tbuckley/cabot-search huggingface dataset:
Phase II study of denileukin diftitox for previously treated low grade non-Hodgkin’s lymphoma: E1497 final report
Authors: J. W. Eklund, E. Weller, T. M. Kuzel, F. Foss, R. Gascoyne, N. Abramson, J. F. Schwerkoske, S. Horning
Journal: Journal of Clinical Oncology (2005)

6684 Background: Denileukin diftitox (DD), a recombinant fusion protein of diphtheria toxin linked to interleukin-2, is FDA approved for the tx of cutaneous T-cell NHL. Initial studies of DD included several heavily pretreated pts with B-cell NHL, and objective responses were observed. This phase II trial was designed to evaluate the response rate (RR) and toxicity of DD in pts with relapsed low grade B-cell NHL, and to evaluate RR by tumor interleukin-2 receptor (IL-2R) expression. Methods: Eligible patients were stratified into two arms: pts with >20% IL-2R expression (IL-2R+) or patients with <20% IL-2R expression (IL-2R-) with independent response assessment for each group. DD was dosed at 18μg/kg/d for 5 days every 21 days for 2 cycles. Responders continued therapy for up to six cycles. Steroid premedication was not allowed. Results: The study closed prematurely due to slow accrual. Thirty of 35 pts entered were eligible and underwent treatment (18 M, 12 F; 12 IL-2R+ and 18 IL-2R-). The median pt age was 62. Twenty-eight pts (93%) had stage III or IV disease. Pts received a median of 3 prior regimens. Among the 29 pts with response information, the RR observed was 10% (90% CI: [3,25%]). There were no CRs and 3 PRs; 2 whose tumors were IL2R- (11% RR) and 1 whose tumor was IL-2R+ (8% RR). Ten pts maintained stable disease after tx, 10 pts had progressive disease and 6 pts were unevaluable. Eight pts had small lymphocytic NHL (SLL); 2 responded (25% RR; 90% CI: [5,60%]). At a median follow-up of 43 months, the median PFS was 4.1 months and the median OS was 46 months (18 months for IL-2R+ pts; not reached for IL-2R- pts). There was 1 case of lethal toxicity due to thromboembolism. Most toxicities were low grade and transient. Conclusions: DD is well tolerated and induces clinical responses in pts with previously treated low grade B-cell NHL. Responses were seen in IL-2R- tumors; SLL may represent a more sensitive NHL. Responses could not be attributed to corticosteroids as steroid premedication was prohibited. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ligand Ligand
Survival in a phase III, randomized, double-blind study of dacarbazine with or without oblimersen (Bcl-2 antisense) in patients with advanced melanoma and low-normal serum lactate dehydrogenase (LDH; AGENDA).
Authors: A. Y. Bedikian, C. Lebbé, C. Robert, S. S. Agarwala, T. Cousin, J. Wu, C. Garbe, J. J. Grob
Journal: Journal of Clinical Oncology (2011)

8531 Background: Oblimersen (OBL) is a Bcl-2 targeted phosphorothioate antisense that enhances antitumor activity of alkylating agents in preclinical studies. A prior phase III study of dacarbazine + OBL in 771 patients (pts) showed significant improvement in all secondary endpoints, including overall response and progression-free survival (PFS), in pts treated with OBL/DTIC, but that the primary endpoint of ITT overall survival (OS) was narrowly missed (P=0.077). Further analysis showed that OS benefit from OBL plus DTIC clustered in pts with low-normal LDH, who displayed a significant treatment interaction with this adverse prognostic factor. We have completed a similarly designed trial (AGENDA) to evaluate whether addition of OBL to DTIC could confirm the OS benefit previously observed in pts with low-normal LDH. Methods: Inclusion criteria included: unresectable Stage 3 or 4 melanoma; no prior chemotherapy; LDH ≤ 0.8 x ULN; ECOG PS 0-1. Pts were randomized to receive DTIC (1000 mg/m2 IV) preceded by a 5-day continuous IV infusion of either OBL (7 mg/kg/d) or placebo. Up to 8 cycles were administered absent progressive disease. Co-primary endpoints of progression-free survival (PFS) and OS were to be analyzed 6 months and 2 years after last patient was accrued, respectively. The trial was powered to detect an increase in OS (HR=0.69; a = 0.05). Results: Accrual completed in March 2009 with 314 patients. Treatment groups were balanced with respect to baseline characteristics. LDH was poorly correlated with tumor burden (R=0.16). As previously reported, PFS favored the DTIC-OBL regimen but was not significant (HR=0.85; P=0.23). The protocol allowed for "pooling" of survival data between the 2 studies. An exploratory analysis revealed a modest improvement in pooled PFS data (HR=0.71; P=0.0004). The single primary analysis for OS (and the secondary endpoint of durable response) will be conducted in April 2011. Conclusions: Results for the co-primary AGENDA endpoint of OS will be presented.
Comparison of displacement of the silver clips in the cavity determined by KV-plain film and cone-beam computed tomography for the breast cancer patients treated by three-dimensional conformal external-beam partial breast irradiation assisted by active breathing control
Authors: C. Liu, J. B. Li
Journal: Journal of Clinical Oncology (2008)

