tbuckley/cabot-search huggingface dataset:
Comparison of toxicity, efficacy, and dose modifications in obese and non-obese patients receiving modified FOLFOX6 (mFOLFOX) for metastatic colorectal cancer (mCRC).
Authors: Daniel Jerzy Wojenski, Heidi D. Finnes, Ross A. Dierkhising, Kristen Beth McCullough, Steven R. Alberts
Journal: Journal of Clinical Oncology (2013)

572 Background: There is limited data regarding chemotherapy dosing in obese mCRC patients. Methods: A retrospective, single institution, cohort study of mCRC patients receiving mFOLFOX6 (fluorouracil (5-FU) bolus omitted) was conducted between January 2002 and January 2011. Patients were stratified into: obese (BMI &gt; 30) full dose, obese dose reduced (oxaliplatin (OX) and/or 5-FU), non-obese (BMI 18-29.9) full dose, and non-obese dose reduced. The primary endpoint was incidence of grade 3/4 myelosuppression within the first 12 wks of therapy. Secondary endpoints included incidence of any grade diarrhea and neuropathy, progression free (PFS) and overall survival (OS). Results: Of the 236 patients (72 obese, 164 non-obese), 15 obese and 37 non-obese received a dose reduction. Grade 3/4 myelosuppression occurred in 0 obese OX dose reduced, 3 (7.5%) obese full dose, 1 (8.3%) non-obese dose reduced, and 7 (7.8%) non-obese full dose patients (p=0.93). Grade 3/4 myelosuppression occurred in 0 obese 5-FU dose reduced, 3 (7.5%) obese full dose, 2 (12.5%) non-obese dose reduced, and 6 (7%) non-obese full dose patients (p=0.8). There were no statistically significant differences in the incidence of neuropathy or diarrhea between groups. PFS was longer in OX full dose patients (obese dose reduced, 8.8 mos; obese full dose, 10 mos; non-obese dose reduced, 3.7 mos; non-obese full dose, 10.4 mos; p=0.0094). No difference in PFS was found with 5-FU dosing (p=0.0615). OS favored OX full dose patients (obese dose reduced, 1.6 yrs; obese full dose, 2.4 yrs; non-obese dose reduced, 0.7 yrs; non-obese full dose, 2 yrs; p=0.0006) and 5-FU full dose patients (obese dose reduced, 1.6 yrs; obese full dose, 2.2 yrs; non-obese dose reduced, 1.6 yrs; non-obese full dose, 1.9 yrs; p=0.0287). Conclusions: There is no difference in the incidence of grade 3/4 myelosuppression, diarrhea or neuropathy in obese versus non-obese patients, dose reduced or not. OX dose reductions were associated with reduced PFS and OS. 5-FU dose reductions were associated with reduced OS. Our study supports ASCO recommendations against dose reductions in obese patients receiving chemotherapy.
Phase II study of imatinib in patients with WHO B3 and C thymomas
Authors: G. Giaccone, E. F. Smit, C. van Groeningen, P. C. Hogedoorn
Journal: Journal of Clinical Oncology (2008)

14665 Background: Compared to other epithelial malignancies, genetic abnormalities are relatively rare in thymomas, they increase with increasing malignant behavior. C-Kit is highly expressed in thymic carcinomas (80%) but infrequent in thymomas. Scanty information is available on the role of C-Kit mutations in thymic carcinomas. Methods: Patients with surgically unresectable WHO B3 or C thymomas were enrolled in this study. Patients had to have performance status 0–2, good organ function and measurable disease. Imatinib was administered at 600 mg PO daily. The dose was increased to 800 mg (400 mg BID) if progression was observed in absence of clinical deterioration or no major response was achieved after two month treatment. Results: 7 patients were recruited at one institution, form June 2005 to August 2006. Two patients had WHO B3 and 5 had C, 2 had Masaoka stage IVA and 5 stage IVB, 4 had PS 2 and 3 PS 1, 6 were male, median age was 67 (range 36–76) and none had associated paraneoplastic syndromes. Three patients had received no prior chemotherapy. Imatinib was associated with severe nausea and vomiting in one patient, and severe depression in another patient, otherwise it was well tolerated. Dose escalation was successfully performed in one patient only. No patient responded, there were 2 patients with stable disease and 5 with progression. One patient received chemotherapy after imatinib and after a major response was rendered disease free by surgical resection. Three patients are still alive. Median survival was 4 months and median time to progression was 2 months. Mutation analysis could be performed in 5 samples. No mutations were detected in exons 9, 11, 13 and 17 of the C-Kit gene and in exons 12 and 18 of the PDGFR-alpha gene. Conclusions: Imatinib has no major activity in this rare tumor type, and this could be due to absence of C-Kit activating mutations, despite the presence of high protein expression. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis
Divergent Dynamics of Epigenetic and Genetic Heterogeneity in Relapsed Acute Myeloid Leukemia
Authors: Francine E. Garrett-Bakelman, Sheng Li, Stephen S. Chung, Todd Hricik, Rapaport Franck, Jay Patel, Richard Dillon, Priyanka Vijay, Anna L Brown, Alexander E. Perl, B. Joy Cannon, Mathijs A. Sanders, Peter J M Valk, Lars Bullinger, Selina Luger, Michael W. Becker, Ian D. Lewis, L. Bik To, Richard J D'Andrea, David Grimwade, Ruud Delwel, Bob Lowenberg, Hartmut Dohner, Konstanze Dohner, Duane C Hassane, Monica L. Guzman, Gail J Roboz, Martin Carroll, Christopher Y. Park, Donna S. Neuberg, Ross L. Levine, Christopher Mason, Ari Melnick
Journal: Blood (2015)
Evaluation of glycolytic activity and HIF-1α expression in chemoresistant colorectal cancer cells.
Authors: F. Tozzi, Y. Zhou, J. Chen, D. Bose, F. Fan, J. Wang, H. Brusher, W. Widger, Z. Weihua, L. M. Ellis
Journal: Journal of Clinical Oncology (2011)

