Ramesh Rengan

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (62)262.72 Total impact

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    ABSTRACT: Recent advances allow safe and effective delivery of ablative doses of radiation with stereotactic precision to tumours, resulting in very high levels of tumour control. Parallel advances in the understanding of tumour biology enable delivery of systemic drugs that selectively antagonise biological pathways in the tumour and surrounding microenvironment. Data is emerging that these treatments have synergistic effects that might further increase therapeutic efficacy, and they are therefore being increasingly used in combination, primarily in metastatic or recurrent disease. In this Review we summarise the biological rationale and clinical data for both sterotactic ablative radiotherapy (SABR) and targeted therapies, and the emerging experience with combination of these treatments. We describe potential pathways of cooperation in both tumour and normal tissue between SABR and targeted drugs, and, because fatal toxicities have been reported, we outline clinical precautions.
    The Lancet Oncology 09/2014; 15(10):e426-e434. · 25.12 Impact Factor
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    ABSTRACT: In previously performed animal studies and Phase I-II human trials, Bowman-Birk inhibitor concentrate (BBIC) appeared to be a promising cancer chemopreventive agent. The present study describes the results of two phase I randomized double-blind placebo-controlled trials performed in male subjects to assess the safety and toxicity of the original and new formulations of BBIC administered in a single dose as a suspension in orange juice. The dose of BBIC varied from 800-2,000 chymotrypsin inhibitor (CI) units. The BBI concentration in the serum samples collected from the subjects was analyzed by a dot-blot analysis procedure using the 5G2 monoclonal antibody, which is specific for reduced BBI. A total of 41 subjects were enrolled, 20 in the initial BBIC study and 21 in the second BBIC study. In these human trials, no clinically relevant changes in hematological or biochemical parameters were observed. Overall, BBIC was found to be well-tolerated. For these BBIC single-dose phase I trials, there was no dose-limiting toxicity for BBIC, even at the highest dose evaluated, and there were no apparent differences between the clinical trial results for the two formulations of BBIC. The bioavailability of BBI in the second clinical trial, which used the new BBIC formulation, was approximately 40 to 43% of the BBI bioavailability reached in the first clinical trial, which used the original BBIC formulation. The observed bioavailability difference was attributed to the different BBIC formulations used in these two clinical trials. These trials demonstrated that BBIC is safe when administered in a single dose of up to 2,000 CI units. Therefore, the results from the two trials indicate that a multi-dose trial of BBIC may be safely performed with doses of up to 2,000 CI units per day.
    Oncology letters 04/2014; 7(4):1151-1158. · 0.24 Impact Factor
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    ABSTRACT: Whole brain radiation therapy (WBRT) may cause cognitive and neuropsychological impairment and hence objective assessment of adverse effects of radiation may be valuable to plan therapy. The purpose of our study was to determine the potential of echo planar spectroscopic imaging (EPSI) and diffusion tensor imaging (DTI) in detecting subacute radiation induced injury to the normal brain. Four patients with brain metastases and three patients with lung cancer underwent cranial irradiation. These patients were subjected to 3D-EPSI and DTI at two time points (pre-radiation, and 1 month post-irradiation). Parametric maps of N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), mean diffusivity (MD), and fractional anisotropy (FA) were generated and co-registered to post-contrast T1-weighted images. Normal appearing gray-matter and white-matter regions were compared between the two time points to assess sub-acute effects of radiation using independent sample t-tests. Significantly increased MD (P = .02), Cho/Cr (P = .02) and a trend towards a decrease in NAA/Cr (P = .06) was observed from the hippocampus. Significant decrease in FA (P = .02) from the centrum-semiovale and a significant increase in MD (P = .04) and Cho/Cr (P = .02) from genu of corpus-callosum was also observed. Our preliminary findings suggest that 3D-EPSI and DTI may provide quantitative measures of radiation induced injury to the normal brain.
