tbuckley/cabot-search huggingface dataset:
Combination of the AKT Inhibitor Perifosine with the HSP90 Inhibitor 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin (17-DMAG) Has Synergistic Activity in Multiple Myeloma (MM).
Authors: Alissa Huston, Lanie Francis, Yazan Alsayed, Ujjal Singha, Ganwei Lu, Judy Anderson, Suzanne Lentzsch, G. David Roodman, Irene Ghobrial
Journal: Blood (2005)
Effect of PEDF on the in vivo antitumor activities of low-dose chemotherapy in CRPC.
Authors: Thomas Nelius, Everardo Cobos, Jennifer Hirsch, Stephanie Filleur
Journal: Journal of Clinical Oncology (2013)

173 Background: The development of metronomic/low dose administration of conventional chemotherapeutic drugs has shown great promise in the treatment of castration-refractory prostate cancer (CPRC). Pigment Epithelium-Derived Factor (PEDF) is a natural angio-inhibitor which is down-regulated in prostate cancer. We have previously demonstrated that the over-expression of PEDF in human CRPC PC3 cells decreased tumor growth in vivo. In the present study, we further validated PEDF anti-tumor properties in the highly metastatic CRPC LNCaP-derivative CL1 cells. We also hypothesized that PEDF may enhance the cytotoxicity effects of low dose docetaxel (DTX) and cyclophosphamide (CTX) chemotherapies in vivo. Methods: PC3 and CL1 cell lines were genetically modified to stably express the fluorescent DsRed Express protein with PEDF. Resulting cells were characterized in vitro for PEDF expression by western blot and, for proliferation by growth curves and clone formation in matrigel. PEDF anti-tumor effects were assessed on established s.c. xenografts in mice treated with DTX (5mg/kg ip every 4 days, 1mg/kg ip daily for 10 days, 0.5mg/kg every other day), CTX (10-20mg/kg in the drinking water) or placebo. Survival studies were performed by injecting CL1-PEDF or -control cells into the left lobe of the dorsal prostate of anesthetized mice. Results: We showed that PEDF expression inhibits the proliferation and induces the differentiation of CPRC cells in vitro, and decreases by 85% and 70% the development of s.c. PC3 and CL1 tumors, respectively. In the survival study, PEDF expression prolongs significantly (P=0.01; 95% confidence interval) the median survival of CL1 tumor-bearing mice (53±0.001 days versus 57±1). Furthermore, we demonstrated that PEDF enhances the cytotoxicity effects of low dose chemotherapy on established s.c. tumors (best Doc dose: 1mg/kg for PC3 and 5mg/kg for CL1; best CTX dose: 10mg/kg for PC3 and CL1) and prolongs significantly the survival of tumor-bearing mice undergoing low dose chemotherapy. Conclusions: These data reinforce the significance of PEDF as a potent target for the treatment of CRPC. It also emphasizes PEDF as a promising new agent to enhance the anti-tumor efficacy of low dose chemotherapies.
The role of cytoreductive surgery in patients with carcinomatosis from high-grade appendix cancer in the era of modern systemic chemotherapy.
Authors: H. M. El Halabi, P. Ledakis, V. Gushchin, J. Francis, N. Athas, R. Macdonald, K. Studeman, A. Sardi
Journal: Journal of Clinical Oncology (2011)

4080 Background: Peritoneal carcinomatosis due to high-grade appendiceal neoplasm is optimally treated with cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) in selected patients. Systemic chemotherapy is often administered either prior or after surgery utilizing the same regimens applied in advanced colon cancer despite the very limited data to support such approach. The potential benefit of systemic chemotherapy in patients that underwent CRS and HIPEC was evaluated in this study. Methods: A retrospective analysis of patients with high-grade appendix cancer after CRS and HIPEC. Different chemotherapy regimens were evaluated. Overall survival (OS) and relapse free survival (RFS) were calculated using Kaplan Meier estimates. Results: From 150 patients with disseminated appendix cancer, 77 patients had high-grade disease and underwent their first CRS and HIPEC at our institution. The 5 years OS was 40.4 %, it was 52.7 % for patients with complete cytoreduction (CC) and 0 % for incomplete cytoreduction (P<0.001). Complete cytoreduction was achieved in 36/41 (88%) patients who underwent CRS within 6 months from diagnosis, while it was achieved in 22/36 (61%) patients if surgery was performed 6 months after diagnosis (P=0.009). The following OS and RFS were found among these chemotherapy groups (Table). Conclusions: Complete cytoreduction is essential to achieve long-term survival. The use of systemic chemotherapy should not delay surgical intervention, since that hinders efforts for complete cytoreduction. Role of systemic chemotherapy is not well established and randomized clinical trials are needed in that regard. Chemotherapy and outcomes Yes No P value Oxaliplatin or irinotecan 50 14 3 years OS 53.9% 81.8% 0.39 3 years RFS 45.1% 75.8% 0.289 Bevacizumab 20 47 3 years OS 78.7% 41.9% 0.338 3 years RFS 38.3% 62.9% 0.485 Preop chemo 29 43 5 years OS 33.1% 47.1% 0.358 5 years RFS 45.3% 54.7% 0.938
Siginificance of platinum concentration in blood and red blood cell in patients with oxaliplatin-based chemotherapy [UMIN000009128].
Authors: Jun Higashijima, Mitsuo Shimada, Takashi Iwata, Kozo Yoshikawa, Toshihiro Nakao, Masaaki Nishi, Chie Takasu, Shohei Eto
Journal: Journal of Clinical Oncology (2015)

