tbuckley/cabot-search huggingface dataset:
Phase II study to evaluate the efficacy of capecitabine combined with bevacizumab as first-line treatment in elderly patients with advanced or metastatic colorectal adenocarcinoma
Authors: J. Feliu, M. Safont, A. Salud, F. Losa, C. García-Girón, C. Bosch, P. Escudero, R. López, C. Madroñal, M. González-Barón
Journal: Journal of Clinical Oncology (2009)

4119 Background: Colorectal adenocarcinoma is the most common cancer in subjects over 70 years old. New therapies have been developed but limited data about their activity are available in elderly population. Results obtained with capecitabine have shown an appropriate safety and efficacy profile in these patients. The aim of the present study is to evaluate the overall response rate in that patient's population who presents colorectal adenocarcinoma and are treated with the combination of capecitabine+BVZ. Methods: This is a multicentric, non-controlled, open label, phase II clinical trial. Capecitabine(1250mg/m 2 bid, orally)+BVZ(7.5mg/kg, intravenously) treatment was administered in 3-week length cycles until disease progression. Capecitabine dose was reduced to 1000mg/m 2 when the creatinine clearance was between 30 and 50ml/min. Results: A total of 59 patients were included (57.6%, male). Mean age was 76±4.1 years. ECOG status was 0–1 in 96.5 % of the patients. Activities of daily living: moderate to severe dependence and functional incapacity in 24.5% and 5.6% of the patients by Lawton and Barthel scales, respectively. Comorbidities: hypertension (61%), venous thrombosis (5.1%), cardiac disease (5.1%) and acute cerebrovascular accident history (3.4%). Metastases were detected in liver (84.7%), lung (45.8%), local/regional (18.6%) and other locations (5.1%). Mean number of cycles of capecitabine+BVZ was 6.8±6.1. Most frequent grade 3–4 toxicities observed were hand-foot-syndrome (18.6%), diarrhea (8.5%), deep venous thrombosis (6.8%), pain (5.1%) and mucositis (3.4%). Four patients died due to toxicity (mucositis, digestive hemorrhage, hematological toxicity and sepsis, respectively). Metastasis resection was performed in 10.2% of the patients. Treatment response was: 33.3% partial response and 59.0% stable disease. Median progression-free survival was 10.8 months. Conclusions: The combination capecitabine+BVZ in elderly patients appears to have a manageable safety profile and achieves promising results in terms of response rates and progression free-survival. No significant financial relationships to disclose.
Unknown primary cancer (UPC): Accuracy of tissue of origin prediction by molecular profiling
Authors: F. A. Greco, D. R. Spigel, D. A. Yardley, M. Erlander, X. Ma, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2009)

11070 Background: Molecular profiling may be useful to identify the primary site and direct therapy for patients (pts) with UPC. Since most UPC pts never have a primary site identified, the accuracy of molecular profiling diagnoses are difficult to verify. We identified a group of UPC pts who had a primary site subsequently identified during their clinical course, and performed a 92-gene real time polymerase chain reaction (RT-PCR) assay (Arch Pathol Lab Med 130:465, 2006) on tissue from the initial diagnostic biopsy. We then compared the RT-PCR diagnosis with the subsequent clinical diagnosis. Methods: 38 of 501 UPC pts (7%) seen between 2000 and 2008 had their primary tumor subsequently identified during life. 24 of the 38 pts had tissue biopsies (excluding FNA cytology) and are the subject of this study. The RT-PCR assay was performed on unstained slides from the formalin-fixed, paraffin-embedded (FFPE) initial diagnostic biopsy, and the assay predictions were compared to the actual primary sites (found later). No clinical or pathologic data (other than sex, biopsy site, and 1 H&amp;E stained slide) were used in the prediction of the primary site. Results: 16 of 24 assays were successful (8 had no tumor or RNA in the material). 11 of 16 predictions of the site of origin (68%) were correct, corresponding to the actual primary sites found 3–58 months (median 8.5 months) after the initial diagnosis of UPC. Primary sites correctly identified included breast 2, ovary/peritoneal 4, NSCLC 1, colorectal 2, gastric 1, melanoma 1. 3 predictions were inaccurate (colorectal, testicular, sarcoma) in patients with gastroesophageal, pancreas and NSCLC, respectively. 2 assays were unclassifiable. Conclusions: RT-PCR performed on FFPE initial diagnostic tissue was accurate in predicting the primary site of origin in 11 of 16 pts with UPC who eventually had their primary site identified clinically. These data provide a direct validation of the reliability of this RT-PCR assay in predicting the primary site in pts with UPC. When used in concert with clinical features and IHC stains, molecular profiling may provide the basis for more successful site-directed therapy for many of these pts. Prospective studies of RT-PCR in UPC are ongoing. [Table: see text]
M10-04: Telomerase immortalized human bronchial epithelial cells (HBECs) have stem cell characteristics
Authors: Jerry W. Shay, Mitsuo Sato, Woochang Lee, Luc Girard, Xian-jin Xie, Yang Xie, James Sullivan, Monica Spinola, John D. Minna
Journal: Journal of Thoracic Oncology (2007)
Effect of Aurora A kinase inhibitor MLN8237 combined with rituximab on antitumor activity in preclinical B-cell non-Hodgkin's lymphoma models
Authors: M. Zhang, J. Huck, M. Hyer, J. Ecsedy, M. Manfredi
Journal: Journal of Clinical Oncology (2009)