    Journal of neuroimaging: official journal of the American Society of Neuroimaging 11/2013; · 3.36 Impact Factor
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    ABSTRACT: This study examined rates of tumor progression in treatment-naive patients with non-small-cell lung cancer (NSCLC) as determined by repeat treatment-planning fluorine-18 ((18)F) fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT). This study assessed patients who underwent PET/CT simulation for NSCLC stage II/III, radiation-naive, nonmetastatic NSCLC. It compared planning PET/CT with previous PET/CT images. Patients were analyzed for change in stage, treatment intent, or both. Progression was defined as a change in TNM status leading to upstaging, and standardized uptake value (SUV) velocity was defined as [(SUVscan2 - SUVscan1)/interscan interval in days]. Of 149 consecutive patients examined between April 2009 and April 2011, 47 had prior PET/CT scans and were included. The median age was 68 years. New nodal disease or metastatic disease was identified in 24 (51%) of 47 patients. Fourteen (30%) had evidence of extrathoracic metastatic disease; the remaining 10 (21%) had new nodal disease that required substantial alteration of treatment fields. At a scan interval of 20 days, the rate of upstaging was 17%. SUV velocity was analyzed in the subset of patients who had their studies on the identical PET/CT scanner (n = 14). Nonupstaged patients had a mean SUV velocity of 0.074 units per day, compared with 0.11 units per day in patients that were upstaged by their second PET/CT scan (P = .020). Radiation treatment planning with hybrid PET/CT scans repeated within 120 days of an initial staging PET/CT scan identified significant upstaging in more than half of patients. For a subset of patients who underwent both scans on the same instrument, SUV velocity predicts upstaging, and the difference between those upstaged and those not was statistically significant.
    Clinical Lung Cancer 10/2013; · 2.04 Impact Factor
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    ABSTRACT: Concurrent chemoradiation therapy (CCRT) improves survival compared with sequential treatment for locally advanced non-small cell lung cancer, but it increases toxicity, particularly radiation esophagitis (RE). Validated predictors of RE for clinical use are lacking. We performed an individual-patient-data meta-analysis to determine factors predictive of clinically significant RE. After a systematic review of the literature, data were obtained on 1082 patients who underwent CCRT, including patients from Europe, North America, Asia, and Australia. Patients were randomly divided into training and validation sets (2/3 vs 1/3 of patients). Factors predictive of RE (grade ≥2 and grade ≥3) were assessed using logistic modeling, with the concordance statistic (c statistic) used to evaluate the performance of each model. The median radiation therapy dose delivered was 65 Gy, and the median follow-up time was 2.1 years. Most patients (91%) received platinum-containing CCRT regimens. The development of RE was common, scored as grade 2 in 348 patients (32.2%), grade 3 in 185 (17.1%), and grade 4 in 10 (0.9%). There were no RE-related deaths. On univariable analysis using the training set, several baseline factors were statistically predictive of RE (P<.05), but only dosimetric factors had good discrimination scores (c > .60). On multivariable analysis, the esophageal volume receiving ≥60 Gy (V60) alone emerged as the best predictor of grade ≥2 and grade ≥3 RE, with good calibration and discrimination. Recursive partitioning identified 3 risk groups: low (V60 <0.07%), intermediate (V60 0.07% to 16.99%), and high (V60 ≥17%). With use of the validation set, the predictive model performed inferiorly for the grade ≥2 endpoint (c = .58) but performed well for the grade ≥3 endpoint (c = .66). Clinically significant RE is common, but life-threatening complications occur in <1% of patients. Although several factors are statistically predictive of RE, the V60 alone provides the best predictive ability. Efforts to reduce the V60 should be prioritized, with further research needed to identify and validate new predictive factors.
