61.08 Curcumin-Mediated Regulation of Notch1/HES1/Survivin: Molecular Targeting in Cholangiocarcinoma

Posted on December 22, 2014

S. T. Koprowski1, K. M. Sokolowski1, S. Kunnimalaiyaan1, T. C. Gamblin1, M. Kunnimalaiyaan1  1Medical College Of Wisconsin,Surgical Oncology/Department Of Surgery/Medical College Of Wisconsin,Milwaukee, WI, USA

Introduction: Cholangiocarcinoma (CCA) is highly malignant and characterized by poor prognosis with chemotherapeutic resistance. Therefore, continued development of novel, effective approaches are needed. Notch1 is highly expressed in CCA, but the utility of Notch1 inhibition is not defined. Based on recent findings, we hypothesized that curcumin, a polyphenolic phytochemical, suppresses CCA growth in vitro via inhibition of Notch1 signaling.  

Methods: Established CCA cell lines CCLP-1 and SG-231 were treated with varying concentrations of curcumin (0-20µM). Viability was assessed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colonogenic assays. Cell lysates were analyzed via Western blotting for Notch1/HES1/Survivin pathway expression, apoptosis, and cell cycle progression. Following curcumin treatment, quantitative real-time polymerase chain reaction (qPCR) was utilized to determine mRNA expression of Notch signaling components.

Results: Curcumin-treated CCA cells exhibited reduced viability compared to control treatment. Statistically significant reductions in cell viability were observed with curcumin treatment at concentrations of 7.5, 10, and 15µM by approximately 10%, 48%, and 56% for CCLP-1 and 13%, 25%, and 50% for SG-231 respectively. Upon Western analysis, concentrations of 10µM and above showed reductions in Notch1, HES1, and Survivin. Apoptosis was evidenced by an increase in expression of cleaved PARP (Poly [ADP] ribose polymerase). Cyclin D1 (cell cycle progression) expression levels were also reduced with treatment. Data collected from qPCR similarly indicated significant reductions in Notch1, HES-1, and Survivin mRNA expression in CCA treatment groups.

Conclusion: Curcumin effectively induces CCA (CCLP-1 and SG-231) growth suppression and apoptosis at relatively low treatment concentrations when compared to previous research. A concomitant reduction of Notch1, HES1, and Survivin expression in CCA cell lines provides novel evidence for a potential anti-tumorigenic mechanism-of-action. To our knowledge, this is the first report showing reduction in HES-1 expression via both mRNA and protein analysis following treatment with curcumin. Such findings merit further investigation of curcumin-mediated inhibition of Notch signaling in CCA either alone or in combination with chemotherapeutic agents.

 

 

61.09 S1P forms a feed-forward loop with the Ang2 and VEGF-C pathways in lymphangiogenesis

Posted on December 22, 2014

L. J. Fernandez1, W. Huang1, K. P. Terracina1, A. Yamada5, T. Aoyagi3, S. Spiegel2, M. Nagahashi4, K. Takabe1,2  1Virginia Commonwealth University,Surgical Oncology,Richmond, VA, USA 2Virginia Commonwealth University,Biochemistry And Molecular Biology,Richmond, VA, USA 3Chiba University,Surgery,Chiba, , Japan 4Nigata University,Digestive And General Surgery,Nigata, , Japan 5Yokohama City University,Surgery,Yokohama, , Japan

Introduction:
It is well established from prior studies that both Angiopoietin2 (Ang2) and vascular endothelial growth factor-C (VEGF-C) in the human lymphatic endothelial cell (HLEC) play important roles in the induction of lymphangiogenesis in inflammation and cancer. Ang2 acts by activating the Tie-2 receptor and VEGF-C through VEGF receptor 3 (VEGFR-3). Sphingosine-1-phosphate (S1P), a lipid mediator, has emerged as an important player in cancer progression that promotes cell proliferation, survival, migration, angiogenesis and lymphangiogenesis. S1P is generated inside cells by sphingosine kinase 1 (SphK1), which is exported and exerts its functions by binding to its specific G protein coupled receptors. In HLECs, S1P binds to S1PR1 and causes lymphangiogenesis. To date, evidence of cross-talk between these pathways has not been reported

Methods:
HLECs were obtained from LONZA, and used after less than 4 splitting-passages. Protein levels of Ang2 and VEGF-C in the supernatant of cell culture were measured by ELISA, mRNA expression by qPCR, and phosphorylation was detected by Western Blot assay. SphK1 activity assay was used to compare the activity after treatment with Ang2 or VEGF-C

Results:
We found that both Ang2 and VEGF-C mRNA expression increased by S1P treatment, with a corresponding significant increase in VEGF-C and Ang2 in the supernatant of cell culture after S1P treatment. This implies that S1P promotes Ang2 and VEGF-C production and secretion from HLECs. Furthermore, with Western-blot we found that Tie2 was phosphorylated after S1P treatment as was VEGFR-3, which implies that Ang2 and VEGF-C bind to their receptors after S1P-induced secretion. We found that Ang-2 treatment to HLEC cells not only resulted in phosphorylated Tie-2 but also in phosphorylated SphK1. This result was similar with VEGF-C treatment which resulting not only VEGFR-3 phosphorylation but also in phosphorylated SphK1. This result is in agreement with that of an S1P activity assay that showed a 1.5 fold increase in SphK1 activity when HLEC were treated by Ang2 or VEGF-C when compared to control. These findings imply that both Ang2 and VEGF-C activate SphK1, which we know produces S1P, via activation of their receptors. Together with our previously published findings, we found that there is an amplification loop type cross-talk between S1P signaling and Ang2 and VEGF-C signaling in LECs

Conclusion:
Our results suggest that there is a feed-forward amplification loop in HLEC where S1P increases the levels and activities of both Ang2 and VEGF-C, then in turn, Ang2 and VGEF-C activate SphK1 that produces S1P. S1P as well as Ang2 and VEGF-C have been independently implicated to be involved in lymphangiogenesis. The feed-forward relationship between these previously separate pathways, will likely potentiate lymphangiogenesis when these pathways are activated. This may have important ramifications in the pathogenesis and treatment of inflammatory and neoplastic conditions

58.20 Anti-Cancer Activity of a p53-Derived Peptide in a Colon Cancer Peritoneal Carcinomatosis Model

Posted on December 22, 2014

B. D. Babcock1, M. F. Shaikh1, K. Davitt1, Y. Piazza2, T. Meckmongkol1, V. Purohit1, R. Patel1, M. Estioko1, E. Gleeson1, M. R. Pincus3, W. B. Bowne1  1Drexel University College Of Medicine,Surgery,Philadelphia, Pa, USA 2Drexel University College Of Medicine,Pathology,Philadelphia, Pa, USA 3New York Harbor Healthcare System VAMC,Pathology,New York, NY, USA

Introduction:  PNC-27 is a p53-derived peptide construct from the MDM-2 binding domain that possesses anti-cancer activity while sparing normal untransformed cells. To further elucidate anti-cancer activity and mechanism we tested PNC-27 in a murine colon cancer (MCC) peritoneal carcinomatosis (PC) model.  

