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Sprague B.L.,University of Vermont | Stout N.K.,Harvard University | Schechter C.,Yeshiva University | Van Ravesteyn N.T.,Erasmus Medical Center | And 10 more authors.
Annals of Internal Medicine | Year: 2015

Background: Many states have laws requiring mammography facilities to tell women with dense breasts and negative results on screening mammography to discuss supplemental screening tests with their providers. The most readily available supplemental screening method is ultrasonography, but little is known about its effectiveness. Objective: To evaluate the benefits, harms, and cost-effectiveness of supplemental ultrasonography screening for women with dense breasts. Design: Comparative modeling with 3 validated simulation models. Data Sources: Surveillance, Epidemiology, and End Results Program; Breast Cancer Surveillance Consortium; and medical literature. Target Population: Contemporary cohort of women eligible for routine screening. Time Horizon: Lifetime. Perspective: Payer. Intervention: Supplemental ultrasonography screening for women with dense breasts after a negative screening mammography result. Outcome Measures: Breast cancer deaths averted, qualityadjusted life-years (QALYs) gained, biopsies recommended after a false-positive ultrasonography result, and costs. Results of Base-Case Analysis: Supplemental ultrasonography screening after a negative mammography result for women aged 50 to 74 years with heterogeneously or extremely dense breasts averted 0.36 additional breast cancer deaths (range across models, 0.14 to 0.75), gained 1.7 QALYs (range, 0.9 to 4.7), and resulted in 354 biopsy recommendations after a falsepositive ultrasonography result (range, 345 to 421) per 1000 women with dense breasts compared with biennial screening by mammography alone. The cost-effectiveness ratio was $325 000 per QALY gained (range, $112 000 to $766 000). Supplemental ultrasonography screening for only women with extremely dense breasts cost $246 000 per QALY gained (range, $74 000 to $535 000). Results of Sensitivity Analysis: The conclusions were not sensitive to ultrasonography performance characteristics, screening frequency, or starting age. Limitation: Provider costs for coordinating supplemental ultrasonography were not considered. Conclusion: Supplemental ultrasonography screening for women with dense breasts would substantially increase costs while producing relatively small benefits. © 2015 American College of Physicians.


Chen L.,Virginia Polytechnic Institute and State University | Xuan J.,Virginia Polytechnic Institute and State University | Xuan J.,Lombardi Comprehensive Cancer Center | Xuan J.,Georgetown University | And 3 more authors.
Nucleic Acids Research | Year: 2013

Identification of differentially expressed subnetworks from protein-protein interaction (PPI) networks has become increasingly important to our global understanding of the molecular mechanisms that drive cancer. Several methods have been proposed for PPI subnetwork identification, but the dependency among network member genes is not explicitly considered, leaving many important hub genes largely unidentified. We present a new method, based on a bagging Markov random field (BMRF) framework, to improve subnetwork identification for mechanistic studies of breast cancer. The method follows a maximum a posteriori principle to form a novel network score that explicitly considers pairwise gene interactions in PPI networks, and it searches for subnetworks with maximal network scores. To improve their robustness across data sets, a bagging scheme based on bootstrapping samples is implemented to statistically select high confidence subnetworks. We first compared the BMRF-based method with existing methods on simulation data to demonstrate its improved performance. We then applied our method to breast cancer data to identify PPI subnetworks associated with breast cancer progression and/or tamoxifen resistance. The experimental results show that not only an improved prediction performance can be achieved by the BMRF approach when tested on independent data sets, but biologically meaningful subnetworks can also be revealed that are relevant to breast cancer and tamoxifen resistance. © 2012 The Author(s).


Michaud K.,University of California at San Francisco | Solomon D.A.,Georgetown University | Oermann E.,Georgetown University | Kim J.-S.,Georgetown University | And 6 more authors.
Cancer Research | Year: 2010

Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study, we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6-specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G1 cell cycle arrest and induction of senescence in each of 16 retinoblastoma protein (Rb)-proficient cell lines regardless of other genetic lesions, whereas 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. Short hairpin RNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 died as a result of disease progression while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy. ©2010 AACR.


