Digital Commons Network^™

Atp-Site Binding Inhibitor Effectively Targets Mtorc1 And Mtorc2 Complexes In Glioblastoma, Jayson Neil, Craig Shannon, Avinash Mohan, Dimitri Laurent, Raj Murali, Meena Jhanwar-Uniyal

NYMC Faculty Publications

The PI3K-AKT-mTOR signaling axis is central to the transformed phenotype of glioblastoma (GBM) cells, due to frequent loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10). The mechanistic target of rapamycin (mTOR) kinase is present in two cellular multi-protein complexes, mTORC1 and mTORC2, which have distinct subunit composition, substrates and mechanisms of action. Targeting the mTOR protein is a promising strategy for GBM therapy. However, neither of these complexes is fully inhibited by the allosteric inhibitor of mTOR, rapamycin or its analogs. Herein, we provide evidence that the combined inhibition of mTORC1/2, using the ATP-competitive binding …

‘Much Clearer With Pictures’: Using Community-Based Participatory Research To Design And Test A Picture Option Grid For Underserved Patients With Breast Cancer, Marie-Anne Durand, Shama Alam, Stuart W. Grande, Glyn Elwyn

Dartmouth Scholarship

Women of low socioeconomic status (SES) diagnosed with early stage breast cancer experience decision-making, treatment and outcome disparities. Evidence suggests that decision aids can benefit underserved patients, when tailored to their needs. Our aim was to develop and test the usability, acceptability and accessibility of a pictorial encounter decision aid targeted at women of low SES diagnosed with early stage breast cancer.

Chronic Ethanol Exposure Enhances The Aggressiveness Of Breast Cancer: The Role Of P38Γ, Mei Xu, Siying Wang, Zhenhua Ren, Jacqueline A. Frank, Xiuwei H. Yang, Zhuo Zhang, Zun-Ji Ke, Xianglin Shi, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Both epidemiological and experimental studies suggest that ethanol may enhance aggressiveness of breast cancer. We have previously demonstrated that short term exposure to ethanol (12–48 hours) increased migration/invasion in breast cancer cells overexpressing ErbB2, but not in breast cancer cells with low expression of ErbB2, such as MCF7, BT20 and T47D breast cancer cells. In this study, we showed that chronic ethanol exposure transformed breast cancer cells that were not responsive to short term ethanol treatment to a more aggressive phenotype. Chronic ethanol exposure (10 days - 2 months) at 100 (22 mM) or 200 mg/dl (44 mM) caused the …

Silibinin-Mediated Metabolic Reprogramming Attenuates Pancreatic Cancer-Induced Cachexia And Tumor Growth., Surendra K. Shukla, Aneesha Dasgupta, Kamiya Mehla, Venugopal Gunda, Enza Vernucci, Joshua J. Souchek, Gennifer Goode, Ryan King, Anusha Mishra, Ibha Rai, Sangeetha Nagarajan, Nina V. Chaika, Fang Yu, Surendra K. Shukla

Journal Articles: Eppley Institute

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic …

Cyclin-Dependent Kinase Inhibitor P1446a Induces Apoptosis In A Jnk/P38 Mapk-Dependent Manner In Chronic Lymphocytic Leukemia B-Cells, Cody Paiva, J. Claire Godbersen, Ryan S. Soderquist, Taylor Rowland, Sumner Kilmarx

Dartmouth Scholarship

CDK (cyclin-dependent kinase) inhibitors have shown remarkable activity in CLL, where its efficacy has been linked to inhibition of the transcriptional CDKs (7 and 9) and deregulation of RNA polymerase and short-lived pro-survival proteins such as MCL1. Furthermore, ER (endoplasmic reticulum) stress has been implicated in CDK inhibition in CLL. Here we conducted a pre-clinical study of a novel orally active kinase inhibitor P1446A in CLL B-cells. P1446A inhibited CDKs at nanomolar concentrations and induced rapid apoptosis of CLL cells in vitro, irrespective of chromosomal abnormalities or IGHV mutational status. Apoptosis preceded inactivation of RNA polymerase, and was accompanied by …