620 Background: Oxaliplatin(Ox) based regimen is widely used in colorectal cancer patients.One of the major adverse effects of Ox is a neuropathy. There is no useful biomarker predicting such adverse effect. The aim of this study is to evaluate platinum concentration as a biomarker predicting the adverse effect. Methods: Ten patients who underwent curative colectomy were included in this study. Final stage of all patients was UICC stage III. All patients underwent adjuvant chemotherapy by CapeOX regimen for eight cycles (or six months). Blood samples were collected after fourth cycle and last cycle. Ox concentration was measured in red blood cells (RBC) and serum, and evaluated the kinetics of platinum (PL) in blood. In addition, we investigated relationship between Ox concentration and adverse effects. Results: 1) Kinetics of PL concentration: PL concentration in RBC tended to be correlated with the difference of RBC numbers between pre- and post-chemotherapy (R 2 =0.358, p=0.068). The PL concentration in RBC siginificantly correlated with the difference of mean corpuscular volume (MCV) between pre- and post-chemotherapy (R 2 =0.661, p=0.004). After four cycle, the platinum concentration in RBC siginificantly correlated with the hemoglobin and hematocrit (R 2 =0.447, p=0.004 and R 2 =0.425, p=0.041). There was no siginificant difference in PL concentration in both RBC and serum between the points after four cycle and last cycle points (RBC: 1380.5±495.2 ng/ml vs. 1107.0±699.2 ng/ml Aserum: 210.1±38.9 ng/ml vs. 221.2±99.2 ng/ml). 2) PL concentration and adverse effects: PL concentration did not elevate depending on cycle number. There was no siginificant correlations between PL concentrations in RBC or serum and the grade of neuropathy. Conclusions: The PL concentration was significantly related with the difference of RBC numbers and MCV between pre- and post-chemotherapy. However, there was no siginificant relationship between Ox concentration in blood and side effects including neuropathy. So Ox concentration in blood could not be a reliable biomarker for predicting the grade of neuropathy. Clinical trial information: 000009128.
Prognostic Impact of Physiological B-Cell Precursors (hematogones) in the Bone Marrow As Determined by Immunophenotyping in the Post-Transplant Period in Patients with AML
Authors: Ulrike Bacher, Maximilian Christopeit, Anneke Heiland, Mascha Binder, Tatjana Zabelina, Francis Ayuk, Christiane Horn, Torsten Haferlach, Carsten Bokemeyer, Nicolaus Kroeger
Journal: Blood (2012)
Genetic polymorphisms and sunitinib outcome in metastatic renal-cell carcinoma: A prospective observational study and validation.
Authors: Carlos A. Farfán, Daniel E. Castellano, Cristina Rodriguez-Antona, Julio Benitez, Guillermo De Velasco, Felipe Villacampa, Federico de la Rosa, Eva Andres, Juan Manuel Sepúlveda
Journal: Journal of Clinical Oncology (2013)