8553 Background: Aurora A kinase is a serine/threonine protein kinase that is essential for the successful transit of cells through mitosis. MLN8237 is a selective small molecule inhibitor of Aurora A kinase that has demonstrated anti-tumor activity in animal models of solid human tumors. In this study we explored the anti-tumor effect of MLN8237 in vivo in pre-clinical models of human Diffuse Large B-cell Lymphoma (DLBCL) both as a single agent and in combination with the anti-CD20 monoclonal antibody Rituximab. Methods: Three human DLBCL models were examined in SCID mice. In two of the models (Ly19 &amp; WSU) the tumor cells expressed a constitutively active luciferase, enabling tumor burden analysis in either a subcutaneous or disseminated setting. The third model was a primary DLBCL recently obtained from a patient. Tumor bearing animals were treated for 21 days with MLN8237 (QD PO dosing at 3–20mg/kg), Rituximab (Q7D IV dosing at 10 mg/kg), or the two agents combined. Tumor burden was measured in the disseminated models as a function of luciferase-induced photon flux, and in the subcutaneous models using vernier calipers. Results: MLN8237 induced anti-tumor activity that was dose-dependent in all three models. In LY19 disseminated model, 3 mg/kg of MLN8237 combined with Rituximab induced synergistic anti-tumor activity (n=2); while 10 mg/kg MLN8237 (dosed QD) combined with Rituximab was additive. Importantly, combining MLN8237 with Rituximab led to complete cures in 100% of the animals. In the WSU model, combining MLN8237(3–10mg/kg) with Rituximab resulted in additive tumor growth inhibition. The mean survival endpoint was significantly longer (p=0.003 and &lt;0.001 respectively) in the combination group when compared to the individual group. In the primary lymphoma model, MLN8237(10–20mg/kg) caused a significant anti-tumor effect during treatment period (TGI = 83–95%). Combining MLN8237 and Rituximab in primary model resulted in additive anti-tumor effect. Conclusions: MLN8237 combined with Rituximab was found to reduce tumor burden in an additive and/or synergistic mechanism in multiple DLBCL tumor models. MLN8237 is currently being tested as a single agent in a phase I clinical trail in patients with DLBCL. [Table: see text]
The role of FDG-PET in low-grade non-Hodgkin lymphoma (NHL): Impact of histology
Authors: M. Kassar, A. Go, H. Fung, P. Venugopal, A. Ali, M. Kumar, M. Farhat, M. Batus, J. Shammo, S. A. Gregory
Journal: Journal of Clinical Oncology (2006)

