Cathepsin D is a lysosomal hydrolase involved in intra- and extracellular proteolysis. This enzyme is aberrantly produced and processed in malignancy, and most notably is over-secreted into the tumor cell microenvironment. This hyper-secretion may lead to excessive degradation of the extracellular matrix, and contribute to tumor progression and metastases. These phenomena have been established in vitro, and there is evidence that Cathepsin D is similarly dysregulated in human breast cancer patients. Because breast cancer lacks an effective screening or surveillance biomarker, here we address the hypothesis that serum Cathepsin D activity may be useful to assess the presence or progression of breast cancer in females. While representative histologic sections from various disease-specific cohorts confirm previous findings that increased Cathepsin D production and secretion correlate with tumor progression, we report no difference in serum Cathepsin D activity between patients who are disease free, patients with pre-invasive or limited invasive disease, and patients with metastatic disease. Furthermore, in patients with known metastatic disease, there were no clinical variables associated with significantly different serum Cathepsin D activity. However, the immunohistochemical localization of Cathepsin D expression in histopathologic sections from breast cancer patients correlates with disease progression. Based on the serum results, and in contradistinction to Cathepsin D localization in breast cancer tissues, our findings support using Cathepsin D as a reliable histopathology biomarker for disease progression, but not for serum screening. Abbott, D. E. Margaryan, N. V. Jeruss, J. S. Khan, S. Kaklamani, V. Winchester, D. Hansen, N. Rademaker, A. Khalkhali-Ellis, Z. Hendrix, M. J. 0 2009-11-21T07:19:50Z 2010-01-15 2009-11-20 %0 Journal Article %A Abbott, D. E. %A Margaryan, N. V. %A Jeruss, J. S. %A Khan, S. %A Kaklamani, V. %A Winchester, D. %A Hansen, N. %A Rademaker, A. %A Khalkhali-Ellis, Z. %A Hendrix, M. J. %D 2010 %T Reevaluating cathepsin D as a biomarker for breast cancer: Serum activity levels versus histopathology. %J Cancer Biol Ther %V 9 %N 1 %M 19923884 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19923884 %X Cathepsin D is a lysosomal hydrolase involved in intra- and extracellular proteolysis. This enzyme is aberrantly produced and processed in malignancy, and most notably is over-secreted into the tumor cell microenvironment. This hyper-secretion may lead to excessive degradation of the extracellular matrix, and contribute to tumor progression and metastases. These phenomena have been established in vitro, and there is evidence that Cathepsin D is similarly dysregulated in human breast cancer patients. Because breast cancer lacks an effective screening or surveillance biomarker, here we address the hypothesis that serum Cathepsin D activity may be useful to assess the presence or progression of breast cancer in females. While representative histologic sections from various disease-specific cohorts confirm previous findings that increased Cathepsin D production and secretion correlate with tumor progression, we report no difference in serum Cathepsin D activity between patients who are disease free, patients with pre-invasive or limited invasive disease, and patients with metastatic disease. Furthermore, in patients with known metastatic disease, there were no clinical variables associated with significantly different serum Cathepsin D activity. However, the immunohistochemical localization of Cathepsin D expression in histopathologic sections from breast cancer patients correlates with disease progression. Based on the serum results, and in contradistinction to Cathepsin D localization in breast cancer tissues, our findings support using Cathepsin D as a reliable histopathology biomarker for disease progression, but not for serum screening. %+ Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 8611 false false 1 Cancer biology & therapy Cancer Biol Ther 2010-01-15 aheadofprint JOURNAL ARTICLE 19923884 Publisher 2009-11-21T07:19:50Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19923884 9 2010 Iannaccone, P. M. Jacob, H. J. 0 2009-09-06T11:55:40Z 2009-05-02 %0 Journal Article %A Iannaccone, P. M. %A Jacob, H. J. %D 2009 %T Rats! %J Dis Model Mech %V 2 %N 5-6 %P 206-210 %M 19407324 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19407324 %K Animals %K *Disease Models, Animal %K Embryonic Stem Cells/cytology %K Humans %K Mice %K Rats Iannaccone, Philip M Jacob, Howard J 2412 false false 5-6 Disease models & mechanisms Dis Model Mech Animals; *Disease Models, Animal; Embryonic Stem Cells/cytology; Humans; Mice; Rats 206-210 ppublish Editorial 19407324 MEDLINE 2009-09-06T11:55:40Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19407324 2 2009 BACKGROUND: The proximal humerus is a common site for tumors, either metastatic or primary. Thus it is a frequent site of intervention in musculoskeletal oncology surgery. We looked at the use of endoprosthetic reconstructions in surgical intervention for tumors of the proximal humerus. METHODS: A review of our database from 1990 to 2005 revealed 83 proximal humeral endoprosthetic reconstructions following an intra-articular, deltoid muscle, and axillary nerve sparing resection. Medical records and radiographs were reviewed to determine shoulder range of motion, MSTS scores, and any complications. The median patient age was 55 years (range, 13-80). The mean follow-up was 30 months (range, 1-199). RESULTS: Mean active abduction was 41 degrees (range, 10-90 degrees) and mean active forward flexion was 42 degrees (range, 5-115 degrees). The mean MSTS score was 63% (range, 40-83%). Implant-related complications included 2 deep infections and 22 patients with proximal migration of the prosthesis. No prostheses loosened. Only 2 required removal (1 for infection and 1 for progression of metastatic disease). CONCLUSIONS: A proximal humeral endoprosthesis provides a durable reconstruction with a relatively low complication rate. Although it provides a stable platform for elbow and hand function, actual shoulder function is limited. Cannon, C. P. Paraliticci, G. U. Lin, P. P. Lewis, V. O. Yasko, A. W. 0 2009-09-06T11:59:36Z 2009-01-30 2009-02-03 %0 Journal Article %A Cannon, C. P. %A Paraliticci, G. U. %A Lin, P. P. %A Lewis, V. O. %A Yasko, A. W. %D 2009 %T Functional outcome following endoprosthetic reconstruction of the proximal humerus. %J J Shoulder Elbow Surg %V 18 %N 5 %P 705-710 %M 19186077 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19186077 %X BACKGROUND: The proximal humerus is a common site for tumors, either metastatic or primary. Thus it is a frequent site of intervention in musculoskeletal oncology surgery. We looked at the use of endoprosthetic reconstructions in surgical intervention for tumors of the proximal humerus. METHODS: A review of our database from 1990 to 2005 revealed 83 proximal humeral endoprosthetic reconstructions following an intra-articular, deltoid muscle, and axillary nerve sparing resection. Medical records and radiographs were reviewed to determine shoulder range of motion, MSTS scores, and any complications. The median patient age was 55 years (range, 13-80). The mean follow-up was 30 months (range, 1-199). RESULTS: Mean active abduction was 41 degrees (range, 10-90 degrees) and mean active forward flexion was 42 degrees (range, 5-115 degrees). The mean MSTS score was 63% (range, 40-83%). Implant-related complications included 2 deep infections and 22 patients with proximal migration of the prosthesis. No prostheses loosened. Only 2 required removal (1 for infection and 1 for progression of metastatic disease). CONCLUSIONS: A proximal humeral endoprosthesis provides a durable reconstruction with a relatively low complication rate. Although it provides a stable platform for elbow and hand function, actual shoulder function is limited. %+ Department of Orthopaedic Oncology - Unit 408, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77230-1402, USA. cpcannon@mdanderson.org Cannon, Christopher P Paraliticci, Giovanni U Lin, Patrick P Lewis, Valerae O Yasko, Alan W 6907 false false 5 Journal of shoulder and elbow surgery / American Shoulder and Elbow Surgeons ... [et al.] J Shoulder Elbow Surg 705-710 ppublish Journal Article 19186077 In-Process 2009-09-06T11:59:36Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19186077 18 2009 The role of chronic hepatitis C virus (HCV) in the pathogenesis of HCV-associated hepatocellular carcinoma (HCC) remains controversial. To understand the transition from benign to malignant, we studied the gene expression patterns