Ujjani C.,Lombardi Comprehensive Cancer Center | Cheson B.,Lombardi Comprehensive Cancer Center
Future Oncology | Year: 2011

B-cell malignancies, including B-cell non-Hodgkins lymphoma (NHL) and chronic lymphocytic leukemia (CLL), are the most common hematologic malignancies in the western world. Although excellent response rates are achieved with standard chemoimmunotherapy, patients often relapse and additional treatment is necessary. Bendamustine, a unique cytotoxic agent with alkylating and antimetabolite properties, has been used for decades in Germany for NHL, CLL and multiple myeloma. In 2008, bendamustine was approved by the US FDA for the treatment CLL and rituximab-refractory indolent B-cell NHL. The approval in NHL was based on the results of this multicenter, single-arm trial in which patients with rituximab-refractory indolent NHL received bendamustine 120 mg/m 2 on days 1 and 2 of each 21-day cycle for six to eight cycles. The primary end points were overall response rate and median duration of response, and the secondary end points were progression-free survival and the safety profile. Bendamustine demonstrated significant efficacy with an overall response rate of 75% median duration of response of 9.2 months and median progression-free survival of 9.3 months, as well as easy tolerability. The most common toxicities were nausea, myelosuppression and infection. These results confirm bendamustines role in rituximab-refractory indolent B-cell NHL.


Potosky A.L.,Lombardi Comprehensive Cancer Center
Journal of the National Cancer Institute | Year: 2011

Myeloid colony-stimulating factors (CSFs) decrease the risk of febrile neutropenia (FN) from high-risk chemotherapy regimens administered to patients at 20% or greater risk of FN, but little is known about their use in clinical practice. We evaluated CSF use in a multiregional population-based cohort of lung and colorectal cancer patients (N = 1849). Only 17% (95% confidence interval [CI] = 8% to 26%) patients treated with high-risk chemotherapy regimens received CSFs, compared with 18% (95% CI = 16% to 20%) and 10% (95% CI = 8% to 12%) of patients treated with intermediate- (10%-20% risk of FN) and low-risk (<10% risk of FN) chemotherapy regimens, respectively. Using a generalized estimating equation model, we found that enrollment in a health maintenance organization (HMO) was strongly associated with a lower adjusted odds of discretionary CSF use, compared with non-HMO patients (odds ratio = 0.44, 95% CI = 0.32 to 0.60, P <. 001). All statistical tests were two-sided. Overall, 96% (95% CI = 93% to 98%) of CSFs were administered in scenarios where CSF therapy is not recommended by evidence-based guidelines. This finding suggests that policies to decrease CSF use in patients at lower or intermediate risk of FN may yield substantial cost savings without compromising patient outcomes. © 2011 The Author.


Smith K.L.,Washington Hospital Center | Isaacs C.,Georgetown University | Isaacs C.,Lombardi Comprehensive Cancer Center
Cancer Journal | Year: 2011

BRCA mutation-associated breast cancer differs from sporadic breast cancer with regard to future cancer risks and sensitivity to systemic therapies. Now that rapid genetic testing for BRCA1 and BRCA2 mutations is available at the time of breast cancer diagnosis, BRCA mutation status can be considered when making treatment and prevention decisions for BRCA mutation carriers with breast cancer. This article reviews surgical options for management of affected BRCA mutation carriers with emphasis on the risks of ipsilateral recurrence and contralateral breast cancer. The roles of breast-conserving surgery, prophylactic mastectomy, and oophorectomy are reviewed. In addition, the sensitivity of BRCA mutation-associated breast cancer to endocrine therapy, platinum chemotherapy, and poly (ADP-ribose) polymerase inhibitors is reviewed. Copyright © 2011 by Lippincott Williams & Wilkins.


Etzioni R.,Fred Hutchinson Cancer Research Center | Gulati R.,Fred Hutchinson Cancer Research Center | Mallinger L.,Fred Hutchinson Cancer Research Center | Mandelblatt J.,Lombardi Comprehensive Cancer Center
Annals of Internal Medicine | Year: 2013

Knowledge of the likelihood that a screening-detected case of cancer has been overdiagnosed is vitally important to make treatment decisions and develop screening policy. An overdiagnosed case is an excess case detected by screening. Estimates of the frequency of overdiagnosis in breast and prostate cancer screening vary greatly across studies. This article identifies features of overdiagnosis studies that influence results and shows their effect by using published research. First, different ways to define and measure overdiagnosis are considered. Second, contextual features and how they affect overdiagnosis estimates are examined. Third, the effect of estimation approach is discussed. Many studies use excess incidence under screening as a proxy for overdiagnosis. Others use statistical models to make inferences about lead time or natural history and then derive the corresponding fraction of cases that are overdiagnosed. This article concludes with questions that readers of overdiagnosis studies can use to evaluate the validity and relevance of published estimates and recommends that authors of studies quantifying overdiagnosis provide information about these features. © 2013 American College of Physicians.