    International journal of radiation oncology, biology, physics 09/2013; · 4.59 Impact Factor
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    ABSTRACT: The standard of care in Locally-Advanced Non-Small Cell Lung Cancer (LA-NSCLC) is chemotherapy and radiation; however, Radiation-Induced Lung Injury (RILI), which may be prevented by the anti-inflammatory and anti-oxidant properties of Flaxseed (FS), impedes its maximum benefit. Patients with LA-NSCLC requiring definitive RT were randomized to one FS or control muffin daily from start to 2 weeks after RT. Blood and urine were collected to quantify plasma FS metabolites, Enterodione (ED) and Enterolactone (EL), and urinary oxidative stress biomarkers, 8, 12-iso-iPF2a-VI (isoprostane) and 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxo-dGuo). Tolerability was defined as consuming ≥ 75% of the intended muffins and no ≥ grade 3 gastrointestinal toxicities. Fourteen patients (control,7; FS,7) were enrolled. The tolerability rates were 42.9 versus 71.4% (p=0.59) for FS and control, respectively. Mean percentages of intended number of muffins consumed were 37% versus 73% (p=0.12). ED and EL increased at onset of FS and decreased with discontinuation, confirming bioavailability. Isoprostane and 8-oxo-dGuo were detectable. There was a trend towards decreased rates of pneumonitis in FS. This is the first study to report FS bioavailability and quantify oxidative stress markers in NSCLC patients. FS in the administered muffin formulation did not meet tolerability criteria. Given the promising mechanism of FS as a radioprotectant, further investigations should focus on the optimal method for administration of FS.
    Journal of pulmonary & respiratory medicine. 08/2013; 3(4):154.
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    ABSTRACT: The purpose of this study was to examine the impact of body mass index (BMI) on breast cancer patients' self-reported health-related quality of life among patients treated with radiation therapy (RT). Women with breast cancer undergoing RT were prospectively enrolled in an Institutional Review Board-approved clinical trial between 2009 and 2012. Quality of life (QOL) assessments were collected pre-RT, during RT, and within 3 months post-RT using Euroqol (EQ-5D), MD Anderson Symptom Inventory, and functional assessment of cancer therapy-general (FACT-G). 183 breast cancer patients were enrolled, of whom 140 completed assessments at one or more time-point. After adjusting for age, chemotherapy, prior RT, type of breast surgery, and comorbidities, higher BMI remained significantly associated with worse QOL pre-RT, during RT, and post-RT in breast cancer patients. Higher BMI was strongly associated with worse overall FACT-G score on treatment and greater decline in physical well-being on treatment, which persisted after treatment. While effects on QOL of patients in the underweight and normal weight group peaked during treatment, rapidly improving by follow-up, obese patients had worse functional well-being that was more persistent at follow-up. Higher BMI was associated with worse QOL for breast cancer patients before, during, and after RT, and also was associated with reduced return to baseline QOL 3 months post-RT.
    Breast Cancer Research and Treatment 08/2013; · 4.47 Impact Factor
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    ABSTRACT: INTRODUCTION: Post-operative radiotherapy (PORT) for stage IIIA completely-resected non-small cell lung cancer (CR-NSCLC) has been shown to improve local control; however, it is unclear that this translates into a survival benefit. One explanation is that the detrimental effect of PORT on critical organs at risk (OARs) negates its benefit. This study reports an in-silico comparative analysis of passive scattering proton therapy (PSPT)- and intensity modulated proton therapy (IMPT) with intensity modulated photon beam radiotherapy (IMRT) PORT. METHODS: The computed tomography treatment planning scans of ten patients with pathologic stage IIIA CR-NSCLC treated with IMRT were used. IMRT, PSPT, and IMPT plans were generated and analyzed for dosimetric endpoints. The proton plans were constructed with two or three beams. All plans were optimized to deliver 50.4 Gy(RBE) in 1.8 Gy(RBE) fractions to the target volume. RESULTS: IMPT leads to statistically significant reductions in maximum spinal cord, mean lung dose, lung volumes treated to 5, 10, 20, and 30 Gy (V5, V10, V20, V30), mean heart dose, and heart volume treated to 40 Gy (V40), when compared with IMRT or PSPT. PSPT reduced lung V5 but increased lung V20, V30, and heart and esophagus V40. CONCLUSIONS: IMPT demonstrates a large decrease in dose to all OARs. PSPT, while reducing the low-dose lung bath, increases the volume of lung receiving high dose. Reductions are seen in dosimetric parameters predictive of radiation pneumonitis and cardiac morbidity and mortality. This reduction may correlate with a decrease in dose-limiting toxicity and improve the therapeutic ratio.