in liver tissues at different stages, including normal, cirrhosis, and different HCC stages. We studied 108 liver tissue samples obtained from 88 distinct patients (41 HCV-cirrhotic tissues, 17 HCV-cirrhotic tissues from patients with HCC, and 47 HCV-HCC tissues). Differentially expressed genes (DEG) were studied by use of high-density oligonucleotide arrays. Among probe sets identified as differentially expressed via the F test, all pairwise comparisons were performed. Cirrhotic tissues with and without concomitant HCC were further evaluated, and a classifier was used to predict whether the tissue type was associated with HCC. Differential expression profiles were analyzed using Interaction Networks and Functional Analysis. Characteristic gene signatures were identified when normal tissue was compared with cirrhosis, cirrhosis with early HCC, and normal with HCC. Pathway analysis classified the cellular and biological functions of the DEG as related to cellular growth and proliferation, cell death and inflammatory disease in cirrhosis; cell death, cell cycle, DNA replication, and immune response in early HCCs; and cell death, cell growth and proliferation, cell cycle, and DNA repair in advanced HCCs. Characteristic gene signatures were identified at different stages of HCV-HCC progression. A set of genes were identified to predict whether the cirrhotic tissue was associated with HCC. Mas, V. R. Maluf, D. G. Archer, K. J. Yanek, K. Kong, X. Kulik, L. Freise, C. E. Olthoff, K. M. Ghobrial, R. M. McIver, P. Fisher, R. 0 2009-09-06T12:00:38Z 2008-12-15 2008-12-23 %0 Journal Article %A Mas, V. R. %A Maluf, D. G. %A Archer, K. J. %A Yanek, K. %A Kong, X. %A Kulik, L. %A Freise, C. E. %A Olthoff, K. M. %A Ghobrial, R. M. %A McIver, P. %A Fisher, R. %D 2009 %T Genes involved in viral carcinogenesis and tumor initiation in hepatitis C virus-induced hepatocellular carcinoma. %J Mol Med %V 15 %N 3-4 %P 85-94 %M 19098997 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19098997 %X The role of chronic hepatitis C virus (HCV) in the pathogenesis of HCV-associated hepatocellular carcinoma (HCC) remains controversial. To understand the transition from benign to malignant, we studied the gene expression patterns in liver tissues at different stages, including normal, cirrhosis, and different HCC stages. We studied 108 liver tissue samples obtained from 88 distinct patients (41 HCV-cirrhotic tissues, 17 HCV-cirrhotic tissues from patients with HCC, and 47 HCV-HCC tissues). Differentially expressed genes (DEG) were studied by use of high-density oligonucleotide arrays. Among probe sets identified as differentially expressed via the F test, all pairwise comparisons were performed. Cirrhotic tissues with and without concomitant HCC were further evaluated, and a classifier was used to predict whether the tissue type was associated with HCC. Differential expression profiles were analyzed using Interaction Networks and Functional Analysis. Characteristic gene signatures were identified when normal tissue was compared with cirrhosis, cirrhosis with early HCC, and normal with HCC. Pathway analysis classified the cellular and biological functions of the DEG as related to cellular growth and proliferation, cell death and inflammatory disease in cirrhosis; cell death, cell cycle, DNA replication, and immune response in early HCCs; and cell death, cell growth and proliferation, cell cycle, and DNA repair in advanced HCCs. Characteristic gene signatures were identified at different stages of HCV-HCC progression. A set of genes were identified to predict whether the cirrhotic tissue was associated with HCC. %K Carcinoma, Hepatocellular/etiology/*genetics/pathology/*virology %K *Cell Transformation, Neoplastic %K Disease Progression %K Gene Expression Profiling %K *Gene Expression Regulation, Neoplastic %K Gene Regulatory Networks %K Hepacivirus/genetics/*pathogenicity %K Humans %K Liver Neoplasms/etiology/*genetics/pathology/*virology %K Oligonucleotide Array Sequence Analysis %K ROC Curve %K Reproducibility of Results %+ Division of Transplantation, Department of Surgery, Virginia Commonwealth University, Richmond, Virginia, USA. vmas@mcvh-vcu.edu Mas, Valeria R Maluf, Daniel G Archer, Kellie J Yanek, Kenneth Kong, Xiangrong Kulik, Laura Freise, Chris E Olthoff, Kim M Ghobrial, Rafik M McIver, Paula Fisher, Robert 7704 false false 3-4 Molecular medicine (Cambridge, Mass.) Mol Med Carcinoma, Hepatocellular/etiology/*genetics/pathology/*virology; *Cell Transformation, Neoplastic; Disease Progression; Gene Expression Profiling; *Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Hepacivirus/genetics/*pathogenicity; Humans; Liver Neoplasms/etiology/*genetics/pathology/*virology; Oligonucleotide Array Sequence Analysis; ROC Curve; Reproducibility of Results 85-94 ppublish Journal Article 19098997 MEDLINE 2009-09-06T12:00:38Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19098997 15 2009 A therapy gaining rapid clinical adoption involves radioembolization with the use of Yttrium-90 (90Y) microspheres. The 20-60 microm-sized microspheres are injected trans-arterially and flow to hepatic tumors given their preferential blood supply from the hepatic artery. Once they lodge in the arterioles, they impart a very intense local radiotherapeutic effect. Given the combined radiation and embolic effect, the imaging findings imparted by this mode of action differ significantly from other treatments. This work represents a comprehensive review of the imaging findings following radioembolization in patients with primary liver tumors. The report discusses imaging response, benign secondary effects, and complications. This should help educate the radiologist on imaging findings that should be expected following radioembolization and therefore aid in the proper image interpretation. Ibrahim, S. M. Nikolaidis, P. Miller, F. H. Lewandowski, R. J. Ryu, R. K. Sato, K. T. Senthilnathan, S. Riaz, A. Kulik, L. Mulcahy, M. F. Omary, R. A. Salem, R. 0 2009-09-06T11:56:49Z 2008-09-09 %0 Journal Article %A Ibrahim, S. M. %A Nikolaidis, P. %A Miller, F. H. %A Lewandowski, R. J. %A Ryu, R. K. %A Sato, K. T. %A Senthilnathan, S. %A Riaz, A. %A Kulik, L. %A Mulcahy, M. F. %A Omary, R. A. %A Salem, R. %D 2009 %T Radiologic findings following Y90 radioembolization for primary liver malignancies. %J Abdom Imaging %V 34 %N 5 %P 566-581 %M 18777189 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18777189 %X A therapy gaining rapid clinical adoption involves radioembolization with the use of Yttrium-90 (90Y) microspheres. The 20-60 microm-sized microspheres are injected trans-arterially and flow to hepatic tumors given their preferential blood supply from the hepatic artery. Once they lodge in the arterioles, they impart a very intense local radiotherapeutic effect. Given the combined radiation and embolic effect, the imaging findings imparted by this mode of action differ significantly from other treatments. This work represents a comprehensive review of the imaging findings following radioembolization in patients with primary liver tumors. The report discusses imaging response, benign secondary effects, and complications. This should help educate the radiologist on imaging findings that should be expected following radioembolization and therefore aid in the proper image interpretation. %+ Department of Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA. Ibrahim, Saad M Nikolaidis, Paul Miller, Frank H Lewandowski, Robert J Ryu, Robert K Sato, Kent T Senthilnathan, Sean Riaz, Ahsun Kulik, Laura Mulcahy, Mary F Omary, Reed A Salem, Riad 4177 false false 5 Abdominal imaging Abdom Imaging 566-581 ppublish Journal Article 18777189 In-Process 2009-09-06T11:56:49Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18777189 34 2009 We have recently discovered that de-N-acetyl GM3 [NeuNH(2)LacCer, d-GM3], a derivative of ganglioside GM3, is specifically expressed in metastatic tumor cells and that its expression correlates with an enhanced metastatic phenotype. Although the classic N-acetylated form of GM3 (NeuAcLacCer, c-GM3) is found in both normal and tumor cells, metastatic tumor cells (but not other cells) predominantly express d-GM3 (82-95% of total GM3). d-GM3 expression is mainly found in metastatic melanomas, but not in benign nevi or the majority of primary melanomas. Using metastatic (d-GM3-positive) and poorly invasive (d-GM3-negative) human melanoma cell lines, we found that d-GM3 stimulates cell migration and invasion by increasing the expression and activation of urokinase-like plasminogen activator (uPA). Further studies showed that d-GM3 activates matrix metalloproteinase-2 (MMP-2), but not MMP-9, when uPA