415 Background: Overcoming drug resistance in colorectal cancer (CRC) involves understanding the mechanisms by which cancer cells adapt to the genotoxic stress. We established a model of oxaliplatin resistant cells derived from HCT116/HT29 (HCT116 OxR/HT29 OxR). How these resistant clones reprogram their energy metabolism to gain a survival advantage remains unknown. We hypothesized that chemoresistant CRC cells exhibit altered cellular metabolism to survive following chronic genotoxic stress. Methods: The expression levels of glycolytic enzymes were detected by Western Blotting. Glucose and lactate concentrations were measured in the culturing media (CM). Intracellular ATP/ADP levels, oxygen consumption rate (OCR) and mitochondria ATP production were measured. In vivo xenograft study was used to compare the growth rate and angiogenesis of parental and oxaliplatin-resistant cells. Results: Both HT29-OxR and HCT116-OxR cells compared to parental cells exhibit increased aerobic glycolysis. Consistently, Glut1, Hexokinase 2 and LDHA glycolytic enzymes are upregulated. The OxR cells are defective in mitochondria complex I/II substrate and ATP production despite increased OCR. Importantly, the OXR cells maintain higher intracellular ATP and ATP/ADP ratio, increased HIF1a and VEGF levels in the CM. In tumor xenograft model, HT29 OxR cells grow significant slower than parental HT29 cells. Interestingly, when OxR cells were mixed with parental HT29 cells (50:50 and 90:10), tumor growth and microvessel counts were significantly accelerated. Conclusions: OxR cells demonstrate: 1) high aerobic glycolytic activity; 2) defective mitochondria functions; 3) increased ATP production; 4) increased HIF1a and angiogenesis. Likely, this metabolic switch contributes to the resistant phenotype. Metabolism intervention such as targeting HIF1a may provide a novel strategy to overcome drug-resistance in CRC. No significant financial relationships to disclose.
Profiling Retroviral Integration Sites in Donor T-Lymphocytes for Suicide Gene Therapy.
Authors: Frank A. Giordano, Stephanie Laufs, Katalin Z. Nagy, Boris Fehse, Agnes Hotz-Wagenblatt, Daniel Lauterborn, Kurt Fellenberg, Klaus Kuehlcke, Sonja Naundorf, Axel R. Zander, Jens W. Zeller, Stefan Fruehauf
Journal: Blood (2004)
Feasibility of RNA sequencing to detect TMPRSS2:ERG fusions following laser capture microdissection of prostate cancer.
Authors: Won Kim, Adam Foye, Henrik Bengtsson, Hyunsung John Kim, Barry S. Taylor, Nader Pourmand, Phillip G. Febbo
Journal: Journal of Clinical Oncology (2013)