    Radiation Oncology 06/2013; 8(1):144. · 2.11 Impact Factor
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    ABSTRACT: Lung cancer remains the leading cause of death worldwide. Because many patients with non-small cell lung cancer are elderly and have multiple comorbid conditions, many with potentially curable disease are unfit to undergo definitive surgical resection. Stereotactic body radiation therapy (SBRT) is increasingly being used to treat patients with medically inoperable stage I non-small cell lung cancer. SBRT combines reproducible and accurate anatomic targeting with the delivery of a very high dose per fraction of radiation to a target. Planning and delivery of SBRT is a coordinated effort between the radiation oncology team and consulting services. Clinical outcomes, toxicity profiles, treatment delivery, and indications for SBRT are reviewed. Services currently billed during planning and treatment of SBRT are detailed. This article introduces to consulting specialists and subspecialists a new Current Procedural Terminology code that has been proposed to more accurately reflect work performed during SBRT by these consulting providers. This code is described, and its implications for patient care are discussed.
    Chest 06/2013; 143(6):1784-90. · 5.85 Impact Factor
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    ABSTRACT: Lung cancer accounts for nearly one-fifth of all cancer deaths worldwide and is the most common cause of cancer-related death in the United States. Outcomes for locally advanced non-small cell lung cancer remain extremely poor with regards to both local control and overall survival. Modest gains in local control were obtained with the incorporation of multimodality treatment, including preoperative chemotherapy followed by surgical resection; combination chemoradiotherapy also improved survival, secondary to improved local control. While the natural progression to trimodality therapy resulted in superior local control, it did not translate to improved overall survival, secondary to increased toxicity. The additional morbidity is likely from radiation toxicity, the minimization of which will be crucial to the future success of trimodality therapy. One strategy to decrease toxicity is to utilize charged particles, such as protons, which deposit a high dose at the Bragg peak with a minimal dose beyond the peak, thereby reducing the dose to distal normal tissues. Trimodality therapy incorporating preoperative proton radiation therapy and chemotherapy, followed by surgery, is currently being evaluated as a potential strategy to achieve improved local control and overall survival in locally advanced non-small cell lung cancer.
    Thoracic Cancer. 05/2013; 4(2).
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    ABSTRACT: INTRODUCTION:: Although positron emission tomography computed tomography (PET-CT) has been widely used for small-cell lung cancer (SCLC) staging, no study has examined the clinical impact of PET staging in limited-stage (LS) SCLC. METHODS:: We identified patients with LS-SCLC treated definitively with concurrent chemoradiation. Outcomes were assessed using the Kaplan-Meier approach, Cox regression, and competing risks method. RESULTS:: We treated 54 consecutive LS-SCLC patients with concurrent chemoradiation from January 2002 to August 2010. Forty underwent PET, 14 did not, and all underwent thoracoabdominopelvic CT and magnetic resonance imaging neuroimaging. Most patient characteristics were balanced between the comparison groups, including age, race, sex, bone scanning, median dosage, and performance status. More number of PET-staged patients presented with nodal metastases (p = 0.05). Median follow-up was similar for PET-staged and non-PET-staged patients (p = 0.59). Median overall survival from diagnosis in PET-staged patients was 32 versus 17 months in patients staged without PET (p = 0.03), and 3-year survival was 47% versus 19%. Median time-to-distant failure was 29 versus 12 months (p = 0.04); median time-to-local failure was not reached versus 16 months (p = 0.04). On multivariable analysis, PET staging (odds ratio [OR] = 0.24; p = 0.04), performance status (OR = 1.89; p = 0.05), and N-stage (OR = 4.94; p < 0.01) were associated with survival. CONCLUSION:: LS-SCLC patients staged with PET exhibited improved disease control and survival when compared with non-PET-staged LS-SCLC patients. Improved staging accuracy and better identification of intrathoracic disease may explain these findings, underscoring the value of PET-CT in these patients.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2013; · 4.55 Impact Factor
