear and lifestyle with their durable canvas construction and utilitarian designs. These long-wearing designs are very popular for all-around mountain living. Reinforced seat and knees means durability and true jobsite functionality. If serious workwear is what you are after, you will find Helly Hansen and Carhartt rain bibs, insulated overalls and gear designed for the industrial jobsite environment.
We're Available:
Mon-Fri: 7:30am-4:00pm PST
Sat-Sun: CLOSED


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Monday-Friday 10am-5pm MST
Flyclothing.com started selling rock and roll clothing 12 years ago in the infancy of the web. We pioneered many brands online and built a strong reputation delivering the best product selection, price and service. We also pride ourselves in selling only the coolest clothing and accessories available and we reward you for shopping with us.
Most orders are processed within 24 hours (unless noted under product description). Returns and exchanges are very simple. Simply send the item back within 15 day of receiving and we'll exchange the item or credit your account. See Return Policy for more information.
We also reward you for shopping with us! When you shop with Flyclothing, you gain Customer Reward Points (CRP). CRP points can be used like money towards discounts off future purchases. For more information, please see the link below.
Why Shop at Flyclothing.com?
Shop securely 24-7 without having to leave home
Excellent product selection, competitive prices and excellent customer service
24-hour email response time (maybe even 24 minute)
Pay no sales tax (if shopping outside of AZ)
Products usually ship within 24 hours (Monday - Thursday)
We ship internationally to many countries including: Europe, Canada, Asia, Australia and many other countries
Read Our Testimonials


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PAGE 2 BOMBSHELL Commanding Officer - Robert Sears PUBLISHED SEMI-MONTHLY BY THE EMPLOYEES OF THE OGDEN ARSENAL Administration Building, Room 211 Editor - Georgia Long Associate Editor - Edna Leaver Art Department - Slack W. Winburn, Director Lee K. Parkinson, Betty Hakalo, James M. Mullen Photographer - John Seegmiller Printing - Fred E. Parker On Tuesday, November 10,1942, the United States Marines celebrated their One-hundred and sixty-seventh year of fighting from "The Halls of Montezuma to the Shores of Tripoli." On November 10, 1775, the U. S. Marines Corps was created as a fighting unit. Now, 167 years later they are still fighting for the freedom of all men, all races and all creeds. The United States of the year 1775 had to fight to live. The work day then was not eight hours with lunch on the company time, and no work uniforms or work shoes were furnished them free of charge. No, they worked from daylight until dark, toiled with bare hands, and shed blood and tears to lay the groundwork of the greatest nation in the world -- a nation that is well worth fighting for with bare hands and blood and tears. Yet, in a world that is now twirling madly on its axis, there are a surprising number of people who are absent from work each day for reasons so insignificant that they would make our fighting ancestors not only turn over in their graves but dig deeper into them. Many of you employees of this Arsenal, alone, have sweethearts, husbands, or sons in the armed forces, fighting somewhere in the world. Stop for a moment and think how you would feel if you knew the extra shell or extra bomb you might have helped produce, had you been working today, would be the shell or bomb that would save the life of your loved one. But that extra shell or extra bomb was not produced because Mr. Jones had a stomach ache or Miss Smith had a headache. Fellow employees, we've got a job to do. Let's not help the fighting Marines celebrate THEIR birthday by OUR getting drunk and then being absent from work two or three days with a hangover. Let's all get damn mad and go to war, "Praise the Lord and Pass the Ammunition Down the Assembly Line." Bernard R. Diamond Bomb Loading Plant. We all know our rights and will undoubtedly insist upon them, but there is an old law that wherever there is a Right, there is an Obligation. Let us" not be summer patriots or sunshine soldiers. Those of us who came from Virginia will remember "noblesse oblige." Those of us who claim old Puritan ancestry which settled New England may possibly remember Whittier's injunction along that line: "Sons of sires who sat in council With their Bibles 'round the board, Answering England's royal missive With the plain 'Thus Saith the Lord.'" We others who are descended from the Mormon stock that settled so much of the West may well remember an old hymn sung by pioneer fathers: "Shall I be carried to the skies On beds of flowery ease While others fight to win the prize And sail through bloody seas?" Right now: Hitler has all Europe at his feet. In a few months with all the wealth of Europe organized, he will be able to build three ships to our one. Hirohito has all the wealth of the Orient under his control. In a very short time he will be able to mass it against us. There is no time to waste. Every man must prove before the bar of his own soul whether he measures up. We all depend upon our soldiers to bear the brunt of this war, but, if, as we expect, our boys and our brothers are to furnish the blood, should we not at least furnish the sweat? Joseph Peach Retiring Editor Our compliments to John E. Samara, retiring Editor of the Bombshell, and best wishes for success in his new job, the Daily Activity Report which keeps him so busy that it has been impossible for him to continue his work on this paper. He is remaining with us, however, in an advisory capacity, so his fine influence will still be felt. HALLOWEEN PARTY The Halloween party at the White City, sponsored by the West Plant Oct. 29, was a great success. The $25.00 Defense Bond given as grand prize was won by Mrs. Carl Cowan. Defense Stamp books and merchandise certificates were given as secondary prizes. Miss Illa Hill carried away the honors for the ladies costumed as "Sadie Thompson," and Oscar Rice for the opposite sex as "honest George Washington." John Ellis' popularity was upped 50% when he won gorgeous "Ella Elephant" the gingham doll. All the girls wanted to dance with Ella! The West Plant wishes to thank the Arsenal employees for their fine cooperation. LOST AND FOUND Lost articles should be reported, to the Identification Bureau at Guard Headquarters. Likewise anything found should be left at the same place where it can be returned to owner. Through identification, the following articles may be released at the Identification Bureau: One pair of glasses One camera One kodak One 38 revolver One lady's belt Visitor, being shown thru the Plant: "Does a bomb that size often hit a man?" Foreman: "Naw only once." We are all Capable of more than we are doing
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Medium Travel Tote
best complemented withPrevious Page
Expandable Carry-On
was: $445
Companion Tote
Electric Grounded Adaptor
Bluetooth Smart Key Fob
was: $145
Passport Case
- Alpha
- Medium Travel Tote
- Style #: 22117
- Free Shipping! See Details
Some will use this as a travel tote to carry all the essentials, others will use it as an everyday bag for transporting an iPad, electronic and personal accessories. It offers organization inside and out with numerous pockets and has a main compartment that expands by 3". Top carry handles and a removable, adjustable shoulder strap. Made from our signature ballistic nylon.