receptor signaling is activated. These results implicate d-GM3 as a specific marker for metastatic melanoma and a novel therapeutic target for neoplastic diseases. [Cancer Res 2009;69(22):8662-9]. Liu, J. W. Sun, P. Yan, Q. Paller, A. S. Gerami, P. Ho, N. Vashi, N. Le Poole, I. C. Wang, X. Q. 0 2009-11-13T07:19:52Z 2009-11-10 2009-11-12 %0 Journal Article %A Liu, J. W. %A Sun, P. %A Yan, Q. %A Paller, A. S. %A Gerami, P. %A Ho, N. %A Vashi, N. %A Le Poole, I. C. %A Wang, X. Q. %D 2009 %T De-N-acetyl GM3 promotes melanoma cell migration and invasion through urokinase plasminogen activator receptor signaling-dependent MMP-2 activation. %J Cancer Res %V 69 %N 22 %P 8662-8669 %M 19903858 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19903858 %X We have recently discovered that de-N-acetyl GM3 [NeuNH(2)LacCer, d-GM3], a derivative of ganglioside GM3, is specifically expressed in metastatic tumor cells and that its expression correlates with an enhanced metastatic phenotype. Although the classic N-acetylated form of GM3 (NeuAcLacCer, c-GM3) is found in both normal and tumor cells, metastatic tumor cells (but not other cells) predominantly express d-GM3 (82-95% of total GM3). d-GM3 expression is mainly found in metastatic melanomas, but not in benign nevi or the majority of primary melanomas. Using metastatic (d-GM3-positive) and poorly invasive (d-GM3-negative) human melanoma cell lines, we found that d-GM3 stimulates cell migration and invasion by increasing the expression and activation of urokinase-like plasminogen activator (uPA). Further studies showed that d-GM3 activates matrix metalloproteinase-2 (MMP-2), but not MMP-9, when uPA receptor signaling is activated. These results implicate d-GM3 as a specific marker for metastatic melanoma and a novel therapeutic target for neoplastic diseases. %+ Department of Oncology, the First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China. 8588 false false 22 Cancer research Cancer Res 8662-8669 2009-11-15 ppublish JOURNAL ARTICLE 19903858 In-Process 2009-11-17T07:21:11Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19903858 69 2009 PURPOSE: Our purpose was to investigate the tolerability of accelerated, twice-daily, high-dose radiotherapy. The secondary endpoints were survival and locoregional tumor control. METHODS AND MATERIALS: Thirty consecutive patients with histologically/cytologically proven non-small-cell lung cancer were enrolled. Tumor Stage I, II, IIIA, and IIIB was found in 7, 3, 12, and 8 patients, respectively. We applied a median of 84.6 Gy (range, 75.6-90.0 Gy) to the primary tumors, 63.0 Gy (range, 59.4-72.0 Gy) to lymph nodes, and 45 Gy to nodes electively (within a region of about 6 cm cranial to macroscopically involved sites). Fractional doses of 1.8 Gy twice daily, with an interval of 11 hours, were given, resulting in a median treatment time of 35 days. In the majority of patients the conformal target-splitting technique was used. In 19 patients (63%) two cycles of induction chemotherapy were given. The median follow-up time of survivors is 72 months (range, 62-74 months). RESULTS: We found Grade 1, 2 and 3 acute esophageal toxicity in 11 patients (37%), 2 patients (7%), and 2 patients (7%), respectively. Grade 2 acute pneumonitis was seen in 2 patients (7%). No late toxicity greater than Grade 1 was observed. The actual overall survival rates at 2 and 5 years are 63% and 23%, respectively; the median overall survival, 27.7 months. In 9 patients a local failure occurred, 7 of them presenting initially with an atelectasis without availability of 18-fluorodeoxyglucose-positron emission tomography staging at that time. In 4 patients recurrence occurred regionally. CONCLUSIONS: This Phase I/II trial with long-term follow-up shows low toxicity with promising results for survival and locoregional tumor control. Wurstbauer, K. Deutschmann, H. Kopp, P. Kranzinger, M. Merz, F. Nairz, O. Studnicka, M. Sedlmayer, F. 0 2009-11-18T07:16:21Z 2009-11-10 2009-11-17 %0 Journal Article %A Wurstbauer, K. %A Deutschmann, H. %A Kopp, P. %A Kranzinger, M. %A Merz, F. %A Nairz, O. %A Studnicka, M. %A Sedlmayer, F. %D 2009 %T Nonresected Non-Small-Cell Lung Cancer in Stages I Through IIIB: Accelerated, Twice-Daily, High-Dose Radiotherapy-A Prospective Phase I/II Trial with Long-Term Follow-Up. %J Int J Radiat Oncol Biol Phys %M 19910140 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19910140 %X PURPOSE: Our purpose was to investigate the tolerability of accelerated, twice-daily, high-dose radiotherapy. The secondary endpoints were survival and locoregional tumor control. METHODS AND MATERIALS: Thirty consecutive patients with histologically/cytologically proven non-small-cell lung cancer were enrolled. Tumor Stage I, II, IIIA, and IIIB was found in 7, 3, 12, and 8 patients, respectively. We applied a median of 84.6 Gy (range, 75.6-90.0 Gy) to the primary tumors, 63.0 Gy (range, 59.4-72.0 Gy) to lymph nodes, and 45 Gy to nodes electively (within a region of about 6 cm cranial to macroscopically involved sites). Fractional doses of 1.8 Gy twice daily, with an interval of 11 hours, were given, resulting in a median treatment time of 35 days. In the majority of patients the conformal target-splitting technique was used. In 19 patients (63%) two cycles of induction chemotherapy were given. The median follow-up time of survivors is 72 months (range, 62-74 months). RESULTS: We found Grade 1, 2 and 3 acute esophageal toxicity in 11 patients (37%), 2 patients (7%), and 2 patients (7%), respectively. Grade 2 acute pneumonitis was seen in 2 patients (7%). No late toxicity greater than Grade 1 was observed. The actual overall survival rates at 2 and 5 years are 63% and 23%, respectively; the median overall survival, 27.7 months. In 9 patients a local failure occurred, 7 of them presenting initially with an atelectasis without availability of 18-fluorodeoxyglucose-positron emission tomography staging at that time. In 4 patients recurrence occurred regionally. CONCLUSIONS: This Phase I/II trial with long-term follow-up shows low toxicity with promising results for survival and locoregional tumor control. %+ Department of Radiation Oncology, Paracelsus Medical University, Salzburg, Austria; radART-Institute for Research and Development on Advanced Radiation Technologies,, Paracelsus Medical University, Salzburg, Austria. 8599 false false International journal of radiation oncology, biology, physics Int J Radiat Oncol Biol Phys 2009-11-10 aheadofprint JOURNAL ARTICLE 19910140 Publisher 2009-11-18T07:16:21Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19910140 2009 BACKGROUND:: Studies have demonstrated volume-outcome relationships for numerous operations, providing an impetus for regionalization; however, volume-based regionalization may not be feasible or necessary. Our objective was to determine if low-risk patients undergoing surgery at Community Hospitals have perioperative mortality rates comparable with Specialized Centers. METHODS:: From the National Cancer Data Base, 940,718 patients from approximately 1430 hospitals were identified who underwent resection for 1 of 15 cancers (2003-2005). Patients were stratified by preoperative risk according to age and comorbidities. Separately for each cancer, regression modeling stratified by high- and low-risk groups was used to compare 60-day mortality at Specialized Centers (National Cancer Institute-designated and/or highest-volume quintile institutions), Other Academic Institutions (lower-volume, non-National Cancer Institute), and Community Hospitals. RESULTS:: Low-risk patients had statistically similar perioperative mortality rates at Specialized Centers and Community Hospitals for 13 of 15 operations. High-risk patients had significantly lower perioperative mortality rates at Specialized Centers compared with Community Hospitals for 9 of 15 cancers. Regardless of risk group, perioperative mortality rates were significantly lower for pancreatectomy and esophagectomy at Specialized Centers. Risk-based referral compared with volume-based regionalization of most patients would require fewer patients to change to Specialized Centers. CONCLUSIONS:: Perioperative mortality for low-risk patients was comparable at Specialized Centers and Community Hospitals for all cancers except esophageal and pancreatic, thus questioning volume-based regionalization of all patients. Rather, only high-risk patients may need to change hospitals. Mortality rates could be reduced if factors at Specialized Centers resulting in better outcomes for high-risk patients can be identified and transferred to other hospitals. Bilimoria, K. Y. Bentrem, D. J. Talamonti, M. S. Stewart, A. K. Winchester, D. P. Ko, C. Y. 