Methods:  1 x 104 CT-26 MCC cells and untransformed colonic fibroblasts (CF) were treated with PNC-27 and control peptide. Cellular proliferation (MTT), necrosis (LDH), and apoptosis (caspase-3) were measured.  Quantification of MDM-2 in CT-26 and CF was performed using western blot analysis.  Confocal microscopy localized PNC-27/MDM-2 interaction.  Nu/Nu mice with established PC determined by in-vivo bioluminescent imaging (IVIS-BLI) were treated by intra-peritoneal peptide injection for 14 days.  BLI, tumor volume, and histology were studied.

Results:  PNC-27 showed no elevation of pro-apoptotic proteins but induced rapid (4h) dose-dependent CT-26 specific cellular necrosis with 3-fold increase in LDH release (p<0.001) and 92.3% decrease in proliferation (p<0.001). This observed anti-cancer activity may, in part, be due to increased expression of MDM-2 detected in CT-26 plasma membranes compared to CF. Moreover, confocal microscopy demonstrated specific co-localization of PNC-27 and MDM-2 along CT-26 plasma membrane.  Importantly, tumor volume decreased by nearly 40% in PNC-27 treated mice (versus controls; p = 0.1) which was in accordance to observed reduction in BLI and histologically confirmed tumor specific coagulation necrosis.  No toxicity was observed in PNC-27 treated mice. 

Conclusion:  Our results suggest a mechanism of PNC-27 binding to MDM-2 on the CT-26 plasma membrane, leading to rapid targeted necrosis with a potential role in the treatment of colon cancer PC.

 

58.07 Validating Novel p53-Derived Anti-Cancer Peptide Activity Against a Human Colon Cancer Cell Line

Posted on December 22, 2014

M. F. Shaikh1, B. Babcock1, E. Gleeson1, K. Davitt1, P. Love1, A. Desai1, D. Zimmerman1, M. R. Pincus2, W. B. Bowne1  1Drexel University College Of Medicine,Philadelphia, Pa, USA 2New York Harbor Healthcare System VAMC,New York, NY, USA

Introduction:  PNC-27 is an anti-cancer peptide derived from the MDM-2 binding domain of p53, residues 12-26, attached to a membrane residency peptide. Previously, this peptide has been shown to be effective against murine colon cancer. We now test PNC-27 against a human colon cancer cell line, HCT-116, to further characterize anti-cancer activity and mechanism.

Methods: 1 x 104 HCT-116 cells and untransformed colonic fibroblasts (CF) were treated with PNC-27 and control peptide. Anti-cancer activity was assessed using the MTT cell proliferation assay. Mechanism of cancer cell death (necrosis vs. apoptosis) was assessed using the LDH and caspase-3 assays, respectively. Western blot analysis determined HDM2 expression in both HCT-116 and CF. PNC-27/HDM-2 interaction was studied using immunofluorescent staining and confocal microscopy.

Results: PNC-27 demonstrated specific anti-cancer effects in HCT-116 cells with a greater than 80% reduction in cell proliferation after treatment (p<.007). Mechanism studies revealed no elevation of pro-apoptotic proteins but did reveal rapid cell death by 5-fold increase in LDH release (p<.0001), signifying necrosis. Western blot analysis showed increased expression in HCT-116 cells as compared to untransformed CF cells. Moreover, confocal microscopy demonstrated specific co-localization of PNC-27 and MDM-2 along the cancer plasma membrane.

Conclusion: Our results suggest that PNC-27 targets HDM-2 on the HCT-116 cancer cell membrane, leading to specific anti-cancer necrosis. This peptide shows promise in the treatment of colon cancer.

58.08 Improvements to a Murine Colon Cancer Model for Cancer Progression and the Tumor Microenvironment

Posted on December 22, 2014

K. P. Terracina1, T. Aoyagi3, W. Huang1, A. Yamada4, M. Nagahashi2, K. Takabe1  1Virginia Commonwealth University,Surgical Oncology,Richmond, VA, USA 2Nigata University,Surgery,Nigata, , Japan 3Chiba University,Surgery,Chiba, , Japan 4Yokohama City University,Surgery,Yokohama, , Japan

Introduction:  Over the past several decades, it has become clear that the murine xenograft models, which implant human cancer cells into immune-deficient nude mice, used in the majority of preclinical studies, poorly predict the outcome of human clinical trials. The emerging understanding of the important role of immune responses in the tumor microenvironment for cancer progression necessitates animal models that do not preclude the immune response. As new targets for cancer treatment are discovered and investigated, preclinical studies should be conducted with murine models that include intact immune responses, and that allow real time monitoring of cancer progression to provide a closer correlation with human cancer. In our laboratory, we have recently developed a modified syngeneic orthotopic murine colon cancer model that mimics human colon cancer progression with consistent results.

Methods:  We have genetically engineered a murine colon adenocarcinoma cell line, CT26, to overexpress the firefly luciferase gene (CT26-luc1), which allowed real time in vivo monitoring of tumor burden when the substrate, D-luciferin, was injected intraperitoneally using In Vivo Imaging System (IVIS). We have established a syngeneic orthotopic colon cancer model using CT26-luc1 cells suspended in matrigel and either injected submucosally into the cecum wall under direct visualization, or directly injected into the cecum wall as a control. 

Results: Our syngeneic orthotopic colon cancer submucosal injection model has demonstrated consistent implantation in the cecum compared to the direct injection technique. In contrast, the direct injection model demonstrated complications such as premature peritoneal carcinomatosis prior to development of lymph node metastasis. In vivo bioluminescence allowed real time monitoring of total tumor burden. We have also found that perioperative care has a significant impact on reproducibility of the model. Finally, we found that total tumor burden quantified with bioluminescence enabled us to estimate lymph node metastasis in vivo. 

Conclusion: Our newly established method that maintains intact immune response in the tumor microenvironment is expected to provide an invaluable murine metastatic colon cancer model particularly in preclinical studies for drug development targeting those mechanisms. 

