tbuckley/cabot-search huggingface dataset:
Expression of Cyclic GMP‐AMP Synthase in Patients With Systemic Lupus Erythematosus
Authors: Jie An, Laura Durcan, Reynold M. Karr, Tracy A. Briggs, Gillian I. Rice, Thomas H. Teal, Joshua J. Woodward, Keith B. Elkon
Journal: Arthritis & Rheumatology (2016)

Objective Type I interferon (IFN) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and interferonopathies such as Aicardi‐Goutières syndrome. A recently discovered DNA‐activated type I IFN pathway, cyclic GMP‐AMP synthase (cGAS), has been linked to Aicardi‐Goutières syndrome and mouse models of lupus. The aim of this study was to determine whether the cGAS pathway contributes to type I IFN production in patients with SLE. Methods SLE disease activity was measured by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index. Expression of messenger RNA for cGAS and IFN‐stimulated genes (ISGs) was determined by quantitative polymerase chain reaction analysis. Cyclic GMP‐AMP (cGAMP) levels were examined by multiple reaction monitoring with ultra‐performance liquid chromatography tandem mass spectrometry. Results Expression of cGAS in peripheral blood mononuclear cells (PBMCs) was significantly higher in SLE patients than in normal controls (n = 51 and n = 20 respectively; P &lt; 0.01). There was a positive correlation between cGAS expression and the IFN score ( P &lt; 0.001). The expression of cGAS in PBMCs showed a dose response to type I IFN stimulation in vitro, consistent with it being an ISG. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of the SLE patients (7 of 48) but none of the normal (0 of 19) or rheumatoid arthritis (0 of 22) controls. Disease activity was higher in SLE patients with cGAMP versus those without cGAMP. Conclusion Increased cGAS expression and cGAMP in a proportion of SLE patients indicates that the cGAS pathway should be considered as a contributor to type I IFN production. Whereas higher cGAS expression may be a consequence of exposure to type I IFN, detection of cGAMP in patients with increased disease activity indicates potential involvement of this pathway in disease expression.
"ARMY": First-in-human study of the humanized, defucosylated monoclonal antibody (mAb) MEN1112/OBT357 targeting CD157 antigen, in relapsed or refractory (R/R) acute myeloid leukemia (AML).
Authors: Adriano Venditti, Dimitri Breems, Violaine Havelange, Giovanni Martinelli, Simone Baldini, Monica Binaschi, Attilio Crea, Eugen Leo, Carlo Alberto Maggi, Stefano Manzini, Mariagiuseppa Matera, Paolo Mazzei, Cristina Rossi, Simona Scartoni, Alessandra Scordari, Giulia Tonini, Keith Wilson, Angela Capriati, Cecilia Simonelli
Journal: Journal of Clinical Oncology (2015)

TPS3100 Background: Defucosylated mAbs enhance antibody dependent cell-mediated cytotoxicity (ADCC) through an improved affinity for Fc receptors. MEN1112/OBT357 is a humanized, defucosylated mAb targeting Bst1/CD157, a GPI-anchored transmembrane protein highly expressed on blasts of AML patients either at primary diagnosis or relapse. Preclinical findings show that MEN1112/OBT357 has the potential to exert powerful ADCC against AML (Aud et al ASH 2014; Venditti et al ASH 2014). Methods: Multi-center, non-randomized, 3+3 dose escalation/expansion cohort trial of MEN1112/OBT357 intended to recruit approximately 50 adult patients (pts) with R/R AML. Refractory pts must have failed ≥ 1 cycle of cytotoxic chemotherapy or hypomethylating agents. A baseline WBC count ≤ 10 x 109/L is required (pre-treatment with hydroxyurea is permitted). Main exclusion criteria are acute promyelocytic leukemia, hematopoietic stem cell transplant within 3 months prior to screening and active central nervous system involvement. MEN1112/OBT357 is given intravenously at 5 incremental doses on Days 1, 8, and 15 in a 21-day cycle for a total of 2 cycles; monthly maintenance is allowed in pts achieving clinical benefit. Primary objective is to identify dose limiting toxicities and maximum tolerated dose of MEN1112/OBT357 in pts with R/R AML; secondary objectives include (1) clinical pharmacokinetics, (2) potential immunogenicity, (3) clinical activity (complete- and composite complete remission rate, best response rate, overall survival) in treated pts and (4) its correlation with target expression/saturation, natural killer cells status, ex vivo activity at baseline and clinical/biological AML features. AEs will be graded according to NCI CTCAE v. 4.03 guidelines. Study variables will be presented by dose-cohort and overall using appropriate descriptive statistics. Efficacy will be evaluated in each cohort in pts completing the first cycle and with ≥ 1 post-cycle assessment using modified IWG 2003 criteria. The individual study duration is 6 months. The enrolment began on December 2014. Clinical trial information: NCT02353143 Clinical trial information: NCT02353143.
<sup>18</sup>F-Fluorothymidine (FLT) as tumor response predictor for anti-epidermal growth factor receptor (EGFR) antibody in human lung cancer xenograft
Authors: S. Takeuchi, S. Zhao, Y. Kuge, Y. Zhao, Y. Jin, T. Hatano, Y. Shimizu, I. Kinoshita, H. Dosaka-Akita, N. Tamaki
Journal: Journal of Clinical Oncology (2009)

e22088 Background: Specific EGFR inhibition therapies are currently promising and advanced in the clinical setting. It is revealed patients with a colorectal cancer bearing mutated K-ras do not benefit from cetuximab, a chimeric mouse-human antibody to EGFR. However, appropriate evaluation of the therapeutic effects has not been clarified yet, because of the lack of reliable tumor response predictors. Measurement of tumor proliferative activity by PET using FLT may serve to assess early response of the therapy. The purpose of this study is to determine whether 18 F- FLT is useful to evaluate very early response to cetuximab treatment in human lung cancer cell line xenograft. Methods: Human tumor xenograft model was established in male BALB/c athymic mice by human lung cancer cell line NCI-H1975, which expresses L858R/T790M-EGFR. These mice were assigned to two groups (n=5, each group): control and cetuximab-treated groups. Cetuximab was intra-peritoneally given 1.0mg/body once on the first day. Biodistribution of 3 H-FLT (%Inject Dose/g/kg) were studied two days after the treatment. Immunohistochemical staining of EGFR, phosphorylated EGFR (pEGFR), and nuclear antigen Ki-67 as a tumor cell proliferation marker in tumor tissues were also studied to assess early effects of cetuximab. Results: FLT uptake was high in tumors compared with any other organs. Two days after the cetuximab therapy, the mean value of FLT uptake in tumor was significantly decreased to 55% of control value (0.38 ± 0.03 in control group vs. 0.21 ± 0.07 in cetuximab-treated group; p &lt; 0.05). There were no statistical differences in the tumor volume and body weight of mice between each group. High expression of EGFR and Ki-67 were observed in this xenograft. As compared with control, Ki-67 expression was remarkably decreased in cetuximab-treated group, while there were no definite changes in expression of EGFR and pEGFR. Conclusions: In this animal model, FLT uptake and Ki-67 expression were decreased in cetuximab- treated group just two days after the treatment start. These results indicate FLT-PET can be a useful predictor to evaluate very early response to molecular targeted medicine such as cetuximab before significant change of tumor size. No significant financial relationships to disclose.
High-dose thiotepa: Neurotoxicity and risk factors in children with solid tumors.
Authors: Christophe Maritaz, Francois Lemare, Amani Cherif, Sylvie Demirdjian, Dominique Valteau Couanet, Christelle Dufour
Journal: Journal of Clinical Oncology (2012)

9572 Background: Thiotepa (TTP) is a cytotoxic agent used in children with solid tumors at high doses followed by autologous stem cell transplantation (ASCT). During these treatments, neurological adverse events (NAE) were observed. Causal relationships and risk factors were investigated. Methods: Patients with solid tumors treated with high-dose thiotepa with ASCT between May 1987 and March 2011 were retrospectively identified. Clinico-biological data were collected and NAE were identified from medical and nursing records. Toxicity was graded according to the NCI CTCAE v4.03 classification. Imputability of thiotepa was assessed according to Begaud et al. method. Analysis of risk factors was assessed with Fisher's exact test (alpha 0.05) and relative risk was estimated by calculating odds ratios with their 95% confidence interval. Results: 251 patients received 307 courses (56 patients received twice) of high-dose thiotepa (600 mg/m²: 82 courses; 720 mg/m²: 76 courses; 900 mg/m²: 149 courses) with ASCT. The median age was 8.33 years (range, 1 - 31.2 years). 81 NAE (26.4%) were described. NAE were considered “possibly” related to TTP in 9 courses, “likely” related to TTP in 35 courses and “very likely” related to TTP in 13 courses. Other NAE were assessed “doubtful” or “incompatible”. In these 57 NAE, neurological symptoms appeared at a median time of 2 days (range, 0 - 4 days) after the introduction of TTP. Symptoms were headache, tremor, dizziness and confusion, blurred vision, seizure, pyramidal tract syndrome, cerebellar syndrome, opsoclonus-myoclonus syndrome and coma. These events disappeared without sequelea in a median time of 3 days (range, 1 - 8 days). TTP was reintroduced in 21 cases. NAE reappeared in 12 cases. For 3 patients with seizure during the first course, premedication with clonazepam prevented NAE during the second course. The use of analgesic for moderate to severe pain, such as tramadol or codeine, increased the probabiblity to have NAE (OR 5.6467; 95CI [1.5523-21.2786]; p 0.037). Conclusions: In our study, the incidence of NAE related to TTP was 18.6%. The outcome was favorable without sequelea in all cases. TTP could be reintroduced after NAE. The association of TTP with tramadol increases the risk of neurotoxicity.
Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictive and prognostic markers in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation.
Authors: Shaan Dudani, Horia Marginean, Patricia A. Tang, Jose Gerard Monzon, Soundouss Raissouni, Timothy R. Asmis, Rachel Anne Goodwin, Joanna Gotfrit, Winson Y. Cheung, Michael M. Vickers
Journal: Journal of Clinical Oncology (2017)

758 Background: A standard therapy for locally advanced rectal cancer (LARC) includes fluoropyrimidine (FP)-based neoadjuvant chemoradiation (nCRT). Previous studies have inconsistently demonstrated that baseline neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR) are predictive of response to nCRT or prognostic of outcomes in LARC. Methods: We performed a review of patients with LARC undergoing nCRT followed by surgery with curative intent from 2005-2013 in 3 academic cancer centers from 2 Canadian provinces. Data regarding demographics, staging, baseline hematologic variables (&lt;4 weeks prior/up to 2 weeks after initiating nCRT) and treatment details were collected. Outcome measures of interest were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for an association between baseline hematologic variables and outcomes. Results: Of 1081 identified patients, 845 were included in the DFS/OS analysis. Median age was 61 (range 23-87), 70% male, 85% performance status (PS) 0-1. 31% and 67% had clinical stage II and III disease, respectively. 25% had elevated NLR (≥ 4), and 64% had elevated PLR (≥ 150). 98% of patients received FP-based nCRT, with 96% receiving ≥ 44 Gy (median 50 Gy [range 20-74]). 80% completed neoadjuvant chemotherapy and 94% completed neoadjuvant radiotherapy, with a pCR rate of 23%. After a median follow up time of 64 months, 6% developed local recurrence, 20% developed distant recurrence and 19% have died. 5-year OS and DFS were 78% (95% CI 74-81%) and 76% (95% CI 73-79%), respectively. In multivariate analyses, elevated baseline NLR and PLR were not prognostic for OS or DFS. Elevated NLR was a negative predictor of pCR (OR 0.61, p=0.037, 95% CI 0.38-0.97); there was no association with elevated PLR. Conclusions: Elevated NLR was a negative predictor of pCR, but not prognostic for DFS and OS. PLR was neither predictive nor prognostic.
Cranberry Capsules for Bacteriuria Plus Pyuria in Nursing Home Residents
Authors: Chloé Anderson, Kevin McGregor, James A. Hanley
Journal: JAMA (2017)

To the Editor The randomized clinical trial1 of cranberry capsules to prevent bacteriuria plus pyuria among older women in nursing homes found no significant differences between groups. However, 2 features of the study make the results less than definitive.
Risk of second primary malignancy (SPM) and survival of adult patients with polycythemia vera (PV): A U.S. population-based study.
Authors: Nabin Khanal, Smith Giri, Smrity Upadhyay, Vijaya Raj Bhatt
Journal: Journal of Clinical Oncology (2015)

e18081 Risk of Second Primary Malignancy (SPM) and Survival of Adult Patients with Polycythemia Vera (PV): A US population-based study Background: Although the median survival in PV is as high as 14 years, overall mortality is still higher compared to age and sex matched population. Leukemic transformation or SPM are among the leading causes of death in PV. Methods: We included 8155 PV patients between 1973- 2010 from SEER 18 registry, using International Classification of Diseases for Oncology (ICD-O-3) code 9950 to calculate age standardized 5 year survival. The incidence of SPM, defined as any metachronous malignancy developing six months after the diagnosis of PV, was analyzed from SEER 13 Registry (n=2961; patients > 18 years old) between 1992-2010. We used multiple primary standardized incidence ratio (SIR) (observed/expected ratio) session of the SEER*Stat software to calculate SIR and excess risk of SPM. Results: Overall the age standardized cause specific 5-year survival was 94.6%, higher for patient <50 years vs. above 50 (99.3% vs. 93.2%). At 10 years of follow-up (n=2961), a total of 245 patients (8.2 %) developed SPM and 29 (1%) developed leukemia. SPMs occurred at SIR of 1.35 -95% confidence interval, (CI) 1.19-1.53, p<0.05 with an absolute excess risk (AER) of 52.49 per 10,000 population. The risk was significantly higher in age group 18-60 years vs patients > 60 years (SIR 2.07, 95% CI: 1.64-2.58 vs SIR 1.16, 95% CI: 0.99-1.35, p<0.05). A significantly higher risk was noted for acute myeloid leukemia (SIR 12.44; 95% CI 7.37-19.66, p<0.05). Risk of SPM in PV Follow-up duration 6-11 month 12-59 month 60-119 month All sites 1.54 (1.06-2.18 ) 1.45 (1.24-1.68 ) 1 (0.72-1.36 ) All solid tumors 1.58 (1.06-2.27 ) 1.29(1.08-1.53 ) 0.84 (0.57-1.19 ) Leukemia 3.46 (0.42-12.5 ) 6.27(3.88-9.58 ) 4.99 (1.83-10.87 ) AML 0 15.92(8.91-26.25 ) 8.91 (1.84-26.04 ) Values indicate SIR (95%CI) Conclusions: PV patients, especially patients <60 years of age, are at an increased risk of SPM. The risk of leukemic transformation affects patients of all age groups and is higher after 12 months of diagnosis. Early detection and management of SPM has a potential to improve outcomes in PV.
A randomized double-blind phase II study of the combination of oral WX-671 plus capecitabine versus capecitabine monotherapy in first-line HER2-negative metastatic breast cancer (MBC).
Authors: Lori J. Goldstein, Celia Tosello Oliveira, Bernhard Heinrich, Salomon M. Stemmer, Carola Mala, Sabine Kastner, Paul Bevan, Lisa Richters, Barbara Schmalfeldt, Nadia Harbeck
Journal: Journal of Clinical Oncology (2013)

508 Background: uPA and its inhibitor PAI-1 play a key role in tumor invasion, metastasis and tumor growth. uPA and PAI-1 are biomarkers validated at highest level of evidence in breast tumors and are recommended for clinical decision making by ASCO. WX-UK1 is a competitive inhibitor of uPA with an inhibition constant in the submicromolar range. WX-671 (upamostat) is an oral prodrug of WX-UK1. Methods: Female patients aged &gt;18, with HER2 negative MBC were randomized in a double-blind fashion to receive upamostat (200 mg orally daily for 21 days) plus C (1000 mg/m 2 orally twice daily for 14 days) vs. C (same regimen) in 3 week treatment cycles until progressive disease or unacceptable toxicity. 132 from five countries were enrolled. The primary objective was to evaluate the efficacy of the combination of upamostat and C compared to C alone by assessment of progression free survival (PFS). The study also evaluated the objective response rate and safety as well as pharmacokinetics (PK). Efficacy was evaluated by RECIST by independent central read. Results: Median treatment duration was 8 cycles in both arms. In the total study population (intent to treat; ITT) upamostat led to an increase of median PFS from 7.5 months (95% CI: 4.2; 12.8) in the control group to 8.3 months (95% CI: 5.6; 9.6) in the combination therapy. An unexpectedly high rate (50%) of study patients presented within their first two years after initial diagnosis. In patients who had received prior adjuvant chemotherapy, PFS improved from 4.3 months (95% CI: 2.6; 9.7) in the C alone group to 8.3 months (95% CI: 5.6; 10.9) in the upamostat plus C group. The overall response rate was higher in the combination group compared to C alone (20% vs. 12% at Week 24). PK analysis demonstrated no drug-drug interactions between upamostat and C. The combination therapy was safe and well tolerated. Conclusions: This is the first proof of efficacy of an anti-uPA therapy in breast cancer. The heterogeneity of the patients in this study may underestimate the potential treatment effects of upamostat. Additional subset analyses will be presented. Future biomarker-stratified strategies may reveal better efficacy. Clinical trial information: NCT00615940.
A phase I (Ph1) study of dasatinib (D) with cetuximab (Cet) /radiation (IMRT) +/- cisplatin (P) in stage II, III/IV head and neck squamous cell carcinoma (HNSCC).
Authors: Shanthi Marur, Hao Wang, Harry Quon, Christine H. Chung, Maura L. Gillison, Nishant Agrawal, Jeremy Richmon, Rathan M. Subramaniam, Wayne Koch, Christine Gail Gourin, Arlene A. Forastiere
Journal: Journal of Clinical Oncology (2015)

e17036 Background: In preclinical HNSCC models, combined EGFR and Src inhibition with radiation has additive and possibly synergistic effects. We conducted a 3+3 standard Ph1 trial to determine the maximum tolerated dose (MTD) of D, a multi-targeted tyrosine kinase inhibitor with activity against Src, combined with the EGFR monoclonal antibody Cet + IMRT +/- P in early stage II/III HNSCC (Cohort A) and more locally advanced stage III/IVa,b HNSCC (Cohort B) as definitive treatment for HNSCC. Secondary objectives were response, disease free survival and correlation with FDG-PET, exploratory biomarkers of EGFR, Src pathways and HPV status. Methods: Both cohorts A and B had a 14 day “run-in” prior to starting IMRT consisting of Cet 400mg/m2 on day 1, then 250mg/m2 day 8 & 14 , daily oral D day 8-14 . IMRT 200cGy/fx for 35 fractions began day 15-64 with concurrent D + Cet in Cohort A and D + Cet + P 75mg/m2 q 3 wk for Cohort B. Dose levels for daily D were 70 mg, 100 mg, 150 mg. Exploratory biomarkers, and PET scan were performed at baseline, day 14/15 and 8 weeks post chemoradiation. Results: A total of 21 pts enrolled, 3 withdrew consent. Primary site were Oropharynx (15), hypopharynx (3), Larynx (1). Sex: male (15), female (4). Tumor HPV ISH was positive (10) and HPV negative (8) pts. Within Cohort A: 70 mg (3), 100mg (3) was completed without DLT. In Cohort B:70 mg (7pts enrolled, 1 DLT with grade 3 infection, one pt was replaced), 100mg (3) completed with no DLT, and 150mg (2), noted DLT in 1 pt with febrile neutropenia. The study was closed due to slow accrual, MTD was not reached for Cohort A or B. Grade 3-4 toxicities: Cohort A :rash (1), mucositis (1), radiation dermatitis (1) Cohort B: febrile neutropenia (1), grade 3 skin infection(1), mucositis(2), dry mouth (1), dysphagia(1), diarrhea(1)and hypophosphatemia(1) were noted. The best overall response 8 wks post-treatment in Cohort A, CR+PR (5) and PD (1), in Cohort B , CR+PR ( 11/11). With longer follow-up, survival outcomes will be correlated with response and correlatives. Conclusions: Combination of D/Cet/IMRT and D/Cet/P/IMRT appears to be safe and well-tolerated only at dose level 70 and 100mg in HNSCC. Clinical trial information: NCT00882583.
Effect of adjuvant chemotherapy following pathologic complete response on long-term survival in rectal cancer: A propensity score matched analysis.
Authors: Ali Mokdad, Sergio Huerta, Rebecca M Minter, John C. Mansour, Michael A. Choti, Patricio Polanco
Journal: Journal of Clinical Oncology (2017)

717 Background: The role of adjuvant chemotherapy following resection in patients with rectal cancer that achieve pathologic complete response (pCR) after neoadjuvant therapy is unclear. Current data have been limited by small sample size series. This study examined the impact of adjuvant chemotherapy following pCR on overall survival in a national cohort of patients. Methods: Patients with rectal adenocarcinoma were identified in the National Cancer Data Base between 2006 and 2012. Those with locally advanced tumor (clinical stage II or III) that achieved pCR (defined as ypT0N0 in surgical specimens) after neoadjuvant chemoradiotherapy (nCRT) were included in the study. We matched by propensity score patients that received adjuvant chemotherapy (ACT) and patients that did not receive postoperative treatment (no-ACT) controlling for demographic as well as perioperative patient and tumor characteristics. Overall survival was compared using a Cox proportional hazards model. Results: We identified 2,543 patients (ACT: 732, no-ACT: 1,811 patients) with resected locally advanced rectal adenocarcinoma that achieved pCR after nCRT. Among patients that received ACT, 711 were matched with 711 patients in the no-ACT group. Adjuvant chemotherapy was associated with improved overall survival compared to no-ACT (hazard ratio[HR] = 0.46, 95% confidence interval [CI] = 0.29 – 0.75). Overall survivals at 1, 3, and 5 years in the ACT and no-ACT groups were 100% vs 98% (P=0.1), 98% vs 94% (P&lt;0.01), and 94% vs 89% (P&lt;0.01), respectively. In subgroup analyses, adjuvant chemotherapy improved overall survival in patients with clinical stage II (HR = 0.43, 95% CI = 0.22 – 0.85) as well as stage III tumor (OR = 0.50, 95% CI = 0.26 – 0.98). Among patients that received adjuvant chemotherapy, there was no difference in overall survival between single agent and multiagent regimens (HR = 1.37, 95% CI = 0.57 – 3.29). Conclusions: Adjuvant chemotherapy may providea small long-term survival benefit in patients with resected locally advanced rectal cancer and pCR after nCRT.
Pediatric-Based Versus Adult Treatment Protocols in Young Adults (18-40 years) with Standard Risk Acute Lymphoblastic Leukemia: The BC Cancer Agency Experience
Authors: David Simon Kliman, Michael J Barnett, Raewyn Broady, Donna L. Forrest, Alina S. Gerrie, Donna E. Hogge, Stephen H. Nantel, Sujaatha Narayanan, Thomas J. Nevill, Maryse M Power, Kevin Song, Heather J. Sutherland, Cynthia L. Toze, Yasser Abou Mourad
Journal: Blood (2015)