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You J.J.,McMaster University | You J.J.,Institute for Clinical Evaluative science | Wong R.K.S.,University of Toronto | Darling G.,McMaster University | And 2 more authors.
Journal of Thoracic Oncology | Year: 2013

Introduction: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) may play an important role in staging patients with potentially resectable esophageal cancer but its impact on clinical management remains unclear. Methods: In a multicenter prospective cohort study of patients with potentially resectable esophageal cancer, we compared stage of disease based on PET/CT with the stage based on conventional staging performed before PET/CT (American Joint Committee on Cancer, 6th edition). The primary outcome was the proportion of patients with a clinically important change in stage, based on PET/CT findings. We used health administrative databases to track health services use and mortality after the index PET/CT scan. Results: Four hundred ninety-one patients who received a PET/CT scan for staging of potentially resectable esophageal cancer were included in the study cohort. PET/CT led to clinically important changes in stage for a total of 188 patients (24.0%): 107 patients (21.8%) were upstaged and 11 patients (2.2%) were downstaged. Results of PET/CT were associated with differences in actual management. At the 6-month follow-up, use of surgery was greater in patients with M0 disease (54.4%) compared with those with M1a (25.0%; p < 0.001) or M1b (7.3%; p < 0.001) disease based on PET/CT. The overall cohort had a median survival of 603 days, and higher stage of disease on PET/CT (i.e., M stage) was associated with shorter survival (p < 0.001). Conclusions: PET/CT identifies disease not otherwise detected on conventional staging and results in clinically important changes in stage for an appreciable number of patients with potentially resectable esophageal cancer and can make important contributions to the management of these patients. Copyright © 2013 by the International Association for the Study of Lung Cancer.


Oh W.K.,Dana-Farber Cancer Institute | Vargas R.,Pennsylvania State University | Jacobus S.,Dana-Farber Cancer Institute | Leitzel K.,Pennsylvania State University | And 9 more authors.
Cancer | Year: 2011

Background: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has paradoxical multifunctional roles in tumorigenesis: inhibition of the catalytic activity of matrix metalloproteinases and apoptosis as well as promotion of angiogenesis and tumor growth. Elevated TIMP-1 levels have been associated with a poorer prognosis in multiple cancers. Methods: Ethylenediaminetetraacetic acid plasma TIMP-1 was determined in 362 castration-resistant prostate cancer (PC) patients using a TIMP-1 enzyme-linked immunosorbent assay. All patients with castration-resistant PC and available plasma were identified from an institutional database. Overall survival was analyzed using the Kaplan-Meier method and Cox modeling on plasma TIMP-1 tertiles. Results: Patients were evaluated in pilot (n = 60) and primary (n = 302) sets. Median follow-up from diagnosis was 5.8 and 6.6 years, respectively. Median plasma TIMP-1 levels were 335 and 183 ng/mL in the pilot and primary sets, respectively. Overall survival was significantly shorter with each higher tertile of TIMP-1 in both datasets (P<.001). For the primary cohort, hazard ratio of (HR) death and median survival by plasma TIMP-1 tertile levels were: low, HR 1.0, 43 months; middle, HR 1.7, 27 months; high, HR 2.4, 19 months. In the primary set, significant covariates in the adjusted Cox regression model were: TIMP-1 level (mid or high vs low tertile), prostate-specific antigen (>20 vs ≤ 20 ng/mL), alkaline phosphatase (>102 vs â102 U/L), Eastern Cooperative Oncology Group performance status (1 + vs 0), and Gleason score (7 or 8 vs ≤ 6). Conclusions: Elevated plasma TIMP-1 levels predicted decreased survival in metastatic castration-resistant PC patients, independent of known prognostic markers. © 2010 American Cancer Society.