 

58.09 Establishment of a Xenogenic Model of Hepatic Oligo- and Polymetastases of Colorectal Cancer

Posted on December 22, 2014

G. Oshima1,2, S. C. Wightman1, A. Uppal1, J. Oskvarek2, M. Stack1, X. Huang2, T. E. Darga2, M. C. Posner1, N. Khodarev2, R. R. Weichselbaum2  1University Of Chicago,Department Of Surgery,Chicago, IL, USA 2University Of Chicago,Department Of Radiation & Cellular Oncology, Ludwig Center For Metastasis Research,Chicago, IL, USA

Introduction: Patients with colorectal cancer (CRC) often present with liver metastases, which, despite systemic treatment, frequently results in a fatal outcome. Between 5 to 20% of patients with limited numbers of hepatic metastases and slow rates of progression/recurrence (oligometastases) are successfully treated with local treatment approaches, with or without systemic therapy. Yet, little is known about molecular basis of oligometastatic disease. Animal models are critical to study pathophysiological mechanisms and new treatments for patients with metastatic CRC. We propose here a xenogenic animal model of hepatic metastasis of CRC that simulate oligo- and polymetastases,

Methods: We generated a panel of monoclonal HCT116-derived cell lines double-labeled with luciferase and tdTomato protein using lentiviral-based gene delivery. Hepatic tumors were generated by injecting 2 million cells into spleens in mice. Five minutes post-injection splenectomies were performed to avoid carcinomatous peritonitis and residual growth in spleen. Bioluminescent signals were measured weekly using the Xenogen IVIS 200 (MA, United States) imaging system. Two to 4 weeks after injections, livers were harvested and ex vivo fluorescent intensities of liver tumors were quantified. The number and size of liver tumors were directly measured to see the correlation between fluorescent intensities and macroscopic disease. Twenty individual monoclonal cell lines were tested to select candidates for oligo- and polymetastatic phenotype. Diffuse Luminescent Imaging Tomography (DLIT) was performed for evaluation of tumor burden and organ distribution using real-time 3D reconstruction of bioluminescence signals.

Results: Monoclonal cell lines varied in the ability to form liver metastases with 2 cell lines demonstrating oligometastatic phenotype (O1 and O2) and 2 other cell lines-polymetastatic phenotype (P1 and P2). Bioluminescent intensities of P1 and P2 were higher than O1 and O2 at 1 to 3 weeks after injection. Mean tumor number of P1 was higher than P2, O1 and O2 (p < 0.05). Mean tumor size of P2 was larger than P1, O1 and O2 (p < 0.05). Tumor burden estimated by tumor number and size correlated with bioluminescent intensity and fluorescent intensity (R = 0.99). DLIT showed tumor distribution and size dependent signal intensity comparable to macroscopic findings.

Conclusion: An animal model of metastatic CRC to the liver can reproducibly mimic oligo- and polymetastatic CRC in humans. Cell lines double-labeled with luciferase and tdTomato protein can be used as a reliable method to evaluate tumor burden using live imaging which enable sequential monitoring in the same mice and detailed information about tumor size and distribution in secondary site(s). This animal model can be used to improve pre-clinical testing of novel therapies. It may also facilitate evaluation of new biological mechanisms discriminating oligo-and polymetastatic disease in liver.

58.11 BMP signaling within glioblastoma mediates GSC quiescence and treatment resistance.

Posted on December 22, 2014

S. Das1,2, M. Wu2, M. Srikanth6,7, H. Kim4, A. Celebre2, D. Brat5, J. Kessler6, J. Karamchandani2,3, M. Bredel5  1St. Michael’s Hospital, University Of Toronto,Neurosurgery/Surgery,Toronto, ON, Canada 2Ann And Arthur Labatt Brain Tumour Centre, Hospital For SickKids,Cell Biology,Toronto, ON, Canada 3Montreal Neurological Institute,Laboratory Medicine,Montreal, QC, Canada 4University Of Alabama,Radiation Oncology,Birmingham, Alabama, USA 5Emory University School Of Medicine,Pathology,Atlanta, GA, USA 6Northwestern University,Chicago, IL, USA 7Harvard School Of Medicine,Brookline, MA, USA

Introduction:  The role of intratumoral heterogeneity as a determinant of treatment failure and disease recurrence has become increasingly appreciated.  In glioblastoma, intratumoral heterogeneity—on the functional, genetic, and transcriptional level—likely accounts for the inability of conventional and targeted therapies to achieve long-term remission. In the neural stem cell (NSC) niche, NSCs have been shown to shuttle between a quiescent and activated state. This dynamic has also been shown to be present in the hair follicle stem cell niche, where oscillating levels of bone morphogenetic protein (BMP) and TGF-β2 expression regulate activation of hair follicle stem cell proliferation following physiologic quiescence. We postulated that glioma stem cells (GSCs) could also shuttle between a quiescent and activated state, and that these fate choices could be directed by TGF-β and BMP signaling within the tumor microenvironment.  Further, we postulated that TGF-β and BMP might construe cell identities in glioblastoma that could be relevant to glioblastoma treatment resistance, disease evolution and disease progression.

Methods: We performed immunohistochemical analysis for in situ evidence of TGF-β and BMP signaling in glioblastoma using surgical specimens, then confirmed our findings using in vitro stem cell assay systems. Using knockdown and overexpression stuides, we characterized the quiescent and activated GSC states. We then confirmed the basis for our phenomonological hypothesis in mouse glioblastoma long-term label retaining and chemoradiation treatment models.

Results: We demonstrate that TGF-β and BMP signaling are active in the glioblastoma microenvironment, and regulate the shuttling of GSCs from an activated to a quiescent state through their effects on p21, Stat3 and EGFR. In vivo, BMPhi GSCs are long-term retaining cells, consistent with the quiescent phenotype. BMP-mediated quiescence protects GSCs from genotoxic stress and treatment-associated DNA damage. Further, BMPhi GSCs serve as a cellular reservoir for tumour recurrence following chemotherapy. 

Conclusion: Our findings demonstrate a role for BMP-mediated quiescence in glioblastoma disease resistance and recurrence, and suggest that targeted inhibition of BMP during chemoradiation and TGF-β following its conclusion could favorably alter the natural history of this disease.