403 Background: Sunitinib (SU) is an oral small-molecule, multi-targeted receptor tyrosine kinase inhibitor, which is approved as first-line treatment for metastatic renal cell carcinoma (RCC). In a previous study, using a commercially available DNA microarray genotyping system, we identified a group of single nucleotide polymorphisms (SNPs) associated with survival and toxicity in RCC patients, treated with SU. In this study, we validated our previous data using an independent series (García-Donas J, et al. Lancet Oncol 2011). Methods: 27 metastatic RCC treatment-naive patients, recruited prospectively from January 2010 to May 2011. All the patients received SU standard treatment. A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes involved in the pharmacokinetic and pharmacodynamic pathways of drugs, were analyzed using Drug inCode pharmacogenetic service. For validation we performed genotyping in 83 samples using the KASPar SNP genotyping system. Results: In patients with CYP1A2*1F and CYP2C19 *2 and *4 polymorphisms, no statistically significant associations were observed, among drug metabolizing genes and toxicity or survival. Catechol-O-methyltransferase(COMT) is involved in the inactivation of several substances suchs as cathecolamines and estrogens and Val(158)Met polymorphism which were associated with PFS and OS, it was observed in our initial study. Met/Met and Val/Met carriers had statistical significant difference in PFS and OS (p = 0.0001 and p = 0.0001, respectively) compared to Val/Val carriers. In the validation series, we were able to confirm the effect on PFS (p = 0.0102). Conclusions: Our preliminary analysis suggested that CYP1A2*1F and CYP2C19*2 and *4polymorphism may be associated with SU toxicity in RCC patients, but findings were not validated in an independent series. However, we could confirm an association between COMT VAl(158)Met polymorphisms and PFS. To our knowledge this is the first study to report COMT polymorphism to be associated with RCC survival.
Cancer Research UK Stratified Medicine Programme.
Authors: J. Peach, A. Tuff, J. Bull, F. Hemsley, L. Jones, M. Jones, C. Westwood, P. W. M. Johnson
Journal: Journal of Clinical Oncology (2011)

TPS247 Background: Advances in understanding of the molecular pathology of cancer mean that treatments are increasingly being shown to preferentially benefit sub-groups of patients (stratified medicine). Molecular characterisation of tumours and normal tissue is now required for the testing and introduction of targetted therapies. However, the availability of molecular diagnostics in the UK is uneven, with commercial laboratories, academic research departments, regional genetics services and NHS pathology services contributing, but none providing a comprehensive service for unselected cases outside the confines of a clinical trial. Only a national approach linked to research can meet this clinical need, while establishing large-scale datasets. Aims: Cancer Research UK will demonstrate scalable prospective molecular characterisation for NHS cancer patients, with routine consent for the collection, storage and research use of population-scale genetic and outcomes data. Plan: Phase One will deliver and assess an improved model for consented sample collection, biomarker panel testing to clinical standards and timescales, and routine clinical data analysis. Once this is proven in 6 hospitals and 3 labs on 9,000 patient samples by 2013, we hope to roll out the approach nationally, increasing the tumour types and biomarkers included, while developing a unique national database of genotypes, treatments and outcomes. The Programme is supported by AstraZeneca, Pfizer, and the UK government (Dept. of Health, NHS, Technology Strategy Board). Methods: Working with clinicians in our Experimental Cancer Medicine Centres and with genetic testing labs, the programme will prospectively consent lung, breast, colorectal, prostate, ovarian and melanoma patients for a panel of biomarker tests, including KRAS, BRAF, EGFR, P53, PI3KCA, EML4-ALK, PTEN. Results will be returned to the physician in clinically relevant timescales. Genotype data will be linked to routine treatment and outcomes data, and made available to researchers in academia and industry. The call for sample collection and analysis sites opened on 25 January, with sample collection running June 2011-2013.
The accuracy of preoperative U.S.-guided vacuum-assisted breast biopsy (VABB) in determining ER, PgR, HER2, and Ki67 status in early breast cancer.
Authors: Keitaro Kamei, Takashi Fujita, Toshikazu Ito, Hiroshi Yagata, Minoru Ono, Ryoji Watanabe, Naoya Gomi, Kiyoshi Onishi, Naomi Sakamoto, Hideyuki Hashimoto, Tetsuya Taguchi, Takahiro Nakayama
Journal: Journal of Clinical Oncology (2013)