17534 Background: FDG-PET scan was proved important diagnostic and prognostic tool in patients with aggressive (NHL). The objective of this study is to investigate the correlation between the histology subtype in low-grade NHL and the sensitivity of the FDG-PET. Methods: We included all patients who presented to our institution during the period from April 2001 till April 2004 and underwent staging evaluation by FDG-PET during the course of their disease. All patients had histologically confirmed low-grade NHL. Patients with history of active malignancy, other than NHL, within the last five years were excluded. Correlation was made with the CT-scan findings. Results: 53 patients were included. Age (range 30–82, median 54), 57% of them were male. 34 patients had follicular lymphoma (FL), 9 patients had marginal zone lymphoma (MZL), and 10 patients had small lymphocytic lymphoma (SLL). 24/34 patients with FL underwent FDG-PET during the initial evaluation of their disease, and 10/34 patients underwent FDG-PET as part of their restaging assessment. 33 patients had true positive FDG-PET findings when compared to CT-scan results. One patient had negative FDG-PET with CT-scan findings suggestive of pathologic lymphadenopathy (sensitivity 97%). The highest SUV was in the range of 3.5–15 (median = 7). 8/9 patients with MZL had true positive FDG-PET findings and one had false negative FDG-PET result (sensitivity 89%). The highest SUV was in the range of 2–6.30 (median 2.6). Among the ten patients with SLL, 5 had FDG-PET during the initial evaluation and 8 patients during re-staging workup. 13 FDG-PET results were available for analysis. 5 cases were false negative, 1 case was false positive, 5 cases were true positive, and 2 cases were true negative (sensitivity 50%). The highest SUV was in the range of 1.8–6.2 (median of 2.5). Conclusion: Histology in low-grade NHL has a major impact on the sensitivity of the FDG-PET imaging results. Whereas it is a highly sensitive diagnostic method in patients with FL, and to a lesser degree in patients with MZL, it has poor sensitivity in patients with SLL. No significant financial relationships to disclose.
Impact of the size of metatases on the outcome of patients with non-resectable colorectal liver metastases treated with percutaneous laser-induced thermoablation (pLIT)
Authors: G. Aprile Esq., M. Sponza, A. Vit, N. Pella, D. Gasparini, E. Zanon, E. Iaiza, F. De Pauli, A. Marzio, A. Piga
Journal: Journal of Clinical Oncology (2006)

13556 Background: whenever surgical resection of liver metastases from colorectal cancer is not possible, thermal ablation is a mini-invasive local treatment that can be considered as an alternative approach. Complete thermal ablation can be achieved by laser treatment. When thermoablation is obtained by radiofrequency, patients treated for a small dominant lesion (less than 3 cm) experience a better outcome. This evidence is less clear when pLIT is used. Patients and Methods: 30 patients (22 with a single lesion, 8 with up to three metastases) were consecutively treated. Maximum diameter of the dominant lesion was less than 3 cm in 20 pts and more than 3 cm in ten. With mild sedation and local anaesthesia, optical fibers were inserted directly into the tumor with echo-guided percutaneous needle placement. Each optical fiber was connected to a neodymium:yttrium-aluminium-garnet (ND:YAG) laser, which delivers concentrated light at a wave-length of 1064 nm, with a 5-Watt power and a 1800-Joule energy per single fiber. A minimum of two and a maximum of four needles were used, with a 5 to 8 mm distance from one needle to another. Results: all patients tolerated LIT procedure well, without major complications. Post-treatment CT-scan demonstrated complete thermonecrosis in 39 out of 44 (87%) of the treated lesions, and almost complete in the remaining 5, 4 of which of diameter larger than 3 cm. Local failure was reported in 12% of the lesions at six-month follow-up. The median Kaplan-Meier survival for all patients was 607 days, with survival rate of 82% at one year and 55% at three years. Patients treated for a smaller dominant lesion had a significantly better survival than the others (850 vs 420 days, p=0.04, logrank). Conclusions: pLIT permitted in most cases a complete ablation of liver metastases with a high local tumor control rate and a low complication rate. Patients with a smaller dominant lesion do best after pLIT procedure. Local treatment coupled with systemic chemotherapy offers a chance of prolonged survival in patients not amenable to hepatic surgery. No significant financial relationships to disclose.
Response to high-dose interleukin-2 (HD IL-2) therapy in patients with brain metastases from metastatic melanoma
Authors: S. F. Powell, A. Z. Dudek
Journal: Journal of Clinical Oncology (2009)

