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Vanamala J.K.P.,Pennsylvania State University | Vanamala J.K.P.,Pennsylvania State Hershey Cancer Institute | Knight R.,University of California at San Diego | Spector T.D.,King's College London
Cell Metabolism | Year: 2015

Prospects for using the gut microbiome for personalized medicine are substantial since the gut microbiome is known to modulate metabolism and varies substantially among individuals. Zeevi et al. (2015) demonstrate that the gut microbiota can be used to predict individualized blood glucose responses to particular foods, which differ between individuals. © 2015 Elsevier Inc.


Hart L.S.,University of Pennsylvania | Dolloff N.G.,Pennsylvania State Hershey Cancer Institute | Dicker D.T.,Pennsylvania State Hershey Cancer Institute | Koumenis C.,University of Pennsylvania | And 3 more authors.
Cell Cycle | Year: 2011

Cancer stem cells (CSCs) are recognized as contributors of cancer progression and therapeutic resistance in liquid and solid malignancies. We analyzed a panel of human colon cancer cell lines for CSC populations by side population and aldehyde dehydrogenase activity. IGF-1 enriches these putative colon CSC populations in a β-catenin-dependent manner. Chemical inhibition of Akt depletes SP cells, and conversely, the overexpression of a constitutively active mutant version of Akt is sufficient to enrich CSC populations. CP-751,871, a fully human antibody with specificity to the IGF-1 receptor, is currently being tested in clinical trials for a variety of solid tumors. CP-751,871 reduces CSC populations in colon cancer cell lines in vitro and reduces tumor growth in vivo. We have identified a novel role for IGF-1 in the enrichment of chemoresistant CSC populations. Our results suggest that CP-751,871 has preferential activity against putative CSC populations and therefore, may compliment current standard chemotherapeutic regimens that target cycling cells. © 2011 Landes Bioscience.


PubMed | Kyiv City Oncology Hospital, Pennsylvania State Hershey Cancer Institute, Tennessee Oncology PLLC, Ironwood Cancer and Research Center and 3 more.
Type: Journal Article | Journal: Clinical lung cancer | Year: 2016

Bavituximab is a phosphatidylserine-targeting antibody with a selective tumor, vascular-directed immune response. In this phase II trial the efficacy and safety of bavituximab combined with docetaxel for previously treated, advanced nonsquamous non-small-cell lung cancer were evaluated.Patients were randomized 1:1:1 to receive docetaxel 75 mg/m(2) every 21 days for up to 6 cycles combined with weekly, blinded infusions of placebo, bavituximab 1 mg/kg, or bavituximab 3 mg/kg until disease progression or unacceptable toxicity. The primary end point was overall response rate (ORR), with a predefined end point of 26% in the bavituximab arms. After study unblinding, vial-coding discrepancies were discovered in the placebo and bavituximab 1 mg/kg groups. In exploratory analyses, data from these groups were pooled to form the control group and compared with the 3 mg/kg group.Efficacy end points in the bavituximab 3 mg/kg group (n= 41) and in the placebo/bavituximab 1 mg/kg group (n= 80), respectively, were as follows: ORR, 17.1% (95% confidence interval [CI], 5.6%-28.6%) and ORR, 11.3% (95% CI, 4.3%-18.2%); median progression-free survival 4.5 and 3.3 months (hazard ratio [HR], 0.74 [95% CI, 0.45-1.21]; P= .24); median overall survival 11.7 and 7.3 months (HR, 0.66 [95% CI, 0.40-1.10]; P= .11). Toxicities were manageable and similar between arms.The combination of bavituximab and docetaxel is well tolerated. Although no firm efficacy conclusions can be drawn and the trial did not meet the predefined primary end point, exploratory analyses suggest trends favoring the combination of bavituximab 3 mg/kg with docetaxel. This regimen is being evaluated in the ongoing, global, phase III SUNRISE trial.