 

58.12 A novel steroidal lactone targets head and neck cancer stem cells blocking migration and EMT.

Posted on December 22, 2014

P. T. White1, C. Subramanian1, P. T. Grogan1, E. Brandes1, H. Zhang2, R. Gallagher2, B. N. Timmermann2, M. S. Cohen1  1University Of Michigan,Department Of Surgery,Ann Arbor, MI, USA 2University Of Kansas,Department Of Medicinal Chemistry,Lawrence, KS, USA

Introduction: Head and neck squamous cell carcinoma (HNSCC) survival rates have been stagnant for the last four decades highlighting the need for novel therapeutic approaches and a better understanding of the disease biology. Recent advances indicate that cancer stem cells (CSCs) in the tumor are responsible for recurrence and metastasis, and that standard cisplatin treatment enriches CSC numbers via BMI-1 upregulation. Withanolides are 28-carbon steroidal lactones that have been shown by our group and others to have potent anticancer activity through inhibition of HSP90-chaperoned kinases. These selectively target key proliferative pathways in cancers (including notch, β-catenin, and NF-κB) that also play a critical role in CSC maintenance. We hypothesize that a novel withanolide, withalongolide A (WGA) and its triacetate derivative (WGA-TA) will prevent tumor growth and invasion through inhibition of CSC epithelial to mesenchymal transition (EMT) and cell migration.

Methods:   Validated human HNSCC cell lines (JMAR, MDA1986,UMSCC-11B) were grown in 2D culture and treated with 0.1 to 5μM WGA or WGA-TA for 24h. Proteins involved in the maintenance of CSCs and EMT were analyzed by Western blot (WB) and matrigel invasion assays were performed post treatment to evaluate migration. Orosphere formation assay was conducted to determine self-renewal after treatment. The percentage of apoptotic CSCs was determined by flow cytometry (FC) and confirmed by WB.

Results:  Treatment of HNSCC cells with WGA-TA demonstrated a dose dependent increase in inhibition of CSC markers compared to WGA, including BMI-1, CD44, EZH2, notch1 and other proteins involved in CSC maintenance. 5 µM WGA-TA treatment had the highest inhibition on CSC regulatory proteins and markers (80% for EZH2, 45%BMI-1, 60% for CD44) which was significant (p<0.01)vs. 5 µM WGA (30% inhibition for EZH2, 35% for CD44, and none for BMI-1) and vs. controls (p<0.01). Similarly 5 µM WGA-TA significantly inhibited levels of Akt (95%), p-Akt (80%), and p-GSK3β (90%) compared to WGA (95%, 80% and 30%, respectively, p<0.001 vs controls). 5 µM WGA-TA treatment also decreased the EMT protein vimentin by 60%. In the migration assay, treatment with 5μM WGA-TA showed greater than 80% suppression of migration compared to control (p<0.001), as opposed to 20-30% for 5 µM WGA treatment (p<0.01 vs WGA-TA). An increase in apoptotic CSCs by >50% vs controls, and decrease in orosphere formation occured in a dose-dependent manner with WGA-TA.

Conclusions: WGA-TA represents a novel therapy for HNSCC targeting key pathways and kinases implicated in the maintenance of CSCs, EMT, and invasion. These withanolides target BMI-1, EZH2 and its downstream effectors in HNSCC CSCs resulting in decreased EMT and tumor migration. Further in vivo translation is needed to define the role of this CSC inhibition on tumor growth kinetics, invasion, and metastatic spread.

 

58.13 Evaluating the activity of Tasquinimod (ABR-215050) in head and neck squamous cell carcinoma (HNSCC)

Posted on December 22, 2014

M. B. Burch1, J. M. Warram1, N. G. Patel1, T. M. Zimmermann2, E. L. Rosenthal1  1University Of Alabama At Birmingham,Division Of Otolaryngology, Department Of Surgery,Birmingham, AL, USA 2Mayo Clinic,Department Of Otorhinolaryngology,Rochester, MN, USA

Introduction:
S100A9, a subunit of the protein calprotectin, is released during tissue damage and has been implicated in the progression of inflammation and cancer metastasis. Recent studies suggest that extracellular matrix metalloproteinase inducer (EMMPRIN) can act as a cell-surface receptor for S100A9. EMMPRIN is a well-characterized factor in the progression of many head and neck tumors. Therefore, evidence of an S100A9-EMMPRIN interaction would serve to further demonstrate a possible role for S100A9 in local tumor invasion and disease progression.

Methods:
Human SCC1-Luc+ HNSCC cells were injected into the unilateral flank of nude athymic mice. Tumors were grown for 1 week before exposure to trial compounds. Studies incorporated exposure of these tumors to the S100A9 inhibitor Tasquinimod (TASQ) via drinking water at a dose of 10 mg/kg/day, as well as anti-EMMPRIN monoclonal antibody (CNTO3899). Groups included exposure to TASQ (n=5), anti-EMMPRIN (n=5), TASQ + anti-EMMPRIN concurrently (n=5), and untreated (n=5). Microcalipers and bioluminescence imaging via luciferase were used to quantify tumor size. Tumors were resected, sectioned, and mounted. Immunohistochemistry was performed using primary antibodies to EMMPRIN and S100A9. Corresponding fluorescently-labeled secondary antibodies and fluorescence microscopy were used to assess localized expression. Scores were assigned descriptively using a modified Allred scoring method by assigning a relative expression of 0 to 5 based on fluorescence intensity and 0 to 5 based on fluorescence distribution within each sample. Aggregated scores were then used for statistical analysis.

Results:
Upon study termination, tumors exposed to TASQ alone and exposed to TASQ + anti-EMMPRIN were significantly larger than untreated tumors (p= 0.015 and p=0.009, respectively). In vivo analysis revealed that mice administered TASQ alone exhibited an increase in tumor size 110.77% over untreated tumors, whereas tumors exposed to both TASQ and anti-EMMPRIN concurrently demonstrated a 113.04% increase in tumor size over untreated tumors during this same period. Tumors exposed only to anti-EMMPRIN decreased 78.26% in size compared to untreated tumors. Tumors exposed to TASQ demonstrated a significant decrease in EMMPRIN expression compared to untreated tumors (p=0.015).

Conclusion:
Inhibition of S100A9 activity by TASQ in HNSCC leads to accelerated tumor growth, suggesting a possible protective role for this molecule in squamous cell tumors. The concurrent inhibition of S100A9 and EMMPRIN contributes to enhanced disease progression in HNSCC. Inhibition of EMMPRIN alone decreases HNSCC progression. Inhibition of S100A9 by TASQ leads to a significant decrease in cellular EMMPRIN expression.
 

