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Thakur M.K.,Karmanos Cancer Center | Wozniak A.J.,Karmanos Cancer Center
Lung Cancer: Targets and Therapy | Year: 2017

The treatment options for metastatic non-small-cell lung cancer (NSCLC) have expanded dramatically in the last 10 years with the discovery of newer drugs and targeted therapy. Epidermal growth factor receptor (EGFR), when aberrantly activated, promotes cell growth and contributes in various ways to the malignant process. EGFR has become an important therapeutic target in a variety of malignancies. Small-molecule tyrosine kinase inhibitors (TKIs) of EGFR are being used to treat advanced NSCLC and are particularly effective in the presence of EGFR mutations. Monoclonal antibodies have also been developed that block the EGFR at the cell surface and work in conjunction with chemotherapy. Necitumumab is a second-generation fully human IgG1 monoclonal antibody that has shown promise in metastatic NSCLC. The benefit has mostly been restricted to squamous cell lung cancer in the frontline setting. Considering that the survival advantage for these patients was modest, there is a need to discover biomarkers that will predict which patients will likely have the best outcomes. This review focuses on the development and clinical trial experience with necitumumab in NSCLC. © 2017 Thakur and Wozniak.


News Article | May 17, 2017
Site: www.eurekalert.org

WASHINGTON (May 17, 2017) -- A team of investigators led by researchers at Georgetown Lombardi Comprehensive Cancer Center has found that the tumor mutation load, or TML, in a patient's cancer biopsy varied by age and the type of cancer, along with several other factors. Researchers say the findings are some of the most comprehensive analyses of TML to date as they include 14 types of solid tumors. Over 8,000 tissue samples were included in the study making this one of the larger collections of tumors examined for TML. The abstract describing the work was released today. Additional details will be presented at the American Society of Clinical Oncology annual meeting next month in Chicago. TML is a measurement of the number of mutations in DNA. Mutated DNA can be subsequently translated to harmful changes in proteins. Mutated proteins often appear foreign to the immune system and can therefore activate a robust immune response that can be boosted by immunotherapeutic agents. "One of our more interesting findings was the fact that mutation load increased with age in many cancers," says the study's principal investigator, Mohamed E. Salem, M.D., assistant professor of medicine at Georgetown Lombardi. "Older age correlated closely with TML in most of the cancers we examined, but in some cancers, such as bladder cancer, there was no correlation by age, which also makes for an important observation in a difficult to treat type of cancer." Looking for high levels of mutations in tumor may seem to be a contrary way of looking for what therapies might be most effective to fight cancer. Because immunotherapies work by taking the brakes off the immune system, and hence allowing immune-fighting cells to go after cancer cells, the more mutations a cancer cell has may make it appear more alien to the immune-fighting cells and therefore, a more focused object of attack. If a cell's TML is high, an immunotherapy could be more effective and hence Salem's interest in quantifying TML. Tumor mutation load also could be used as a marker to determine which types of cancer and which patients, or subsets of patients, could most benefit from immunotherapy. "We found that, as expected, melanoma had the highest TML as we know clinically that this type of cancer responds best to immunotherapy," says Salem, also a member of Georgetown Lombardi's Ruesch Center for the Cure of GI Cancer. "Indeed, the mean TML for melanoma was nearly double that of the next highest mean, non-small cell lung cancer. In addition, we see that high TML often occurs in tumors lacking well-known cancer-related genes, like BRAF or NRAS genes in melanoma and EGFR or ALK genes in non-small cell lung cancer. This suggests that immune checkpoint inhibitors may be particularly effective in patients who are not candidates for common targeted therapies in these types of cancer." "Our next step is to validate and correlate TML levels with outcomes in patients who have received immunotherapy. We'll look to see if patients had high TML levels before they started therapy and then determine if those with the highest levels had the best clinical outcome, which is what we might expect," he says. "If validation studies prove helpful, they could be very useful in designing clinical trials for many types of cancer," Salem concludes. Co-authors include John Marshall, Michael Atkins, Jimmy J. Hwang, Geoffrey Thomas Gibney, Georgetown Lombardi; Joanne Xiu, Zoran Gatalica, and Nianqing Xiao, Caris Life Sciences; Heinz-Josef Lenz, USC Norris Comprehensive Cancer Center; Philip Agop Philip, Karmanos Cancer Center: Antoinette R. Tan and Derek Raghavan, Levine Cancer Institute; Wafik S. El-Deiry, Fox Chase Cancer Center; and Edward S. Kim and Anthony Frank Shields, Wayne State University. The work was supported by the Ruesch Center for the Cure of GI Cancers. CARIS provided analysis of the tumor samples. Salem and the other co-authors report having no personal financial interests related to the study. Georgetown Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute as a comprehensive cancer center -- the only cancer center of its kind in the Washington, DC area. A part of Georgetown University Medical Center and MedStar Georgetown University Hospital, Georgetown Lombardi seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Connect with Georgetown Lombardi on Facebook (Facebook.com/GeorgetownLombardi) and Twitter (@LombardiCancer). Georgetown University Medical Center (GUMC is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health. Connect with GUMC onFacebook (Facebook.com/GUMCUpdate), Twitter (@gumedcenter) and Instagram (@gumedcenter).