Integrin Α6Β4 Promotes Autocrine Epidermal Growth Factor Receptor (Egfr) Signaling To Stimulate Migration And Invasion Toward Hepatocyte Growth Factor (Hgf), Brittany L. Carpenter, Min Chen, Teresa Knifley, Kelley A. Davis, Susan M.W. Harrison, Rachel L. Stewart, Kathleen O'Connor

Markey Cancer Center Faculty Publications

Integrin α6β4 is up-regulated in pancreatic adenocarcinomas where it contributes to carcinoma cell invasion by altering the transcriptome. In this study, we found that integrin α6β4 up-regulates several genes in the epidermal growth factor receptor (EGFR) pathway, including amphiregulin (AREG), epiregulin (EREG), and ectodomain cleavage protease MMP1, which is mediated by promoter demethylation and NFAT5. The correlation of these genes with integrin α6β4 was confirmed in The Cancer Genome Atlas Pancreatic Cancer Database. Based on previous observations that integrin α6β4 cooperates with c-Met in pancreatic cancers, we examined the impact of EGFR signaling on hepatocyte growth factor (HGF)-stimulated migration and …

Beyond The One-Locus-One-Mirna Paradigm: Microrna Isoforms Enable Deeper Insights Into Breast Cancer Heterogeneity., Aristeidis G Telonis, Phillipe Loher, Yi Jing, Eric R Londin, Isidore Rigoutsos

Computational Medicine Center Faculty Papers

Here we describe our study of miRNA isoforms (isomiRs) in breast cancer (BRCA) and normal breast data sets from the Cancer Genome Atlas (TCGA) repository. We report that the full isomiR profiles, from both known and novel human-specific miRNA loci, are particularly rich in information and can distinguish tumor from normal tissue much better than the archetype miRNAs. IsomiR expression is also dependent on the patient's race, exemplified by miR-183-5p, several isomiRs of which are upregulated in triple negative BRCA in white but not black women. Additionally, we find that an isomiR's 5' endpoint and length, but not the genomic …

Invariant Characteristics Of Carcinogenesis., Simon Sherman, Nirosha Rathnayake, Tengiz Mdzinarishvili

Journal Articles: Eppley Institute

Carcinogenic modeling is aimed at mathematical descriptions of cancer development in aging. In this work, we assumed that a small fraction of individuals in the population is susceptible to cancer, while the rest of the population is resistant to cancer. For individuals susceptible to cancer we adopted methods of conditional survival analyses. We performed computational experiments using data on pancreatic, stomach, gallbladder, colon and rectum, liver, and esophagus cancers from the gastrointestinal system collected for men and women in the SEER registries during 1975-2009. In these experiments, we estimated the time period effects, the birth cohort effects, the age effects …

A Phase 3 Trial Of 2 Years Of Androgen Suppression And Radiation Therapy With Or Without Adjuvant Chemotherapy For High-Risk Prostate Cancer: Final Results Of Radiation Therapy Oncology Group Phase 3 Randomized Trial Nrg Oncology Rtog 9902., Seth A. Rosenthal, Daniel Hunt, A. Oliver Sartor, Kenneth J. Pienta, Leonard G. Gomella, David Grignon, Raghu Rajan, Kevin J. Kerlin, Christopher U. Jones, Michael Dobelbower, William U Shipley, Kenneth Zeitzer, Daniel A. Hamstra, Viroon Donavanik, Marvin Rotman, Alan C. Hartford, Jeffrey Michalski, Michael Seider, Harold Kim, Deborah A. Kuban, Jennifer Moughan, Howard Sandler

Department of Urology Faculty Papers

PURPOSE: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS).