11585 Background: To compare the margins of CTV extended to PTV depending on the displacement of the silver clips in the cavity determined by KV-plain film and cone-beam computed tomography for the breast cancer patients treated by external-beam partial breast irradiation (EB-PBI) assisted by active breathing control (ABC). Methods: Ten patients were enrolled in the study. The patients received CT simulated positioning assisted by ABC to get the CT image sets based on the respiratory condition of moderate deep inspiration breath hold (mDIBH), and the clips located at the cephal, pedal, lateral border and bottom of the cavity were delineated respectively. Before each irradiation, twice CBCT and KV-plain film were received assisted by ABC device, and then 3D-3D automatic registration based on pixel between the CBCT image and the planning CT image and 2D-2D automatic registration based on pixel between KV-plain film and the planning digitally reconstructed radiograph (DRR) were finished, and then the margins determined by KV-plain film and CBCT were compared to observe the significance of difference. Results: By comparison, the displacement of the marked clips determined by KV-plain film and CBCT on every directions had no significant difference (P>0.05), the margins from CTV to PTV calculated by the marked clips displacement determined by KV- plain film on LAT, LNG, VRT directions were 4.9, 7. 8, 9.3 mm based on the cephal clip; 4.4, 6.4, 6.7 mm based on the pedal clip, 5.0, 8.6, 10.5 mm based the lateral clip and 5.4, 8.5, 10.8 mm based on the bottom clip. The margins from CTV to PTV calculated by the marked clips displacement determined by CBCT were 5.718, 7.968, 9.774 mm of the cephal clip, 5.0, 7.1, 7.8 mm based the pedal clip, 5.3, 12. 8, 10. 7 mm based on the lateral clip and 5.3, 7.5, 10.9 mm based on the bottom clip. Conclusions: Silver clips in the cavity can be clearly discovered on the KV-plain film and CBCT image; CBCT and KV-plain are all the ideal image-guided methods to determine the displacement of silver clips for EB-PBI, comparedly KV-plain film is a more feasible method. No significant financial relationships to disclose.
The requirement for freshly isolated human tumor cells for the study of colorectal cancer stem cells.
Authors: Seth Albert Bellister, Fan Fan, Federico Tozzi, Jia Lu, Ling Xia, Yunfei Zhou, Rajat Bhattacharya, Xiangcang Ye, Lee M. Ellis
Journal: Journal of Clinical Oncology (2013)