76 Background: Recent sequencing efforts continue to fuel our growing insight into the genetic basis of prostate cancer (PCa). One of the key challenges remaining is to identify genetic events that drive PCa biology. RNA sequencing (RNA-seq) is commonly used to determine unbiased gene expression as a proxy for tumor biology. However, tumors often contain a mixture of cancer and normal cells that can confound data analysis. Cancer cells can be isolated by laser capture microdissection (LCM), but the feasibility of RNA-seq on small amounts of RNA following LCM of PCa tissue needs to be assessed. Methods: A set of 5 localized PCa specimens, frozen at the time of prostatectomy, was analyzed. RNA was isolated following LCM from these 5 specimens and assessed for quality with an Agilent Bioanalyzer and for quantity with RiboGreen. Paired-end, 300-bp insert sequencing libraries were prepared from the 5 specimens in duplicate; one specimen was also prepared for sequencing without LCM. The 12 samples were then sequenced on a single lane of an Illumina HiSeq. Sequencing reads were aligned with Tophat to build hg19 of human genome. Initial quality control was performed with Picard using refFlat and ribosomal RNA (rRNA) annotations provided by UCSC. PCR using previously published primer pairs was used to confirm the presence of TMPRSS2:ERG fusions. Results: 4-5mm2 of tumor was targeted by LCM from each PCa specimen. At least 100ng of total dsDNA was generated for library construction. For the first run, an average of 8,743,722 reads per paired-end was obtained (range: 1,335,939 to 16,134,097); the second run was comparable (mean: 8,612,188 reads; range: 1,312,823 to 15,842,480). Mapping of the sequences revealed no 5’ or 3’ read coverage bias, but the percentage of mappable reads per sample was less than 30%; sequencing was inefficient due to a high percentage of rRNA (mean: 38% per sample; range 28 to 44%). However, TMPRSS2:ERG fusions were confirmed in the samples with known fusion-positive status. Conclusions: RNA-seq is feasible and can detect fusions that are known and highly expressed. The inclusion of rRNA reduces the depth of coverage of the transcriptome and additional optimization is required to maximize efficiency.
Hypertension and myelosuppression as biomarkers of sunitinib efficacy in Chinese patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Shukui Qin, Jie Jin, Jun Guo, Jin-Wan Wang, Fang-Jian Zhou, Yi-Ran Huang, Xiu-Bao Ren, Ding-Wei Ye, Sharon Pan, Peter Sajben, Qiao Wang
Journal: Journal of Clinical Oncology (2013)

426 Background: In an open-label, phase IV study of sunitinib as 1st-line treatment (Tx) in Chinese pts with mRCC, median progression-free survival (PFS) and overall survival (OS) were 61.7 and 133.4 wk, respectively; objective response rate (ORR) was 31.1% (Ann Oncol 2012;23:851P). We retrospectively investigated correlations between on-Tx hypertension (HTN), neutropenia (N), and thrombocytopenia (T) and efficacy endpoints in pts from this trial. Methods: HTN was defined by either maximum systolic blood pressure ≥140 mm Hg (S-HTN) or maximum diastolic blood pressure ≥90 mm Hg (D-HTN). Using CTCAE assessment, N grade ≥2 and T grade &gt;1 were used as cut-points for the analyses. Median PFS and OS were estimated by Kaplan−Meier method. The log-rank test was used to compare PFS and OS between groups with and without HTN, N grade ≥2, or T grade &gt;1. Fisher’s exact test was used for ORR. Results: 102 pts were included in the HTN analyses, 60% with S-HTN versus 40% without S-HTN. Pts with S-HTN had greater ORR and longer PFS and OS than pts without S-HTN (Table). (Results were similar with D-HTN; see Table.) 103 pts were included in the N and T analyses, 67% with N grade ≥2 versus 33% with N grade &lt;2, and 56% with T grade &gt;1 versus 44% with T grade ≤1. Pts with N grade ≥2 had significantly greater ORR and significantly longer PFS and OS than pts with N grade &lt;2 (Table). Pts with T grade &gt;1 had greater ORR and significantly longer PFS and OS than pts with T grade ≤1 (Table). Conclusions: The developments of N grade ≥2 and T grade &gt;1 during Tx with sunitinib were significantly associated with better outcome. Median PFS was more than twice as long for pts with S-HTN as for those without S-HTN, but the association did not reach statistical significance. [Table: see text]
Improving cancer care by linking community cancer center physicians to disease site-specific experts.
Authors: Patricia H. Hardenbergh
Journal: Journal of Clinical Oncology (2012)