58.02 SPATA20 Expression is Associated with Rectal Cancer Pathologic Response to Neoadjuvant Chemoradiation

Posted on December 22, 2014

L. C. Duraes1,2, G. Gantt1,2, J. DeVecchio2, A. Mace1,2, G. Karagkounis1,2, L. Thai1,2, M. F. Kalady1,2  1Cleveland Clinic,Colorectal Department,Cleveland, OH, USA 2Cleveland Clinic,Department Of Stem Cell Biology And Regenerative Medicine – Lerner Research Institute,Cleveland, OH, USA

Introduction:

Patients with a pathologic complete response (pCR) to neoadjuvant chemoradiation have improved oncologic outcomes.  Unfortunately only about 20% of patients achieve pCR and ways to improve this number remain elusive.  Our laboratory studies genetic factors that may provide insight to the biology underlying response to treatment.  Preliminary work by our group has suggested that spermatogenesis associated 20 (SPATA20), which is a gene important for cell differentiation, multicellular organismal development, and spermatogenesis, may be associated with poor outcome in rectal cancer.  The purpose of this study is to determine the association between SPATA20 expression and response to neoadjuvant treatment in rectal cancer patients.

Methods:

Thirty-three rectal adenocarcinoma patients treated with neoadjuvant chemoradiation had pretreatment tumor biopsies snap frozen according to an IRB-approved protocol. Total tumor mRNA was extracted from the biopsies and gene expression was determined using high-throughput microarrays on an Illumina platform. Chemoradiation response was evaluated based on American Joint Committee on Cancer (AJCC) criteria (0 – complete response; 1 – small group of tumor cells; 2 – residual cancer outgrown by fibrosis; 3 – minimal tumor kill) and correlated with gene expression levels.  Gene expression levels as determined by microarray were validated using quantitative real-time PCR (qPCR). Protein expression was analyzed using immunofluorescence. Statistical analysis was performed and p<0.05 was considered significant.

Results:

SPATA20 expression was significantly decreased in complete responders (AJCC 0) compared to partial and non-responders (AJCC 1-3); and increased in non-responders (AJCC 3) compared to partial and complete responders (AJCC0-2) on microarray analysis. These results were further validated by qPCR (p<0.05) (figure).  Furthermore, SPATA20 protein levels were also decreased in complete responders and most elevated in non-responders, as measured by protein immunofluorescence.

Conclusion:

SPATA20 may serve as a novel biomarker in predicting rectal cancer response to chemoradiation.  Further prospective validation and exploration into the biological mechanism of how it may contribute to treatment resistance is warranted.

58.03 The Clonal Evolution of Metastatic Colorectal Cancer

Posted on December 22, 2014

J. G. Grossman1, C. Maher2,4, B. S. White2,4, A. C. Lockhart3,4, T. Fleming1,3, K. Lim3,4, B. Goetz3, E. Pittman1, S. M. Strasberg1,3, D. C. Linehan1,3, W. Hawkins1,3, S. P. Goedegebuure1,3, E. Mardis2,5, R. K. Wilson2,3,5, T. Ley2,4,5, R. C. Fields1,3  1Washington University,Department Of General Surgery,St. Louis, MO, USA 2Washington University,The Genome Institute,Saint Louis, MO, USA 3Alvin J. Siteman Cancer Center,Saint Louis, MO, USA 4Washington University,Department Of Medicine, Oncology Division,Saint Louis, MO, USA 5Washington University,Department Of Genetics,Saint Louis, MO, USA

Introduction:
Colorectal cancer is the second leading cause of cancer mortality in the United States, and death from CRC occurs via sequelae of metastases.  Our lack of understanding of mechanisms of metastasis formation has prevented the identification and direct targeting of pathways necessary for growth and survival of metastaseis.   Next-generation sequencing gives us the capability to better study the evolutionary biology of metastasis, however a comprehensive analysis comparing matched primary and metastatic colorectal tumors has not been performed to date.  Our group in collaboration with the Washington University Genome Institute is currently analyzing 10 patients’ primary and metastatic tumors by whole genome and transcriptome sequencing.  We present the evolution of the clonal relationships of primary and metastatic tumors from three cases completed to date. 

Methods:
Patients with metastatic colorectal cancer were consented, and primary tumor and liver metastases were procured during operative resection. Additionally, uninvolved colon, uninvolved liver, and peripheral blood were collected (germline controls). If necessary, tissue from prior resections was obtained from paraffin blocks.  Deep exome and WGS were used to calculate variant allele frequency (VAFs) for the somatic single nucleotide variants. We chose to incorporate deep exome sequencing thereby enabling us to more accurately calculate VAFs, which in turn improves our ability to reconstruct the clonal architecture. To accomplish this, we used SciClone, a tool developed at Washington University Genome Institute for identifying VAF clusters via variational Bayesian Beta mixture modeling.

Results:
Among the primary tumors prevalent somatically altered genes were APC, TP53, KRAS, PIK3CA, and SMAD4. Upon evaluating the clonal evolution from primary to metastases, phylogenetic trees were generated for each patient illustrating tumor similarities and differences to each other and in relation to normal tissue. Additionally, the clonal evolution from primary to metastases was mapped and clearly shows every tumors’ subclonal makeup and how they relate to one another. Every patient had a dominant clone originating from the primary tumor that was present in all of its corresponding metastases. However, unique subclones appear to arise in all metastatic samples. In some cases, these subclones are shared among various metastases of the same patient, and these similarities may be due to the spatial or temporal proximity  of the tumors.

Conclusion:
Exploring the clonal evolution from primary tumor to metastasis provides a greater understanding of cancer biology, and further elucidates the importance of tumor heterogeneity.  Continued investigation is necessary to evaluate which subclones may be biologically relevant to disease progression and treatment  resistance. In addition, future identification of altered genes associated with metastatic clones may lead to targeted cancer therapies. 
 

58.04 NPTX2 Downregulation is Associated with Sensitivity to Chemoradiation in Rectal Cancer

Posted on December 22, 2014

G. Karagkounis1,2, J. DeVecchio2, L. Thai1,2, L. C. Duraes1,2, G. A. Gantt1,2, M. F. Kalady1,2  1Cleveland Clinic,Colorectal Surgery,Cleveland, OH, USA 2Cleveland Clinic,Stem Cell Biology And Regenerative Medicine,Cleveland, OH, USA

Introduction:  Neoadjuvant chemoradiation (CRT) is the standard of care for locally advanced rectal cancer. Response is highly variable, from complete pathologic response to no treatment effect. The mechanisms behind CRT resistance remain unclear and the paucity of pretreatment predictors of response leads to a significant proportion of patients undergoing therapies from which they may derive minimal or no benefit. The goal of this study was to identify gene expression profiles associated with rectal cancer resistance to CRT.