- Monogramming Available: Yes
- External Dimensions (wheeled items include handles and wheels) H x W x D: 14" x 10.5" x 5"
- Expanded Depth: 8"
- Construction Material: Fabric
- External Features:
- Front U-zip pocket
- Zip pocket
- Open pocket
- Back zip pocket
- Back open pocket
- Carry handles
- Removable/adjustable shoulder strap
- ID tag
- Internal Features:
- Pocket for iPad
- Phone pocket
- Zip pocket
- Elastic pockets
- Card pocket
Everyday Free Returns
We want you to be fully satisfied with every product that you purchase from www.tumi.com. If you are not satisfied with a product that you have purchased, you may return the product within 30 days of delivery for a full refund of the purchase price, minus the shipping, handling, gift box, and other charges. Please note, however, that monogrammed and personalized items, including Accent Your Alpha, cannot be returned. Return shipping is free. You will be provided with a pre-paid UPS domestic label to return your purchase. If you cannot find the prepaid shipping label, please call our Customer Service Department at 1-800-299-TUMI (8864) or contact us by email.
We ask that the product be unused, in original boxes (whenever possible), and with all paperwork, parts and accessories in order to ensure credit. Sale merchandise will be issued a credit at the current selling price. Unused items purchased on www.tumi.com can also be returned to a US Tumi full price location. Please make sure to have all paperwork, parts and accessories to ensure credit. Store credit will be issued for items without documentation.
Welcome to the world of Tumi – the finest international brand of travel, business and lifestyle accessories. Since our founding in 1975, Tumi has been dedicated to providing our customers with an outstanding ownership experience.
Specifically, we make three commitments to our customers:
1. You will enjoy using our innovative products that are designed and manufactured to be the best;
2. You will experience world-class, after-sales customer service;
3. For a limited time after you purchase a Tumi product from an authorized Tumi store or dealer, you will be covered by our Limited Warranty.
Tumi's warranty extends to the original owner; it is straightforward and comprehensive, and just part of the total Tumi ownership experience.
Please click here to learn more about the Tumi Warranty.
The Tumi Difference
Add-a-bag system
Quickly and easily add another travel piece or business case using our patented Add-A-Bag hook with secure fastened tab closure that holds in excess of 200 pounds. Also, many Tumi business cases and totes feature a back sleeve that slips over extended luggage handles allowing you to stack and carry heavier bags on your wheeled luggage. Used together, these features allow travelers to effortlessly carry two or three items at the same time with one hand.
Omega Closure System®
Tumi's patented closure system significantly reduces the risk of damage to the zipper. The Omega zipper puller is designed to break away from the bag if it becomes caught. The puller, rather than the entire zipper, is then quickly and easily replaced.
Secure Slide® Shoulder Strap Attachment
Our exclusive, patented shoulder strap attachment design features a cover that slides into place to ensure that the clip stays closed securely. This feature eliminates the risk of bags accidentally falling from the shoulder strap and damaging the cases contents. It can only be opened manually when the hook is placed parallel to the strap attachment.
FXT Ballistic Nylon®
Tumi was the first to bring ballistic nylon to the consumer market over 30 years ago. Now we have perfected it with our exclusive FXT ballistic fabric, which combines a unique weave and a special coating to make it ultra-tough and virtually abrasion proof.
Tumi Tracer®
The Tumi Tracer® is an exclusive, complimentary program that helps reunite Tumi customers with their lost or stolen items. The core of the program is a unique 20-digit individual product number printed on a special metal plate that is permanently affixed to Tumi products. That number, along with the owners contact information, is entered into our Tracer database when a bag is registered with us, and used to help aid in the recovery of lost or stolen items that are reported to us.
This item has a pocket or compartment that is designed to hold eReaders including the iPad, Kindle and Nook.