411 Background: Reliable methods for the isolation of an enriched cancer stem cell (CSC) population in colorectal cancer (CRC) may provide new approaches for the identification of therapeutic targets. There is no consensus regarding the best methods to isolate a CRC tumor cell population enriched for CSCs. The goal of this study was to determine the utility of various CSC markers in both established cell lines and freshly isolated patient-derived tumor xenografts in order to validate methods of CSC isolation. Methods: Established human CRC cell lines (HCT116, HT29, SW480) and three freshly isolated CRC cell lines were studied. Freshly isolated cell lines were generated by first injecting CRC cells derived from clinical specimens into nude mice. Xenografted tumors were resected and FAC-sorted to isolate human cells. These cells were FAC-sorted for CD133, CD44, and ALDH activity. Tumorsphere formation and in vivo dilutional and serial tumorigenicity studies were done to validate methods for CSC enrichment. Results: Using established human CRC cell lines, none of the markers studied could be used to enrich for the CSC population as assessed by sphere formation or tumor initiating capacity; this suggests that cells grown in culture for long periods of time lose their hierarchy. In the freshly isolated CRC cells, CD133 and CD44 were unable to enrich for CSC-ness. In contrast, freshly isolated CRC cells with high ALDH activity formed spheres whereas cells with low ALDH activity did not. In validation studies, freshly isolated cells from patient-derived xenografts with high ALDH activity demonstrated enhanced tumorigenic capacity in murine models. Furthermore, the tumorigenicity of ALDH high cells was maintained after serial passage of cells harvested from tumors generated by ALDH high cells, while ALDH low cells did not form tumors. Conclusions: CRC cells from patient-derived tumor xenografts can be used to study CSC properties using ALDH activity as a marker. In contrast, CD44 and CD133 are not reliable markers for enriching for the CSC population from established cell lines or patient xenografts. Established CRC cell lines should not be used to study CSC biology.
Outcomes following stereotactic body radiotherapy for patients with Child-Pugh B/C hepatocellular carcinoma.
Authors: Shaelyn Culleton, Haiyan Jiang, Joon-Hyung J. Kim, James D. Brierley, Anthony M. Brade, Jolie Ringash, Laura A. Dawson
Journal: Journal of Clinical Oncology (2013)

167 Background: Assessment of outcomes in patients with hepatocellular carcinoma (HCC) and Child-Pugh B or C liver function treated with stereotactic body radiotherapy (SBRT). Methods: From 2004 – July 2012, 39 patients with HCC and Child-Pugh B/C liver function were treated with SBRT. Inclusion criteria included Child-Pugh B/C, treatment with SBRT, 5 to 15 fractions, and radical or palliative intent. Univariate analyses (UVA) were performed to assess relationships of patient demographics, liver function tests and treatment characteristics on overall survival (OS) and time to progression (TTP). Results: The majority of the 39 patients had Child-Pugh B7 liver function (69%), performance status ECOG 0-1 (82%), radiological evidence of tumor vascular thrombosis (62%) and hepatitis C as underlying liver disease (49%). 10 patients treated as bridge-to-transplant. The median dose was 3300 cGy in 6 fractions (range: 2000-4500 cGy in 5-15 fractions), individualized based on spared liver volume and underlying liver function. The median survival for all patients was 9.9 months (95% CI: 3.4-18.4). UVA demonstrated significantly reduced survival with Child-Pugh score &gt; B7, baseline AFP &gt; 1049 ng/mL (upper quartile) and gross tumor volume &gt; 93 cm3. The median survival of patients treated with SBRT as a bridge-to-transplant versus the non-bridge-to–transplant patients was 30.7 months (95% CI: 0.6-not reached) versus 7.9 months (95% CI: 3.4-15.1; p=0.008). No HCC tumors treated with SBRT demonstrated local progression during the follow-up time. The median TTP for all patients was 18.8 months (95% CI: 6.2-not reached). Model for end stage liver disease (MELD) score &gt; 12 was the only factor associated with reduced TTP on UVA. 31% of patients had a decline in Child-Pugh score by 2 or more points at 3 months. No acute treatment related toxicities of grade 3 or higher were reported. Conclusions: SBRT may be considered as a treatment option for HCC with impaired liver function. Survival is best in patients who are treated as a bridge-to-transplant, have smaller tumors, are Child-Pugh class B7, and have lower AFP levels. Randomized trials of radiation therapy in HCC patients with impaired liver function are warranted.
Translational Modeling to Identify Human Dosing of Filgrastim to Improve Overall Survival (OS) in Acute Radiation Syndrome (ARS)
Authors: John Harrold, Philippe Jacqmin, Per Olsson, Isabelle Delor, Phuong Khanh Morrow, Bing-Bing Yang, Andrew Chow, Juan Jose Perez-Ruixo
Journal: Blood (2014)
Continuum of care: Establishment of a comprehensive cardio-oncology program.
Authors: Olexiy Aseyev, Nina Gosh, Jeffrey Allen Sulpher, Christopher Johnson, Ellamae Stadnick, Michele Turek, Susan Faye Dent
Journal: Journal of Clinical Oncology (2016)