METHODS AND MATERIALS: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was …

Deubiquitinase Usp47/Ubp64e Regulates Β-Catenin Ubiquitination And Degradation And Plays A Positive Role In Wnt Signaling, Jiandang Shi, Yajuan Liu, Xuehe Xu, Wen Zhang, Tianxin Yu, Jianhang Jia, Chunming Liu

Markey Cancer Center Faculty Publications

Wnt signaling plays important roles in development and tumorigenesis. A central question about the Wnt pathway is the regulation of β-catenin. Phosphorylation of β-catenin by CK1α and GSK3 promotes β-catenin binding to β-TrCP, leading to β-catenin degradation through the proteasome. The phosphorylation and ubiquitination of β-catenin have been well characterized; however, it is unknown whether and how a deubiquitinase is involved. In this study, by screening RNA interference (RNAi) libraries, we identified USP47 as a deubiquitinase that prevents β-catenin ubiquitination. Inactivation of USP47 by RNAi increased β-catenin ubiquitination, attenuated Wnt signaling, and repressed cancer cell growth. Furthermore, USP47 deubiquitinates itself, …

Pkcε Is An Essential Mediator Of Prostate Cancer Bone Metastasis., Alvaro Gutierrez-Uzquiza, Cynthia Lopez-Haber University Of Pennsylvania, Danielle L. Jernigan, Alessandro Fatatis, Marcelo G. Kazanietz

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

UNLABELLED: The bone is a preferred site for metastatic homing of prostate cancer cells. Once prostate cancer patients develop skeletal metastases, they eventually succumb to the disease; therefore, it is imperative to identify key molecular drivers of this process. This study examines the involvement of protein kinase C epsilon (PKCε), an oncogenic protein that is abnormally overexpressed in human tumor specimens and cell lines, on prostate cancer cell bone metastasis. PC3-ML cells, a highly invasive prostate cancer PC3 derivative with bone metastatic colonization properties, failed to induce skeletal metastatic foci upon inoculation into nude mice when PKCε expression was silenced …

Erbb3-Erbb2 Complexes As A Therapeutic Target In A Subset Of Wild-Type Braf/Nras Cutaneous Melanomas., Claudia Capparelli, Sheera Rosenbaum, Lisa D. Berman-Booty, Amel Salhi, Nadège Gaborit, Tingting Zhan, Inna Chervoneva, Jason Roszik, Scott E. Woodman, Michael A. Davies, Yulius Y. Setiady, Iman Osman, Yosef Yarden, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

The treatment options remain limited for patients with melanoma who are wild-type for both BRAF and NRAS (WT/WT). We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand neuregulin-1 (NRG1). In WT/WT melanoma cells displaying high levels of phospho-ErbB3, knockdown of NRG1 reduced cell viability and was associated with decreased phosphorylation of ErbB3, its coreceptor ErbB2, and its downstream target, AKT. Similar effects were observed by targeting ErbB3 with either siRNAs or the neutralizing ErbB3 monoclonal antibodies huHER3-8 and NG33. In addition, pertuzumab-mediated inhibition of ErbB2 …

Rac1 P29s Regulates Pd-L1 Expression In Melanoma., Ha Linh Vu, Sheera Rosenbaum, Timothy J. Purwin, Michael A. Davies, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5-9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho-protein expression, we identified cyclin B1, PD-L1, Ets-1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion. Using the melanoma patient samples in TCGA, we found PD-L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants. The finding that PD-L1 …

Expression Of The Il-11 Gene In Metastatic Cells Is Supported By Runx2-Smad And Runx2-Cjun Complexes Induced By Tgfβ1., Xuhui Zhang, Hai Wu, Jason R. Dobson, Gillian Browne, Deli Hong, Jacqueline Akech, Lucia R. Languino, Gary S. Stein, Jane B. Lian