0 2009-11-11T07:21:39Z 2009-11-05 2009-11-10 %0 Journal Article %A Bilimoria, K. Y. %A Bentrem, D. J. %A Talamonti, M. S. %A Stewart, A. K. %A Winchester, D. P. %A Ko, C. Y. %D 2009 %T Risk-based Selective Referral for Cancer Surgery: A Potential Strategy to Improve Perioperative Outcomes. %J Ann Surg %M 19898231 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19898231 %X BACKGROUND:: Studies have demonstrated volume-outcome relationships for numerous operations, providing an impetus for regionalization; however, volume-based regionalization may not be feasible or necessary. Our objective was to determine if low-risk patients undergoing surgery at Community Hospitals have perioperative mortality rates comparable with Specialized Centers. METHODS:: From the National Cancer Data Base, 940,718 patients from approximately 1430 hospitals were identified who underwent resection for 1 of 15 cancers (2003-2005). Patients were stratified by preoperative risk according to age and comorbidities. Separately for each cancer, regression modeling stratified by high- and low-risk groups was used to compare 60-day mortality at Specialized Centers (National Cancer Institute-designated and/or highest-volume quintile institutions), Other Academic Institutions (lower-volume, non-National Cancer Institute), and Community Hospitals. RESULTS:: Low-risk patients had statistically similar perioperative mortality rates at Specialized Centers and Community Hospitals for 13 of 15 operations. High-risk patients had significantly lower perioperative mortality rates at Specialized Centers compared with Community Hospitals for 9 of 15 cancers. Regardless of risk group, perioperative mortality rates were significantly lower for pancreatectomy and esophagectomy at Specialized Centers. Risk-based referral compared with volume-based regionalization of most patients would require fewer patients to change to Specialized Centers. CONCLUSIONS:: Perioperative mortality for low-risk patients was comparable at Specialized Centers and Community Hospitals for all cancers except esophageal and pancreatic, thus questioning volume-based regionalization of all patients. Rather, only high-risk patients may need to change hospitals. Mortality rates could be reduced if factors at Specialized Centers resulting in better outcomes for high-risk patients can be identified and transferred to other hospitals. %+ From the *Cancer Programs, Division of Research and Optimal Patient Care, American College of Surgeons, Chicago, IL; daggerDepartment of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL; double daggerDepartment of Surgery, NorthShore University Health System, Evanston, IL; and section signDepartment of Surgery, University of California, Los Angeles (UCLA) and VA Greater Los Angeles Healthcare System, Los Angeles, CA. 8578 false false Annals of surgery Ann Surg 2009-11-05 aheadofprint JOURNAL ARTICLE 19898231 Publisher 2009-11-11T07:21:39Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19898231 2009 Protein kinases are a growing drug target class in disorders in peripheral tissues, but the development of kinase-targeted therapies for central nervous system (CNS) diseases remains a challenge, largely owing to issues associated specifically with CNS drug discovery. However, several candidate therapeutics that target CNS protein kinases are now in various stages of preclinical and clinical development. We review candidate compounds and discuss selected CNS protein kinases that are emerging as important therapeutic targets. In addition, we analyse trends in small-molecule properties that correlate with key challenges in CNS drug discovery, such as blood-brain barrier penetrance and cytochrome P450-mediated metabolism, and discuss the potential of future approaches that will integrate molecular-fragment expansion with pharmacoinformatics to address these challenges. Chico, L. K. Van Eldik, L. J. Watterson, D. M. 0 2009-11-01T06:20:22Z 2009-10-31 %0 Journal Article %A Chico, L. K. %A Van Eldik, L. J. %A Watterson, D. M. %D 2009 %T Targeting protein kinases in central nervous system disorders. %J Nat Rev Drug Discov %V 8 %N 11 %P 892-909 %M 19876042 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19876042 %X Protein kinases are a growing drug target class in disorders in peripheral tissues, but the development of kinase-targeted therapies for central nervous system (CNS) diseases remains a challenge, largely owing to issues associated specifically with CNS drug discovery. However, several candidate therapeutics that target CNS protein kinases are now in various stages of preclinical and clinical development. We review candidate compounds and discuss selected CNS protein kinases that are emerging as important therapeutic targets. In addition, we analyse trends in small-molecule properties that correlate with key challenges in CNS drug discovery, such as blood-brain barrier penetrance and cytochrome P450-mediated metabolism, and discuss the potential of future approaches that will integrate molecular-fragment expansion with pharmacoinformatics to address these challenges. %K Animals %K Blood-Brain Barrier/metabolism %K Central Nervous System Diseases/*drug therapy/enzymology/physiopathology %K Clinical Trials as Topic %K Drug Delivery Systems %K Drug Design %K Drug Evaluation, Preclinical %K Humans %K Protein Kinase Inhibitors/metabolism/pharmacokinetics/*therapeutic use %K Protein Kinases/*drug effects/metabolism %+ Center for Molecular Innovation and Drug Discovery, Northwestern University, Chicago, Illinois 60611, USA. Chico, Laura K Van Eldik, Linda J Watterson, D Martin 8550 false false 11 Nature reviews. Drug discovery Nat Rev Drug Discov Animals; Blood-Brain Barrier/metabolism; Central Nervous System Diseases/*drug therapy/enzymology/physiopathology; Clinical Trials as Topic; Drug Delivery Systems; Drug Design; Drug Evaluation, Preclinical; Humans; Protein Kinase Inhibitors/metabolism/pharmacokinetics/*therapeutic use; Protein Kinases/*drug effects/metabolism 892-909 2009-11-01 ppublish Journal Article 19876042 MEDLINE 2009-11-17T07:21:33Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19876042 8 2009 Lung cancer is now the leading cancer killer of women, having surpassed breast cancer in 1987. Over 30,000 more US women are expected to die from lung cancer than from breast cancer annually. The vast majority of lung cancer cases are attributable to smoking, and smoking prevalence rates remain unacceptably high in US women. Mounting evidence suggests that there are significant differences in lung cancer between the sexes. Although the magnitude of the effect of smoking on the development of lung cancer may not be different, smoking appears to have an impact on the histology of lung cancer. Hormonal and biologic effects may play a role in lung cancer carcinogenesis, and may impact treatment response. A more thorough understanding of the biologically different aspects of lung cancer across different populations may lead to innovations in prevention and treatment. Patel, J. D. 0 2009-10-31T06:20:03Z 2009-10-30 %0 Journal Article %A Patel, J. D. %D 2009 %T Lung cancer: a biologically different disease in women? %J Womens Health (Lond Engl) %V 5 %N 6 %P 685-691 %M 19863471 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19863471 %X Lung cancer is now the leading cancer killer of women, having surpassed breast cancer in 1987. Over 30,000 more US women are expected to die from lung cancer than from breast cancer annually. The vast majority of lung cancer cases are attributable to smoking, and smoking prevalence rates remain unacceptably high in US women. Mounting evidence suggests that there are significant differences in lung cancer between the sexes. Although the magnitude of the effect of smoking on the development of lung cancer may not be different, smoking appears to have an impact on the histology of lung cancer. Hormonal and biologic effects may play a role in lung cancer carcinogenesis, and may impact treatment response. A more thorough understanding of the biologically different aspects of lung cancer across different populations may lead to innovations in prevention and treatment. %+ Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, 676 N St Clair Street, Suite 850, Chicago, IL 60611, USA. jd-patel@northwestern.edu Patel, Jyoti D 8547 false false 6 Women's health (London, England) Womens Health (Lond Engl) 685-691 2009-11-01 ppublish Journal Article 19863471 In-Process 2009-10-31T06:20:03Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19863471 5 2009 Several prodrug approaches were taken to mask amino groups in two potent and selective neuronal nitric oxide