74 Background: Cardiac disease in individuals with cancer is common, impacts survival, the ability to tolerate cancer treatments and quality of life. Cardio-oncology is a novel interdisciplinary approach to the management of cancer patients with treatment-induced cardiotoxicity. The goal of our program is two-fold: a) establishment of a hospital based cardio-oncology clinic to rapidly assess and manage cancer patients with cardiotoxicity related to their cancer treatment and b) provide continuum of care for these patients with the establishment of a cardiovascular survivorship program. Methods: In 2008, in collaboration with oncologists, cardiologists, pharmacy and nursing we established a multidisciplinary cardio-oncology clinic at The Ottawa Hospital. Referrals are primarily form treating oncologists. The clinics take place 3-4 half days per month and are conducted by 3 dedicated cardiologists. Patient data including demographics, cancer type and treatment, cardiovascular risk factors, treatment and clinical outcomes of each patient are being collected. Results: We have seen over 800 patients with solid and hematological malignancies. Clinical outcomes of patients referred from 10/2008 to 01/2013 have previously been reported (Sulpher J. et al 2014). The majority of patients referred were able to successfully complete their cancer therapy (79.7%), reflective of the large breast cancer population seen in this clinic. A third of patients achieved stable left ventricular ejection fractions with cardiac intervention and 41% received cardiac medications. Overall survival and long term cardiac outcomes will be reported. Conclusions: While these initial results are encouraging the impact of cardiotoxicity experienced by cancer patients and long term cardiac outcomes are unknown. In an effort to improve the cardiovascular care of cancer survivors we are currently developing a Cardiovascular Survivorship Program; patients will be referred from our hospital based cardio-oncology clinic to a specialized community clinic, for long-term surveillance and optimization of cardiovascular health. This initiative represents a continuum of care from hospital to community and is the first such program in Canada.
Generation and application of a colorectal cancer microarray library to identify a novel prognostic biomarker, adipose differentiation related protein (adipophilin).
Authors: John Hogan, Laura O Byrne, Michael O Callaghan, Matthew F. Kalady, John C. Coffey
Journal: Journal of Clinical Oncology (2014)

508 Background: Substantial volumes of genetic expression data are archived within public gene expression repositories (PGER). Although the data contained is reported according to particular standards, it is not feasible to search the data using clinically relevant search terms (i.e., oncologic outcome). This study aimed to generate an archive of microarray expression data that could be searched using oncologically-relevant terminology, and then to test this facility. Methods: A UL Colorectal Cancer Archive was established based on data derived from the Gene Expression Omnibus (GEO). A software (Rover) was developed to permit clinically relevant searches using terminology such as stage and disease-free survival. As a first test, experiments were identified that compared early and late stage colorectal cancer. From these, consensus profiles were developed and adipocyte differentiation related protein identified as the top-most frequently dysregulated gene. As a second test, the cancer archive was again challenged to identify data sets annotated with outcome data. The association between ADFP and outcome was assessed using a regression-tree (CRT) based approach and Kaplan-Meier estimates. Results: The UL Colorectal cancer archive was constructed so as to permit the novice-user to search for gene expression data associated with particular clinical parameters. Rover was a graphic user interface that permitted these searches. ADFP was identified as dysregulated across the majority of experiments comparing early and late stage colorectal cancer. CRT-analyses identified levels of ADFP above which adverse outcomes were identified. In general, increasing ADFP was independently associated with adverse disease-free outcomes in stage II and III cancer. Conclusions: A novel archive of gene expression data was generated that (a) related to colorectal cancer and (b) could be searched using clinically-relevant terms. Using this archive ADFP was identified as dysregulated between early and late stage colorectal cancer. Increasing ADFP expression levels were associated with adverse disease-free survival in stages II and III colorectal cancer.
Sera cytokine levels to predict survival in men with progressive castration-resistant prostate cancer.
Authors: Sumit Kumar Subudhi, Glenn Heller, Daniel Costin Danila, Aseem Anand, Kristine Peregrino Lacuna, Aliaksandra Samoila, Martin Fleisher, Howard I. Scher
Journal: Journal of Clinical Oncology (2013)