Methods:  Freshly frozen pretreatment rectal adenocarcinoma biopsies were collected according to an established IRB-approved protocol. Thirty-three patients who underwent standard long course neoadjuvant treatment including 5-FU and external beam radiation were identified. Post-treatment resection specimens were evaluated for response based on American Joint Committee on Cancer (AJCC) criteria. Total tumor mRNA was extracted from pretreatment biopsies and gene expression levels were determined using high-throughput microarrays on an Illumina platform. Gene expression levels between complete responders (AJCC 0) to partial and non-responders (AJCC 1-3) were compared using non-parametric Wilcoxon test. Real-time quantitative PCR (RT-qPCR) was used to validate microarray gene expression levels in the same sample set.

Results: Neuronal pentraxin 2 (NPTX2), a gene normally involved in neuronal development and recently implicated in renal cell carcinoma progression, was found to be significantly downregulated among complete responders (AJCC 0) compared to partial and non-responders (AJCC 1-3) by microarray analysis (fold change 29.8, p=0.02). NPTX2 downregulation among complete responders was confirmed by RT-qPCR (p=0.012), with gradually increasing NPTX2 expression levels through the different AJCC grades (p=0.029).

Conclusion: NPTX2 is relatively under expressed in human rectal adenocarcinomas that are sensitive to neoadjuvant CRT. As response to CRT is a strong predictor of oncological outcomes, NPTX2 expression may serve as an early prognostic biomarker and could serve as a potential target for CRT sensitization. These findings provide an opportunity for further studies to elucidate its biological role in rectal cancer.

58.05 The H1047R Mutation in p110 Alpha Increases Filopodia Formation of Human Colon HCT116 Cancer Cells

Posted on December 22, 2014

A. Rajput1, G. Wan1, A. Rajput1  1University Of New Mexico HSC,Surgical Oncology/Surgery,Albuquerque, NM, USA

Introduction:
Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase through which a number of receptor tyrosine kinases signal. Gain of function mutations in the catalytic subunit p110α (PIK3CA) of Class 1A PI3K occur in up to one-third of human colorectal cancers (CRC),  and result in dysregulation of cell signaling.  Our group has previously shown that in in vivo orthotopic models, that human colon cancer cell lines bearing the H1047R point mutation in p110α are more metastatic than cells carrying wild type p110α. The purpose of this study was to compare changes in cell morphology in wild type and mutant PI3K bearing cells. We hypothesized that the H1047R mutation in PI3K would result in rearrangement of the cytoskeleton and thus morphology and cell motility.

Methods:
1) HCT116 cells with either the WT or the MUT PIK3CA allele alone were grown and fixed on coverslips. Following permeablization, F-actin was labeled by AlexaFluorR 488 phalloidin and confocal images of F-actin labeled WT and MUT cells were acquired. The cell morphology was analyzed by Image J and the degree of difference between the structures of actin filopodia in WT and MUT cells was assessed using a custom Matlab script. The actual length of the cell border between the start and end points of these line segments was then measured. The ratio between the sum of the lengths of the 5µm line segments and the total cell border length, R (eq 1), is a measure of the surface roughness of the cell, which corresponds to the number of filopodia present. Therefore, an R-value close to 1 indicates a smooth surface, whereas an R-value close to 0 is a rougher surface. 2) F-actin level was measured by Flow Cytometer and 3) cell motility was tested by wound healing assay.

Results:
HCT116 H1047R MUT bearing cells compared to WT PIK3CA cells demonstrated increased levels of PIP3 which is reflective of gain of PI3K function. There was also a decrease in F-actin levels in MUT vs. WT bearing cells. MUT bearing cells also demonstrated significantly increased numbers of cell filopodia as shown in Figure 1. Wound healing assay demonstrated increased cell motility in MUT as compared to WT cells.

Conclusion:
Our findings indicate that the H1047R mutation reorganizes actin structure; generates higher PIP3 levels and decreases F-actin levels. This function possibly contributes to the enhanced migratory capacity of HCT116 MUT cells. Our results further confirmed that the accumulation of PIP3 and change in the appearance of cytoskeleton of cells are important aspects in regulating cell motility and therefore possibly metastasis. Thus the PI3K pathway remains a desirable therapeutic target for patients with colorectal cancer.
 

58.06 Conditional Mouse Model of Colon Cancer Using Adenoviral Delivery with Murine Colonoscopy

Posted on December 22, 2014

J. W. Harris1, P. Rychahou1, M. Evers1  1University Of Kentucky,Department Of General Surgery,Lexington, KY, USA

Introduction: Colorectal cancer (CRC) is the second leading cause of cancer death in the US. The K-ras gene is mutated in 30-50% of patients with CRC; mutations in the gene encoding p53 acquire oncogenic properties that enable them to promote invasion, metastasis, proliferation and cell survival and are present in up to 50% of CRCs.  The purpose of this study was to develop a novel model of de novo CRC through activation of oncogenic K-ras and the loss of function of p53 in combination with the intracolonic delivery of adenovirus.
 

Methods: K-ras/p53 mutant mice (3 male, 3 female) received an intracolonic submucosal injection of 30 µL (3×107) Ad-CMV-Cre adenovirus under endoscopic guidance using a high resolution mouse video endoscopic system. The mice underwent surveillance endoscopy and were sacrificed 8 wks after initial adenovirus injection.  Endoscopy video and images were recorded for technical evaluation and confirmation of tumor formation. Colonic tissues were sectioned and stained with H&E to confirm histologic presence of tumor.
 

Results: K-ras/p53 mutant mice do not spontaneously develop de novo CRCs without exposure to an oncogenic vector, nor do wild type mice typically develop CRCs when exposed to adenovirus. De novo CRC was noted in all male mice (n=3); one mouse developed a colo-cutaneous fistula, one developed an obstructing tumor, and the last mouse had a nearly obstructing tumor. H&E staining confirmed the presence of CRC in the male mice. In contrast, none of the female mice developed tumors.

Conclusion: Our technique using adenovirus to establish a primary intracolonic mucosal CRC is novel and reproducible. This conditional orthotopic model is important to better investigate genetically induced tumors and targeted therapeutics in their natural environment. Further research is required to better address the impact of genetic mutations and gender differences of CRC development in animal and human studies.

 

52.02 Geographic Clustering of Guideline Adherence in Colon Cancer Care Using Spatial Autocorrelation

Posted on December 22, 2014

R. L. Hoffman1, K. D. Simmons1, G. C. Karakousis1, N. N. Mahmoud1, R. R. Kelz1  1Hospital Of The University Of Pennsylvania,Philadelphia, PA, USA

Introduction: Stage-specific, evidence-based guidelines to assist with the delivery of quality cancer care were first released in 1996. Adherence to guideline-based therapy has been shown to have an impact on overall and recurrence free survival for colon cancer patients. In order to identify high yield regions for educational campaigns regarding colon cancer guidelines, we analyzed the geographic distribution of guideline-adherent care using spatial autocorrelation.

