tbuckley/cabot-search huggingface dataset:
Association of a genetic variant in the <i>ABCC2</i> gene with high methotrexate plasma concentrations in pediatric malignancies.
Authors: M. M. Hagleitner, M. J. Coenen, M. Schrauwen, S. H. Vermeulen, E. S. de Bont, P. Hoogerbrugge, D. M. Te Loo
Journal: Journal of Clinical Oncology (2010)

9522 Background: High-dose Methotrexate (HD-MTX) forms a cornerstone in the treatment of several pediatric malignancies including acute lymphoblastic leukemia (ALL) and osteosarcoma. Delayed MTX elimination necessitates increased leucovorin rescue and additional hospitalization for hydration and urinary alkalinization. We hypothesized that common genetic variations may contribute to delayed MTX elimination. Identification of these genetic variations might help recognize those patients at risk. Therefore, in the present study, we used a pharmacological pathway gene approach and investigated if functional polymorphisms in 20 genes involved in the folate pathway, the key pathway in the processing of MTX in the body, are associated with delayed MTX elimination. Methods: In total 92 children with ALL (n=49) and osteosarcoma (n=43) were genotyped. MTX plasma concentrations at 48 hours following the start of MTX were assessed in all patients. Differences in MTX levels between genotype groups were tested using generalized estimated equations (GEE) with robust standard errors in Stata version 9.0 to take the repeated measurements into account. Analyses were performed for an additive (trend) and genotypic model. Results: Overall, 41 single nucleotide polymorphisms in the folate pathway were studied. A polymorphism in the ABCC2 gene (rs3740066), a member of the ATP-binding cassette which is involved in active efflux of MTX, was significantly associated with higher plasma MTX concentrations (p=0.007, Coefficient 0.219, 95% Confidence Interval: 0.059-0.379). Patients with the TT genotype had a mean plasma concentration of 0.53 umol/l compared to 0.29 umol/l in patients with a CC genotype. Conclusions: A polymorphism in the ABCC2 gene is associated with higher MTX plasma concentrations. These results suggest that this polymorphism may be used for identification of patients at risk for delayed MTX clearance. No significant financial relationships to disclose.
Sequential plasmid vaccinations targeting normal melanocytes protects against challenge with melanoma in a syngenic murine model
Authors: G. A. Daniels, R. G. Vile
Journal: Journal of Clinical Oncology (2004)

2570 Background: Malignant melanoma is one of a handful of tumors responsive to immunotherapy. Tumor regression correlates with an expanded epitope response and induction of vitiligo. In fact, expansion of the immune response to include multiple melanoma differentiation antigen (MDA) targets correlates with clinical response in newer vaccine approaches. We hypothesized that a vaccine designed to induce epitope spreading against melanocytic antigens may be useful in melanoma. By directly targeting normal melanocytes in situ, we hoped to induce both autoimmunity and a broad anti-melanocytic response. To accomplish this, we utilized sequential plasmid vaccinations in an immune competent murine model for melanoma. Methods: C57/b6 mice were vaccinated with plasmid DNA encoding either the gene for chicken ovalbumin (cOVA) or empty vector intramuscularly (IM) weekly for two weeks. Mice (n=9) were then vaccinated intradermally (ID) with either cOVA or a control gene under the control of the tyrosinase promoter weekly for three weeks. Mice were challenged with subcutaneous injections of 105 B16 melanoma tumor cells or B16 containing the transgene cOVA (B16cOVA). Tumor size and survival were followed. Results: Vaccination with the cOVA gene IM resulted in 90% to 100% protection against B16cOVA tumor cells compared to 0% to 10% of control plasmid injected mice. Challenge with B16 resulted in equally poor survival between the two groups with 100% of mice being sacrificed by day 26. Surprisingly, if the mice were vaccinated with the cOVA gene ID under the control of the tyrosinase promoter after the initial IM vaccination with cOVA and subsequent tumor challenge, B16 growth was delayed compared to controls. Delay was not observed without the initial IM cOVA vaccination. Conclusions: Ectopic expression of antigens for which a strong pre-existing cellular immune response exists may allow targeting of an immune response to normally tolerant antigens. This system provides a relatively simple approach in understanding the requirements of both autoimmunity and cancer immunotherapy. No significant financial relationships to disclose.
Purine nucleoside phosphorylase inhibitors - an immunotherapy with novel mechanism of action for the treatment of melanoma
Authors: Shanta Bantia
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Contrary to expectations based on the immuno-compromised clinical phenotype of the PNP-deficient patients, the present study demonstrates that PNP inhibitors (PNPi) can activate immune cells that can help mount a robust antitumor response. PNP deficiency in humans lead to
Calibration of quality-adjusted life years (QALYs) for oncology clinical trials (OCT).
Authors: J. A. Sloan, P. J. Novotny, D. J. Sargent, P. A. Decker, R. Marks, H. Nelson
Journal: Journal of Clinical Oncology (2010)