e20007 Background: HD IL-2 has been shown to produce durable responses in patients with metastatic melanoma. The purpose of this study was to determine whether the University of Minnesota's outcomes were comparable to previously published data and to analyze subsets of patients to find further data on prognosis and response. Methods: A retrospective analysis was performed all adult patients with Stage IV melanoma treated with HD IL-2 from January 2000 to October 2008 at our institution. HD IL-2 was given I.V. every eight hours as a bolus over 15 minutes at a dose of 600,000 IU/kg. A maximum of 14 doses for each course was given. Results: A total of 15 patients with metastatic melanoma had been treated with HD IL-2 at our institution. Complete response (CR) was seen in 6.67% (N=1), partial response (PR) in 6.67% (N=1), mixed response (MR) in 6.67% (N=1), and stable disease (SD) in 13.33% (N=2). Average time to disease progression (TTDP) was 5.67 months in those with a PR or SD. Two patients with brain metastases had subsequently complete resolution of the brain lesions after HD IL-2 therapy. One of these patients has a CR and is disease free 34 months out from therapy. The other had PR and is currently alive with disease, but has no recurrence of the brain lesion after over 19 months. Twelve of the fifteen patients were able to receive 2 courses of therapy. On average patients tolerated 10.5 HD IL-2 doses with the first course and 8.8 doses with the second course. Common grade (G) 3 and 4 adverse events included hyperbilirubinemia (G 3 = 26.67%), hypotension (G 3 = 6.67%, G 4 = 6.67%), peripheral edema (G 3 = 26.67%), pulmonary edema (G 3 = 13.33%), and hypophosphatemia (G 3 = 6.67%, G 4 = 6.67%). Conclusions: The CR rate of 6.67% and TTDP in those with SD or a PR are comparable to previously published studies. Observed adverse events were also similar to other reports. HD IL-2 has typically been avoided in patients with brain metastases due to concern for neurologic complications from the capillary leak syndrome caused by treatment. We propose further evaluation of this ineligibility for HD IL-2, since carefully selected patients with brain metastases may derive benefit from this treatment. No significant financial relationships to disclose.
HDM2 overexpression and promoter polymorphism (SNP309) genotype: Comparison between African American (AA) and Caucasian American (CA) prostate cancer patients (pts)
Authors: G. Wang, E. Blochin, P. Christos, D. Pollens, J. Z. Yu, M. Mazumdar, W. Gerald, P. Lee, C. Oddoux, I. Osman
Journal: Journal of Clinical Oncology (2008)

5133 Background: HDM2 overexpression occurs in a number of tumor types by different mechanisms. The G allele of the HDM2 promoter polymorphism, SNP309 (rs2279744), enhances transcriptional activation, which leads to greater HDM2 expression and accelerated tumor formation at a younger age for patients with Li Fraumeni syndrome and colon cancers. Here we evaluate the HDM2 overexpression in prostate tumors from AA and CA (pts) and examine the association between the G allele with HDM2 protein expression levels, early onset of prostate cancer, and worse clinical outcome. Methods: We studied 51 AA and 50 CA pts prospectively enrolled at the VAMC/New York University. Protein expression of HDM2 in prostate tumor was assessed using immunohistochemistry on tissue microarray. Germline DNA was isolated from normal prostate tissue; a 352bp HDM2 fragment containing SNP309 was amplified; the PCR products were digested with MspA1I restriction enzyme and run on agarose gels. The results were confirmed by DNA sequencing. We calculated HDM2 SNP309 genotype and allele frequencies and examined the association between HDM2 SNP309 genotype, tumor HDM2 protein and clinicopathological features. Results: HDM2 overexpression, defined as HDM2 expression in >10% of tumor cells in 3 cores, was significantly greater in CA pts (78%) vs. AA pts (55%, p=0.0007). The SNP309 allele frequency was not significantly different between AA and CA (81% T, 19% G among the AA pts vs. 72% T, 28% G among CA pts, P=0.41). There was a trend of HDM2 overexpression in AA pt with TG and/or GG compared to TT genotype (63% vs. 37%, respectively, p=0.09) that was not observed in CA pts. No significant associations were observed between a specific genotype and age at diagnosis, tumor stage, Gleason grade, PSA recurrence or death. Conclusions: HDM2 overexpression is significantly more common among CA pts. Although the frequency of the SNP309 G allele is higher in CA pts, in these same pts, HDM2 overexpression does not correlate with presence of the GT or GG genotype. Our data suggest that different mechanisms of HDM2 overexpression might exist in prostate cancer and may operate in pts of different races. No significant financial relationships to disclose.
Next-generation sequencing in pancreatic cancer: Revealing genomic mutations beyond KRAS.
Authors: Andrea S. Teague, Benjamin R. Tan, Albert C. Lockhart, Joel Picus, Steven M. Strasberg, William G. Hawkins, Ryan C. Fields, David Linehan, Andrea Wang-Gillam
Journal: Journal of Clinical Oncology (2014)