Department of Cancer Biology Faculty Papers

In tumor cells, two factors are abnormally increased that contribute to metastatic bone disease: Runx2, a transcription factor that promotes expression of metastasis related and osteolytic genes; and IL-11, a secreted osteolytic cytokine. Here, we addressed a compelling question: Does Runx2 regulate IL-11 gene expression? We find a positive correlation between Runx2, IL-11 and TGFβ1, a driver of the vicious cycle of metastatic bone disease, in prostate cancer (PC) cell lines representing early (LNCaP) and late (PC3) stage disease. Further, like Runx2 knockdown, IL-11 knockdown significantly reduced expression of several osteolytic factors. Modulation of Runx2 expression results in corresponding changes …

The Development And Application Of An Oncology Therapy-Related Symptom Checklist For Adults (Trsc) And Children (Trsc-C) And E-Health Applications., Arthur R. Williams, David D. Williams, Phoebe D. Williams, Farrokh Alemi, Hosai Hesham, Blaine Donley, Raya E. Kheirbek

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Studies found that treatment symptoms of concern to oncology/hematology patients were greatly under-identified in medical records. On average, 11.0 symptoms were reported of concern to patients compared to 1.5 symptoms identified in their medical records. A solution to this problem is use of an electronic symptom checklist that can be easily accessed by patients prior to clinical consultations.

PURPOSE: Describe the oncology Therapy-Related Symptom Checklists for Adults (TRSC) and Children (TRSC-C), which are validated bases for e-Health symptom documentation and management. The TRSC has 25 items/symptoms; the TRSC-C has 30 items/symptoms. These items capture up to 80% of the …

Increased Expression Of Fatty Acid Synthase Provides A Survival Advantage To Colorectal Cancer Cells Via Upregulation Of Cellular Respiration, Yekaterina Y. Zaytseva, Jennifer W. Harris, Mihail I. Mitov, Ji Tae Kim, D. Allan Butterfield, Eun Young Lee, Heidi L. Weiss, Tianyan Gao, B. Mark Evers

Markey Cancer Center Faculty Publications

Fatty acid synthase (FASN), a lipogenic enzyme, is upregulated in colorectal cancer (CRC). Increased de novo lipid synthesis is thought to be a metabolic adaptation of cancer cells that promotes survival and metastasis; however, the mechanisms for this phenomenon are not fully understood. We show that FASN plays a role in regulation of energy homeostasis by enhancing cellular respiration in CRC. We demonstrate that endogenously synthesized lipids fuel fatty acid oxidation, particularly during metabolic stress, and maintain energy homeostasis. Increased FASN expression is associated with a decrease in activation of energy-sensing pathways and accumulation of lipid droplets in CRC cells …

Structure-Based Screen Identifies A Potent Small Molecule Inhibitor Of Stat5a/B With Therapeutic Potential For Prostate Cancer And Chronic Myeloid Leukemia., Zhiyong Liao, Lei Gu, Jenny Vergalli, Samanta A. Mariani, Marco De Dominici, Ravi K. Lokareddy, Ayush Dagvadorj, Puranik Purushottamachar, Peter A. Mccue, Edouard J. Trabulsi, Costas D. Lallas, Shilpa Gupta, Elyse Ellsworth, Shauna Blackmon, Adam Ertel, Paolo Fortina, Benjamin E. Leiby, Guanjun Xia, Hallgeir Rui, David T. Hoang, Leonard G Gomella, Gino Cingolani, Vincent Njar, Nagarajan Pattabiraman, Bruno Calabretta, Marja T. Nevalainen

Department of Cancer Biology Faculty Papers

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic …

Numerical Chromosomal Instability Mediates Susceptibility To Radiation Treatment, Samuel F. Bakhoum, Lilian Kabeche, Matthew D. Wood, Christopher D. Laucius

