Faculty Publications

Accurate dosimetry of the narrow beam tends to be difficult to perform due to the absence of lateral electronic equilibrium and the steep dose gradient, as well as the finite size of detectors. Thus, although the high dose rate 6 MV beam on the VARIAN Trilogy accelerator is increasingly utilized for stereotactic radiosurgery (SRS) treatment, there is no general agreement in the SRS beam output factor values among the Trilogy user community. Trilogy SRS beams are confined by cone collimators and the available collimator sizes range from 5 and 10 to 30 mm, in every 2 mm increment. A range of the relative output factors are in clinic use. This variation may impair observations of dose response and optimizations of the prescribed dose. It is necessary to investigate an accurate, easily performable, and detector independent method for the narrow beam output factor measurement. In this study, a scanning beam/scanning chamber method was proposed to overcome the limitation/ difficulty of using a relatively large detector in narrow beam output factor measurement. Specifically, for the scanning beam method, multiple narrow beams are used for the dose measurement using a finite size chamber. These multiple scanning beams form an equivalent large uniform field which provides lateral electron equilibrium condition. After the measurement, the contributions from neighboring beams are deconvolved and the value is used for output factor determinations. For a Linac that cannot move a beam laterally, the scanning chamber method can be used to achieve the same result. The output factors determined in such a method were compared to chambers (a 0.015 cc PTW PinPoint ion chamber and a 0.125 cc PTW ion chamber) and film measurement, as well as with Monte Carlo simulation. Film and Monte Carlo results are found to be in excellent agreement with the measurement using the scan beam method. However, the VARIAN recommended output factors measured directly by Wellhofer CC01 chamber and Scanditronix photon field diode are consistently higher for all the cones. Especially for the 5 mm cone, the difference is more than 10%. Overall, the results suggested that the new method can help overcoming the detector volume averaging effect and the positioning uncertainties, which constitute the major challenge in small radiosurgical beam output factor measurement, and provide reliable output factors. (C) 2009 American Association of Physicists in Medicine. [DOI: 10.1118/1.3232217]

The mammalian target of rapamycin (mTOR) is clearly an important therapeutic target for advanced renal cell carcinoma (RCC), although its mechanisms of activation are not completely understood. In first-line treatment of patients who have both advanced RCC and multiple risk factors for short survival, temsirolimus improves overall survival (OS) compared with interferon. In patients whose tumors have progressed after sunitinib and/or sorafenib therapy, everolimus improves progression-free survival compared with placebo. Beyond the initial phase 3 studies demonstrating efficacy, many important questions remain in the clinical application of mTOR inhibition and in developing other inhibitors of PI3K/Akt/mTOR signaling. Important objectives of current and future clinical investigations include a more detailed description of the molecular pathology of RCC and identification of potential biomarkers that are predictive of tumor sensitivity to PI3K/Akt/mTOR targeted therapies. This information may identify other groups of RCC patients that are likely to benefit from inhibition of this signaling pathway. Additional questions concern mechanisms by which tumors become resistant to mTOR inhibitor therapy and how such resistance can be defeated. Possible mechanisms include the loss of feedback inhibition of insulin receptor substate/PI3K signaling resulting from the inhibition of mTOR complex 1 by rapamycin analogs and the activating phosphorylation of Akt by mTOR complex 2. Laboratory studies indicate that these resistance mechanisms could be countered by using other targeted agents in combination with mTOR inhibitors. Cancer 2009;115(10 suppl):2313-20. (c) 2009 American Cancer Society.

Over the past 10 years, a dramatic shift has occurred toward web-based applications and information dissemination both for medical students applying to residency programs and for current housestaff seeking specialty-specific information. This shift has been witnessed in urology with adoption of the Internet-based Electronic Residency Application Service for residency application submission. Currently, most residency programs devote significant attention to developing and maintaining an attractive web page, as studies have suggested departmental websites may impact applicants' decisions regarding residency preference lists.(1,2) Recently, some third-party websites have been established to provide information to medical students and residents in a variety of specialties. No studies are available that evaluate the impact of these external websites on residency decision making. In 2003, a website under the domain name www.UrologyMatch.com was created by 2 coauthors (A.K. and T.M.M.) with the purpose of assisting medical students through the American Urological Association (AUA) match process. Additionally, by providing a discussion forum for students, residents, and faculty, it sought to aid with the dissemination of information between urology programs and applicants. The website has been gradually expanded to provide educational content for urology trainees at a wide range of levels. Components of the website include an introduction to the field of urology, a detailed description of the match process, an "expert advice" section from urologic leaders, a library of relevant Internet links, a digital surgical atlas, and program-specific questionnaire responses provided by residency directors and department chairs. A discussion board providing an uncensored forum for visitors is integrated into the website to aid with the dissemination of information between and among urology programs, residents, and applicants. The high usage of this site has suggested that external websites may have a marked impact on the residency application process. The purpose of the current study was to evaluate the role of www.UrologyMatch.com in the AUA match process. During the 2007-2008 urology residency match, we evaluated whether information disseminated through the website influenced medical students' decisions to enter the field of urology and whether this information factored into the generation of residency preference lists. We hypothesized that information on this website played a significant role in decision making throughout the urology residency match experience.