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    ABSTRACT: Precise patient positioning is critical due to the large fractional doses and small treatment margins employed for thoracic stereotactic body radiation therapy (SBRT). The goals of this study were to evaluate the following: (1) the accuracy of kilovoltage x-ray (kV x-ray) matching to bony anatomy for pretreatment positioning; (2) the magnitude of intrafraction tumor motion; and (3) whether treatment or patient characteristics correlate with intrafraction motion. Eighty-seven patients with lung cancer were treated with SBRT. Patients were positioned with orthogonal kV x-rays matched to bony anatomy followed by cone-beam computed tomography (CBCT), with matching of the CBCT-visualized tumor to the internal gross target volume obtained from a 4-dimensional CT simulation data set. Patients underwent a posttreatment CBCT to assess the magnitude of intrafraction motion. The mean CBCT-based shifts after initial patient positioning using kV x-rays were 2.2 mm in the vertical axis, 1.8 mm in the longitudinal axis, and 1.6 mm in the lateral axis (n = 335). The percentage of shifts greater than 3 mm and 5 mm represented 39% and 17%, respectively, of all fractions delivered. The mean CBCT-based shifts after treatment were 1.6 mm vertically, 1.5 mm longitudinally, and 1.1 mm laterally (n = 343). Twenty-seven percent and 10% of shifts were greater than 3 mm and 5 mm, respectively. Univariate and multivariable analysis demonstrated a significant association between intrafraction motion with weight and pulmonary function. Kilovoltage x-ray matching to bony anatomy is inadequate for accurate positioning when a conventional 3-5 mm margin is employed prior to lung SBRT. Given the treatment techniques used in this study, CBCT image guidance with a 5-mm planning target volume margin is recommended. Further work is required to find determinants of interfraction and intrafraction motion that may help guide the individualized application of planning target volume margins.
    Practical radiation oncology. 01/2013; 3(4):307-15.
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    ABSTRACT: Purpose: The objective of this study is to describe the impact of sociodemographic (SOC) factors on the management of lung cancer patients treated at radiation therapy facilities participating in the Quality Research in Radiation Oncology survey. Methods and materials: A 2-stage stratified random sample of lung cancer patients treated in 2006 to 2007 at 45 facilities yielded 340 stage I-III non-small cell lung cancer (NSCLC) and 144 limited-stage small cell lung cancer (LS-SCLC) cases. Five SOC variables based on data from the 2000 US Census were analyzed for association with the following clinical factors: patients living in urban versus rural settings (U/R); median household income (AHI); % below poverty level (PPV); % unemployed (PUE); and % with college education (PCE). Results: The 340 NSCLC patients were stage I, 16%; stage II, 11%; stage III, 62%; stage unknown, 11%. Histologic subtypes were adenocarcinoma, 31.8%; squamous cell carcinoma, 35.3%; large cell carcinoma, 3.2%; and NSCLC NOS, 27.7%. The median age was 66 years. Median Karnofsky performance status (KPS) was 80. The 144 LS-SCLC had a median age of 63; 73 were male (50.7%). Median KPS was 80. Stereotactic body radiation therapy (SBRT) and modern imaging utilization was associated with treatment at facilities located in higher SOC regions. SBRT was employed in 46.8% stage I NSCLC patients treated in centers where %PUE was below median versus 14.8% in centers where %PUE was above median (P = .02). Four-dimensional computed tomography was utilized in 14.2% of patients treated in centers located in regions with %PPV below median versus 3.7% in centers located in regions with %PPV above median (P < .01). SCLC patients were more likely to receive all of their planned RT when treated at centers located in regions with lower PPV (95.0% vs 79.1%; P = .04). Conclusions: SOC factors may impact use of modern treatment planning and delivery and multidisciplinary management of NSCLC and SCLC. These results may suggest an impact of these SOC factors on access to health care.
    Practical radiation oncology. 01/2013; 4(3):e167-79.