287 Background: The goal of this project is to improve quality of cancer care across the United States by connecting community cancer center radiation oncologists with highly specialized, disease site-specific radiation oncologists through the use of online technology. Methods: We have developed a website named chartrounds.com which allows community radiation oncologists to interact online with disease specialists and their peers on a scheduled basis in order to present and review radiation oncology treatment plans and cases in real time. Disease sites currently include breast, head and neck, gastrointestinal, gynecologic, prostate, central nervous systems, pediatric, lymphoma and lung cancers. At the conclusion of each session, participants are asked to complete a feedback questionnaire requesting feedback on quality and relevance of the session and the manner in which it might result in practice changes. Results: 650 community radiation oncology physician members from 49 states and 19 countries have enrolled online. In the initial 18-month period (12/2010-6/2012), 23 disease specialists have lead 188 chart rounds sessions with an average attendance ratio of 10 community physician members to 1 disease specialist. On a 5 point Likert scale with 5 representing the greatest impact possible, the mean response to feedback questions is as follows: session quality: 4.7, time used effectively: 4.6, discussions relevant to daily practice: 4.7, session is likely to result in a change in practice: 4.0.More specifically, members reported that they would make the following changes in their practice: change in clinical management of the radiation patient: 35%, change in the selection of patients for radiation: 17%, change in radiation fields: 15%, change in radiation prescription dose: 9%. Conclusions: Chartrounds.com appears to be impacting radiation oncology practice resulting in changes in management and treatment of patients in community cancer centers. Future directions of this project are aimed at demonstrating how these changes could result in significant improvements in cancer care across the United States. This work is funded by the Improving Cancer Care Grant of the ASCO Conquer Cancer Foundation.
Use of soluble CD27 as a marker of disease burden and the effect of rituximab-induced IgM flare and plasmapheresis in patients with Waldenström’s macroglobulinemia
Authors: B. T. Ciccarelli, E. Hatjiharissi, J. D. Soumerai, Z. R. Hunter, L. Ioakimidis, C. J. Patterson, R. J. Manning, L. Xu, S. Adamia, S. P. Treon
Journal: Journal of Clinical Oncology (2008)

8585 Backgound: Waldenstrom’s macroglobulinemia (WM) is a B-cell, IgM-secreting lymphoplasmacytic lymphoma. In this disease, serum IgM levels are used to assess both progression and response to treatment. Rituximab is an important therapeutic, but one frequently associated with an induced IgM flare, which may complicate response assessment (Treon et al, Ann Oncol 2004). In addition, plasmapheresis is commonly employed and can further complicate this evaluation. We, therefore, sought to identify a novel marker of disease burden which could evade these common clinical challenges. Soluble CD27 (sCD27) is a TNF-family member secreted by WM cells, elevated in patients with WM, and supports tumor cell growth through the induction of CD40L on bone marrow mast cells (Ho et al, Blood 2008). As such, we attempted to delineate its potential as a faithful marker of disease burden in WM. Methods: sCD27 levels were serially measured in 31 WM patients whose clinical outcomes (responder, stable disease, or progressive disease) were determined using consensus panel criteria based on concurrently-measured changes in serum IgM levels. Moreover, sCD27 levels were serially measured in 8 patients who had a rituximab-induced IgM flare, and in one patient, pre- and 48-hours post- plasmapheresis. Results: Serial changes in sCD27 levels paralleled those of serum IgM levels in all outcome categories, and highly-correlated to serial changes in serum IgM levels (r= 0.9760; p<0.0001 by Pearson’s correlation test). Moreover, in 8 patients who experienced an IgM flare related to rituximab, and eventually responded to therapy, IgM levels acutely rose from 3,515 to 5,270 mg/dL (p=0.016), while sCD27 levels declined from 174.1 to 155.9 U/mL (p=0.10). For the one patient undergoing plasmapheresis, IgM levels obtained 48 hours later declined from 4,770 to 2,370 mg/dL, whereas sCD27 levels showed minimal change (125.3 to 123.5 U/mL). Conclusion: sCD27 is a faithful marker of disease burden and is unaffected by the rituximab-induced IgM flare, as well as, plasmapheresis in WM. The use of this marker may aid in correctly predicting clinical outcome in patients undergoing treatment with rituximab and/or plasmapheresis in WM. No significant financial relationships to disclose.
Use of myeloablative Y90-ibritumomab tiuxetan in patients with high-risk CD20+ NHL not eligible for standard ASCT: Five-year results.
Authors: L. Devizzi, A. Guidetti, C. Carlo-Stella, C. Tarella, E. Seregni, M. Magni, M. A. Di Nicola, E. Schiavello, P. Matteucci, S. Viviani, E. Bombardieri, A. M. Gianni
Journal: Journal of Clinical Oncology (2011)