Dartmouth Scholarship

The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy. However, the mechanism for this cell cycle-dependent vulnerability is unknown. Here we show that treatment with IR leads to mitotic chromosome segregation errors in vivo and long-lasting aneuploidy in tumour-derived cell lines. These mitotic errors generate an abundance of micronuclei that predispose chromosomes to subsequent catastrophic pulverization thereby independently amplifying radiation-induced genome damage. Experimentally suppressing whole-chromosome missegregation reduces downstream chromosomal defects and significantly increases the viability of irradiated mitotic cells. Further, orthotopically transplanted human glioblastoma tumours in which …

Targeted Dna Damage At Individual Telomeres Disrupts Their Integrity And Triggers Cell Death, Luxi Sun, Rong Tan, Jianquan Xu, Justin Laface, Ying Gao, Yanchun Xiao, Myriam Attar, Carola Neumann, Guo-Min Li, Bing Su, Yang Liu, Satoshi Nakajima, Arthur S. Levine, Li Lan

Markey Cancer Center Faculty Publications

Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising <1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel approach to generate localized damage to telomere DNA and to monitor the real time damage response at the single telomere level. We found that DNA damage at long telomeres in U2OS cells is not repaired efficiently compared to DNA damage in non-telomeric regions of the same length in heterochromatin. Telomeric DNA damage shortens the average length of telomeres and leads to cell senescence in HeLa cells and cell death in HeLa, U2OS and IMR90 cells, when DNA damage at non-telomeric regions is undetectable. Telomere-specific damage induces chromosomal aberrations, including chromatid telomere loss and telomere associations, distinct from the damage induced by ionizing irradiation. Taken together, our results demonstrate that oxidative damage induces telomere dysfunction and underline the importance of maintaining telomere integrity upon oxidative damage.

3d Thoracoscopic Ultrasound Volume Measurement Validation In An Ex Vivo And In Vivo Porcine Model Of Lung Tumours, V. Hornblower, E. Yu, A. Fenster, J. Battista, R. Malthaner

Richard A. Malthaner

The purpose of this study was to validate the accuracy and reliability of volume measurements obtained using three-dimensional (3D) thoracoscopic ultrasound (US) imaging. Artificial "tumours" were created by injecting a liquid agar mixture into spherical moulds of known volume. Once solidified, the "tumours" were implanted into the lung tissue in both a porcine lung sample ex vivo and a surgical porcine model in vivo. 3D US images were created by mechanically rotating the thoracoscopic ultrasound probe about its long axis while the transducer was maintained in close contact with the tissue. Volume measurements were made by one observer using the …

Is Extended Volume External Beam Radiation Therapy Covering The Anastomotic Site Beneficial In Post-Esophagectomy High Risk Patients?, Edward Yu, Rashid Dar, George Rodrigues, Larry Stitt, Gregory Videtic, Pauline Truong, Anna Tomiak, Robert Ash, Ed Brecevic, Richard Inculet, Richard Malthaner, Mark Vincent, Ian Craig, Walter Kocha, Michael Lefcoe

Richard A. Malthaner

Background and purpose: To assess the impact of extended volume radiation therapy (RT) with anastomotic coverage on local control in high risk post-operative esophageal cancer patients.

Patients and methods: This is a retrospective study of high risk (T(3), T(4), nodes positive, with or without margin involvement) post-operative esophageal cancer patients treated at London Regional Cancer Centre from 1989 to 1999. After esophagectomy, all patients received adjuvant combined modality therapy consisting of four cycles of fluorouracil-based chemotherapy, and loco-regional RT with or without coverage of the anastomotic site. RT dose ranged from 45 to 60 Gy at 1.8-2.0 Gy/fraction with treatment …

The Management Of Thymoma: A Systematic Review And Practice Guideline, Conrad Falkson, Andrea Bezjak, Gail Darling, Richard Gregg, Richard Malthaner, Donna Maziak, Edward Yu, Christopher Smith, Sheila Mcnair, Yee Ung, William Evans