alphabeta and gammadelta T cells arise from a common thymocyte progenitor during development in the thymus. Emerging evidence suggests that the pre-T cell receptor (pre-TCR) and gammadelta T cell receptor (gammadeltaTCR) play instructional roles in specifying the alphabeta and gammadelta T-lineage fates, respectively. Nevertheless, the signaling pathways differentially engaged to specify fate and promote the development of these lineages remain poorly understood. Here, we show that differential activation of the extracellular signal-related kinase (ERK)-early growth response gene (Egr)-inhibitor of DNA binding 3 (Id3) pathway plays a defining role in this process. In particular, Id3 expression served to regulate adoption of the gammadelta fate. Moreover, Id3 was both necessary and sufficient to enable gammadelta-lineage cells to differentiate independently of Notch signaling and become competent IFNgamma-producing effectors. Taken together, these findings identify Id3 as a central player that controls both adoption of the gammadelta fate and its maturation in the thymus.

It is increasingly important for investigators to efficiently and effectively access, interpret, and analyze the data from diverse biological, literature, and annotation sources in a unified way. The heterogeneity of biomedical data and the lack of metadata are the primary sources of the difficulty for integration, presenting major challenges to effective search and retrieval of the information. As a proof of concept, the Prostate Cancer Ontology (PCO) is created for the development of the Prostate Cancer Information System (PCIS). PCIS is applied to demonstrate how the ontology is utilized to solve the semantic heterogeneity problem from the integration of two prostate cancer related database systems at the Fox Chase Cancer Center. As the results of the integration process, the semantic query language SPARQL is applied to perform the integrated queries across the two database systems based on PCO.

Comments on the articles by N. Jurbergs, A. Long, L. Ticona, and S. Phipps (see record 2009-00460-002) and by Markus A. Landolt et al. (see record 2009-00460-003). In the first study, the authors compared a group of parents of children diagnosed with cancer with a group of parents of physically healthy children. Parents of children across a range of treatment phases, including those on treatment, and parents of children who had had a cancer recurrence, were studied. The authors suggest that the first diagnosis may leave parents vulnerable to developing posttraumatic stress symptoms (PTSS) when their child is diagnosed with a relapse or recurrence. In the second study, children who had acquired severe accidental burns were evaluated for posttraumatic stress disorder (PTSD) and the association between PTSD and quality of life outcomes was assessed. These two studies illustrate key issues in the consideration of whether childhood illness and medical injury is a viable framework for studying PTSD and PTSS. In summary, I believe it is important to move beyond debating the prevalence of PTSD as a method of determining whether PTSD is a viable framework for understanding emotional responses to childhood illness and injury. It is clear that a subset of families report significant stress responses and that PTSD and subsyndromal symptoms reduce quality of life. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

Estrogen plays vital roles in human health and diseases. Estrogen mediates its actions almost entirely by binding to estrogen receptors ( ER), alpha and beta which further function as transcription factors. Selective estrogen receptor modulators ( SERMs) are synthetic molecules which bind to ER and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the prototypical SERM, is extensively used for targeted therapy of ER positive breast cancers and is also approved as the first chemo-preventive agent for lowering breast cancer incidence in high risk women. The therapeutic and preventive efficacy of tamoxifen was initially proven by series of experiments in the laboratory which laid the foundation of its clinical use. Unfortunately, use of tamoxifen is associated with de-novo and acquired resistance and some undesirable side effects. The molecular study of the resistance provides an opportunity to precisely understand the mechanism of SERM action which may further help in designing new and improved SERMs. Recent clinical studies reveal that another SERM, raloxifene, which is primarily used to treat post-menopausal osteoporosis, is as efficient as tamoxifen in preventing breast cancers with fewer side effects. Overall, these findings open a new horizon for SERMs as a class of drug which not only can be used for therapeutic and preventive purposes of breast cancers but also for various other diseases and disorders. Major efforts are therefore directed to make new SERMs with a better therapeutic profile and fewer side effects.