6108 Background: Quality-adjusted life year (QALY) estimation is a well-known but little-used technique to compare survival adjusted for complications in OCT. Lack of calibration and interpretation guidance hinder implementation of QALY analyses. Methods: We conducted simulation studies to assess the impact of differences in survival, toxicity rates and utility value on QALY results. Survival comparisons used both log-rank and Wilcoxon testing. We examined power considerations for an NCCTG phase III lung cancer clinical trial (89-20-52). Results: Sample sizes of 100 events evaluable for survival per treatment have low power to generate a statistically significant difference in QALYs unless the toxicity rate is 65% higher in one arm. For sample sizes of 200/arm and equal survival time, toxicity would have to be at least 50% more in one treatment arm for the result to be statistically significant, using a utility of 0.5 for days with toxicity (see Table). Sample sizes of 300 (500)/arm provided 80% power if there is a 40% (33%) toxicity difference. If the overall survival hazard ratio between the two treatment arms is 1.25, then samples of at least 150 pts and 20% increased toxicity are necessary to have 80% power to detect QALY differences. In 89-20-52 there was only 56% power to detect the observed QALY differences, clarifying the enigmatic conclusion of no statistically significant difference in QALY despite an observed 14.5% increase in toxicity between treatments. Conclusions: This calibration analysis allows researchers to interpret the clinical significance of QALY analyses and will facilitate QALY inclusion in OCTs through improved study design. Funded by NCI grant CA25224. Power for QALY test of equality for utility = 0.5 with varying hazard ratios and differences in toxicity rates N HR = 1.00 HR = 1.25 Difference in percent of days with toxicity 20% 40% 60% 10% 20% 30% 50 9 21 46 27 37 50 100 12 38 75 48 65 78 150 16 52 90 68 83 92 200 20 65 97 79 91 98 300 27 81 100 92 98 100 500 41 96 100 99 100 100 1,000 70 100 100 100 100 100 No significant financial relationships to disclose.
Blood brain barrier disruption (BBBD) and intra-arterial methotrexate based therapy for newly diagnosed primary CNS lymphoma: The BBBD Consortium Experience
Authors: L. Angelov, N. D. Doolittle, T. Siegal, D. F. Kraemer, D. Peereboom, K. Jahnke, S. Ference, G. Barnett, J. McGregor, E. A. Neuwelt
Journal: Journal of Clinical Oncology (2007)