37 Background: The intrinsic subtypes are important in the management of patients with early breast carcinoma; however, there have been only a few reports about the accuracy of preoperative subtyping by the preoperative ultrasonography guided vacuum-assisted breast biopsy (U.S.-guided VABB). The aim of this study was to evaluate concordance of the status of ER, PgR, HER2, and Ki67 between U.S.-guided VABB and subsequent surgical specimen. Methods: We retrospectively assessed the concordance of ER, PgR, HER2 and Ki67 status between U.S.-guided VABB and surgical specimen. The patients (n=228) underwent surgical treatment without neoadjuvant chemotherapy at the institute of Japan Association of Breast and Thyroid Sonology (JABTS) Interventional study Group from 2009 to 2012. All the US-guided VABB were performed using 8 or 11-gauge Mammotome or 10-gauge VACORA. The ER and PgR status were determined by IHC and HER2 expression status was tested by both IHC and FISH. The agreement on ER, PgR, HER2 and Ki67 status were evaluated by the absolute concordance rate and the kappa statistic values. Results: The concordance rate of ER, PgR, and HER2 status between U.S.-guided VABB and surgical specimens were 96.4% (134/139), 89.2% (124/139), and 96.3% (130/135), respectively (kappa statistic value of 0.90, 0.77, and 0.84), and the agreement of Ki67 level was 89.6% (112/125) with a Kappa statistic value of 0.79. The concordance rate of the intrinsic subtypes was 84.0% (105 of 125 cases). Conclusions: The judgment of ER status, and HER2 status by preoperative U.S.-guided VABB can be used with confidence to determine the treatment strategies based on molecular subtypes.
Expression of growth and cell proliferation factors in gastric carcinomas: The association with poor overall survival on patients with intestinal type.
Authors: Maria D. Begnami, Jose Ivanildo Neves, Marcos Chaves, Milton Jose De Barros E Silva, Wilson Luiz Costa, Felipe José Fernandez Coimbra, Alessandro Landskron Diniz, Heber Salvador de Castro Ribeiro, Clovis Pinto
Journal: Journal of Clinical Oncology (2013)

52 Background: Gastric carcinomas (GC) express a variety of growth factors and cell proliferation acting in the mechanisms of tumor invasion and spread. The expression of angiogenic factors such as vascular endothelial growth factor (VEGF) has been demonstrated in diffuse type GC, whereas expression of growth factors is associated with intestinal-type carcinomas. Objective: To study the immunohistochemical expression of proteins associated with growth factors and cell proliferation in GC. Methods: We studied 400 GC, arranged in duplicates in 2 blocks of tissue microarray (TMA). Immunohistochemistry was performed using antibodies: c-MET (Novocastra), TGFbetaI (Santa Cruz), TGFbetaII (Santa Cruz), c-erbB-2 (Dako) and VEGF (Santa Cruz). Cases were considered positive for TGFbetaI, TGFbetaII and VEGF when cytoplasmic staining was observed in more than 10% of tumor cells. Positive cases for c-met and c-erbB-2 were detected when strong staining on the membrane cells was observed in more than 10% of neoplastic cells. Results: Expression of TGFbetaI, TGFbetaII and VEGF were detected in 314/385 (81%), 370/382 (96%) and 333/366 (90%) of GC. 333/376 (88%) cases were positive for c-met and 54/385 (14%) for c-erbB-2. Intestinal type carcinomas were more often positive for TGFbetaII (p = 0.01), VEGF (p = 0.001), c-met (p = 0.01), and c-erbB-2 (p = 0.001). According to univariate statistical analyzes expressions of TGFbeta II, c-met and c-erbB-2 were independent factors associated with overall survival of patients with GC. Conclusions: The proteins associated with growth factors and cell proliferations are differentially expressed in intestinal type of GC. Our findings pointed them out as biological factors associated with worse prognosis and important therapeutic targets.
Impact of pancreatic cancer treatment on hospice utilization.
Authors: Lauren M Wancata, Huiying Yin, Sandra L. Wong
Journal: Journal of Clinical Oncology (2015)

52 Background: There is an increasing incidence of pancreatic cancer over time, a cancer with a 5-year survival rate of only 7.2%.For patients with poor prognosis cancers, hospice is an important resource, but it is often not utilized or underutilized. Factors influencing hospice use are difficult to determine. We sought to evaluate the impact of pancreatic cancer treatment on hospice utilization. Methods: National Surveillance Epidemiology and End Results (SEER)-Medicare data was utilized to identify all incident cases of pancreatic cancer patients who died (2005-09, with follow up to 2011). Patients were stratified by primary treatment strategy: surgery, chemotherapy, or no treatment. Hospice utilization in the last 6 months of life, including average and median days enrolled in hospice and average time from diagnosis to hospice was evaluated. Results: 17,031 patients were identified, with 68.5% enrolling in hospice in the last 6 months of life. Patients undergoing surgery were less likely to enroll in hospice compared to patients not undergoing surgery (58.7% vs 69.4%, p &lt; 0.0001). Interestingly, surgical patients spent on average 31.2 days in hospice (median 15.0 days) which was comparable to the non-surgical cohort (average 32.7 days, median 16.0 days; p = 0.32). Patients who received any chemotherapy spent an average of 29.2 days in hospice (median 15 days) compared to those who did not undergo chemotherapy, who spent an average of 34.5 days in hospice (median 16 days); p &lt; 0.0001. While total hospice enrollment was equivalent between the chemotherapy and no chemotherapy cohorts (67.5% vs 69.1%), the time spent in hospice was significantly different (p &lt; 0.0001). Patients not receiving any cancer-directed treatment enrolled in hospice at an average of 78.6 days (median 32 days) from diagnosis. Conclusions: Pancreatic cancer patients undergoing surgery enrolled in hospice to a much lesser extent than patients who did not have surgery. Patients not receiving cancer-directed treatment spend a relatively short time in hospice. Overall, hospice appears to be underutilized, and the majority of patients with this poor prognosis cancer are not realizing the full benefits of hospice.
Development of a genomic-clinical classifier for predicting progression after radical cystectomy in patients with muscle invasive bladder cancer.
Authors: Anirban Pradip Mitra, Nicholas Erho, Lucia L.C. Lam, Ismael A. Vergara, Thomas Sierocinski, Benedikt Zimmermann, Zaid Haddad, Mercedeh Ghadessi, Anamaria Crisan, Timothy J. Triche, Siamak Daneshmand, Christine Buerki, Elai Davicioni, Peter C. Black
Journal: Journal of Clinical Oncology (2013)