Kumar S.K.,Mayo Medical School | LaPlant B.,Mayo Medical School | Chng W.J.,National University of Singapore | Zonder J.,Karmanos Cancer Center | And 5 more authors.
Blood | Year: 2015

Dysregulation of cyclin-dependent kinases is a hallmark of myeloma, and specifically, cdk5 inhibition can enhance the activity of proteasome inhibitors in vitro. Dinaciclib is a novel potent small molecule inhibitor of cyclin-dependent kinases (CDK)1, CDK2, CDK5, and CDK9. Patients with relapsed multiple myeloma and ≤5 prior lines of therapy, with measurable disease, were enrolled. Dinaciclib was administered on day 1 of a 21-day cycle at doses of 30 to 50 mg/m2. Overall, 27 evaluable patients were accrued; the median number of prior therapies was 4. The dose level of 50 mg/m2 was determined to be the maximally tolerated dose. The overall confirmed partial response rate (PR) was 3 of 27 (11%), including 1 patient at the 30 mg/m2 dose (1 very good PR [VGPR]) and 2 patients at the 40 mg/m2 dose (1 VGPR and 1 PR). In addition, 2 patients at the 50mg/mg2 dose achieved a minimal response (clinical benefit rate, 19%). Leukopenia, thrombocytopenia, gastrointestinal symptoms, alopecia, and fatigue were the most common adverse events. The current study demonstrates single agent activity of dinaciclib in relapsed myeloma, with 2 patients achieving a deep response (VGPR) and 10 patients obtaining some degree of M protein stabilization or decrease. © 2015 by The American Society of Hematology.


PHILADELPHIA -- Most studies reporting the prevalence of breast- and ovarian-cancer causing genes have been conducted with Caucasian women, leaving questions about the role that these same genes play in African American patients with inherited cancers. Now, a team led by researchers at the Basser Center for BRCA in the Abramson Cancer Center at the University of Pennsylvania has taken a step towards a better understanding of this complex subject. Among the results, when compared to previous research focusing on Caucasian women, the study revealed differing patterns of cancer-causing mutations in African-American women. The authors say the results of the study, which will be presented Friday at the 2016 San Antonio Breast Cancer Symposium (poster P5-10-04), could help guide testing recommendations for at risk African American patients. "We know African American women are more likely be diagnosed with breast cancer before age 45, and are more likely to die from breast cancer at every age than Caucasian women, but we need more information about the pattern of genetic mutations in order to provide more precise and targeted care," said lead author Payal D. Shah, MD, an assistant professor of Hematology/Oncology in the Perelman School of Medicine at the University of Pennsylvania and the Abramson Cancer Center. "The patterns suggest biological differences, and potentially different genetic factors. Identifying mutations that disproportionately affect African American women, if there are any, could potentially help guide the genetic testing we do for these at-risk patients." In the study, researchers examined DNA samples of 736 women in three patient groups - African-Americans with cancer, African-Americans without cancer, and Caucasian patients without cancer - in search of patterns of 19 genes known to cause breast and/or ovarian cancer. Notably, when compared to previous research using samples from Caucasian women, results of the study showed mutations of the BRCA1 and BRCA2 genes presented similarly in both races, while CHEK2 gene mutations were seen less in young African American women, and cancer-causing mutations of the TP53 gene were more prevalent. Results also found differences in how frequently African Americans received gene mutation results called "variants of uncertain significance" - or mutations for which the implications on cancer risk is not known. In the populations studied, nearly 15 percent of African American women without cancer received these uncertain results, compared to roughly 11 percent of Caucasian women. The authors suggest the disparity may be related to the higher proportion of Caucasians whose genetic information is included in reference databases, and anticipates that the ability to classify these mutations as cancer-causing or not will improve with more widespread testing including African-Americans, and increased data sharing among researchers and commercial laboratories. "This study is a first step towards being able to zero in on the mutations that are more prevalent in African American patients, but future research is needed to better understand the patterns of genetic mutations across patient populations," Shah said. "Our study clearly demonstrates that patients with cancer have more mutations than those without cancer, but studies examining African American and Caucasian patients with cancer might let us better compare the mutations that are disproportionately present in African Americans." Penn co-authors on the study are Susan M. Domchek, Kara N. Maxwell, Laura Digiovanni, Angela R. Bradbury, and Katherine L. Nathanson. The study was conducted in partnership with the Karmanos Cancer Center at Wayne State University and Color Genomics. Funding for the study was provided by the Basser Center. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania(founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