2014 Background: Primary central nervous system lymphoma (PCNSL) incidence in immunocompetent patients has been increasing and now represents 4% of intracranial neoplasms. Similar to systemic lymphoma, PCNSL can display considerable chemosensitivity. Most chemotherapy regimens for PCNSL use intravenous methotrexate, often in combination with whole brain radiation. We present our multi- institutional experience in the treatment of PCNSL using BBBD in conjunction with Intra-arterial methotrexate (IA MTX)-based chemotherapy. Methods: A retrospective IRB approved analysis was performed on 177 newly diagnosed PCNSL patients treated monthly with osmotic BBBD in conjunction with an IA MTX-based chemotherapy regimen (n= 2,469 procedures) at 4 institutions from 1982–2005. No patient had received prior irradiation. Descriptive summaries and Kaplan-Meier survival summaries were estimated. Results: Among 177 patients, median age at diagnosis was 59.1 years (range 5.7 to 82.7 years). 101 patients (57%) achieved a complete response and 41 (23%) achieved a partial response (overall response rate 80.2%). 67 patients (37%) are currently alive (57 [32%] with no evidence of disease). Median overall survival (OS) was 3.1 years (25% estimated survival at 11.3 years). Median progression free survival (PFS) was 1.6 years with 40% progression-free at 5 years. Evaluation of the subgroup of patients &lt; 60 years (n= 100), demonstrated an OS of 5.2 years with a 40% survival plateau after about 8 years, suggesting that some of these patients may be cured. The procedures were generally well tolerated with the most frequently encountered complication being procedure related seizures (9.5%) without long-term sequelae. Conclusions: This large multi-center series demonstrates that BBBD/IA MTX is a generally well tolerated and effective treatment for patients with newly diagnosed PCNSL. Further, it allows for the deferral of radiation and its associated cognitive compromise in these patients. These results are comparable or superior to other published chemotherapy (± radiation) treatment regimens suggesting that BBBD/IA MTX is an excellent treatment option for PCNSL patients and can result in successful and durable tumor control. No significant financial relationships to disclose.
Human immunodeficiency virus-associated systemic lymphomas may be subdivided into two main groups according to Epstein-Barr viral latent gene expression.
Authors: A Carbone, U Tirelli, A Gloghini, R Volpe, M Boiocchi
Journal: Journal of Clinical Oncology (1993)

PURPOSE We report a pathologic characterization of human immunodeficiency virus (HIV)-associated systemic lymphomas, including the association of Epstein-Barr virus (EBV) in different categories. PATIENTS AND METHODS Eighty-seven HIV-associated non-Hodgkin's lymphoma (NHL) were classified according to classic NHL classification and a recent description of morphologic variants of high-grade B-cell NHL. Seventy-one cases were immunophenotypically-genotypically characterized, whereas, in 49 representative cases, the association of EBV was assessed by nonisotopic in situ hybridization (ISH) and the immunohistochemical demonstration of latent membrane protein-1 (LMP-1). In addition, 14 Hodgkin's disease (HD) cases, occurring in patients with HIV infection, were investigated for the frequency of LMP-1 expression. RESULTS Most lymphomas were of B-cell derivation and showed a blastic cell morphology, with (1) small noncleaved cells (SNCCs; 36 cases), (2) large noncleaved cells (10 cases), and (3) immunoblasts, usually polymorphic (12 cases). Moreover, 12 cases were classified as anaplastic large-cell (ALC) Ki-1-positive (Ki-1+) lymphoma. Combined ISH studies (for viral DNA and EBV RNA [EBER]) and immunohistologic demonstration of LMP-1 suggested that there were differences in viral latent gene expression between ALC Ki-1+ or immunoblastic lymphomas (usually EBV+, LMP-1+), and EBV-infected cells of SNCC lymphomas, which did not show LMP-1 expression. A high proportion (10 of 14) of LMP-1+ HD cases was found. CONCLUSION Differences in EBV association and LMP-1 expression were found between a major group of HIV-associated systemic NHL with blastic cell morphology, including SNCC lymphoma and its variants, and anaplastic cell lymphomas. A proportion of immunoblastic (polymorphic) lymphomas was different in viral latent gene expression from other blastic cell systemic lymphomas. It is concluded that only a group of these lymphomas (most ALC Ki-1+ and HD cases, along with a nonnegligible fraction of immunoblastic lymphomas) seems to be linked etiopathologically to EBV.
Preliminary clinical results of accelerated IMRT with concomitant boost after breast conserving therapy (BCT)
Authors: S. C. Lymberis, S. M. MacDonald, B. Rosenstein, E. P. Lief, J. K. Dewyngaert, S. C. Formenti
Journal: Journal of Clinical Oncology (2004)