News Article | December 7, 2016
Site: www.prweb.com

A new study published in the just-published "Oncotarget" peer-reviewed medical journal has concluded that “in the setting of previously treated, advanced pancreatic cancer, liquid biopsies are not yet an adequate substitute for tissue biopsies. Further refinement in defining the optimal patient population and timing of blood sampling may improve the value of a blood-based test.” The study was conducted by a team of researchers and clinicians from Perthera, Inc., a precision medicine company based in McLean, VA, the Pancreatic Cancer Action Network (PanCAN), Lombardi Comprehensive Cancer Center of Georgetown University, Cedars-Sinai Medical Center, Ohio State University, City of Hope Cancer Center, Virginia Mason Medical Center, and the Sidney Kimmel Cancer Center at Thomas Jefferson University. The study is entitled "a pilot study evaluating concordance between blood-based and patient-matched tumor molecular testing within pancreatic patients participating in the Know Your Tumor (KYT) Initiative." Know Your Tumor is a benchmark precision cancer therapy program of the Pancreatic Cancer Action Network that is executed by Perthera. The study asserted that “molecular profiling of the tumor itself should remain the gold standard,” or as approved by the FDA. Liquid biopsies can "go wrong" in a variety of ways: mainly because the tumor isn't dumping DNA into the blood, or because the detection assays aren't sensitive enough to detect the DNA when it is too low in abundance to see. The investigators assessed the ability of the circulating genomic information obtained from a blood sample of 34 consecutively screened pancreatic cancer patients with metastatic disease to accurately recapitulate the genomic information obtained by direct analysis of a tumor biopsy obtained from the same patient taken at the same time. They used the high frequency of KRAS mutation (~90%) in pancreatic cancer as a benchmark for comparison, and they found that KRAS mutations “were only detected in 10/34 (29%) blood samples, compared to 20/23 (87%) tumor tissue biopsies." Dr. Jonathan Brody, the last author on the study and Director of Surgical Research and Co-director of the Jefferson Pancreas, Biliary and Related Cancer Center and on the scientific advisory board at Perthera, cautioned that "the results of this study should give people some pause; we need to be very careful about the state of the liquid biopsy field right now." He said, "we need to be very circumspect- in this study, we detected DNA with KRAS mutations in only a third of the patients that you should see the genomic alteration, so what does it say about being able to reliably detect actionable alterations that doctors would use to make critical treatment decisions?” Dr. Michael Pishvaian, the first author of the study and Perthera’s CMO as well as the Director of the Phase I Clinical Program and Co-Director of the Ruesch Center Pancreatic Cancer Program at Georgetown University added that “there will be times when a tumor biopsy is unable to be performed due to medical issues, and then could a liquid biopsy be considered. Pishvaian says: “There are papers that show good but not perfect concordance between the genomic information in tumor samples and blood samples, and our study in pancreatic cancer reveals something different. Some of the disparate results from these studies come from differences in the clinical aspects of the patients studied, but ultimately if liquid biopsies are to be used routinely for precision medicine applications then the field needs more improvements.” In the meantime, Emanuel “Chip” Petricoin, PhD, Perthera’s Chief Science Officer said, “Central to Perthera’s medical philosophy is that the patient should have as extensive molecular profiling as relevant, and blood-based testing will be great to add to our arsenal of testing options as it becomes more reliable and sensitive. So, we are committed to implementing molecular profiling technologies that have the best evidence of impact to patients' precision cancer therapy outcome and we will be constantly monitoring the state of the field on this topic. As the liquid biopsy technologies and approaches improve and become more sensitive, then we can validate them and implement them." ABOUT PERTHERA, INC.: Perthera is a founder- and venture-backed precision medicine company based in McLean, VA, that has achieved more than 1,000 case histories since it was founded about five years ago, often working in an alliance with cancer advocacy agencies as well as hospitals, community oncology practices, and academia. In every patient instance, the Company seeks to become the precision medicine partner on their cancer care team, providing the widest, deepest, and most independent range of service possible.