Chakravarthy A.B.,Vanderbilt University | Catalano P.J.,Dana-Farber Cancer Institute | Martenson J.A.,Mayo Medical School | Mondschein J.K.,Vanderbilt University | And 4 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: Although chemoradiation using 5-fluorouracil (5-FU) and mitomycin-C (MMC) is the standard of care in the treatment of anal cancer, many patients are unable to tolerate MMC. This Phase II clinical trial was performed to determine whether cisplatin could replace MMC in the treatment of anal cancer. Methods and Materials: Thirty-three patients with localized anal cancer were enrolled. One patient registered but never received any assigned therapy and was excluded from all analyses. Between February 1, 1993, and July 21, 1993, 19 patients were accrued to Cohort 1. Radiation consisted of 45 Gy to the primary tumor and pelvic nodes, followed by a boost to the primary and involved nodes to 59.4 Gy. A planned 2-week treatment break was used after 36 Gy. Concurrent chemotherapy consisted of 5-FU 1,000 mg/m 2/day on Days 1 to 4 and cisplatin 75 mg/m 2 on Day 1. A second course of 5-FU and cisplatin was given after 36 Gy, when the patient resumed radiation therapy. Between April 4, 1996, and September 23, 1996, an additional 13 patients (Cohort 2) were accrued to the study and received the same treatment except without the planned treatment break. Results: Complete response was seen in 78% (90% CI, 63-89) of patients and was higher in patients who did not get a planned treatment break (92% vs. 68%). The overall Grade 4 toxicity rate was 31%. One treatment-related death (Grade 5) occurred in a patient who developed sepsis. The 5-year overall survival was 69%. Conclusions: Radiation therapy, cisplatin, and 5-FU resulted in an overall objective response (complete response + partial response) of 97%. Although the 5-year progression-free survival was only 55%, the overall 5-year survival was 69%. Given the excellent salvage provided by surgery, this study affirms that cisplatin-based regimens may be an alternative for patients who cannot tolerate the severe hematologic toxicities associated with mitomycin-based chemoradiation regimens. © 2011 Elsevier Inc.


PubMed | Pennsylvania State University, Pennsylvania state Hershey cancer institute, pa and University of Houston
Type: Journal Article | Journal: Biomolecules | Year: 2014

Although numerous genetic mutations and amplifications have been identified in pancreatic cancer, much of the molecular pathogenesis of the disease remains undefined. While proteomic and transcriptomic analyses have been utilized to probe and characterize pancreatic tumors, lipidomic analyses have not been applied to identify perturbations in pancreatic cancer patient samples. Thus, we utilized a mass spectrometry-based lipidomic approach, focused towards the sphingolipid class of lipids, to quantify changes in human pancreatic cancer tumor and plasma specimens. Subgroup analysis revealed that patients with positive lymph node metastasis have a markedly higher level of ceramide species (C16:0 and C24:1) in their tumor specimens compared to pancreatic cancer patients without nodal disease or to patients with pancreatitis. Also of interest, ceramide metabolites, including phosphorylated (sphingosine- and sphinganine-1-phosphate) and glycosylated (cerebroside) species were elevated in the plasma, but not the pancreas, of pancreatic cancer patients with nodal disease. Analysis of plasma level of cytokine and growth factors revealed that IL-6, IL-8, CCL11 (eotaxin), EGF and IP10 (interferon inducible protein 10, CXCL10) were elevated in patients with positive lymph nodes metastasis, but that only IP10 and EGF directly correlated with several sphingolipid changes. Taken together, these data indicate that sphingolipid metabolism is altered in human pancreatic cancer and associated with advanced disease. Assessing plasma and/or tissue sphingolipids could potentially risk stratify patients in the clinical setting.


Marks E.I.,Pennsylvania State Hershey Cancer Institute | Brennan M.,Pennsylvania State Hershey Cancer Institute | El-Deiry W.S.,Pennsylvania State Hershey Cancer Institute | El-Deiry W.S.,Molecular Therapeutics
Cancer Biology and Therapy | Year: 2015

We present the case of a 62-year-old-man with moderately differentiated adenocarcinoma of the rectum. This patient underwent neoadjuvant chemoradiation and surgical resection followed by adjuvant chemotherapy. After completing therapy, this patient had 2 instances of CEA elevation, both of which preceded the discovery of recurrent disease. While on treatment for these recurrences, CA 19-9 increased rapidly to 4, 405. This CA 19-9 elevation persisted for approximately 4 months in the absence of clinical, radiographic or additional serologic evidence of progressive disease before returning to baseline. Shortly after this tumor marker normalized, a small area of locally recurrent disease was discovered. This case highlights the utility and pitfalls of colorectal cancer disease monitoring with CEA and CA 19-9. The differential diagnosis of CA 19-9 elevation is discussed in this report. © 2015 Taylor & Francis Group, LLC.


Al-Marrawi M.Y.,Pennsylvania State Hershey Cancer institute | Holder S.L.,Pennsylvania State Hershey Cancer institute
Current Molecular Pharmacology | Year: 2016

Immunotherapy, though not a new modality for cancer treatment, has enjoyed renewed vigor and interest over the last several years. Multiple new targets have been identified, and therapeutic agents are in varying stages of development, with some agents having obtained regulatory approval for administration in the clinic. Renal cell carcinoma is known to potentially respond favorably to immunotherapy, with a small subset of patients achieving durable responses to high dose interleukin-2 therapy. Consequently, renal cell carcinoma is one of the many tumor types in which the efficacy of new agents is being investigated. Here we examine the landscape of current immunotherapeutic options for renal cell carcinoma, including cytokine therapy, immune checkpoint blockade, hematopoietic stem cell transplant, and vaccine therapy. We review approved immune directed therapies as well as new agents undergoing clinical trials in renal cell carcinoma. Immunotherapy has been and remains a promising treatment modality in this tumor type. Hopefully the approval of newer agents will translate into more accessible and efficacious options for patients and oncologists. © 2016 Bentham Science Publishers.