Knill C.,Karmanos Cancer Center | Snyder M.,Karmanos Cancer Center | Snyder M.,Wayne State University
Medical Physics | Year: 2011

Purpose: The report issued by AAPM Task Group No. 119 outlined a procedure for evaluating the effectiveness of IMRT commissioning. The procedure involves measuring gamma pass-rate indices for IMRT plans of standard phantoms and determining if the results fall within a confidence limit set by assuming normally distributed data. As stated in the TG report, the assumption of normally distributed gamma pass rates is a convenient approximation for commissioning purposes, but may not accurately describe the data. Here the authors attempt to better describe gamma pass-rate data by fitting it to different distributions. The authors then calculate updated confidence limits using those distributions and compare them to those derived using TG No. 119 method. Methods: Gamma pass-rate data from 111 head and neck patients are fitted using the TG No. 119 normal distribution, a truncated normal distribution, and a Weibull distribution. Confidence limits to 95% are calculated for each and compared. A more general analysis of the expected differences between the TG No. 119 method of determining confidence limits and a more time-consuming curve fitting method is performed. Results: The TG No. 119 standard normal distribution does not fit the measured data. However, due to the small range of measured data points, the inaccuracy of the fit has only a small effect on the final value of the confidence limits. The confidence limits for the 111 patient plans are within 0.1% of each other for all distributions. The maximum expected difference in confidence limits, calculated using TG No. 119's approximation and a truncated distribution, is 1.2%. Conclusions: A three-parameter Weibull probability distribution more accurately fits the clinical gamma index pass-rate data than the normal distribution adopted by TG No. 119. However, the sensitivity of the confidence limit on distribution fit is low outside of exceptional circumstances. © 2011 American Association of Physicists in Medicine.


Soubani A.O.,Karmanos Cancer Center | Soubani A.O.,Wayne State University | Ruckdeschel J.C.,Nevada Cancer Institute
Journal of Thoracic Oncology | Year: 2011

In recent years, there have been significant advances in the management of patients with lung cancer. This progress is associated with increased use of medical intensive care units (ICUs) for the management of a variety of complications related to cancer, its treatment, or comorbid illnesses. At the same time, there are advances in the care of critically ill patients in general. Over the last decade, there are several studies that report progressive improvement in the outcome of lung cancer patients admitted to the medical ICUs. On average, the ICU and hospital mortality rates of lung cancer patients are 36% and 51%, respectively. These rates are approaching those of critically ill general population. However, it is clear that not all lung cancer patients will benefit from this aggressive care. Although there are no absolute predictors, the current evidence suggests that advanced refractory cancer, poor baseline performance status, the need for mechanical ventilation, and multiple organ system failures are factors associated with worse ICU outcome. Further studies are needed to better triage patients who are going to benefit from ICU care; determine the optimal duration of this care; and assess the impact of this therapy on the long-term survival, cancer treatment, and quality of life of these patients. Copyright © 2011 The International Association for the Study of Lung Cancer.


Soubani A.O.,Karmanos Cancer Center | Pandya C.M.,Karmanos Cancer Center
Hematology/ Oncology and Stem Cell Therapy | Year: 2010

Hematopoietic stem cell transplantation (HSCT) is an established treatment for a variety of malignant and nonmalignant conditions. Pulmonary complications, infectious and noninfectious, are a major cause of morbidity and mortality in these patients. The recent advances in prophylaxis and treatment of infectious complications increased the significance of noninfectious pulmonary conditions. Acute lung injury due to diffuse alveolar hemorrhage or idiopathic pneumonia syndrome are the main acute complications, while bronchiolitis obliterans remains the most challenging pulmonary complications facing clinicians who are taking care of HSCT recipients. There are other noninfectious pulmonary complications following HSCT that are less frequent. This report provides a clinical update of the incidence, risk factors, pathogenesis, clinical characteristics and management of the main noninfectious pulmonary complications following HSCT.