Given high rates of smoking among cancer patients, smoking cessation treatment is crucial; yet limited data exist to guide integration of such trials into the oncologic context. In order to determine the feasibility of conducting smoking cessation clinical trials with cancer patients, screening and baseline data from a large randomized placebo-controlled pharmacotherapy trial were analyzed. Descriptive statistics and regression analyses were used to compare enrollees to decliners, describe program enrollees, and assess correlates of confidence in quitting smoking. Out of 14,514 screened patients, 263 (< 2%) were eligible; 43 (16%) refused enrollment. Among the eligible patients, 220 (84%) enrolled. Enrollment barriers included smoking rate, medical history/contraindicated medication, lack of interest, and language. Compared to enrollees, decliners were more likely to have advanced cancer. The trial enrolled a sample of 67 (> 30%) African Americans; participants had extensive smoking histories; many were highly nicotine dependent; and participants consumed about seven alcoholic beverages/week on average. Head and neck and breast cancer were the most common tumors. About 52 (25%) reported depressive symptoms. A higher level of confidence to quit smoking was related to lower depression and lower tumor stage. Integrating a smoking cessation clinical trial into the oncologic setting is challenging, yet feasible. Recruitment strategies are needed for patients with advanced disease and specific cancers. Once enrolled, addressing participant's depressive symptoms is critical for promoting cessation.

Gastrointestinal stromal tumors (GISTs) typically occur late in life; however, there also are reports of pediatric and young adult patients. This rare subset of GISTs has clinicopathologic and molecular features distinct from their adult counterparts. Most pediatric GIST patients are female and often present with multifocal tumors that are epithelioid in nature. Although these young patients often have metastatic disease, it progresses slowly. Most pediatric GISTs lack the gain-of-function mutation in KIT or PDGFRA commonly found in adult cases. Expression profiling and genomic studies of pediatric GISTs show distinct molecular signatures, suggesting a unique origin as compared with adult GISTs. We and others have shown that the insulin-like growth factor 1 receptor may have a prominent role in driving KIT/PDGFRA mutation-negative adult and pediatric GISTs, and clinical trials are currently being designed to exploit these types of discoveries.

BACKGROUND: Mullerian inhibiting substance (MIS) is a member of the transforming growth factor beta family of growth and differentiation factors that inhibits elongation and branching of mammary ducts and has been shown to inhibit mammary tumor growth in vitro and in animal models. The objective of this study was to determine whether serum MIS levels are associated with breast cancer risk. METHODS: We conducted a prospective case-control study of 309 participants who were registered in the Columbia, Missouri Serum Bank. Each of 105 in situ or invasive breast cancer case patients with prediagnostic serum collected before menopause was matched to two control subjects by age, date, menstrual cycle day, and time of day of blood collection. MIS was measured in serum by using an enzyme-linked immunosorbent assay, and estradiol and testosterone concentrations were quantified by using specific radioimmunoassays. Data were analyzed using conditional logistic regression. All tests of statistical significance were two-sided. RESULTS: The relative odds ratio of breast cancer for women in increasing MIS quartiles were 1, 2.8 (95% confidence interval [CI] = 1.0 to 7.4), 5.9 (95% CI = 2.4 to 14.6), and 9.8 (95% CI = 3.3 to 28.9, P(trend) &lt; .001). The association of MIS with breast cancer was weaker in women who were not taking oral contraceptives at the time of blood collection, but adjustment for estradiol and testosterone levels did not materially alter results for these women. The association of MIS with breast cancer did not vary by age at blood collection but was stronger among women who were diagnosed with breast cancer at an older age than among those who were diagnosed at a younger age. CONCLUSION: MIS may be a novel biomarker of increased breast cancer risk. Additional research including confirmatory epidemiological studies and mechanistic studies is needed.

The compatible osmolyte glycine betaine (GB) is the most efficient osmoprotectant and best excluder from the protein surface. It can reverse protein aggregation and correct mutant protein defects and counter the harmful effects of urea and salts in vivo and in vitro. In this study we have investigated the pH dependence of the stabilizing effect of GB on three different proteins, namely, a-lactalbumin (alpha-LA), lysozyme and ribonuclease-A (RNase-A). We show here that (a) GB stabilizes RNase-A at all pH values, and (b) GB has opposite effects on two proteins at high pH and low pH values, namely, alpha-LA and lysozyme. This conclusion was reached by determining T-m (midpoint of denaturation), Delta H-m (denaturational enthalpy change at T-m), Delta C-p (constant-pressure heat capacity change) and Delta G(D)(o) (denaturational Gibbs energy change at 25 degrees C) of proteins in the presence of different GB concentrations. Another conclusion of this study is that Delta H-m and Delta C-p are not significantly changed in the presence of GB. This study suggests that other methylated glycine osmolytes may also behave in the same manner. (C) 2009 Elsevier B.V. All rights reserved.

PURPOSE: To correlate changes in 2-deoxy-2-[18F]fluoro-d-glucose (18-FDG) positron emission tomography (PET) (18-FDG-PET) uptake with response and disease-free survival with combined modality neoadjuvant therapy in patients with locally advanced rectal cancer. METHODS AND MATERIALS: Charts were reviewed for consecutive patients with ultrasound-staged T3x to T4Nx or TxN1 rectal adenocarcinoma who underwent preoperative chemoradiation therapy at Fox Chase Cancer Center (FCCC) or Robert H. Lurie Comprehensive Cancer Center of Northwestern University with 18-FDG-PET scanning before and after combined-modality neoadjuvant chemoradiation therapy . The maximum standardized uptake value (SUV) was measured from the tumor before and 3 to 4 weeks after completion of chemoradiation therapy preoperatively. Logistic regression was used to analyze the association of pretreatment SUV, posttreatment SUV, and % SUV decrease on pathologic complete response (pCR), and a Cox model was fitted to analyze disease-free survival. RESULTS: A total of 53 patients (FCCC, n = 41, RLCCC, n = 12) underwent pre- and postchemoradiation PET scanning between September 2000 and June 2006. The pCR rate was 31%. Univariate analysis revealed that % SUV decrease showed a marginally trend in predicting pCR (p = 0.08). In the multivariable analysis, posttreatment SUV was shown a predictor of pCR (p = 0.07), but the test results did not reach statistical significance. None of the investigated variables were predictive of disease-free survival. CONCLUSIONS: A trend was observed for % SUV decrease and posttreatment SUV predicting pCR in patients with rectal cancer treated with preoperative chemoradiation therapy. Further prospective study with a larger sample size is warranted to better characterize the role of 18-FDG-PET for response prediction in patients with rectal cancer.

Metastasis is a complex multistep process, which requires the concerted action of many genes and is the primary cause of cancer death. Both pathways that regulate metastasis enhancement and those that regulate its suppression contribute to the tumour dissemination process. To identify new metastasis suppressors, we set up a forward genetic screen in a mouse model. We transduced a genome-wide RNA interference (RNAi) library into the non-metastatic 168FARN breast cancer cell line and orthotopically transplanted the cells into mouse mammary fat pads. We then selected cells that could metastasize to the lung and identified an RNAi for the KLF17 gene. Conversely, we demonstrate that ectopic expression of KLF17 in a highly metastatic 4T1 breast cancer cell line inhibits the ability of cells to metastasize from the mammary fat pad to the lung. We also show that suppression of KLF17 expression promotes breast cancer cell invasion and epithelial-mesenchymal transition (EMT), and that KLF17 protein functions by directly binding to the promoter region of Id1 (which encodes a key metastasis regulator in breast cancer) to inhibit its transcription. Finally, we demonstrate that KLF17 expression is significantly downregulated in primary human breast cancer samples and that the combined expression pattern of KLF17 and Id1 can serve as a potential biomarker for lymph node metastasis in breast cancer.

Introduction: This phase I study was conducted to determine the recommended phase 2 dose of the selective insulin-like growth factor type I receptor (IGF-IR) inhibitor figitumumab (F, CP-751,871) given in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Methods: Patients received paclitaxel 200 mg/m(2), carboplatin (area under the curve of 6), and F (0.05-20 mg/kg) q3 weeks for up to six cycles. Patients with objective response or stable disease were eligible to receive additional cycles of single agent F until disease progression. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints were investigated. Results: Forty-two patients, including 35 with stages IIIB and IV non-small cell lung cancer (NSCLC), were enrolled in eight dose escalation cohorts. A maximum tolerated dose was not identified. Severe adverse events possibly related to F included fatigue, diarrhea, hyperglycemia, gamma glutamyl transpeptidase elevation, and thrombocytopenia (one case each). F plasma exposure parameters increased with dose. Fifteen objective responses (RECIST) were reported, including two complete responses in NSCLC and ovarian carcinoma. Notably, levels of bioactive IGF-1 seemed to influence response to treatment with objective responses in patients with a high baseline-free IGF-1 to IGF binding protein-3 ratio seen only in the 10 and 20 mg/kg dosing cohorts. Conclusions: F was well tolerated in combination with paclitaxel and carboplatin. Based on its favorable safety, pharmacokinetic, and pharmacodynamic properties, the maximal feasible dose of 20 mg/kg has been selected for further investigation.