4542 Background: The mainstay of muscle-invasive bladder cancer treatment is surgical resection with/without multi-agent chemotherapy. Management decisions are based on a small number of clinical and pathologic parameters with poor prognostic and predictive power. There is an urgent need for enhanced biomarkers to guide therapy of this lethal disease. Here we have developed a genomic signature of bladder cancer progression using whole transcriptome profiling technology. Methods: 251 FFPE bladder cancer specimens were obtained from patients undergoing radical cystectomy at the University of Southern California (1998-2004). All patients had pT2-T4a,N0 urothelial carcinoma in the absence of pre-operative chemotherapy. Median follow-up was 5 years. RNA expression levels were measured with 1.4 million feature oligonucleotide microarrays. Patients were divided into a training set (2/3 of cohort) to develop a genomic classifier for risk of progression (defined as any type of bladder cancer recurrence), and a validation set (1/3 of cohort). In parallel, multivariable analysis was used to develop a clinical classifier using typical clinical and pathologic variables. Finally, a genomic-clinical classifier was built combining the genomic classifier with clinical variables using logistic regression. The receiver-operator characteristic (ROC) area under the curve (AUC) metric was used to evaluate each classifier in the validation set. Results: The genomic classifier consisted of 89 features corresponding to 80 genes that were combined in a k-nearest neighbor model (KNN89). KNN89 showed an AUC of 0.77 in ROC analysis on the validation set. The best clinical classifier showed an AUC of 0.72. The genomic-clinical classifier demonstrated an AUC of 0.81. Multivariable analysis incorporating all clinical parameters and KNN89 further revealed that KNN89 was the only significant predictor of bladder cancer progression (p=0.0077). Conclusions: We have developed a combined genomic-clinical classifier that shows improved performance over clinical models alone for prediction of progression after radical cystectomy. External validation of this classifier is ongoing.
Outcomes of surgical intervention in gastric carcinoid disease.
Authors: Ann Falor Callahan, Michael White, Philip HG Ituarte, Yanghee Woo, Gagandeep Singh, Yuman Fong, Laleh Melstrom
Journal: Journal of Clinical Oncology (2016)

112 Background: Gastric carcinoids are rare entities, representing 8.7% of all gastrointestinal carcinoids. Although this disease is often stratified into subtypes with differing clinical courses, the prognosis is generally improved by surgical resection. We evaluated the outcomes of patients with gastric carcinoids in a large cancer registry. Methods: We queried the California Cancer Registry (CCR), merged with the California Office of Statewide Health Planning and Development (OSHPD) database, for patients with a diagnosis of gastric carcinoid disease. Demographic, clinicopathologic characteristics, surgical treatment, and outcomes were analyzed. Results: Among the 1,012 patients who met our criteria, 64% had localized disease (644), 9.4% (95) had regional disease and 13.4% (133) had distant metastases. Most of these patients underwent gastric surgery (56.7%, n = 574 vs 43.2%, n = 438). Surgery at the primary site conferred a survival advantage in patients with local and regional disease (regional disease: 27 months with surgery vs 5 months without, p = 0.007; local disease: median survival was not reached, p &lt; 0.0001). Patients who underwent resection of the primary tumor and any hepatic metastases showed a similar median survival to patients without hepatic metastases (26 vs 27 months, p = 0.8). Conclusions: Although the biology of the disease is the most significant predictor of overall outcome, aggressive surgical intervention, including resection of the primary tumor and any metastatic disease in the liver, should be offered when it is technically feasible. Surgical intervention in patients with hepatic metastases results in a survival similar to surgically managed patients without distant disease.