8019 Background: ASCT is the procedure of choice in poor risk NHL, however conditioning regimens is a challenging procedures because safely delivered only in younger and clinically fit patients, thus new approaches are suggested to enhance its applicability. To extend the probability of cure to pts not eligible to standard ASCT from 12/2003 to 7/2007, 60 high-risk CD20+ NHL pts have been included in a phase II study with myeloablative Y90-Ibritumomab Tiuxetan, supported by ASCT. Methods: CD20+ relapsed/refractory or newly diagnosed high-risk NHL adults defined by IPI>3 DLBCL, MCL or transformed BCL, with no upper limit of age not eligible to standard ASCT have been enrolled. Pts were required to collect ≥9 x 106 CD34+cells/kg. Y90-Ibritumomab Tiuxetan (0.8-1.2 mci/kg) was administered after rituximab based HDCT: DHAP x 3, CTX 5-7g/mq followed stem cells collection, Ara-C 12-24 g/mq with 2x106 CD34+ cells/kg support. To hasten hematopoietic recovery, each pt received two stem-cell autograft of 2x106 CD34+ cells/kg on day +7 and of ≥5x106 CD34+ cells/kg on day +14 from RIT. Rationale of the procedure have been published elsewhere (Devizzi: JCO 2008). Results: Characteristics: M/F: 38/22; median age 63 (26-76); median comorbidities: 2 (1-3); Stage III-IV: 54; BM+: 36; newly high-risk NHL: 20; relapsed/refractory DLBC: 5/7; relapsed FCL/MZL 16/6; relapsed MCL: 6; molecular probe: 47. All pts received PCR – autograft. Fifty-two pts reached CR (87%), 3 GPR (5%) 5 PD (8%). Grade 3-4 neutropenia and thrombocytopenia was 37% and 70% with a median duration of 2 and 4 days. Non hemathological toxicity was: 4 pneumonia (6%); 2 mycetoma (3%); 7 CMV/HVZ reactivations (11%); One death occurred one month after transplant for VOD. Four pts developed sMDS/AML. With a median follow-up of 57 months 36 pts are in CCR, 18 pts relapsed, and 43 pts are still alive; the 5-year PFS and OS are 60% and 72% respectively. Conclusions: High dose90Y ibritumomab tiuxetan is an innovative, highly effective and tolerable myeloablative regimen. The incidence of sMDS/AML is similar to that observed with standard CT-based conditioning. Its use is strongly suggested in pts not eligible for standard ASCT.
The diagnostic and prognostic implications of nucleated red blood cells in myelophthisis.
Authors: J. L. Schering, J. Munoz, E. Raybon, S. Hegab, A. S. Hanbali, P. Kuriakose
Journal: Journal of Clinical Oncology (2011)

6576 Background: The presence of elevated nucleated red blood cells (NRBC) in the peripheral blood smear points towards the presence of myelodysplastic syndrome or myelophthisis. The intent of our study is to assess the prognostic implications of the presence of increased NRBC in patients with myelophthisis. Methods: Retrospective single institution chart review over a period of 7 years. Our study population comprised 40 newly diagnosed cases of myelophthisis from solid tumors whose diagnoses were made by bone marrow (BM) examination. Results: 20 patients were male and 20 patients were female. Median age at diagnosis of myelophthisis was 60.7 years. 17 patients received a new diagnosis of malignancy via bone marrow biopsy while 23 patients already had a diagnosis of cancer. The most common hematologic presentation was bicytopenia (19 cases), followed by anemia (11 cases), pancytopenia (6 cases) and normal complete blood count (4 cases). Alkaline phosphatase was high in 32 patients and normal in 8 patients. Primary sites were documented in 38 of 40 metastatic cases (Table 1). There was no significant difference in survival between patients that had undetectable NRBC prior to BM examination (Algorithm 1) and patients that had increased NRBC prior to BM examination (p = 0.1459). There was no significant difference in survival between patients that had NRBC remain undetectable after BM examination and patients that had increased NRBC after BM examination (p = 0.6912). In this study, there was a significant difference in survival (Figure 1) between patients with metastatic nonhematological tumors that presented with an increased number of peripheral NRBC that subsequently cleared from circulation and patients that showed persistence of increased NRBC after bone marrow examination (p < 0.0001). Conclusions: The presence of nucleated red blood cells in the peripheral blood smear serves as a remarkable clue about a possible underlying malignancy and its disappearance after appropriate treatment portends improved survival. To our knowledge this is the first study documenting the prognostic implications of NRBC in the peripheral circulation of patients with myelophthisis.
Systemic Exposure to Dexamethasone and Asparaginase Affects Risk of Relapse in Children with Acute Lymphoblastic Leukemia
Authors: Jitesh D. Kawedia, Chengcheng Liu, Deqing Pei, Cheng Cheng, Christian A Fernandez, Scott C Howard, Dario Campana, John C Panetta, W. Paul Bowman, William E. Evans, Ching-Hon Pui, Mary V. Relling
Journal: Blood (2011)