Alkhateeb A.A.,Pennsylvania State University | Leitzel K.,Pennsylvania State University | Ali S.M.,Pennsylvania State University | Ali S.M.,Lebanon Medical Center | And 6 more authors.
PLoS ONE | Year: 2012

Approximately half of all HER2/neu-overexpressing breast cancer patients do not respond to trastuzumab-containing therapy. Therefore, there remains an urgent and unmet clinical need for the development of predictive biomarkers for trastuzumab response. Recently, several lines of evidence have demonstrated that the inflammatory tumor microenvironment is a major contributor to therapy resistance in breast cancer. In order to explore the predictive value of inflammation in breast cancer patients, we measured the inflammatory biomarkers serum ferritin and C-reactive protein (CRP) in 66 patients immediately before undergoing trastuzumab-containing therapy and evaluated their progression-free and overall survival. The elevation in pre-treatment serum ferritin (>250 ng/ml) or CRP (>7.25 mg/l) was a significant predictor of reduced progression-free survival and shorter overall survival. When patients were stratified based on their serum ferritin and CRP levels, patients with elevation in both inflammatory biomarkers had a markedly poorer response to trastuzumab-containing therapy. Therefore, the elevation in inflammatory serum biomarkers may reflect a pathological state that decreases the clinical efficacy of this therapy. Anti-inflammatory drugs and life-style changes to decrease inflammation in cancer patients should be explored as possible strategies to sensitize patients to anti-cancer therapeutics. © 2012 Alkhateeb et al.


Vo M.N.,Pennsylvania State University | Evans M.,Pennsylvania State University | Leitzel K.,Pennsylvania State University | Ali S.M.,Pennsylvania State University | And 5 more authors.
Breast Cancer Research and Treatment | Year: 2010

Background Endoglin (CD105) is a co-receptor for TGF-β, is expressed by human vascular endothelial cells, and plays a major role in angiogenesis. Materials and methods Pretreatment EDTA plasma from 224 metastatic breast cancer patients enrolled in a phase III 2nd-line hormone therapy trial and 50 control subjects were assayed for endoglin using an ELISA. Results The female control group (n = 50) plasma endoglin upper limit of normal was defined as the mean + 2 SD (8.7 ng/ml). The breast cancer patient plasma endoglin was 6.40 ± 2.23 ng/ml (range 3.00-19.79 ng/ml). Elevated plasma endoglin levels were detected in 26 of 224 patients (11.6%). Patients with elevated plasma endoglin had a reduced clinical benefit rate (CR + PR + Stable) (15 vs. 42%) (P = 0.01) to hormone therapy. TTP was shorter for patients with elevated plasma endoglin, but did not reach statistical significance (P = 0.2). Patients with elevated plasma endoglin had decreased overall survival (median 645 vs. 947 days) (P = 0.005). Conclusion Elevated pretreatment plasma endoglin levels predicted for decreased clinical benefit and a shorter overall survival in metastatic breast cancer patients treated with 2nd-line hormone therapy. © 2008 Springer Science+Business Media, LLC.


Garg A.,Pennsylvania State University | Leitzel K.,Pennsylvania State University | Ali S.,Pennsylvania State University | Ali S.,Lebanon Medical Center | Lipton A.,Pennsylvania State University
Current Osteoporosis Reports | Year: 2015

Cancer treatment-induced bone loss treatment has an important role to prevent bone loss-related events like fracture, significant morbidity, mortality, disfigurement and loss of self-esteem, and health-care expenditure. Numerous factors, including treatment regimens and bone metastasis, increase the risk of osteoporosis or local bone destruction in most breast and prostate cancer patients. Cytotoxic chemotherapies, radiation, and hormonal therapies can lead to premature menopause and decrease bone mineral density. Over 60 % of breast cancer patients within 1 year of beginning postoperative adjuvant chemotherapy experience ovarian failure. Also, ovarian ablation and aromatase inhibitors used to treat breast cancer and orchiectomy and androgen deprivation therapy (ADT; to treat prostate cancer) cause substantial bone loss. In this article, we will focus mainly on antiresorptive therapy in the management of cancer treatment-induced bone loss (CTIBL). An understanding of CTIBL is critical for determining how to assess the risk and identify which patients may benefit from preventive therapy. © 2015, Springer Science+Business Media New York.