Richard A. Malthaner

INTRODUCTION: Thymoma is a rare tumor for which there is little randomized evidence to guide treatment. Because of the lack of high-quality evidence, a formal consensus-based approach was used to develop recommendations on treatment. METHODS: A systematic refview of the literature was performed. Recommendations were formed from available evidence and developed through a two-round modified Delphi consensus approach. RESULTS: The treatment recommendations are summarized as follows: Stage I--complete resection of the entire thymus without neoadjuvant or adjuvant therapy. Stage II--complete resection of the entire thymus with consideration of adjuvant radiation for high-risk tumors. Stage IIIA--surgery either initially or after neoadjuvant …

Neoadjuvant Or Adjuvant Therapy For Resectable Esophageal Cancer: A Systematic Review And Meta-Analysis, Richard Malthaner, Rebecca Wong, R. Rumble, Lisa Zuraw

Richard A. Malthaner

Background: Carcinoma of the esophagus is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms and mortality, justifies a continued search for optimal therapy. The large and growing number of patients affected, the high mortality rates, the worldwide geographic variation in practice, and the large body of good quality research warrants a systematic review with meta-analysis.

Methods: A systematic review and meta-analysis investigating the impact of neoadjuvant or adjuvant therapy on resectable thoracic esophageal cancer to inform evidence-based practice was produced.MEDLINE, CANCERLIT, Cochrane Library, EMBASE, and abstracts from the American Society of Clinical Oncology and the …

Cyclosporin Versus Tacrolimus For Liver Transplanted Patients, Elizabeth Haddad, Vivian Mcalister, Elizabeth Renouf, Richard Malthaner, Mette Kjaer, Lise Gluud

Richard A. Malthaner

A systematic review of randomized clinical trials (RCT) was undertaken to evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. MEDLINE, EMBASE, Cochrane Central and Hepato-Biliary Group Controlled Trials Registers were searched. Using fixed and random effects model, relative risk (RR), values <1 favoring>tacrolimus, with 95% confidence intervals (CI) were calculated. Of 717 potentially relevant references, 16 RCTs were eligible for inclusion. Mortality and graft loss at 1 year were significantly reduced in tacrolimus-treated recipients (Death: RR 0.85, 95% CI 0.73-0.99; graft loss: RR 0.73, 95% CI 0.61-0.86). Tacrolimus reduced the number of recipients …

3d Thoracoscopic Ultrasound Volume Measurement Validation In An Ex Vivo And In Vivo Porcine Model Of Lung Tumours, V. Hornblower, E. Yu, A. Fenster, J. Battista, R. Malthaner

Richard A. Malthaner

The purpose of this study was to validate the accuracy and reliability of volume measurements obtained using three-dimensional (3D) thoracoscopic ultrasound (US) imaging. Artificial "tumours" were created by injecting a liquid agar mixture into spherical moulds of known volume. Once solidified, the "tumours" were implanted into the lung tissue in both a porcine lung sample ex vivo and a surgical porcine model in vivo. 3D US images were created by mechanically rotating the thoracoscopic ultrasound probe about its long axis while the transducer was maintained in close contact with the tissue. Volume measurements were made by one observer using the …

Is Extended Volume External Beam Radiation Therapy Covering The Anastomotic Site Beneficial In Post-Esophagectomy High Risk Patients?, Edward Yu, Rashid Dar, George Rodrigues, Larry Stitt, Gregory Videtic, Pauline Truong, Anna Tomiak, Robert Ash, Ed Brecevic, Richard Inculet, Richard Malthaner, Mark Vincent, Ian Craig, Walter Kocha, Michael Lefcoe

Richard A. Malthaner

Background and purpose: To assess the impact of extended volume radiation therapy (RT) with anastomotic coverage on local control in high risk post-operative esophageal cancer patients.