208 Background: Pancreatic adenocarcinoma (PA) continues to have one of the worst prognoses of all malignancies, prompting the search for known oncogenic mutations that might be targets for therapy. Methods: We conducted a retrospective analysis of patients with PA who had next generation sequencing (NGS) performed by the Genomics and Pathology Services laboratory at Washington University School of Medicine. Some of main genes included APC, ATM, BRAF, FLT3, NOTCH1, MET, FGFR4, MAPK1, MAP2K2, IDH1, IDH2, RET, JAK2, KRAS, NRAS, PTEN, EGFR, PIK3CA, PDGFRA, RUNX1, KIT, ALK, and TP53. Fluorescence in-site hybridization (FISH) for EGFR gene amplification, and MLL and ALK gene rearrangement was also performed. Results: Among 46 patients with adequate tissue for sequencing, 36 (78.3%) had KRAS mutations (G12D: 44.4%, G12V: 33.3%, G12R:11.1%, Q61H:5.6%, G12A:2.8% and G12R:2.8%). Out of 10 patients with wild type KRAS, 7 patients had either novel mutations or potential targetable mutations (table). TP53 mutations were seen in 73.9% of patients. Among 33 novel mutations not previously described in the COSMIC database, more than 10% are predicted to have deleterious effect by PROVEAN and SIFT. For example, a G1137R variant identified in ALK is predicted to be deleterious and damaging. Of 29 patients whose tumors underwent FISH, 3 patients had EGFR gene amplification, 1 patient had both EGFR gene amplification and ALK gene rearrangement, and 1 patient was positive for the MLL gene rearrangement. Conclusions: NGS of pancreatic cancer not only confirmed common mutations such as KRAS and TP53, but also revealed genomic alterations that may potentially be responsive to available targeted agents. The discovery of novel mutations in wild type KRAS tumors warrants further investigation. [Table: see text]
A phase II study of weekly docetaxel and carboplatin in stage IIIB (with effusion) or stage IV non-small cell lung cancer patients age &lt;65 and performance status 2
Authors: C. H. Weissman, J. F. Sandbach, R. J. Brooker, D. Ilegbodu, L. Asmar
Journal: Journal of Clinical Oncology (2004)

7276 Background: Primary goals of therapy for advanced non-small cell lung cancer (ANSCLC) are an increased survival time, palliation of symptoms, and prolonged time to progression (TTP). This study was designed to explore if ANSCLC patients (pts) with ECOG PS 2 and age ≤65 years could benefit from systemic chemotherapy with acceptable toxicities. Methods: Fifty-nine eligible pts with stage IIIB (effusion) or stage IV NSCLC were registered on study. Patients received docetaxel (Taxotere®) 35 mg/m2 and carboplatin AUC=2 on Days 1, 8, and 15 every 28-day cycle (maximum 8 cycles). Endpoints were 1-year survival, tumor response, TTP, and safety. Results: Among the 59 eligible pts, 1 never received study drug, 58 pts were evaluable for safety, and 49 for response; 9 pts were non-evaluable due to: palliative XRT (1), withdrawal of consent (2), toxicities (1 each; dyspnea, weakness, allergy to study drug) and other illness (3). Responses were: 1 CR (2%), 5 PR (10%), 22 SD (45%), and 21 PD (43%). The 1-year survival was 28%; median survival was 6.0 months (range, <1–24.3). The 1-year progression-free survival was 14% with a median TTP of 3.7 months (range, <1–22.8) and median duration of response for CR+PR was 5.4 months (range, 2.3–9.7). Patients received a median of 3 cycles (range, 1–9); 14 pts (24%) had dose reductions, mainly due to toxicities. The primary Grade 3 or 4 toxicities were neutropenia and fatigue (10.2% each), nausea (8.5%), dehydration (6.8%), and vomiting (5.1%). All 43 deaths were due to PD. Toxicities of this regimen are comparable to other chemotherapy regimens used in this population, thus it may be an alternative treatment choice for patients with ANSCLC who are ≤65 years and PS 2. Conclusions: These results confirm the relatively poor outcome of PS 2 pts with ANSCLC. The overall benefit of chemotherapy doublets, compared to monotherapy, in this patient population remains to be proven. Supported by Aventis Pharmaceuticals, Bridgewater, NJ No significant financial relationships to disclose.