News Article | November 3, 2016
Site: www.chromatographytechniques.com

Doctors have found a disturbing downside to some powerful new drugs that harness the immune system to fight cancer: In rare cases, they may cause potentially fatal heart damage, especially when used together. "The problem is, no one has this on their radar," so patients are not routinely checked for it, said  Javid Moslehi, head of a Vanderbilt University clinic specializing in heart risks from cancer therapies. He led a report Wednesday in the New England Journal of Medicine describing two patients who died of heart trouble two weeks after receiving their first doses of two Bristol-Myers Squibb drugs, Opdivo and Yervoy, for the deadly skin cancer melanoma. Two similar drugs also are on the market, and the study leaders believe they might pose heart risks, too. "My sense is that this is a class effect, not limited to one drug," Moslehi said. The risks do not negate the huge benefits of these relatively new types of drugs, doctors stress. Called checkpoint inhibitors, they have transformed treatment of several types of cancer by helping the immune system see and attack tumors. In rare cases, the immune system seems to attack not only the tumor but also the heart and other muscles, causing dangerous inflammation and heart rhythm problems. Patients need to be told of the risks, monitored closely and treated quickly with medicines to quell the immune response if trouble develops. Besides melanoma, the Opdivo-Yervoy combination is used to treat some lung cancers, though at different doses. Other checkpoint inhibitors include Genentech's Tecentriq, for bladder cancer, and Merck & Co.'s Keytruda, which former President Jimmy Carter received for melanoma that spread to his brain. Many more are in testing. There have been occasional, previous reports of heart troubles with these drugs. After the two recent deaths, doctors asked Bristol-Myers to check patient safety records on Opdivo and Yervoy. As of April, 18 cases of serious heart inflammation were found among 20,594 patients receiving either or both drugs, a rate of 0.09 percent. It was more severe and more common among people on both drugs, affecting 0.27 percent of those patients. Bristol-Myers scientists helped write the journal report, and some other authors consult for the company. Studies have shown that the drug combination gives a stronger anti-cancer effect than either drug alone, but "we've known this is a double-edged sword" because of the risk of over-stimulating the immune system, said Jeffrey Sosman of Northwestern University in Chicago, who treated the two patients who died. "The big question is, is there enough advantage to using the combination, which is much more toxic, than a single drug," he said. That's a larger question facing the cancer field, not just with immune therapies. Some of the newer gene-targeting drugs also have produced major side effects when used in combination. Yet many doctors believe that combos may be the best way to get cancer to go into remission and stay there longer, by shutting down multiple pathways the tumor employs at once. Michael Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center, believes the heart problems with checkpoint inhibitors will turn out to be treatable in most patients. "It just gives us a moment of pause," said Atkins, who led a study that included one of the two patients who died. "This is a rare event ... but it's a particularly serious one."


News Article | November 4, 2016
Site: www.biosciencetechnology.com

Doctors have found a disturbing downside to some powerful new drugs that harness the immune system to fight cancer: In rare cases, they may cause potentially fatal heart damage, especially when used together. "The problem is, no one has this on their radar," so patients are not routinely checked for it, said Dr. Javid Moslehi, head of a Vanderbilt University clinic specializing in heart risks from cancer therapies. He led a report Wednesday in the New England Journal of Medicine describing two patients who died of heart trouble two weeks after receiving their first doses of two Bristol-Myers Squibb drugs, Opdivo and Yervoy, for the deadly skin cancer melanoma. Two similar drugs also are on the market, and the study leaders believe they might pose heart risks, too. "My sense is that this is a class effect, not limited to one drug," Moslehi said. The risks do not negate the huge benefits of these relatively new types of drugs, doctors stress. Called checkpoint inhibitors, they have transformed treatment of several types of cancer by helping the immune system see and attack tumors. In rare cases, the immune system seems to attack not only the tumor but also the heart and other muscles, causing dangerous inflammation and heart rhythm problems. Patients need to be told of the risks, monitored closely and treated quickly with medicines to quell the immune response if trouble develops. Besides melanoma, the Opdivo-Yervoy combination is used to treat some lung cancers, though at different doses. Other checkpoint inhibitors include Genentech's Tecentriq, for bladder cancer, and Merck & Co.'s Keytruda, which former President Jimmy Carter received for melanoma that spread to his brain. Many more are in testing. There have been occasional, previous reports of heart troubles with these drugs. After the two recent deaths, doctors asked Bristol-Myers to check patient safety records on Opdivo and Yervoy. As of April, 18 cases of serious heart inflammation were found among 20,594 patients receiving either or both drugs, a rate of 0.09 percent. It was more severe and more common among people on both drugs, affecting 0.27 percent of those patients. Bristol-Myers scientists helped write the journal report, and some other authors consult for the company. Studies have shown that the drug combination gives a stronger anti-cancer effect than either drug alone, but "we've known this is a double-edged sword" because of the risk of over-stimulating the immune system, said Dr. Jeffrey Sosman of Northwestern University in Chicago, who treated the two patients who died. "The big question is, is there enough advantage to using the combination, which is much more toxic, than a single drug," he said. That's a larger question facing the cancer field, not just with immune therapies. Some of the newer gene-targeting drugs also have produced major side effects when used in combination. Yet many doctors believe that combos may be the best way to get cancer to go into remission and stay there longer, by shutting down multiple pathways the tumor employs at once. Dr. Michael Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center, believes the heart problems with checkpoint inhibitors will turn out to be treatable in most patients. "It just gives us a moment of pause," said Atkins, who led a study that included one of the two patients who died. "This is a rare event ... but it's a particularly serious one."

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