synthase (nNOS) inhibitors containing either a primary or secondary amino group to lower the charge and improve blood-brain barrier (BBB) penetration. The primary amine was masked as an azide and the secondary amine as an amide or carbamate. The azide was not reduced to the amine under a variety of in vitro and ex vivo conditions. Despite the decrease in charge of the amino group as an amide and as carbamates, BBB penetration did not increase. It appears that the uses of azides as prodrugs for primary amines or amides and carbamates as prodrugs for secondary amines are not universally effective for CNS applications. Silverman, R. B. Lawton, G. R. Ranaivo, H. R. Chico, L. K. Seo, J. Watterson, D. M. 0 2009-10-04T06:14:24Z 2009-09-06 2009-10-03 %0 Journal Article %A Silverman, R. B. %A Lawton, G. R. %A Ralay Ranaivo, H. %A Chico, L. K. %A Seo, J. %A Watterson, D. M. %D 2009 %T Effect of potential amine prodrugs of selective neuronal nitric oxide synthase inhibitors on blood-brain barrier penetration. %J Bioorg Med Chem %V 17 %N 21 %P 7593-7605 %M 19796958 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19796958 %X Several prodrug approaches were taken to mask amino groups in two potent and selective neuronal nitric oxide synthase (nNOS) inhibitors containing either a primary or secondary amino group to lower the charge and improve blood-brain barrier (BBB) penetration. The primary amine was masked as an azide and the secondary amine as an amide or carbamate. The azide was not reduced to the amine under a variety of in vitro and ex vivo conditions. Despite the decrease in charge of the amino group as an amide and as carbamates, BBB penetration did not increase. It appears that the uses of azides as prodrugs for primary amines or amides and carbamates as prodrugs for secondary amines are not universally effective for CNS applications. %+ Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, United States. Agman@chem.northwestern.edu 8434 false false 21 Bioorganic & medicinal chemistry Bioorg Med Chem 7593-7605 2009-11-01 ppublish JOURNAL ARTICLE 19796958 In-Process 2009-10-21T06:21:34Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19796958 17 2009 CYP2D6 substrate status is a critical Go/No Go decision criteria in central nervous system (CNS) drug discovery efforts because the polymorphic nature of CYP2D6 can lead to variable patient safety and drug efficacy. In addition, CYP2D6 is disproportionately involved in the metabolism of CNS drugs compared to other drug classes. Therefore, identifying trends in small molecule properties of CNS-penetrant compounds that can help discriminate potential CYP2D6 substrates from nonsubstrates would allow additional prioritization in the synthesis and biological evaluation of new therapeutic candidates. We report here the conversion of the CNS drug minaprine from substrate to nonsubstrate, and the conversion of the related CNS drug minozac from nonsubstrate to substrate through the use of analog synthesis and CYP2D6 enzyme kinetic analyses. No single molecular property strongly correlated with substrate status for this 3-amino-4-methyl-6-phenylpyridazine scaffold, although molecular volume and charge appeared to be indirectly related. A parsed database of CYP2D6 substrates across diverse chemical structures was assembled and analyzed for physical properties trends correlating with substrate status. We found that a complex interplay of properties influenced CYP2D6 substrate status and that the particular chemical scaffold affects which properties are most prominent. The results also identified an unexpected issue in CNS drug discovery, in that some property trends correlative with CYP2D6 substrates overlap previously reported properties that correlate with CNS penetrance. These results suggest the need for a careful balance in the design and synthesis of new CNS therapeutic candidates to avoid CYP2D6 substrate status while maintaining CNS penetrance. Chico, L. K. Behanna, H. Hu, W. Zhong, G. Roy, S. M. Watterson, D. M. 0 2009-09-06T11:59:06Z 2009-08-06 2009-08-08 %0 Journal Article %A Chico, L. K. %A Behanna, H. A. %A Hu, W. %A Zhong, G. %A Roy, S. M. %A Watterson, D. M. %D 2009 %T Molecular properties and CYP2D6 substrates: central nervous system therapeutics case study and pattern analysis of a substrate database. %J Drug Metab Dispos %V 37 %N 11 %P 2204-2211 %M 19661215 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19661215 %X CYP2D6 substrate status is a critical Go/No Go decision criteria in central nervous system (CNS) drug discovery efforts because the polymorphic nature of CYP2D6 can lead to variable patient safety and drug efficacy. In addition, CYP2D6 is disproportionately involved in the metabolism of CNS drugs compared with other drug classes. Therefore, identifying trends in small molecule properties of CNS-penetrant compounds that can help discriminate potential CYP2D6 substrates from nonsubstrates would allow additional prioritization in the synthesis and biological evaluation of new therapeutic candidates. We report here the conversion of the CNS drug minaprine from substrate to nonsubstrate, as well as the conversion of the related CNS drug minozac from nonsubstrate to substrate, through the use of analog synthesis and CYP2D6 enzyme kinetic analyses. No single molecular property strongly correlated with substrate status for this 3-amino-4-methyl-6-phenylpyridazine scaffold, although molecular volume and charge appeared to be indirectly related. A parsed database of CYP2D6 substrates across diverse chemical structures was assembled and analyzed for physical property trends correlating with substrate status. We found that a complex interplay of properties influenced CYP2D6 substrate status and that the particular chemical scaffold affects which properties are most prominent. The results also identified an unexpected issue in CNS drug discovery, in that some property trends correlative with CYP2D6 substrates overlap previously reported properties that correlate with CNS penetrance. These results suggest the need for a careful balance in the design and synthesis of new CNS therapeutic candidates to avoid CYP2D6 substrate status while maintaining CNS penetrance. %+ Center for Drug Discovery and Chemical Biology, Northwestern University, Chicago, Illinois, USA. chico@u.northwestern.edu 6481 false false 11 Drug metabolism and disposition: the biological fate of chemicals Drug Metab Dispos 2204-2211 2009-11-01 ppublish JOURNAL ARTICLE 19661215 In-Process 2009-10-21T06:21:48Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19661215 37 2009 We report the case of an adult patient with pineoblastoma (PBL) who had a complete radiographic response following treatment with vorinostat and retinoic acid. This regimen was used to treat bulky residual tumor that persisted despite radiation therapy (RT) and two cycles of cytotoxic chemotherapy. Vorinostat and retinoic acid were chosen as an alternative to cytotoxic chemotherapy, which our patient was unable to tolerate, based on preclinical data suggesting efficacy of this combination. MRI demonstrated a complete response to this regimen, which continues to remain stable without evidence of recurrence. Deboer, R. Batjer, H. Marymont, M. Goldman, S. Walker, M. Gottardi-Littell, N. Raizer, J. 0 2009-09-06T11:55:17Z 2009-06-09 2009-06-10 %0 Journal Article %A DeBoer, R. %A Batjer, H. %A Marymont, M. %A Goldman, S. %A Walker, M. %A Gottardi-Littell, N. %A Raizer, J. %D 2009 %T Response of an adult patient with pineoblastoma to vorinostat and retinoic acid. %J J Neurooncol %V 95 %N 2 %P 289-292 %M 19506816 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19506816 %X We report the case of an adult patient with pineoblastoma (PBL) who had a complete radiographic response following treatment with vorinostat and retinoic acid. This regimen was used to treat bulky residual tumor that persisted despite radiation therapy (RT) and two cycles of cytotoxic chemotherapy. Vorinostat and retinoic acid were chosen as an alternative to cytotoxic chemotherapy, which our patient was unable to tolerate, based on preclinical data suggesting efficacy of this combination. MRI demonstrated a complete response to this regimen, which continues to remain stable without evidence of recurrence. %+ Feinberg School of Medicine, Northwestern University, 710 N Lake Shore Drive, Abbott Hall, Room 1123, Chicago, IL 60611, USA. becky.deboer@gmail.com 1683 false false 2 Journal of neuro-oncology J Neurooncol 289-292 2009-11-01 ppublish JOURNAL ARTICLE 19506816 In-Process 2009-10-09T06:13:29Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19506816 95 2009 We have previously found that certain stem cells