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    ABSTRACT: BACKGROUND: HIV-infected patients with lung cancer have been reported to have poorer survival than uninfected patients. Whether this outcome holds true in the era of highly active antiretroviral therapy (HAART) is unclear. We examined the effect of HIV infection on clinical outcome in patients with lung cancer who are also receiving HAART. METHODS: Patients diagnosed with non-small-cell lung cancer (NSCLC) from Jan 1, 2000, to Dec 31, 2005, with or without HIV infection were identified by querying the Surveillance, Epidemiology, and End Results registry and the Medicare lung cancer database. Survival analysis by stage and treatment delivered comparing the HIV-infected patients with uninfected controls was done with Kaplan-Meier and Cox models with propensity score adjustments. FINDINGS: 71 976 patients with NSCLC were identified as uninfected controls and 322 patients with NSCLC were identified in the HIV group; median age was 75 years for both groups. Median overall survival for all stages was 7·0 months (95% CI 7·0-7·0) for uninfected controls versus 8·0 months (6·0-10·0) for the HIV group (p=0·16); for those with stage I/II disease it was 37·0 months (36·0-39·0) versus 43·0 months (26·0-58·0; p=0·37); for those with stage IIIA/IIIB disease it was 7·0 months (7·0-7·0) versus 3·0 months (2·0-8·0; p=0·051); and for those with stage IV disease it was 3·0 months for both groups (95% CI 3·0-3·0 for controls; 2·0-5·0 for HIV group; p=0·77). After propensity score adjustment, the survival difference in stage IIIA/IIIB was no longer seen (hazard ratio 0·88; 95% CI 0·71-1·09). The median survival for HIV infected patients with stage I or II NSCLC who underwent surgical resection was 58·0 months (95% CI 57·0-60·0) for uninfected controls versus 50·0 months (42·0 to unestimable) for the HIV group (p=0·88). INTERPRETATION: We noted no significant difference in clinical outcome between patients with HIV and uninfected controls with NSCLC. Survival after curative surgical resection in early-stage patients was similar in HIV-infected individuals and uninfected controls. These data suggest that HIV status should not affect therapeutic decision making in NSCLC. FUNDING: US National Cancer Institute (award number UC2CA148310).
    The Lancet Oncology 11/2012; · 25.12 Impact Factor
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    ABSTRACT: OBJECTIVES:: The objective of this study was to identify predictive factors of occult mediastinal nodal involvement on staging positron emission tomography with F-fluorodeoxyglucose in patients with non-small cell lung cancer. METHODS:: We performed a retrospective review of 665 patients with suspected non-small cell lung cancer who underwent staging positron emission tomography with F-fluorodeoxyglucose from January 1, 2000 through August 31, 2010 at the Hospital of the University of Pennsylvania with clinical stage I or II disease and no evidence of N2 or N3 involvement on staging positron emission tomography (PET). A total of 201 of these patients underwent invasive pathologic staging of the mediastinum at the Hospital of the University of Pennsylvania with pathology reports available at the time of review. RESULTS:: A total of 63 of the 201 patients were found to have N2 disease at the time of pathologic staging. The mean standardized uptake value (SUV) of the primary tumor for patients with occult N2 metastases was significantly higher than the node-negative patients (SUV 9.31 vs. 7.24, P=0.04). Histology, tumor location (central vs. peripheral), sex, and age were not predictive for occult N2 disease. A multivariate analysis was performed and identified primary tumor SUV>6 was the only significant predictor (P=0.02). An analysis by quartile identified a primary tumor SUV>10 to have an odds ratio of 1.72 compared with an SUV<4 of occult N2 involvement. CONCLUSIONS:: Increased primary tumor SUV predicted for increased risk of mediastinal nodal disease. Tumor location was not predictive of PET-occult mediastinal nodal involvement, in contrast to previous publications. Pathologic staging of the mediastinum should be strongly considered in these patients even with a negative mediastinum on PET.