860 Background: Inspired by the Canadian prospective randomized trial that demonstrated comparable 5-year safety and efficacy of accelerated (16 fractions) whole breast RT versus standard RT (25 fractions), we have started a protocol of accelerated intensity-modulated radiation therapy (AIMRT) after BCT. Methods: A protocol of 15 fractions over 3 weeks is offered to Stage I-II patients who have undergone BCT. Patients are treated in the prone position, to reduce breathing motion and to enable treatment of the index breast while sparing the other breast, the lung and heart tissue. Dynamic intensity modulated multiple photon fields are used to deliver 15 daily fractions of 2.7 Gy (40.5 Gy total dose) to the index breast with a simultaneous in-field boost of 0.5 Gy (48 Gy total dose) to the tumor bed(PTV). At prone CT planning, the index breast is defined and is encompassed by beams placed tangentially to the anterior edge of the chest wall. The superior and inferior margins are clinically determined at the time of simulation. Similarly, the PTV is defined as the post-surgical cavity, plus a 1.0 cm margin. Results: Since September 2003, eleven patients with Stage I(n=7) and IIA(n=4) breast cancer entered the study and were treated with either 3 or 4 non-coplanar IMRT fields. DVH Analysis: The median % volume of breast tissue outside the PTV(Br-PTV) receiving 110% and 125% of the prescription dose(PD 40.5 Gy) was 37.6% (SD±10.87) and 4.04% (SD±3.77), respectively. The median % dose covering 95% of the PTV volume(D95) was 118.6 % of the PD (SD±1.93). Five % of the ipsilateral lung received 7.2%(SD±8.4) of the PD(291.6 cGy), while five % of the heart received 7.3%(SD±2.7) of the PD(295.7 cGy). Conclusions: Preliminary data suggest that it is technically feasible to plan and treat by AIMRT the ipsilateral breast with a concomitant boost. Prone positioning reduces breathing movement and spares heart and lung tissue. No significant financial relationships to disclose.
Abstract 17921: Clostridium difficile Infection is Associated with Worse Outcomes in Heart Failure Hospitalizations: National Hospital Discharge Survey
Authors: Mallika Gupta, Sahil Khanna, Amit Noheria
Journal: Circulation (2012)

Introduction: Clostridium difficile infection (CDI) is a leading cause of nosocomial diarrhea with increasing incidence, severity and mortality. We report the first study examining the risk and out...
Oral glucocorticoids have no impact on the efficacy or safety profile of rituximab in rheumatoid arthritis patients with inadequate response to TNF inhibitors (REFLEX study)
Authors: G. R. Burmester, Patrick Durez, E. M. Ruderman, J. Loveless, T. K. Kvien, C. Jackson, L. Burke, M. Cravets, A. M. White
Journal: Annals of the Rheumatic Diseases (2006)
Characterization of lymphoid infiltrates in prostatectomy specimens post neoadjuvant hormonal therapy using quantitative immunofluorescence and RNA FISH
Authors: M. J. Donovan, F. Khan, D. Powell, P. Capodieci, M. Gleave, I. Taylor, J. Gomez-Navarro, C. Cordon-Cardo
Journal: Journal of Clinical Oncology (2009)

e16104 Background: Immunotherapy for advanced prostate cancer requires an understanding of the host response including lymphocyte subsets and cytokine expression. Using quantitative immunofluorescence (IF), image analysis and RNA FISH we examined a series of prostatectomy specimens from patients, ± neoadvjuvant hormonal therapy (NHT) and determined their baseline immune characteristics. Methods: CD4,8,25,45,68,69,86 and Foxp3 were evaluated by IF and IFNg with RNA FISH on prostatectomy specimens from 40 patients with T1c-T3 prostate cancer; 20 control and 20 post long-term NHT. Sections were analyzed with three multiplex IF assays, triplicate images acquired with spectral imaging, digitally masked and processed with IF image analysis software. IFNg RNA transcript localization was performed on all 40 patients using published protocols. Results: There was a predominance of CD8 in both control and NHT patients with a high but variable level of CD86 and 69 across the entire cohort, reflecting T cell activation. CD68 appeared reduced in NHT, but this change was not statistically significant. Number of Treg (CD4+/CD25+/Foxp3+) cells were similar between groups; however, in NHT an increased Treg population was associated with an elevated preoperative PSA compared with controls (p&lt;0.05). IFNg transcript activity was low in the entire cohort and limited to tumor epithelial cells. Conclusions: The prominent CD8 expression and low level of IFNg in both control and NHT groups suggest an ongoing but not overly active immune response. Multiplex IF and in situ RNA FISH are useful tools for developing a disease phenotype and provide the necessary parameters for evaluating gene-protein expression especially in pharmacodynamic studies. [Table: see text]
Molecular cytogenetic study in pediatric b-lineage acute lymphoblastic leukemia (BCP-ALL): A collaborative study group from North India.
Authors: A. Fauzdar, D. Jain, M. Mishra, N. Gupta, D. Bhurani, P. Mishra, A. Mahajan, V. Raina
Journal: Journal of Clinical Oncology (2010)