Methods: Patients aged 65-84 years diagnosed with AJCC stage II and III colon cancer were identified within the SEER-Medicare database (2005-2009). High risk stage II disease was defined as those with a T4 tumor, poor differentiation and <12 lymph nodes examined. Guideline adherence was assigned using stage-specific NCCN guidelines. The percentage of adherence was calculated for each state and county within the SEER registry catchment areas containing more than 10 patients, and translated to a choropleth map. Tests of spatial autocorrelation with queen contiguity-based spatial weights were used to evaluate geographic clustering of guideline-concordant therapy delivery. The Moran’s I and the local indicator of spatial autocorrelation (LISA) were calculated.

Results:There were 17,715 patients identified. A total of 4,933 (28%) were low risk Stage IIA/IIB, 4,446 (34%) were high risk stage IIA/IIB, and 8,336 (47%) were stage IIIA/B/C. A total of 13,017 (73%) patients underwent colectomy, 3,549 (27%) had ≤12 lymph nodes removed, 3,988 (31%) received chemotherapy, and 485 (4%) were treated with radiation.  A total of 331 (3%) were treated with all modalities. Of all those who underwent surgery, 6,348 (49%) received guideline concordant treatment and 6,669 (51%) were discordant (5,837; 45% undertreated, 832; 6% overtreated). Stage IIA/B patients received concordant therapy 53% of the time and are undertreated in 39% of cases while Stage III patients receive concordant care 44% of the time and are undertreated in 52%. Twelve states were represented in the SEER registry and 73 counties. Adherence rates ranged from 43% to 56% by state and ranged from 16% to 87% by county. The value of Moran’s I was 0.187. Clustering of concordant care varied throughout the US (Fig 1).

Conclusion:There is variation in the treatment of stage II and III colon cancer across geographic locations within the United States. Variation seems to be unrelated to the presence of NCI Designated Comprehensive Cancer Centers. Graphical representation of NCCN guideline concordance patterns using spatial autocorrelation represents a new approach to identifying high yield regions for education campaigns. Issues related to cancer care access may be more specifically targeted using this knowledge.

 

52.10 Equal Access to Care Eliminates Racial/Ethnic Disparities in Patients with Operable Breast Cancer

Posted on December 22, 2014

A. C. DuBose1, Q. D. Chu1  1Louisiana State University Health Sciences Center,Division Of Surgical Oncology, Department Of Surgery,Shreveport, LA, USA

Introduction:  A recent study reported that racial/ethnic disparity in breast cancer mortality in the 50 largest cities in the U.S. has risen sharply, which can be attributed to a higher “amenability index”, a measure of accessibility to technologic advances. Our institution provides equal access and technologic advances to all women with breast cancer, irrespective of their socioeconomic status (SES). We determine whether such a practice can eliminate disparities in breast cancer outcome.

Methods: A prospective breast cancer database examined outcome for 977 patients with stage 0 to III breast cancer treated up to April 2013. The majority received standard definitive surgery as well as appropriate adjuvant treatment. Primary endpoint was overall-survival (OS). Statistical analysis performed included Kaplan-Meier survival analysis and independent-samples t test. P ≤ 0.05 was considered statistically significant.

Results: Sixty-one percent of patients were African-Americans (AA), and three-quarters were either free care or Medicaid.  Despite having a more aggressive tumor subtype (a lower percentage of ER/PR-positivity in AA as compared to Caucasian (C) patients; 38% vs. 52%, respectively), the 5-year overall survival (OS) for AA and C patients was similar (84% vs. 87%, respectively; P = 0.23). Multivariate analysis confirmed that race/ethnicity was not an independent predictor of OS (P=0.14);  OS for the entire cohort was comparable with that of the SEER database.

Conclusion: In a predominantly indigent population, equal access to care negates racial disparity in patients with breast cancer.

 

51.01 Improvement in Patient-Reported Outcomes Following Parathyroidectomy for Primary Hyperparathyroidism

Posted on December 22, 2014

K. Zanocco1,2, Z. Butt1,2,3, D. Kaltman1, D. Elaraj1, D. Cella2,3, J. L. Holl2, C. Sturgeon1  1Northwestern University,Department Of Surgery,Chicago, IL, USA 2Northwestern University,Center For Healthcare Studies,Chicago, IL, USA 3Northwestern University,Department Of Medical Social Sciences,Chicago, IL, USA

Introduction:
The majority of patients with primary hyperparathyroidism (PHPT) are diagnosed incidentally and many are without the classic signs of renal or osseous complications. The NIH Patient Reported Outcomes Measurement Information System (PROMIS®) contains validated measures of physical and mental health that can be efficiently administered to patients using computer-adapted testing. The objective of this study was to describe changes in PHPT patient-reported health before and after curative parathyroidectomy and assess the feasibility of PROMIS use in the outpatient clinical setting.  We hypothesized that patients with PHPT would report greater improvement in mental and physical health compared to controls.

Methods:
Adult PHPT patients scheduled for parathyroidectomy and control patients requiring diagnostic thyroid surgery at an academic medical center were prospectively enrolled during a 6-month period. Stakeholders identified 12 of the most relevant PROMIS health domains to assess PHPT symptoms. Patients were administered computer-delivered measures of these domains at a preoperative visit and 3 weeks after surgery. A change in score of 5 or greater for each PROMIS instrument was defined as clinically significant.  Statistical significance of pre/post-surgery changes in scores was determined using paired t-tests. Simple linear regression modeling was performed to examine the relationship between preoperative serum calcium levels and physical health scores.

Results:
35 PHPT patients and 9 control patients completed the study.  The mean number of items answered during an assessment was 67 (range 51 to 121, SD 15.4). Median completion time was 8.2 minutes (range 3.4 to 38.4, SD 4.7).  When compared to the control group, PHPT patients who underwent curative parathyroidectomy had statistically and clinically-significant improvement in the PROMIS domains of Fatigue, Pain Intensity, Physical Function, Sleep-Related Impairment, Anxiety, Applied Cognition, and Depression. (Table 1)  A linear relationship in PHPT patients between serum calcium concentration and PROMIS Fatigue score was observed (p=0.02, adjusted R-squared=0.10, correlation=0.35).

Conclusion:
PROMIS is an efficient clinical assessment platform for patient-reported outcomes in PHPT. Several domains of physical and mental health in patients with PHPT exhibit clinically and statistically significant improvement after parathyroidectomy.
 