    American journal of clinical oncology 10/2012; · 2.21 Impact Factor
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    ABSTRACT: OBJECTIVES:: HIV-infected people have elevated risk for lung cancer and higher mortality following cancer diagnosis than HIV-uninfected individuals. It is unclear whether HIV-infected people with lung cancer receive similar cancer treatment as HIV-uninfected people. DESIGN/METHODS:: We studied adults 18+ years old with lung cancer reported to the Texas Cancer Registry (N = 156,930) from 1995-2009. HIV status was determined by linkage with the Texas enhanced HIV/AIDS Reporting System. For non-small cell lung cancer (NSCLC) cases, we identified predictors of cancer treatment using logistic regression. We used Cox regression to evaluate effects of HIV and cancer treatment on mortality. RESULTS:: Compared with HIV-uninfected lung cancer cases (N = 156,593), HIV-infected lung cancer cases (N = 337) were more frequently young, non-Hispanic black, male, and with distant stage disease. HIV-infected NSCLC cases less frequently received cancer treatment than HIV-uninfected cases (60.3% vs. 77.5%; odds ratio 0.39, 95% confidence interval [CI] 0.30-0.52, after adjustment for diagnosis year, age, sex, race, stage, and histologic subtype). HIV infection was associated with higher lung cancer-specific mortality (hazard ratio [HR] 1.34, 95%CI 1.15-1.56, adjusted for demographics and tumor characteristics). Inclusion of cancer treatment in adjusted models slightly attenuated the effect of HIV on lung cancer-specific mortality (HR 1.25; 95%CI 1.06-1.47). Also, there was a suggestion that HIV was more strongly associated with mortality among untreated than among treated cases (adjusted HR 1.32 vs. 1.16, p-interaction = 0.34). CONCLUSION:: HIV-infected NSCLC cases were less frequently treated for lung cancer than HIV-uninfected cases, which may have affected survival.
    AIDS (London, England) 10/2012; · 4.91 Impact Factor
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    ABSTRACT: We investigated the effect of NVP-BEZ235 (Novartis), a dual PI3K/mTOR inhibitor currently being tested in phase I clinical trials, in radiosensitization. BEZ235 radiosensitized a variety of cancer cell lines including SQ20B head and neck carcinoma cells and U251 glioblastoma cells. BEZ235 also increased in vivo radiation response in SQ20B xenografts. Knockdown of Akt1, p110α, or mTOR resulted in radiosensitization, but not to the same degree as with BEZ235. BEZ235 interfered with DNA damage repair following radiation as measured by the Comet assay and resolution of γH2AX foci. BEZ235 abrogated the radiation-induced phosphorylation of both DNA-PKcs and ATM. Knockdown of either p110α or mTOR failed to decrease phosphorylation of DNA-PKcs, suggesting that the effect of the drug was direct rather than mediated via p110α or mTOR. Treatment of cells with BEZ235 also promoted autophagy. To assess the importance of this process in radiosensitization, we used the autophagy inhibitors 3-methyladenine and chloroquine and found that either drug increased cell killing after BEZ235 treatment and radiation. Knocking down the essential autophagy proteins ATG5 and Beclin1 increased BEZ235-mediated radiosensitization. Furthermore, BEZ235 radiosensitized autophagy deficient ATG5-/- fibroblasts to a greater extent than ATG5+/+ cells. We conclude that BEZ235 radiosensitizes cell and induces autophagy, by apparently distinct mechanisms. Inhibiting autophagy via pharmacologic or genetic means increases radiation killing following BEZ235 treatment; hence, autophagy appears to be cytoprotective in this situation. Our data offer a rationale for combining BEZ235 along with an autophagy inhibitor (i.e. chloroquine) and radiation in future clinical trials.