Sivendran S.,Mount Sinai School of Medicine | Liu Z.,Indiana University | Portas Jr. L.J.,Lebanon Medical Center | Yu M.,Indiana University | And 4 more authors.
Cancer Treatment Reviews | Year: 2012

Background: Several vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI) are now approved by regulatory agencies and are important in the treatment of solid tumor malignancies. The risk of fatal adverse events (FAEs) with these agents is not well characterized. Methods: PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating sunitinib, sorafenib, pazopanib, and vandetanib in patients with all malignancies. Thirteen eligible randomized controlled trials were included in a meta-analysis and the number of FAEs (defined by the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) criteria) was extracted and study quality was calculated. Incidence rates and relative risks were calculated for all thirteen studies as well as for the subset of patients with renal cell carcinoma. Results: Analysis of the 5164 patients across 13 RCTs revealed that the relative risk was 1.64 (95% CI, 1.16, 2.32; P= 0.01; incidence 2.26% vs. 1.26%) for the association of a VEGFR TKI with FAEs using a random-effects model. All exploratory subgroup analyses indicated a trend toward an increase risk of FAEs with VEGFR TKI treatment, though the subgroup analyses reached statistical significance for renal carcinoma studies, studies utilizing placebo as the control arm, and studies evaluating sorafenib. Interpretation: This analysis suggests that VEGFR TKIs are associated with a significant increase in the risk of FAEs in patients with advanced solid tumors. © 2012 Elsevier Ltd.


Lipton A.,Pennsylvania State University | Campbell-Baird C.,Pennsylvania State University | Witters L.,Pennsylvania State University | Harvey H.,Pennsylvania State University | Ali S.,Lebanon Medical Center
Journal of Clinical Gastroenterology | Year: 2010

GOALS AND Background: Cyclooxygenase-2 (COX-2) has been shown to be expressed in a variety of tumors including pancreatic cancer. The combination of gemcitabine and irinotecan is active in pancreatic cancer. The purpose of this study is to determine the toxicity and response rate to the addition of the selective oral COX-2 inhibitor, celecoxib, to gemcitabine and irinotecan in patients with inoperable pancreatic cancer. STUDY: Twenty-one patients with previously untreated inoperable pancreatic cancer were entered on this trial. Seven patients had localized disease, 8 had metastatic disease, and 6 patients were inevaluable. Results: Twenty percent of the patients had a partial response and 80% of the patients had a stable response with a median response rate of 9 months. The median overall survival was 18 months with 80% of the patients achieving 1-year survival and 20% achieving 2-year survival. Using the FACT-PA scale to measure the quality of life (QOL), 13 of the 15 patients reported an improvement in their QOL and 2 patients reported no change. The median CA19-9 levels for the 13 patients with measurable CA19-9 values, decreased by 71% by cycle 2. Adverse events were acceptable and included neutropenia, thrombocytopenia, nausea, fatigue, and anemia. Conclusions: The combination of gemcitabine, irinotecan, and celecoxib is an active therapy for inoperable pancreatic cancer. A marked reduction in CA19-9 is observed in all evaluable patients by cycle 2. Toxicity is tolerable and a majority of patients reported a decrease in pain and a significant improvement in their QOL. Copyright © 2010 by Lippincott Williams & Wilkins.


Tadagavadi R.K.,Pennsylvania State University | Reeves W.B.,Pennsylvania State University | Reeves W.B.,Lebanon Medical Center
Journal of the American Society of Nephrology | Year: 2010

Inflammation contributes to the pathogenesis of acute kidney injury. Dendritic cells (DCs) are immune sentinels with the ability to induce immunity or tolerance, but whether they mediate acute kidney injury is unknown. Here, we studied the distribution of DCs within the kidney and the role of DCs in cisplatin-induced acute kidney injury using a mouse model in which DCs express both green fluorescence protein and the diphtheria toxin receptor. DCs were present throughout the tubulointerstitium but not in glomeruli. We used diphtheria toxin to deplete DCs to study their functional significance in cisplatin nephrotoxicity. Mice depleted of DCs before or coincident with cisplatin treatment but not at later stages experienced more severe renal dysfunction, tubular injury, neutrophil infiltration and greater mortality than nondepleted mice. We used bone marrow chimeric mice to confirm that the depletion of CD11c-expressing hematopoietic cells was responsible for the enhanced renal injury. Finally, mixed bone marrow chimeras demonstrated that the worsening of cisplatin nephrotoxicity in DC-depleted mice was not a result of the dying or dead DCs themselves. After cisplatin treatment, expression of MHC class II decreased and expression of inducible co-stimulator ligand increased on renal DCs. These data demonstrate that resident DCs reduce cisplatin nephrotoxicity and its associated inflammation. Copyright © 2010 by the American Society of Nephrology.