Chao M.,Mount Sinai Medical Center | Yuan Y.,Mount Sinai Medical Center | Sheu R.-D.,Mount Sinai Medical Center | Wang K.,Pennsylvania State Hershey Cancer Institute | And 2 more authors.
Technology in Cancer Research and Treatment | Year: 2016

This study aims to employ 4-dimensional computed tomography to quantify intrafractional tumor motion for patients with lung cancer to improve target localization in radiation therapy. A multistage regional deformable registration was implemented to calculate the excursion of gross tumor volume (GTV) during a breathing cycle. GTV was initially delineated on 0% phase of 4-dimensional computed tomography manually, and a subregion with 20 mm margin supplemented to GTV was generated with Eclipse treatment planning system (Varian Medical Systems, Palo Alto, California). The structures, together with the 4-dimensional computed tomography set, were exported into an in-house software, with which a 3-stage B-spline deformable registration was carried out to map the subregion and warp GTV contour to other breathing phases. The center of mass of the GTV was computed using the contours, and the tumor motion was appraised as the excursion of the center of mass between 0% phase and other phases. Application of the algorithm to the 10 patients showed that clinically satisfactory outcomes were achievable with a spatial accuracy around 2 mm for GTV contour propagation between adjacent phases and 3 mm between opposite phases. The tumor excursion was determined in the vast range of 1 mm through 1.6 cm, depending on the tumor location and tumor size. Compared to the traditional whole image-based registration, the regional method was found computationally a factor of 5 more efficient. The proposed technique has demonstrated its capability in extracting thoracic tumor motion and should find its application in 4-dimensional radiation therapy in the future to maximally utilize the available spatial–temporal information. © 2015, © The Author(s) 2015.


PubMed | Pennsylvania State Hershey Cancer Institute
Type: Case Reports | Journal: Cancer biology & therapy | Year: 2015

We present the case of a 62-year-old-man with moderately differentiated adenocarcinoma of the rectum. This patient underwent neoadjuvant chemoradiation and surgical resection followed by adjuvant chemotherapy. After completing therapy, this patient had 2 instances of CEA elevation, both of which preceded the discovery of recurrent disease. While on treatment for these recurrences, CA 19-9 increased rapidly to 4,405. This CA 19-9 elevation persisted for approximately 4 months in the absence of clinical, radiographic or additional serologic evidence of progressive disease before returning to baseline. Shortly after this tumor marker normalized, a small area of locally recurrent disease was discovered. This case highlights the utility and pitfalls of colorectal cancer disease monitoring with CEA and CA 19-9. The differential diagnosis of CA 19-9 elevation is discussed in this report.


PubMed | Pennsylvania State Hershey Cancer Institute and Mount Sinai Medical Center
Type: Journal Article | Journal: Technology in cancer research & treatment | Year: 2016

This study aims to employ 4-dimensional computed tomography to quantify intrafractional tumor motion for patients with lung cancer to improve target localization in radiation therapy. A multistage regional deformable registration was implemented to calculate the excursion of gross tumor volume (GTV) during a breathing cycle. GTV was initially delineated on 0% phase of 4-dimensional computed tomography manually, and a subregion with 20 mm margin supplemented to GTV was generated with Eclipse treatment planning system (Varian Medical Systems, Palo Alto, California). The structures, together with the 4-dimensional computed tomography set, were exported into an in-house software, with which a 3-stage B-spline deformable registration was carried out to map the subregion and warp GTV contour to other breathing phases. The center of mass of the GTV was computed using the contours, and the tumor motion was appraised as the excursion of the center of mass between 0% phase and other phases. Application of the algorithm to the 10 patients showed that clinically satisfactory outcomes were achievable with a spatial accuracy around 2 mm for GTV contour propagation between adjacent phases and 3 mm between opposite phases. The tumor excursion was determined in the vast range of 1 mm through 1.6 cm, depending on the tumor location and tumor size. Compared to the traditional whole image-based registration, the regional method was found computationally a factor of 5 more efficient. The proposed technique has demonstrated its capability in extracting thoracic tumor motion and should find its application in 4-dimensional radiation therapy in the future to maximally utilize the available spatial-temporal information.

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