that are derived from rat blastocysts and named extraembryonic endoderm precursor (XEN-P) cells, show a unique molecular signature sharing some of the characteristics of embryonic stem cells (ES), trophoblast stem cells (TS) and extraembryonic endoderm stem cells (XEN). These XEN-P cells are positive for AP, SSEA1, Oct4 and Rex1 markers similar to ES cells and also express signature markers of TS - eomesodermin (Eomes) and XEN - Gata6. Here we show that these cells integrate not only into the visceral and parietal extraembryonic endoderm lineages as observed before, but also into the inner cell mass (ICM), the primitive endoderm, and the polar and mural trophectoderm of cultured embryos. In addition, we find that the XEN-P cells colonize yolk sac and contribute to trophoblast lineages of post-implantation embryos following transfer to surrogate mothers. We also find that the XEN-P cell culture propagates by shedding cell clusters into the media in addition to typical expansion of colonies. Interestingly, the cell cultures exist as mixed populations of two interconvertible phenotypes of flat and round cells with preferential expression of stem cell markers Oct 4 and SSEA1 in round cells. We believe these cells represent a metastable stage during ICM cellular segregation. These results are important to developing hypotheses of cell fate plasticity in the ICM and provide a model for the study of development and differentiation along the extraembryonic lineages. Galat, V. Binas, B. Iannaccone, S. Postovit, L. M. Debeb, B. Iannaccone, P. 0 2009-09-06T11:55:40Z 2009-06-02 %0 Journal Article %A Galat, V. %A Binas, B. %A Iannaccone, S. %A Postovit, L. M. %A Debeb, B. G. %A Iannaccone, P. %D 2009 %T Developmental potential of rat extraembryonic stem cells. %J Stem Cells Dev %V 18 %N 9 %P 1309-1318 %M 19480599 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19480599 %X We have previously found that certain stem cells that are derived from rat blastocysts and named extraembryonic endoderm precursor (XEN-P) cells show a unique molecular signature sharing some of the characteristics of embryonic stem cells (ES), trophoblast stem cells (TS), and extraembryonic endoderm stem cells (XEN). These XEN-P cells are positive for AP, SSEA1, Oct4, and Rex1 markers similar to ES cells and also express signature markers of TS-eomesodermin (Eomes) and XEN-Gata6. Here we show that these cells integrate into the visceral and parietal extraembryonic endoderm lineages as well as into the inner cell mass (ICM), the primitive endoderm, and the polar and mural trophectoderm (TE) of cultured embryos. In addition, we find that the XEN-P cells colonize yolk sac and contribute to trophoblast lineages of postimplantation embryos following transfer to surrogate mothers. We also find that the XEN-P cell culture propagates by shedding cell clusters into the media in addition to typical expansion of colonies. Interestingly, the cell cultures exist as mixed populations of two interconvertible phenotypes of flat and round cells with preferential expression of stem cell markers Oct4 and SSEA1 in round cells. We believe these cells represent a metastable stage during ICM cellular segregation. These results are important for developing hypotheses of cell fate plasticity in the ICM and provide a model for the study of development and differentiation along the extraembryonic lineages. %+ Developmental Biology Program, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60614, USA. v-galat@northwestern.edu 2411 false false 9 Stem cells and development Stem Cells Dev 1309-1318 2009-11-01 ppublish JOURNAL ARTICLE 19480599 In-Process 2009-11-17T07:20:54Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19480599 18 2009 PURPOSE: To evaluate the safety and efficacy of yttrium-90 ((90)Y) radioembolization with extended-shelf-life glass microspheres. We postulated that this approach, for the same planned tissue dose of 120 Gy, would increase the embolic load, improve distribution, and result in enhanced tumor response without causing additional adverse events. MATERIALS AND METHODS: Between June 2007 and September 2008, 50 patients with extensive tumor burden and/or markedly hypervascular tumors (13 hepatocellular carcinomas, and 37 liver metastases) underwent radioembolization with extended-shelf-life microspheres at a planned dose of 120 Gy. Baseline and follow-up imaging and laboratory data were obtained. Response in the target lesion was assessed with cross-sectional imaging by using World Health Organization (WHO) and European Association for the Study of the Liver (EASL) guidelines. RESULTS: The mean delivered radiation dose was 126 Gy. The mean increase in embolic load with this approach was 111%, corresponding to an increase from 3.6 to 7.3 million microspheres. Clinical toxicities included fatigue (28 patients, 56%), abdominal pain (19 patients, 38%), and nausea/vomiting (six patients, 12%). Grade 3-4 bilirubin toxicity was seen in one patient. Two gastroduodenal ulcers were observed. With cross-sectional imaging, response rates according to WHO and EASL guidelines were 51% and 69%, respectively. CONCLUSIONS: The results demonstrate the safety and efficacy of extended-shelf-life (90)Y glass microspheres. The increased embolic load and lowered activity per microsphere theoretically resulted in better tumor coverage and, hence, improved response rates. This standardizable treatment paradigm provides a minimally embolic therapy for liver tumors. Lewandowski, R. J. Riaz, A. Ryu, R. K. Mulcahy, M. F. Sato, K. T. Kulik, L. M. Gates, V. L. Baker, T. Omary, R. Salem, R. 0 2009-10-28T06:22:13Z 2009-10-23 2009-10-27 %0 Journal Article %A Lewandowski, R. J. %A Riaz, A. %A Ryu, R. K. %A Mulcahy, M. F. %A Sato, K. T. %A Kulik, L. M. %A Gates, V. L. %A Baker, T. %A Omary, R. %A Salem, R. %D 2009 %T Optimization of Radioembolic Effect with Extended-shelf-life Yttrium-90 Microspheres: Results from a Pilot Study. %J J Vasc Interv Radiol %M 19854068 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19854068 %X PURPOSE: To evaluate the safety and efficacy of yttrium-90 ((90)Y) radioembolization with extended-shelf-life glass microspheres. We postulated that this approach, for the same planned tissue dose of 120 Gy, would increase the embolic load, improve distribution, and result in enhanced tumor response without causing additional adverse events. MATERIALS AND METHODS: Between June 2007 and September 2008, 50 patients with extensive tumor burden and/or markedly hypervascular tumors (13 hepatocellular carcinomas, and 37 liver metastases) underwent radioembolization with extended-shelf-life microspheres at a planned dose of 120 Gy. Baseline and follow-up imaging and laboratory data were obtained. Response in the target lesion was assessed with cross-sectional imaging by using World Health Organization (WHO) and European Association for the Study of the Liver (EASL) guidelines. RESULTS: The mean delivered radiation dose was 126 Gy. The mean increase in embolic load with this approach was 111%, corresponding to an increase from 3.6 to 7.3 million microspheres. Clinical toxicities included fatigue (28 patients, 56%), abdominal pain (19 patients, 38%), and nausea/vomiting (six patients, 12%). Grade 3-4 bilirubin toxicity was seen in one patient. Two gastroduodenal ulcers were observed. With cross-sectional imaging, response rates according to WHO and EASL guidelines were 51% and 69%, respectively. CONCLUSIONS: The results demonstrate the safety and efficacy of extended-shelf-life (90)Y glass microspheres. The increased embolic load and lowered activity per microsphere theoretically resulted in better tumor coverage and, hence, improved response rates. This standardizable treatment paradigm provides a minimally embolic therapy for liver tumors. %+ Department of Radiology, Section of Interventional Radiology, 676 N St Clair, Ste 800, Chicago, IL 60611. 