PubMed | Penn State Milton rshey Medical Center, WILEX and Lebanon Medical Center
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

405 Background: The transmembrane protein MN (carbonic anhydrase IX)(CAIX) catalyzes the hydration of carbon dioxide to carbonic acid and decreases pH. In cancer, up-regulation of CAIX gene expression occurs under hypoxic conditions within tumors. Significant levels of CAIX protein have been detected in a variety of cancers including kidney, cervix, lung, bladder, colon, breast, liver, gall bladder, and pancreas.Pretreatment plasma CAIX and VEGF-A levels were determined from 52 metastatic renal cell cancer patients enrolled in a phase III first-line trial of sunitinib vs. interferon alpha (IF). The CAIX and VEGF-A ELISAs (WILEX/Oncogene Science, Cambridge MA) were used for determination of plasma biomarker levels. 51 of 52 patients had an MSKCC score of 0 or 1. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling with both continuous and dichotomous (median) plasma CAIX and VEGF levels.Pretreatment plasma CAIX levels averaged 371 pg/ml, with a median of 194 pg/ml and 25Elevated pretreatment plasma CAIX predicted for reduced PFS and overall survival in metastatic renal cancer patients. In addition, sunitinib was superior to interferon, regardless of plasma CAIX status.


PubMed | Lebanon Medical Center, WILEX and Penn State Milton rshey Medical Center
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

97 Background: Three angiogenesis-related serum biomarkers [TIMP-1 (tissue inhibitor of metalloproteinase-1), CA IX (carbonic anhydrase 9), and VEGF] and PSA were correlated with outcome in the phase II zibotentan [endothelin A (ETPretreatment serum samples were available from 206 of 312 patients enrolled in the multicenter phase II trial evaluating zibotentan in patients with metastatic CRPC and bone metastases who were pain free or mildly symptomatic for pain, with a 1:1:1 randomization to zibotentan 10mg, 15mg, or placebo. The CA IX, TIMP-1, and VEGF ELISAs were from WILEX Inc./ Oncogene Science, Cambridge, MA. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling.In the final efficacy report, there were no statistical differences in PFS, but a trend for OS improvement was observed in the zibotentan arms compared with placebo: 15 mg (HR 0.76; 80% CI 0.61-0.94; p= 0.103) and 10 mg (HR 0.83; 80% CI 0.67-1.02; p= 0.254) (James et al, BJUI 106L966-973, 2010). In the retrospective serum biomarker analysis (206 patients), there were no apparent differences for PFS with any of the 3 novel biomarkers in the whole population, or within treatment arms. For OS in the whole population, patients with higher serum TIMP (> median) had reduced OS (17.5 mos), compared with patients who had lower serum TIMP-1 (< median) (28.4 mos). Within treatment arms, patients with higher serum CA IX (> median) treated with zibotentan had increased OS in both the 10 mg arm (median 28.4 mos), and the 15 mg arm (median 25.7 mos) compared with those in the placebo arm (median 15.4 mos). In a Cox model, including serum biomarkers and bisphosphonate use, for PFS only PSA was significant (p< 0.0001); for OS only PSA (p< 0.0001) and TIMP-1 (p< 0.002) were significant.Higher pretreatment serum CA IX (a marker of hypoxia) may identify a cohort of metastatic CRPC patients more sensitive to zibotentan treatment, and higher serum TIMP-1 may identify patients at risk for reduced overall survival. These serum biomarkers deserve further study in larger ET

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