Lack D.W.,Karmanos Cancer Center
Journal of applied clinical medical physics / American College of Medical Physics | Year: 2014

At our institution the standard delivery quality assurance (DQA) procedure for tomotherapy plans is accomplished with a water equivalent phantom, EDR2 film, and ion chamber point-dose measurements. Most plans deliver at most 5 Gy to the dose plane; however, recently a stereotactic body radiotherapy (SBRT) protocol has produced plans delivering upwards of 12 Gy to the film plane. EDR2 film saturates at a dose of ~ 7 Gy, requiring a modification of our DQA procedure for SBRT plans. To reduce the dose to the film plane and accommodate a possible move to SBRT using Varian RapidArc, a Teflon phantom has been constructed and tested. Our Teflon phantom is cylindrical in shape and of a similar design to the standard phantom. The phantom was MVCT scanned on the TomoTherapy system with images imported into the TomoTherapy and Varian Eclipse planning systems. Phantom images were smoothed to reduce artifacts for treatment planning purposes. Verification SBRT plans were delivered with film and point-dose benchmarked against the standard procedure. Verification tolerance criteria were 3% dose difference for chamber measurements and a gamma pass rate > 90% for film (criteria: 3 mm DTA, 3% dose difference, 10% threshold). The phantom sufficiently reduced dose to the film plane for DQA of SBRT plans. Both planning systems calculated accurate point doses in phantom, with the largest differences being 2.4% and 4.4% for TomoTherapy and Rapid Arc plans. Measured dose distributions correlated well with planning system calculations (γ < 1 for > 95%). These results were comparable to the standard phantom. The Teflon phantom appears to be a potential option for SBRT DQA. Preliminary data show that the planning systems are capable of calculating point doses in the Teflon, and the dose to the film plane is reduced sufficiently to allow for a direct measured DQA without the need for dose rescaling.


Smith S.T.,Karmanos Cancer Center | Szlaczky M.C.,Karmanos Cancer Center
Journal of Oncology Pharmacy Practice | Year: 2014

Method: The ChemoGlo™ sampling kit and analysis services were used to test for cyclophosphamide contamination levels on the syringe plungers of Becton Dickinson® Phaseal and Equashield® syringes that underwent cycles of drug transfer in a Forma Class II, 2A Biological Safety Cabinet. Prior to testing, the syringes were divided into three equal groups for the Equashield® and Becton Dickinson® syringes. A 50mL aliquot of cyclophosphamide was drawn into each syringe and then injected back into the cyclophosphamide vial. This drug transfer procedure was immediately repeated twice for the syringes in group 1, four times for group 2, and eight times for group 3. After the completion of the drug transfers with the Equashield® and Becton Dickinson® Phaseal syringes, the plungers were retracted back to the nominal syringe marking, and a wipe test of the exposed plunger was done using the ChemoGlo™ sampling kit.Results: Significant contamination levels of 2000 ng and greater were detected on most Becton Dickinson® syringe plungers with Phaseal® Closed System Transfer Devices, whereas all Equashield® syringes remained uncontaminated at undetectable levels.Aim: The purpose of this study was to perform a comparative cyclophosphamide contamination level test with Becton Dickinson® syringe plungers with Phaseal® Closed System Transfer Devices and Equashield® syringe plungers under routine oncological compounding conditions. © The Author(s) 2013.


Weyh A.,Karmanos Cancer Center
Journal of applied clinical medical physics / American College of Medical Physics | Year: 2013

This study seeks to compare fixed-field intensity-modulated radiation therapy (FF IMRT), RapidArc (RA), and helical tomotherapy (HT) to discover the optimal treatment modality to deliver SBRT to the peripheral lung. Eight patients with peripheral primary lung cancer were reviewed. Plans were prescribed a dose of 48 Gy and optimized similarly with heterogeneity corrections. Plan quality was assessed using conformality index (CI100%), homogeneity index (HI), the ratio of the 50% isodose volume to PTV (R50%) to assess intermediate dose spillage, and normal tissue constraints. Delivery efficiency was evaluated using treatment time and MUs. Dosimetric accuracy was assessed using gamma index (3% dose difference, 3 mm DTA, 10% threshold), and measured with a PTW ARRAY seven29 and OCTAVIUS phantom. CI100%, HI, and R50% were lowest for HT compared to seven-field coplanar IMRT and two-arc coplanar RA (p < 0.05). Normal tissue constraints were met for all modalities, except maximum rib dose due to close proximity to the PTV. RA reduced delivery time by 60% compared to HT, and 40% when compared to FF IMRT. RA also reduced the mean MUs by 77% when compared to HT, and by 22% compared to FF IMRT. All modalities can be delivered accurately, with mean QA pass rates over 97%. For peripheral lung SBRT treatments, HT performed better dosimetrically, reducing maximum rib dose, as well as improving dose conformity and uniformity. RA and FF IMRT plan quality was equivalent to HT for patients with minimal or no overlap of the PTV with the chest wall, but was reduced for patients with a larger overlap. RA and IMRT were equivalent, but the reduced treatment times of RA make it a more efficient modality.

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