8530 false false Journal of vascular and interventional radiology : JVIR J Vasc Interv Radiol 2009-10-23 aheadofprint JOURNAL ARTICLE 19854068 Publisher 2009-10-28T06:22:13Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19854068 2009 BACKGROUND: Improved outcomes have been associated with the use of adjuvant therapy after resection of pancreas adenocarcinoma. However, the frequency with which patients receive adjuvant therapy and the factors impacting its use remain largely undefined. We hypothesized that nonutilization of adjuvant therapy was primarily associated with patient comorbidity and onset of postoperative complications. METHODS: A prospectively maintained database was reviewed to identify patients who underwent potentially curative resection of histologically confirmed pancreas adenocarcinoma at our institution from January 1996 to May 2007. Clinicopathological data and postoperative treatment history were collected to identify variables associated with receipt of adjuvant therapy. RESULTS: Of 119 patients, 33% did not receive adjuvant therapy. The frequency with which patients underwent adjuvant therapy did not change over time. On multivariate analysis, patient age 70 years or greater, major postoperative complications, distal pancreatectomy, absence of nodal metastases, and absence of perineural invasion were associated with decreased utilization of adjuvant therapy. DISCUSSION: One-third of patients in this contemporary dataset of patients did not go on to receive adjuvant therapy. The likelihood of receiving adjuvant treatment is negatively impacted by the course of postoperative recovery. Moreover, the fact that adjuvant therapy was undertaken less often for older patients and patients with favorable pathological features highlights the selection bias impacting the decision to pursue postoperative therapy for this disease. This selective utilization of postoperative therapy for patients with adverse oncological characteristics is likely to bias any retrospective analysis attempting to measure the efficacy of adjuvant treatment for pancreas adenocarcinoma. Russ, A. J. Weber, S. M. Rettammel, R. J. Mahvi, D. M. Rikkers, L. F. Cho, C. S. 0 2009-10-25T06:21:18Z 2009-10-23 2009-10-24 %0 Journal Article %A Russ, A. J. %A Weber, S. M. %A Rettammel, R. J. %A Mahvi, D. M. %A Rikkers, L. F. %A Cho, C. S. %D 2009 %T Impact of Selection Bias on the Utilization of Adjuvant Therapy for Pancreas Adenocarcinoma. %J Ann Surg Oncol %M 19851808 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19851808 %X BACKGROUND: Improved outcomes have been associated with the use of adjuvant therapy after resection of pancreas adenocarcinoma. However, the frequency with which patients receive adjuvant therapy and the factors impacting its use remain largely undefined. We hypothesized that nonutilization of adjuvant therapy was primarily associated with patient comorbidity and onset of postoperative complications. METHODS: A prospectively maintained database was reviewed to identify patients who underwent potentially curative resection of histologically confirmed pancreas adenocarcinoma at our institution from January 1996 to May 2007. Clinicopathological data and postoperative treatment history were collected to identify variables associated with receipt of adjuvant therapy. RESULTS: Of 119 patients, 33% did not receive adjuvant therapy. The frequency with which patients underwent adjuvant therapy did not change over time. On multivariate analysis, patient age 70 years or greater, major postoperative complications, distal pancreatectomy, absence of nodal metastases, and absence of perineural invasion were associated with decreased utilization of adjuvant therapy. DISCUSSION: One-third of patients in this contemporary dataset of patients did not go on to receive adjuvant therapy. The likelihood of receiving adjuvant treatment is negatively impacted by the course of postoperative recovery. Moreover, the fact that adjuvant therapy was undertaken less often for older patients and patients with favorable pathological features highlights the selection bias impacting the decision to pursue postoperative therapy for this disease. This selective utilization of postoperative therapy for patients with adverse oncological characteristics is likely to bias any retrospective analysis attempting to measure the efficacy of adjuvant treatment for pancreas adenocarcinoma. %+ Section of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. 8527 false false Annals of surgical oncology Ann Surg Oncol 2009-10-23 aheadofprint JOURNAL ARTICLE 19851808 Publisher 2009-10-25T06:21:18Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19851808 2009 PURPOSE: It is unclear what role pretreatment tumor vascularity plays in determining outcomes after yttrium-90 radioembolization. A hypothesis was tested that radiographic vascularity of a tumor does not affect patient survival. MATERIALS AND METHODS: In this two-institution retrospective study, 137 patients with metastatic liver disease underwent (90)Y radioembolization. Primary sites were categorized as colon, neuroendocrine, and other. All patients underwent triphasic contrast-enhanced computed tomography (CT) or magnetic resonance imaging, as well as detailed hepatic angiography. Two board-certified interventional radiologists interpreted all images and evaluated them for the presence of enhancement. Median survival times, as well as 1- and 2-year survival rates, were compared between patients with hypervascular and hypovascular tumors on (i) cross-sectional imaging and (ii) angiography with use of the log-rank statistic (alpha = 0.05). RESULTS: On angiography, 108 patients had hypervascular tumors and 29 had hypovascular tumors. Median survival times for the two subgroups were 300 days and 261 days, respectively (P = .95). On CT, 24 patients had hypervascular tumors and 113 had hypovascular tumors. Median survival times for these subgroups were 306 days and 284 days, respectively (P = .67). Eighty-four patients' tumors that were hypovascular on CT were hypervascular on angiography. There were no statistical differences in survival between patients with hypervascular and hypovascular tumors, regardless if vascularity was defined based on CT or angiography. CONCLUSIONS: Radiographic vascular appearance of liver tumors, regardless of imaging modality, does not affect survival after radioembolization. Therefore, hypovascular tumors should not be considered contraindicated for radioembolization. Sato, K. T. Omary, R. A. Takehana, C. Ibrahim, S. Lewandowski, R. J. Ryu, R. K. Salem, R. 0 2009-10-24T06:20:38Z 2009-10-19 2009-10-23 %0 Journal Article %A Sato, K. T. %A Omary, R. A. %A Takehana, C. %A Ibrahim, S. %A Lewandowski, R. J. %A Ryu, R. K. %A Salem, R. %D 2009 %T The Role of Tumor Vascularity in Predicting Survival after Yttrium-90 Radioembolization for Liver Metastases. %J J Vasc Interv Radiol %M 19846320 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19846320 %X PURPOSE: It is unclear what role pretreatment tumor vascularity plays in determining outcomes after yttrium-90 radioembolization. A hypothesis was tested that radiographic vascularity of a tumor does not affect patient survival. MATERIALS AND METHODS: In this two-institution retrospective study, 137 patients with metastatic liver disease underwent (90)Y radioembolization. Primary sites were categorized as colon, neuroendocrine, and other. All patients underwent triphasic contrast-enhanced computed tomography (CT) or magnetic resonance imaging, as well as detailed hepatic angiography. Two board-certified interventional radiologists interpreted all images and evaluated them for the presence of enhancement. Median survival times, as well as 1- and 2-year survival rates, were compared between patients with hypervascular and hypovascular tumors on (i) cross-sectional imaging and (ii) angiography with use of the log-rank statistic (alpha = 0.05). RESULTS: On angiography, 108 patients had hypervascular tumors and 29 had hypovascular tumors. Median survival times for the two subgroups were 300 days and 261 days, respectively (P = .95). On CT, 24 patients had hypervascular tumors and 113 had hypovascular tumors. Median survival times for these subgroups were 306 days and 284 days, respectively (P = .67). Eighty-four patients' tumors that were hypovascular on CT were hypervascular on angiography. There were no statistical differences in survival between patients with hypervascular and hypovascular tumors, regardless if vascularity was defined based on CT or angiography. CONCLUSIONS: Radiographic vascular appearance of liver tumors, regardless of imaging modality, does not affect survival after radioembolization. Therefore, hypovascular tumors should not be considered contraindicated for radioembolization. %+ Department of Radiology, Northwestern University, 251 East Huron, Room 4-710R Feinberg, Chicago, IL 60611. 8524 false false Journal of vascular and interventional radiology : JVIR J Vasc Interv Radiol 2009-10-19 aheadofprint JOURNAL ARTICLE 19846320 Publisher 2009-10-24T06:20:38Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19846320 2009 Kaklamani, V. G. Cianfrocca, M. Ciccone, J. Kindy, K. Rademaker, A. Wiley, E. L. Gradishar, W. O'Regan, R. M. 0 2009-10-22T06:20:44Z 2009-10-19 2009-10-21 %0 Journal Article %A Kaklamani, V. G. %A Cianfrocca, M. %A Ciccone, J. %A Kindy, K. %A Rademaker, A. %A Wiley, E. L. %A Gradishar, W. %A O'Regan, R. M. %D 2009 %T Increased HER2/neu expression in recurrent hormone receptor-positive breast cancer. %J Biomarkers %M 19839717 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19839717 %+ Division of Hematology/Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. 