51.02 The Current Status of Shared Decision Making in Cancer: Patient and Physician Views

Posted on December 22, 2014

N. Tamirisa1,2, A. Kandalam1, S. K. Linder1, S. Weller1, S. Turrubiate1, C. Silva1, T. S. Riall1  1University Of Texas Medical Branch,Surgery,Galveston, TX, USA 2University Of California – San Francisco,East Bay Foundation,Oakland, CA, USA

Introduction: Engaging patients in shared decision making involves: 1) A thorough patient understanding of the risks and benefits of treatment options and 2) Elicitation of patient preferences and treatment expectations at the time of decision making. Our aim was to explore patient and physician perceptions of shared decision making in clinical encounters for cancer care.

Methods: Twenty cancer patients with a range of cancer diagnoses, stages of cancer, and time from diagnosis and/or treatment participated in one-on-one interviews. Eight physicians, including surgeons, oncologists, gastroenterologists, and palliative care physicians, were interviewed. Patients and physicians were asked open-ended questions regarding their perceptions of shared decision making throughout their cancer care. Transcripts of interviews were coded and analyzed for shared decision making themes. The number of patients and physician who mentioned specific themes were tallied with examples of themes given in quotations in Table 1.

Results: All physicians described providing information regarding treatment options, risks, and benefits (Table 1); 62.5% of physicians reported providing patients with written information. Concern for overwhelming patients with too much information, including prognostication, was mentioned by 37.5% of physicians. 80% of patients wanted to play an active role in the treatment decision. However, 50% of patients mentioned that written information provided was too detailed and not useful; 20% of patients felt that the physicians did not assess the level of information they wished to receive. To assist with treatment decisions, 75% of patients also wanted the physician’s recommendation including the option that a physician would choose for him/herself or family member in a similar situation. 62% of physicians incorporated patient autonomy in the shared decision making process but provided evidence-based data without framing treatment recommendations in the format preferred by most patients. 37.5% of physicians’ comments suggested a projection of their own values in making treatment recommendations.

Conclusion: We identified several communication gaps in cancer care. While patients want to be involved in the decision making process, they also want physicians to provide evidence-based recommendations in the context of their individual preferences. However, physicians often are reluctant to provide recommendations and inadvertently project their own priorities and values when communicating treatment options to patients. Better physician assessment of patients’ informational needs and development of their ability to elicit patients’ preferences will improve the shared decision making process in cancer patients.

51.03 The Oldest Old and Hospital Resource Use After Pancreaticoduodenectomy at High Volume Hospitals

Posted on December 22, 2014

R. C. Langan1,2, K. Harris1,2,3, C. Zheng1, R. Verstraete4, W. B. Al-Refaie1,2,3, L. B. Johnson1,2,3  1Georgetown University Hospital,Department Of Surgery,Washington, DC, USA 2MedStar-Georgetown Surgical Outcomes Research Center,Washington, DC, USA 3MedStar Health Research Institute,Washington, DC, USA 4Georgetown University Hospital,Washington, DC, USA

Introduction: Studies examining post-pancreaticoduodenectomy (PD) operative outcomes in patients older than 80-years have found higher complications, longer length of stay (LOS) and higher mortality. However, there is limited data reporting hospital resources consumed in caring for the oldest-old.  We examined the use of PD-relevant hospital resources in patients treated in high-volume-hospitals (HVH) participating in the University HealthSystem Consortium (UHC).

Methods: Using the UHC database, we identified 210 U.S. hospitals performing ≥ 12 PD/year between 2010 and 2014. We compared mortality, complications, ICU-use, TPN-use, blood transfusions, LOS, readmissions and direct costs by increasing age groups. Index hospitals performed a total of 12,766 PDs (< 70 years n=8,564, 70-79 years n=3,302, ≥ 80 years n=900). We used linear regression models with and without adjusting for covariates to assess the impact of older age. Hospital means were weighted based on age-specific procedure volume.

Results: Compared to younger patients, those ≥ 80-years experienced more cardiopulmonary, genitourinary and infectious complications, more blood transfusions, greater TPN use, longer LOS and higher direct costs (Table 1). However, they experienced fewer readmissions and had equivalent ICU-use and mortality rates to both younger cohorts.

Conclusion: With growing pressure to control and reduce hospital costs, it is imperative to identify, understand, and modify factors that contribute to elevated resource use both within the hospitals and post-discharge. We found increased resource utilization in the oldest-old as compared to younger patients. However, the oldest-old had comparable mortality and intensive care use, fewer readmissions and as compared to septuagenarians had no differences in TPN-use or direct costs. Our findings suggest that substantial differences in resource use may underlie otherwise comparable clinical outcomes.

 

51.04 Locally Advanced Primary Recto-Sigmoid Cancers: Improved survival with multivisceral resection

Posted on December 22, 2014

G. Laurence1, R. Grim1, T. Bell1, N. Ahuja2  1York Hospital,York, PA, USA 2Johns Hopkins University School Of Medicine,Baltimore, MD, USA

Introduction:  Multivisceral resection (MVR) is a radical, often controversial last-resort operation. However, when locally advanced colorectal cancers invade adjacent organs, MVR is an important consideration for select patients wanting to take aggressive action to increase survival. The current study addresses the outcomes of MVR in locally advanced recto-sigmoid cancer patients and hypothesizes that MVR improves survival compared to standard and no surgery.

Methods:  SEER data (1988-2008) was used to identify patients with MVR. Patients were limited to single primary locally advanced non-metastatic colorectal cancers originating from the sigmoid and rectum. Surgery groupings were MVR, standard surgery (SS; low anterior and abdominoperineal resections), and no surgery (NS).

Results: The study included 4,111 (SS=60.7%, NS=23.2%, MVR=16.1%) locally advanced non-metastatic recto sigmoid cancer patients. Predictors of survival were female, radiation and MVR (Table 1). Kaplan Meier analysis showed that overall five-year survival was highest for MVR (43.1%), followed by SS (31.5%) and NS (9.7%), p<0.001. With radiation treatment, five-year survival improved for all groups, with the highest being MVR (47.8%), followed by SS (36.3%), and NS (14%), p<0.001. With no radiation treatment, five-year survival decreased for all groups, but remained the highest for MVR (35.3%), followed by SS (21.5%), and NS (2.3%, p<0.001).

Conclusion: While MVR is an extensive surgical procedure with significant morbidity that usually requires specialized training and coordination, the present study supports that MVR offers greater survival advantage in patients with locally advanced recto-sigmoid cancer. 

 

« Previous Page
Next Page »