Patients and methods: This is a retrospective study of high risk (T(3), T(4), nodes positive, with or without margin involvement) post-operative esophageal cancer patients treated at London Regional Cancer Centre from 1989 to 1999. After esophagectomy, all patients received adjuvant combined modality therapy consisting of four cycles of fluorouracil-based chemotherapy, and loco-regional RT with or without coverage of the anastomotic site. RT dose ranged from 45 to 60 Gy at 1.8-2.0 Gy/fraction with treatment …

Subsets More Likely To Benefit From Surgery Or Prophylactic Cranial Irradiation After Chemoradiation For Localized Non-Small-Cell Lung Cancer, Bruce Keith, Mark Vincent, Larry Stitt, Anna Tomiak, Richard Malthaner, Edward Yu, Pauline Truong, Richard Inculet, Michael Lefcoe, A. Dar, Walter Kocha, Ian Craig

Richard A. Malthaner

After chemoradiation for localized non-small-cell lung cancer, surgery and prophylactic cranial irradiation (PCI) have been used as additional therapies. Less than a third of patients develop brain recurrences, or have local recurrence as their sole initial site of recurrence; these are groups that would benefit from PCI or surgery, respectively. Pretreatment identification of patients more likely to benefit from surgery or PCI would be useful. A retrospective analysis of 80 patients was performed to determine prognostic factors for such patterns of failure. Twenty-nine patients were subsequently selected for surgery in a nonrandomized manner. Seventeen patients had isolated local initial recurrence …

The Management Of Thymoma: A Systematic Review And Practice Guideline, Conrad Falkson, Andrea Bezjak, Gail Darling, Richard Gregg, Richard Malthaner, Donna Maziak, Edward Yu, Christopher Smith, Sheila Mcnair, Yee Ung, William Evans

Richard A. Malthaner

INTRODUCTION: Thymoma is a rare tumor for which there is little randomized evidence to guide treatment. Because of the lack of high-quality evidence, a formal consensus-based approach was used to develop recommendations on treatment. METHODS: A systematic refview of the literature was performed. Recommendations were formed from available evidence and developed through a two-round modified Delphi consensus approach. RESULTS: The treatment recommendations are summarized as follows: Stage I--complete resection of the entire thymus without neoadjuvant or adjuvant therapy. Stage II--complete resection of the entire thymus with consideration of adjuvant radiation for high-risk tumors. Stage IIIA--surgery either initially or after neoadjuvant …

Neoadjuvant Or Adjuvant Therapy For Resectable Esophageal Cancer: A Systematic Review And Meta-Analysis, Richard Malthaner, Rebecca Wong, R. Rumble, Lisa Zuraw

Richard A. Malthaner

Background: Carcinoma of the esophagus is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms and mortality, justifies a continued search for optimal therapy. The large and growing number of patients affected, the high mortality rates, the worldwide geographic variation in practice, and the large body of good quality research warrants a systematic review with meta-analysis.

Methods: A systematic review and meta-analysis investigating the impact of neoadjuvant or adjuvant therapy on resectable thoracic esophageal cancer to inform evidence-based practice was produced.MEDLINE, CANCERLIT, Cochrane Library, EMBASE, and abstracts from the American Society of Clinical Oncology and the …

Cyclosporin Versus Tacrolimus For Liver Transplanted Patients, Elizabeth Haddad, Vivian Mcalister, Elizabeth Renouf, Richard Malthaner, Mette Kjaer, Lise Gluud

Richard A. Malthaner

A systematic review of randomized clinical trials (RCT) was undertaken to evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. MEDLINE, EMBASE, Cochrane Central and Hepato-Biliary Group Controlled Trials Registers were searched. Using fixed and random effects model, relative risk (RR), values <1 favoring>tacrolimus, with 95% confidence intervals (CI) were calculated. Of 717 potentially relevant references, 16 RCTs were eligible for inclusion. Mortality and graft loss at 1 year were significantly reduced in tacrolimus-treated recipients (Death: RR 0.85, 95% CI 0.73-0.99; graft loss: RR 0.73, 95% CI 0.61-0.86). Tacrolimus reduced the number of recipients …