e20001 Background: Chromosome abnormalities of leukemia cells have important prognostic significance in childhood acute lymphoblastic leukemia (ALL). The prevalence of various chromosomal abnormalities shows geographical and racial variation. There is limited data from the Indian sub- continent. Methods: Bone marrow samples of 89 children between age group of 1-18 diagnosed with ALL were analyzed for chromosomal abnormalities with conventional G-banding techniques and interphase fluorescence in situ hybridization (FISH) using locus specific probes to detect cryptic TEL/AML1 t(12:21)(p13-q22),BCR/ABL t(9;22)(q34;q11) and MLL rearrangement for 11q23 by dual color fluorescence in situ hybridization (FISH). Results: The median age at diagnosis was 7 years. The male to female (sex ratio) in our group was 2.7:1. Bone marrow cytogenetics results were available for 77 (86.5%) patients and out of these 37 (48%) had normal karyotype, 40 (51%) patients had structural and numeric chromosomal abnormality, 21(27%) patients had hyperdiploidy (>50 chromosomes), 4 (5%) case were hypodipoidy (<46 chromosomes) and 15 (19%) had structural abnormalities. FISH analysis for ETV6/RUNX1 t(12:21)(p13-q22) was available for 21 B lineage-ALL patients with normal karyotypes and it showed fusion signals in 9 (42%) cases and amplification of AML(RUNX1) with four and more copies was observed in 4 (19%) patients. Conclusions: Bone marrow karyotype in combination with molecular cytogenetic techniques like FISH has improved the sensitivity and accurate identification of prognostic markers in childhood ALL patients. Though the numbers are small, we report increased prevalence of ETV6/RUNX1 (alias TEL/AML1) involving t(12:21)(p13- q22) in B lineage ALL than previously reported in studies from this region. No significant financial relationships to disclose.
Natural history of castration-resistant nonmetastatic prostate cancer: Secondary analyses of a multicenter randomized controlled trial.
Authors: M. R. Smith, R. J. Cook, J. B. Nelson
Journal: Journal of Clinical Oncology (2010)

4653 Background: Castration-resistant prostate cancer is a common but poorly characterized clinical disease state. To better understand the natural history, we analyzed data from the placebo group of a large randomized controlled trial. Methods: The 470 patients in these analyses were from the placebo group of a randomized controlled trial to evaluate atrasentan in men with prostate cancer, no radiographic evidence of metastases, and rising PSA levels despite androgen deprivation therapy (Nelson et al 2008 Cancer 113: 2478). Main outcomes were time to disease progression (defined as onset of metastases), time to first bone metastasis, and overall survival. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were age, BMI, prior prostatectomy, prior bilateral orchiectomies, Gleason sum, PSA, PSA velocity, urinary NTx, serum BAP, albumin, lactate dehydrogenase, and hemoglobin. Results: Median time to disease progression, time to first bone metastasis, and overall survival were 22.4, 25.2, and 46.8 months, respectively. Only PSA and PSA velocity were consistently associated with each of the clinical outcomes. In multivariate analyses, PSA greater than the median value of 13.1 ng/mL was associated with shorter time to disease progression (relative risk 2.21, p<0.0001), time to first bone metastasis (relative risk 1.98, p<0.0001), and overall survival (relative risk 2.34, p<0.0001). Similarly, higher PSA velocity was independently associated with each outcome. Higher urinary NTx was associated with shorter overall survival but not with time to disease progression or time to first bone metastasis. BMI was not associated with any clinical outcome. Conclusions: In men with castration-resistant nonmetastatic prostate cancer, higher baseline PSA and PSA velocity were independently associated with shorter time to disease progression, time to first bone metastasis, and overall survival. Biochemical markers of bone turnover were not associated with time to first bone metastasis. Obesity was not associated with any clinical outcomes. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories