tbuckley/cabot-search huggingface dataset:
Quality indicator for esophagogastroduodenoscopy in screening gastric cancer.
Authors: Yong Chan Lee, Chan Hyuk Park, Hyun Soo Chung, Hyuk Lee, Jun Chul Park, Sang Kil Lee
Journal: Journal of Clinical Oncology (2014)

25 Background: The national gastric cancer screening program including endoscopy has been introduced in Korea in which the high incidence of gastric cancer have been reported. The good quality indicators of screening endoscopy for gastric cancer are mandatory to improve the detection rate. However, most quality indicators were focused on the standardization of an endoscopy unit rather than the individual assessment of endoscopists for cancer screening ability. We aimed to identify quality-assessment indicators associated with screening gastric cancer. Methods: The database records for 54,889 subjects who underwent esophagogastroduodenoscopy (EGD) for screening purpose at the Yonsei University Severance Hospital Health Promotion Center, Seoul, Korea between February 2006 and July 2013 were analyzed. All the endoscopists (n=66) involved in this study were experienced endoscopists who performed 1,000 or more EGDs. The detection rate of early gastric neoplasm according to endoscopists were assessed. The detection rates of various gastric lesions other than gastric epithelial neoplasms were also analyzed. The scoring formula for predicting the qualified endoscopists was proposed and analyzed. Results: Of the enrolled subjects, mean age was 48 years and the percentage of males was 59.7%. The percentage of gastric dysplasia, early gastric cancer, and advanced gastric cancer was 0.18%, 0.10%, and 0.04%, respectively. Most frequently detected lesions were gastric erosions (22.30%) followed by atrophic gastritis and intestinal metaplasia. In multivariate analysis, the detection rates of gastric subepithelial lesion or gastric diverticulum were independent associate factors with early gastric neoplasm detection. Cochran-Armitage trend test confirmed that higher quality score group was associated with significant higher early gastric neoplasm detection rate. Conclusions: The detection rates of gastric subepithelial lesion or gastric diverticulum are well correlated with early gastric neoplasm detection. the proposed quality score formula can be a good indicator assessing endoscopist's ability to detect early gastric neoplasm.
Contrasting the vascular response to sunitinib as measured by DCE-CT, DCE-MRI, and DCE-US.
Authors: John M. Hudson, Ross Williams, Colleen Bailey, Alex Kiss, Laurent M. Milot, Mostafa Atri, Greg J. Stanisz, Peter N. Burns, Georg A. Bjarnason
Journal: Journal of Clinical Oncology (2013)

378 Background: Medical imaging (DCE-MRI, DCE-CT, DCE-US) provides localized information about the integrity and hemodynamics of the tumor microvasculature. Methods: 34 treatment (Rx) naive pts with mRCC and an abdominal tumor suitable for imaging received Sunitinib 50 mg on a 4wk-on/2wk-off schedule. DCE-US, DCE-CT, and DCE-MRI were done at baseline, during the first course of Rx and after 2wks off Rx. Imaging parameters obtained included vessel permeability (Ktrans), extracellular volume fraction (v e ) and Ktrans/v e =Kep (by DCE-MRI), permeability surface product (PS, by DCE-CT), blood volume (BV, by DCE-CT and DCE-US), and blood flow (by DCE-US). We also developed a morphology parameter (MP) that relates the flow kinetics of an intravascular microbubble contrast agent to tumor vascular morphology using DCE-US. Results: A range of imaging parameters that predicted for progression free survival (PFS) were identified in responding pts (N = 26). Baseline imaging parameters correlated with PFS: Ktrans by DCE-MR (r = 0.53, p = 0.01, N = 24), BV by DCE-CT (r = 0.48, p = 0.02, N = 25) and disorganized vessel morphology (large MP) by DCE-US (Spearman r = 0.-0.45, p = 0.02, N = 24). Changes from baseline imaging parameters correlated with PFS: BV by DCE-US at 2 wks (r = -0.46, p = 0.02, N = 24), Kep by DCE-MR at 2 wks (r = -0.45, p = 0.03, N = 24) and MP at 1wk (r = 0.67, p = 0.02, N = 12). There was a correlation between imaging methods: BV measured by DCE-CT correlated with BV by DCE-US (r = 0.46, p = 0.03, N = 23) and Kep by DCE-MR (r = 0.59, p = 0.003, N = 22); Permeability measured by DCE-MR (Ktrans) and DCE-CT (PS) correlated at 2wks (r = 0.56, p = 0.01, N = 21). Conclusions: This is the first study to contrast DCE-US, DCE-CT, and DCE-MRI imaging in pts receiving antiangiogenic therapy. Baseline parameters for all three methods can predict for PFS. Changes from baseline in DCE-US and DCE-MRI parameters also predict for PFS. There is a correlation between imaging methods in parameters that measure BV and permeability. A novel DCE-US parameter was developed (MP) that quantifies the degree of tumor vascular disorganization. Baseline values in MP and changes during Rx correlate with PFS. Clinical trial information: OCT1205, SU Timing RCC.
Survival after nonmyeloablative versus myeloablative allotransplantation for AML/MDS.
Authors: M. R. Khawaja, J. E. Schwartz, M. Yu, M. J. Robertson, G. H. Vance, S. Srivastava, L. L. Wood, R. Abonour, K. Cornetta, S. Farag, L. D. Cripe, R. P. Nelson
Journal: Journal of Clinical Oncology (2011)

6563 Background: Results from the few retrospective studies comparing nonmyeloablative (NMAT) vs conventional myeloablative (CMAT) allotransplant for the treatment of AML/MDS are mixed. Methods: 143 consecutive patients with AML (n=104) or MDS (n=39) underwent HLA-matched allogeneic peripheral hematopoietic cell (PHC, n=119) or bone marrow (BM, n=24) transplantation from a matched related (MRD, n=84) or unrelated (MUD, n=59) donor between January 2000 and June 2010. Patients were treated with CMAT (n=80) or NMAT cyclophosphamide/fludarabine (n=63) conditioning. Among patients with AML, 87 (90.6%) had intermediate/poor risk cytogenetics; among patients with MDS, 32 (84.2%) had intermediate/high IPSS. Patients in frank relapse at transplant were not included. Follow-up was until death or > 120 days. Kaplan-Meier, log-rank and Cox-regression methods were used to retrospectively compare disease/progression free survival (DFS/PFS) and overall survival (OS). Results: The distribution of gender, cytogenetic risk (for AML) and donor source (MRD/MUD) were similar between NMAT and CMAT groups. The NMAT group was older (median age 58 vs. 45 years; p<0.001), more likely to have received PHC (98.4% vs. 71.3%; p<0.001) and have MDS (42.9% vs. 15%; p<0.001). Among patients with AML, the CMAT group was more likely to be in 1st remission or untested relapse (69.1% vs. 33.3%, p<0.001); the NMAT group was more likely to be in 2nd or 3rd remission or have uncategorizable remission status owing to concurrent MDS (n=8) or second hematologic condition (n=2). Among patients with MDS, the NMAT group had higher IPSS (median 1.0 vs. 0.5; p=0.004). Nineteen patients (32.8%) in the NMAT group experienced relapse/progression compared to 24 (32.4%) after CMAT; median DFS/PFS were 426 days and 428 days, respectively (p=0.822). The median OS was 597 and 421 days for NMAT and CMAT groups, respectively (p=0.943). After adjusting for age, graft source (PHC/BM), donor source (MRD/MUD) and disease (MDS/AML), DFS/PFS [hazard ratio 0.90 (p=0.777)] and OS [hazard ratio 0.76 (p=0.401)] were not different between groups. Conclusions: NMAT and CMAT conditioning appear to provide equivelent disease control and survival in patients with high risk, low burden AML/MDS.
Association of activated transcription factor NF-kappaB with chemo-radiotherapy resistance and poor outcome in esophageal adenocarcinoma
Authors: J. G. Izzo, T. T. Wu, R. Luthra, M. G. Luthra, S. Swisher, B. B. Aggarwal, R. S. Bresalier, L. Milas, Z. Liao, W. N. Hittelman, J. Ajani
Journal: Journal of Clinical Oncology (2005)

4029 Background: The incidence of esophageal/gastroesophageal junction adenocarcinoma (E/GEJAC) is rapidly rising in Western countries. Chemo-radiotherapy (CT-XRT) followed by surgery has been used for localized E/GEJAC. However, while 30% of patients achieve a pathologic complete response (pCR), most patients present with radioresistant residual, highly aggressive tumor. Thus there is a need to identify and target new molecular pathways associated with cancer resistance. Through microarray gene expression profiles we identified differentially expressed transcription factor NF-kappa B (NF-κB) associated signaling pathway in CT-XRT non-responders group. To validate our findings, we examined activated NF-κB protein expression, CT-XRT response and clinical outcome. Methods: Pre-treatment tumor biopsies and post-treatment resected residual tumor were obtained from patients enrolled in a phase II trial of pre-operative induction chemotherapy and CT-XRT for potentially resectable E/GEJAC. Activated (p65 nuclear localization) NF-κB protein expression was evaluated by immunohistochemistry and correlated with pCR and clinical outcome. Results: 31 patients, clinically staged II and III, were included in the analysis. Activated NF-κB was significantly associated with presence of residual tumor in the resected esophagectomy specimen [NF-κB positive in 1/9 (11%) pCR vs 12/22 (54.5%) non-pCR; P=.044]. Activated NF-κB expression was sustained in pre- and post-treatment tumor in 6 and de novo acquired in the remaining 6 of 12 NF-kB positive non-pCR group. Independent of clinical stage, tumor histology and lymph nodes invasion, activated NF-κB in the post-treatment tumor was associated with increased frequencies of perineural/connective/vascular invasion [NF-κB positive 10/13 (77%) vs NF-κB negative 0/7; P=.003], and distant metastasis [NF-κB positive 5/13 (38.5%) vs NF-κB negative 0/7; P=.08]. Conclusions: Our results suggest that activated NF-κB is associated with poor response to CT/CT-XRT and worse outcome in E/GEJAC, and thus may serve as a potential molecular target to improve treatment efficacy. No significant financial relationships to disclose.
Metformin use and renal cell cancer outcomes among patients with diabetes.
Authors: Farhad Khimani, Nilay Shah, Brendan F. Curley, Michael David Newton, Thomas F. Hogan, Manish Monga
Journal: Journal of Clinical Oncology (2014)

543 Background: Renal Cell Carcinoma (RCC) is the third most prevalent urologic malignancy, and the sixth leading cause of cancer deaths in the United States. RCC is resistant to conventional treatment (chemotherapy, hormonal therapy and radiotherapy) therefore there is tremendous need for the development of new treatment strategies. Evidence indicates that metformin may reduce the risk of cancer and inhibit growth of several cancers, including prostate, breast, liver and colon. Metformin has been shown to inhibit RCC growth in in vitro and in vivo assays. Hence, it is pertinent to explore the role of metformin in RCC. Methods: At West Virginia University we performed an IRB approved retrospective chart review of all patients who were diagnosed with RCC at our institution from 2008-2012. Patients with Diabetes mellitus Type II (DM) were selected and stratified in to two cohorts based on metformin use. Statistical analysis was performed with SPSS Version 20.0. Results: A total of 290 patients with RCC were identified through the institutional tumor registry. Among patients with RCC, 25.1% (73) had DM. Of those DM patients, 60.2% (44) were on metformin therapy at diagnosis of RCC and 50.7% (37) were on metformin at last follow up. 84.9% (39) underwent radical or partial nephrectomy and 17.8% (13) patients received immunotherapy, targeted agents or chemotherapy. 26% (19) either had metastatic disease at diagnosis or developed recurrent disease. The metformin cohort had 27% (12) of patients with metastatic disease or a noted recurrence whereas in the non-metformin cohort 24.1% (7) had metastatic disease or recurrence. This was not statistically significant (p=0.76). No significant association was found between metformin use and mortality (p=0.46) or with stage of disease at diagnosis (p=0.35). Conclusions: Our limited retrospective review did not reveal any association between metformin usage and RCC outcomes, stage at diagnosis, or recurrence rates. However, in vitro and in vivo assays showing metformin inhibits RCC growth encourage further studies on larger patient populations to continue to explore this possible association. [Table: see text]
Successful desensitization with cetuximab (CET) after hypersensitivity reaction (HSR) to panitumumab (PAN) and CET in patients (pts) with metastatic colorectal cancer (mCRC)
Authors: M. M. Shah, S. Hotchkiss, J. Shanley, M. J. Davies, T. M. Ferencz, K. I. Syrigos, K. Syrigos, M. W. Saif
Journal: Journal of Clinical Oncology (2008)

15092 Background: CET and PAN are chimeric and fully human monoclonal antibodies respectively against epidermal growth factor receptor (EGFR) used in treatment of mCRC. Incidence of documented HSR is more common with CET (all grades [g]: 15 - 21%; g 3/4: 2 - 5%) than PAN (all g: 4%; g 3/4: 1%). Anecdotal reports suggest successful challenge with PAN following HSR with CET. However, safety of CET after HSR with PAN is not known. We report two pts successfully desensitized with CET after HSR with PAN and CET respectively. Methods: A 42-yr-old female with mCRC received PAN as a third-line agent. She developed severe chest tightness, pain and SOB, 5 mins after 1st PAN infusion. She responded to O2, fluid replacement, dexamethasone, and diphenhydramine. A 70-yr-old male with mCRC received PAN plus irinotecan as a second-line therapy. 1st administration was uneventful. He developed severe facial flushing, back pain, SOB, tachycardia and hypotension, 5 mins after 2nd dose of PAN. He responded to O2, fluid replacement, and dexamethasone. Both pts were premedicated with prednisone 50 mg PO 24 hrs, 12 hrs and 3 hrs from receiving CET, diphenhydramine 50 mg iv and famotidine 20 mg iv prior to CET. Then they received desensitization protocol for CET after a test dose of 20mg iv over 10 mins followed by a slow infusion 10% of original rate in 0–2 hrs, 25% of original rate in 2–2.5 hrs, 50% reduced rate in 2.5–3 hrs and then 100% infusion rate after 3 hrs. Pts were observed 4 hrs after completion of infusion. Results: First pt is currently on 10th cycle of CET with stable disease, no recurrence of HSR and grade 1 acneiform rash that developed after 3rd cycle. Second pt is currently on 7th cycle of CET with no recurrence of HSR. Conclusions: Thanks to hybridoma technology that HSR are less frequent with fully human and humanized antibodies. Though anecdotal reports suggest safety of PAN in pts following HSR with CET but PAN can also cause severe HSR. Our experience suggests that in case of limited options, such pts can be successfully challenged with CET in a hospital after appropriate desensitization and premedication. Further studies focusing on desensitization and identifying hypersensitivity profile of different anti-EGFR antibodies are warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Bristol-Myers Squibb ImClone
Characterization of novel potent and selective anaplastic lymphoma kinase (ALK) inhibitors.
Authors: C. M. Lovly, E. de Stanchina, H. Chen, C. Liang, W. Pao
Journal: Journal of Clinical Oncology (2011)

e13600 Background: Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers and represent rational therapeutic targets. Crizotinib (PF-02341066), a dual ALK/MET tyrosine kinase inhibitor (TKI), has demonstrated significant activity in ALK-fusion positive lung cancer patients. Unfortunately, as with other TKIs in clinical use, patients who initially respond to crizotinib eventually display disease progression. New agents and combinations of targeted therapies are needed to improve the care of these patients. Methods: We report identification and characterization of X-376 and X-396, two potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). These agents were tested against crizotinib in cancer cell lines harboring ALK fusions as well as activating ALK point mutations. Xenograft studies were completed in mice harboring EML4-ALK E13;A20 fusion positive tumors. In addition, X-376 and X-396 were tested in combination with the mTOR inhibitor, rapamycin. Results: X-376 and X-396 were 3-fold and 10-fold more potent, respectively, than PF-1066 in H3122 lung adenocarcinoma cells harboring an EML4-ALK E13;A20 fusion (IC50: PF-1066 180nM, X-376 77nM, X-396 15nM). Similar results were obtained with H2228 lung cancer cells, SUDHL-1 lymphoma cells, and SY5Y neuroblastoma cells, which harbor an EML4-ALK E6a/b;A20 fusion, an NPM-ALK fusion, and an activating point mutation within the ALK kinase domain (F1174L), respectively. In H3122 xenograft studies, both X-376 and X-396 demonstrated potent anti-tumor activity in vivo with favorable pharmacokinetic and toxicity profiles. The gatekeeper mutant (L1196M) engineered into the EML4-ALK E13;A20 fusion variant was more potently inhibited by X-396 compared to PF-1066. Finally, X-396 displayed synergistic anti-tumor activity in vitro when combined with the mTOR inhibitor, rapamycin. Conclusions: These novel ALK inhibitors and combinations of ALK inhibitors plus mTOR inhibitors have the potential to improve the therapeutic outcomes of patients with mutant ALK-driven malignancies. X-396 is expected to enter clinical trials later this year.
Effect of lenalidomide and pomalidomide combined with IgG1-isotype antibodies on antibody-dependent cellular cytotoxicity (ADCC) via cytokine signaling and effector cell granzyme B and FasL expression
Authors: L. Wu, M. Adams, P. Schafer, G. Muller, D. Stirling, B. Bartlett
Journal: Journal of Clinical Oncology (2008)

3058 Background: Lenalidomide and pomalidomide (CC-4047) display anti-angiogenic and immunomodulatory activities in a variety of in vitro assay systems. Evidence from single agent patient studies indicate enhancement of T cell and NK cell function in patients either with hematological or solid tumors. There is also in vitro and preclinical evidence that both drugs can enhance NK cell mediated ADCC. Methods: We have utilized an in vitro ADCC system to investigate the mechanism(s) whereby lenalidomide and pomalidomide are able to enhance human NK cell and monocyte effector function in response to FCγ receptor signaling initiated by therapeutic antibodies. Results: Pre-treatment of NK cells or monocytes with pomalidomide or lenalidomide (but not thalidomide) greatly enhanced ADCC of Her2/neu overexpressing breast cancer cells pre-coated with trastuzumab and EGFR positive colorectal cancer cells pre-coated with cetuximab. NK cell and monocyte-mediated killing of antibody coated tumor cells was dose-dependent. There was minimal tumor cell killing by antibody alone or by either drug alone or in the presence of panitumumab, an anti-EGFR IgG2a antibody that does not efficiently engage NK cell FCγ receptors. NK cell-mediated killing is associated with distinct changes in intracellular signaling (decreased pSHIP-1, increased PLCγ2, pERK) and increased granzyme B and FasL expression. Monocyte-mediated ADCC takes longer to initiate (16 hrs vs 4 hrs) is also associated with increased granzyme B and FasL and is blocked by anti-IL-12mAb. ADCC is completely blocked by an inhibitor of granzyme B activity and partially blocked by an antibody that blocks FasL-Fas interaction. Conclusions: Pomalidomide and lenalidomide (but not thalidomide) strongly enhance the ability of therapeutic IgG1 antibodies to induce ADCC via NK cell/monocyte-mediated killing of tumor cells in vitro. Furthermore, granzyme B activity and concurrent cytokine signaling is crucial to enable the synergistic combination of either drug with antibodies to tumor-specific surface antigens the potential utility of which is being assesses in upcoming clinical studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene Corp Celgene Corp
High-grade gliomas treated with bevacizumab: Assessment of tumor response with functional MR.
Authors: F. Bidault, M. Sahnoun, T. de La Motte Rouge, V. Rousseau, J. Domont, C. Massard, F. Dhermain, D. Ducreux, A. Laplanche, C. Caramella, S. Canale, C. Balleyguier, B. Boulet, C. Dromain
Journal: Journal of Clinical Oncology (2011)

e12505 Background: High grade gliomas are tumors with a poor prognosis. Bevacizumab (Bvz) is commonly employed for treatment of recurrence and is currently being evaluated as first line therapy. Bvz is known to alter imaging contrast enhancement that is sometime difficult to be interpreted. fMR (Functional Magnetic Resonance) can be used to measure CBV (cerebral blood volume) and vascular permeability and can be employed with widely used MR sequences and software. The goal of this study was to assess CBV and permeability as potentially biomarkers for survival at baseline and after treatment with Bvz. Methods: Retrospective study. Twenty-five patients with recurrent high grade glioma treated with Bvz, were evaluated with fMR at baseline and after treatment. Corticosteroids treatment was noted. All MRI examinations were reviewed by two radiologists reaching consensus about OMS size criteria, qualitative alterations, and quantitative functional criteria: CBV, permeability, calculated with DSC (dynamic susceptibility contrast) MR sequence and DPTools software (published and free available software). Statistical analysis compared actuarial survival with baseline and post Bvz fMR (Kaplan Meier curves). Results: Survival was not statistically related to baseline or post Bvz CBV or permeability (Logrank test: p>5%). There was no significant relationship between corticosteroid dose and vascular permeability at baseline (Spearman test: p>5%). The permeability values significantly decrease after Bvz (median=85%). Survival was not related to initial tumor size but was significantly decreased if the tumor progressed during Bvz treatment (Logrank test: p=0.011). Conclusions: This study confirms the ability of fMRI to demonstrate impact of Bvz on tumor vascular permeability. Our study did not find a significant effect of corticosteroid dose on vascular permeability in these recurrent tumors. CBV and vascular permeability measured by fMRI were not efficient biomarkers of survival in our study. Tumor progression in size remains an indicator of poor prognosis. Further studies are necessary to determine the role of fMRI for the prognostication of gliomas.