8503 false false Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals Biomarkers 2009-10-19 aheadofprint JOURNAL ARTICLE 19839717 Publisher 2009-10-22T06:20:44Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19839717 2009 We present the results of an open-label clinical trial and the clinical use of alemtuzumab in 19 heavily pretreated patients with advanced erythrodermic cutaneous T-cell lymphomas (CTCL) (erythrodermic mycosis fungoides and Sezary syndrome). Ten patients received alemtuzumab intravenously using an escalating dose regimen with a final dose of 30 mg three times weekly for 4 weeks followed by subcutaneous administration for 8 weeks. Nine patients were treated with only the SQ or IV dosing. The overall response rate was 84%, with 9 (47%) complete and 7 (37%) partial remissions. The median follow-up was 24 months (range, 6 to 62+ months). Median overall survival was 41 months whereas median progression free survival was 6 months. Minimal residual disease by T-cell gene rearrangement studies was detected in 11 patients who achieved complete response and partial response. Toxicities included myelosuppression and infections; however, the majority of side effects were of Grade 2 in severity and transient. One patient was diagnosed with a concurrent lymphoma (mantle cell lymphoma) 6 months after completing alemtuzumab therapy. Alemtuzumab is particularly effective in patients with erythrodermic CTCL with acceptable toxicities. Combined strategies with alemtuzumab may achieve molecular remissions with longer response durations. Querfeld, C. Mehta, N. Rosen, S. T. Guitart, J. Rademaker, A. Gerami, P. Kuzel, T. M. 0 2009-10-30T06:22:11Z 2009-10-08 2009-10-29 %0 Journal Article %A Querfeld, C. %A Mehta, N. %A Rosen, S. T. %A Guitart, J. %A Rademaker, A. %A Gerami, P. %A Kuzel, T. M. %D 2009 %T Alemtuzumab for relapsed and refractory erythrodermic cutaneous T-cell lymphoma: a single institution experience from the Robert H. Lurie Comprehensive Cancer Center. %J Leuk Lymphoma %M 19860617 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19860617 %X We present the results of an open-label clinical trial and the clinical use of alemtuzumab in 19 heavily pretreated patients with advanced erythrodermic cutaneous T-cell lymphomas (CTCL) (erythrodermic mycosis fungoides and Sezary syndrome). Ten patients received alemtuzumab intravenously using an escalating dose regimen with a final dose of 30 mg three times weekly for 4 weeks followed by subcutaneous administration for 8 weeks. Nine patients were treated with only the SQ or IV dosing. The overall response rate was 84%, with 9 (47%) complete and 7 (37%) partial remissions. The median follow-up was 24 months (range, 6 to 62+ months). Median overall survival was 41 months whereas median progression free survival was 6 months. Minimal residual disease by T-cell gene rearrangement studies was detected in 11 patients who achieved complete response and partial response. Toxicities included myelosuppression and infections; however, the majority of side effects were of Grade 2 in severity and transient. One patient was diagnosed with a concurrent lymphoma (mantle cell lymphoma) 6 months after completing alemtuzumab therapy. Alemtuzumab is particularly effective in patients with erythrodermic CTCL with acceptable toxicities. Combined strategies with alemtuzumab may achieve molecular remissions with longer response durations. %+ Section of Dermatology, University of Chicago, Chicago, IL, USA. 8538 false false Leukemia & lymphoma Leuk Lymphoma 2009-10-08 aheadofprint JOURNAL ARTICLE 19860617 Publisher 2009-10-30T06:22:11Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19860617 2009 PURPOSE: Alpha-fetoprotein (AFP) is considered to be an indicator of tumor activity in hepatocellular carcinoma (HCC). We present a novel correlation of AFP response to radiologic response, time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS) in patients treated with locoregional therapies. PATIENTS AND METHODS: Four hundred sixty-three patients with HCC were treated with chemoembolization or radioembolization at our institution. One hundred twenty-five patients with baseline AFP higher than 200 ng/mL were studied for this analysis. AFP response was defined as more than 50% decrease from baseline. One hundred nineteen patients with follow-up imaging were studied for the AFP imaging correlation analysis. AFP response was correlated to radiologic response, TTP, PFS, and OS. Multivariate analyses were performed. RESULTS: Eighty-one patients (65%) showed AFP response. AFP response was seen in 26 (55%) of 47 and 55 (70%) of 78 of patients treated with chemoembolization and radioembolization, respectively (P = .12). WHO response was seen in 41 (53%) of 77 and 10 (24%) of 42 of AFP responders and nonresponders, respectively (P = .002). The hazard ratio (HR) for TTP in AFP nonresponders compared with responders was 2.8 (95% CI, 1.5 to 5.1). The HR for PFS was 4.2 (95% CI, 2.4 to 7.2) in AFP nonresponders compared with responders. The HR for OS in AFP nonresponders compared with responders was 5.5 (95% CI, 3.1 to 9.9) and 2.7 (95% CI, 1.6 to 4.6) on univariate and multivariate analyses, respectively. CONCLUSION: The data presented support the use of AFP response seen after locoregional therapy as an ancillary method of assessing tumor response and survival, as well as an early objective screening tool for progression by imaging. Riaz, A. Ryu, R. K. Kulik, L. M. Mulcahy, M. F. Lewandowski, R. J. Minocha, J. Ibrahim, S. M. Sato, K. T. Baker, T. Miller, F. H. Newman, S. Omary, R. Abecassis, M. Benson, A. B. 3rd Salem, R. 0 2009-10-08T06:11:47Z 2009-10-05 2009-10-07 %0 Journal Article %A Riaz, A. %A Ryu, R. K. %A Kulik, L. M. %A Mulcahy, M. F. %A Lewandowski, R. J. %A Minocha, J. %A Ibrahim, S. M. %A Sato, K. T. %A Baker, T. %A Miller, F. H. %A Newman, S. %A Omary, R. %A Abecassis, M. %A Benson, A. B. 3rd %A Salem, R. %D 2009 %T Alpha-Fetoprotein Response After Locoregional Therapy for Hepatocellular Carcinoma: Oncologic Marker of Radiologic Response, Progression, and Survival. %J J Clin Oncol %M 19805671 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19805671 %X PURPOSE: Alpha-fetoprotein (AFP) is considered to be an indicator of tumor activity in hepatocellular carcinoma (HCC). We present a novel correlation of AFP response to radiologic response, time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS) in patients treated with locoregional therapies. PATIENTS AND METHODS: Four hundred sixty-three patients with HCC were treated with chemoembolization or radioembolization at our institution. One hundred twenty-five patients with baseline AFP higher than 200 ng/mL were studied for this analysis. AFP response was defined as more than 50% decrease from baseline. One hundred nineteen patients with follow-up imaging were studied for the AFP imaging correlation analysis. AFP response was correlated to radiologic response, TTP, PFS, and OS. Multivariate analyses were performed. RESULTS: Eighty-one patients (65%) showed AFP response. AFP response was seen in 26 (55%) of 47 and 55 (70%) of 78 of patients treated with chemoembolization and radioembolization, respectively (P = .12). WHO response was seen in 41 (53%) of 77 and 10 (24%) of 42 of AFP responders and nonresponders, respectively (P = .002). The hazard ratio (HR) for TTP in AFP nonresponders compared with responders was 2.8 (95% CI, 1.5 to 5.1). The HR for PFS was 4.2 (95% CI, 2.4 to 7.2) in AFP nonresponders compared with responders. The HR for OS in AFP nonresponders compared with responders was 5.5 (95% CI, 3.1 to 9.9) and 2.7 (95% CI, 1.6 to 4.6) on univariate and multivariate analyses, respectively. CONCLUSION: The data presented support the use of AFP response seen after locoregional therapy as an ancillary method of assessing tumor response and survival, as well as an early objective screening tool for progression by imaging. %+ Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center; Department of Medicine, Divisions of Hepatology and Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center; and the Department of Transplant Surgery, Northwestern University, Chicago, IL. 8446 false false Journal of clinical oncology : official journal of the American Society of Clinical Oncology J Clin Oncol 2009-10-05 aheadofprint JOURNAL ARTICLE 19805671 Publisher 2009-10-08T06:11:47Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19805671 2009