    Molecular pharmacology 09/2012; · 4.53 Impact Factor
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    ABSTRACT: Abstract The primary goals of this study were to determine the biodistribution and excretion of (18)F-EF5 in oncologic patients, to estimate the radiation-absorbed dose and to determine the safety of this drug. Methods: Sixteen patients with histologically confirmed malignancy received a mean intravenous infusion of 217 MBq (range 107-364 MBq) of (18)F-EF5. Over a 4-6-hour period, four to five serial positron emission tomography (PET) or PET/computed tomography (CT) scans were obtained. To calculate the radiation dosimetry estimates, volumes of interest were drawn over the source organs for each PET scan or on the CT for each PET/CT scan. Serial blood samples were obtained to measure (18)F-EF5 blood clearance. Bladder-wall dose was calculated based on urine activity measurements. Results: The urinary bladder received the largest radiation-absorbed dose, 0.12±0.034 mSv/MBq (mean±SD). The average effective dose equivalent and the effective dose of (18)F-EF5 were 0.021±0.003 mSv/MBq and 0.018±0.002 mSv/MBq, respectively. (18)F-EF5 was well tolerated in all subjects. Conclusions: (18)F-EF5 was demonstrated to be safe for patients, and the radiation exposure is clinically acceptable. As with any radiotracer with primary excretion in the urine, the bladder-wall dose can be minimized by active hydration and frequent voiding.
    Cancer Biotherapy & Radiopharmaceuticals 08/2012; 27(7):412-9. · 1.44 Impact Factor
  • New England Journal of Medicine 06/2012; 366(24):2327-9. · 51.66 Impact Factor
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    ABSTRACT: BACKGROUND: Radiation pneumonitis is a dose-limiting toxicity for patients undergoing concurrent chemoradiation therapy (CCRT) for non-small cell lung cancer (NSCLC). We performed an individual patient data meta-analysis to determine factors predictive of clinically significant pneumonitis. METHODS AND MATERIALS: After a systematic review of the literature, data were obtained on 836 patients who underwent CCRT in Europe, North America, and Asia. Patients were randomly divided into training and validation sets (two-thirds vs one-third of patients). Factors predictive of symptomatic pneumonitis (grade ≥2 by 1 of several scoring systems) or fatal pneumonitis were evaluated using logistic regression. Recursive partitioning analysis (RPA) was used to define risk groups. RESULTS: The median radiation therapy dose was 60 Gy, and the median follow-up time was 2.3 years. Most patients received concurrent cisplatin/etoposide (38%) or carboplatin/paclitaxel (26%). The overall rate of symptomatic pneumonitis was 29.8% (n=249), with fatal pneumonitis in 1.9% (n=16). In the training set, factors predictive of symptomatic pneumonitis were lung volume receiving ≥20 Gy (V(20)) (odds ratio [OR] 1.03 per 1% increase, P=.008), and carboplatin/paclitaxel chemotherapy (OR 3.33, P<.001), with a trend for age (OR 1.24 per decade, P=.09); the model remained predictive in the validation set with good discrimination in both datasets (c-statistic >0.65). On RPA, the highest risk of pneumonitis (>50%) was in patients >65 years of age receiving carboplatin/paclitaxel. Predictors of fatal pneumonitis were daily dose >2 Gy, V(20), and lower-lobe tumor location. CONCLUSIONS: Several treatment-related risk factors predict the development of symptomatic pneumonitis, and elderly patients who undergo CCRT with carboplatin-paclitaxel chemotherapy are at highest risk. Fatal pneumonitis, although uncommon, is related to dosimetric factors and tumor location.
    International journal of radiation oncology, biology, physics 06/2012; · 4.59 Impact Factor

Publication Stats

338 Citations
262.72 Total Impact Points


  • 2008–2014
    • University of Pennsylvania
      • Department of Radiation Oncology
      Philadelphia, Pennsylvania, United States
  • 2013
    • Seattle Cancer Care Alliance
      Seattle, Washington, United States
    • Montefiore Medical Center
      New York City, New York, United States
  • 2008–2013
    • Hospital of the University of Pennsylvania
      • • Department of Radiation Oncology
      • • Department of General Internal Medicine
      Philadelphia, Pennsylvania, United States
  • 2004–2008
    • Memorial Sloan-Kettering Cancer Center
      • Department of Radiation Oncology
      New York City, NY, United States