5083 Background: Serum cytokines have been proposed as immunologic biomarkers of clinical responses based on their role in tumor biology. Recently, two whole blood mRNA signatures, which included immunomodulatory gene transcripts, were found to be predictive of survival in CRPC. This study explores serum cytokines, measured with analytically valid assays, as prognostic biomarkers in CRCP. Methods: Serum was collected from 75 progressive CRPC patients treated at MSKCC. A panel of 10 cytokines (M-CSF, IFN-γ, TNF-α, IL-1 β, IL-4, IL-5, IL-6, IL-10, IL-12 and IL-13) was measured in a CLIA-certified laboratory by clinically validated ELISAs. To create a risk group classification based on the 10 cytokines, a regression tree methodology was used with the intent to maximize the survival differences between risk groups. In addition to the cytokine risk groups, PSA, LDH, albumin, hemoglobin and CTC enumeration were also independently prognostic. The Cox model was developed to determine the factors that jointly predicted survival. The concordance probability estimate (CPE) was used to determine the discriminatory power of this model. Results: Among the 10 cytokines, M-CSF (stimulates monocytes and macrophages) and IL-10 (suppresses T-cell-mediated anti-tumor responses), were most predictive of overall survival in a 3 risk-group model. The relative risk for log CTC was 1.78 (95% CI 1.43 – 2.21). The combination of the cytokine risk groups and CTC enumeration provided the best discriminatory power for predicting survival, yielding a discrimination index measured by the CPE equal to 0.77 (se = 0.03). Conclusions: A risk group classification, based on two serum cytokines, M-CSF and IL-10, and log CTC measured by analytically valid assays, predicted survival in patients with progressive CRPC. These cytokines may reflect the biology within the tumor microenvironment, and may also serve as biomarker for clinical benefit. Independent validation in a similar cohort of patients is ongoing. [Table: see text]
The in situ local immune response, tumour senescence, and proliferation in colorectal cancer.
Authors: Campbell SD Roxburgh, Colin H Richards, Arfon Powell, Donald C. Mcmillan, Joanne E. Edwards, Paul G. Horgan, Paul G. Shiels
Journal: Journal of Clinical Oncology (2013)

412 Background: Immune cell infiltrates play a key role in determining colorectal cancer outcome. It is unclear whether they are tumour or host specific. Increased immunogenicity may relate to senescence or proliferation. Senescence, a state of cell-cycle arrest, slows tumour progression. In animal models, senescence associated regression is mediated by upregulated antitumour immune responses. High proliferation may provoke immune responses. Relationships between senescence, proliferation and immune cell infiltrates have not previously been studied. We explore whether p16 ink4a associated senescence relates to T cell infiltrates in colorectal tumours and whether p16 ink4a expression, proliferation and T cell infiltrates confer similar survival relationships. Methods: Immunostaining of nuclear p16 inka and Ki67 was performed using a tissue microarray. Nuclear p16 inka and Ki67 were scored as high or low expression. (T cell markers CD3/CD45RO/CD8/FOXP3) were scored high/low grade on corresponding full sections (margin/stroma/ cancer cell nest). Results: 230 Stage I-III cancers were studied. High nuclear p16 ink4a was expressed in 63% and high proliferation (Ki67 &gt;15% ) in 61%. P16 ink4a expression related to reduced margin, stroma and cancer cell nest (CCN) CD45RO cells (P=0.054, P=0.062, P=0.025) and reduced margin CD8 cells (P=0.016). High Ki67 labeling related to increased margin, and CCN CD3 cells (P=0.017, P&lt;0.001), increased margin and CCN CD45RO cells (P=0.023, P&lt;0.001), increased margin, stroma and CCN FOXP3 cells (P&lt;0.001, P=0.001, P&lt;0.001) and increased margin and CCN CD8 cells (P=0.026, P=0.001). On multivariate analysis, TNM stage (P&lt;0.001), low margin CD3 (P=0.014), low margin CD8 (P=0.037), low proliferation (Ki67) (P=0.013) and low senescence (P16 ink4a ) (P=0.002) conferred poorer cancer survival. Conclusions: p16 ink4a expression, proliferation and immune cell infiltrates are independent prognostic factors in colorectal cancer. Proliferation relates to increasing T cell infiltrates but independently influences survival. P16 ink4a associated senescence does not appear to mediate improved outcome by upregulating T cell responses. Relationships observed here suggest the opposite.
Final Results of Phase II Trial of Pegylated Liposomal Doxorubicin (PLD) Followed by Bexarotene (Bex) in Advanced Cutaneous T-Cell Lymphoma (CTCL)
Authors: David J. Straus, Madeleine Duvic, Steven M. Horwitz, Kenneth B. Hymes, Andre Goy, Francisco J. Hernandez-Ilizaliturri, Tatyana Feldman, Brett Wegner, Patricia Myskowski
Journal: Blood (2011)