tbuckley/cabot-search huggingface dataset:
Preliminary findings from a phase I, multicenter, open-label study of the anti-CD37 antibody-drug conjugate (ADC), IMGN529, in adult patients with relapsed or refractory non-Hodgkin lymphoma (NHL).
Authors: Anastasios Stathis, Kami J. Maddocks, Ian Flinn, Alex Mejia, Maria Lia Palomba, Sybil Zildjian, Mary Murphy, Jutta Deckert, Rodrigo Ruiz-Soto, Arnold Freedman
Journal: Journal of Clinical Oncology (2014)

8526 Background: IMGN529 is a CD37-targeting ADC comprising a CD37-binding antibody conjugated to the maytansinoid anti-mitotic, DM1. CD37 is present on the surface of normal and malignant B lymphocytes. In preclinical studies, IMGN529 exhibits potent antitumor activity against NHL cells via direct inhibition, effector function and delivery of the maytansinoid payload. Methods: Study objectives are: determine the maximum tolerated dose/recommended phase 2 dose of IMGN529 in adult patients (pts) with relapsed or refractory NHL, and evaluate safety, pharmacokinetics, pharmacodynamics, and evidence of preliminary efficacy. IMGN529 is given intravenously on Day (d) 1 of each 21d cycle (C). Results: To date, 22 pts have been enrolled across four dose levels ranging from 0.1 to 0.8 mg/kg. NHL subtypes enrolled: 10 Follicular lymphoma (FL), 7 Diffuse large B-cell (DLBCL), 5 other. A reduction in lymphocyte count seen early after dosing (d 2) in the majority of pts suggests a CD37-mediated reduction in lymphocytes. One pt with DLBCL treated at 0.4 mg/kg, and 1 pt with FL treated at 0.2 mg/kg achieved partial remission in C 3 and C 5 respectively. Dose limiting toxicities (DLTs) consisted of grade (G) 4 neutropenia > 7 days (1pt) and G2 peripheral neuropathy (1pt) at 0.8 mg/kg and G3 febrile neutropenia (2 pts) at 0.4 mg/kg. Adverse events (AEs) of G3 or higher occurred in 8 pts; those reported in more than 1 pt were: neutropenia (5 pts) and febrile neutropenia (2pts). Four of these pts experienced transient, early onset (C1d2-4) G3 neutropenia which may be a manifestation of cytokine release. The protocol was amended to provide peri-infusional steroids as a prophylactic regimen and dose re-escalation is ongoing; 3 patients treated at 0.4 mg/kg have completed C 1 with no DLTs. Clinical trial enrollment is ongoing with additional data expected. Preclinical studies to investigate the mechanism of the transient neutropenia are underway. Conclusions: IMGN529, a CD37-targeting ADC, has demonstrated early evidence of clinical activity and has the potential to be a novel therapeutic for B-cell lymphoproliferative malignancies. Clinical trial information: 01534715.
Association of tumor-specific GPR87 overexpression with poor prognosis in non-small cell lung cancer.
Authors: Kazuhito Nii, Dage Liu, Yoshimasa Tokunaga, Xia Zhang, Shinya Ishikawa, Reiji Haba, Yoshiyuki Kakehi, Hiroyasu Yokomise
Journal: Journal of Clinical Oncology (2013)

e22108 Background: GPR87 is a member of G-protein-coupled receptors (GPCRs). Recently, GPR87 was suggested to contribute to the viability of human tumor cells, and the overexpression of GPR87 mRNA was found in many malignant tumors including lung cancer. However, the clinical significance of GPR87 expression in non-small cell lung cancer (NSCLC) has not been well studied. Methods: 127 NSCLC patients who underwent surgery from 1999 to 2004 were investigated. There were 59 adenocarcinomas, 55 squamous cell carcinomas and 13 others. The intratumoral expression of GPR87 was evaluated by immunohistochemistry. The Ki-67 proliferation index was also evaluated. Results: A tumor-specific expression of GPR87 was found in NSCLC in comparison with the surrounding normal tissue. Fifty-nine tumors (46.5%) were found to be high-GPR87 tumors. The high-GPR87 tumors were more frequently found in squamous cell carcinoma than in adenocarcinoma (60.0% versus 37.3%, p=0.02). Regarding the tumor proliferation, the Ki-67 index was significantly higher in high-GPR87 tumors than in low-GPR87 tumors (p=0.04). There was a tendency that the overall survival was worse in patients with high-GPR87 tumors than in low-GPR87 tumors (p=0.22). For the patients with adenocarcinoma, the overall survival was significantly worse in patients with high-GPR87 tumors than in low-GPR87 tumors (p=0.04). Conclusions: GPR87 expression may become a poor prognostic predictor for patient with NSCLC, especially for those with adenocarcinoma. GPR87 may contribute to the cell viability by promoting cell proliferation, has a potential to become a novel therapeutic target for cancer treatment.
Oblimersen sodium (Bcl-2 antisense) plus rituximab in patients with recurrent B-cell non-Hodgkin's lymphoma: Preliminary phase II results
Authors: B. Pro, M. R. Smith, A. Younes, L. E. Fayad, A. H. Goy, F. B. Hagemeister, P. McLaughlin, M. A. Rodriguez, S. R. Frankel, J. A. Zwiebel
Journal: Journal of Clinical Oncology (2004)

6572 Background: Oblimersen sodium (Genasense;GNS), a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 codons of Bcl-2 mRNA, enhances the anti-tumor activity of rituximab (RIT) in NHL cell lines and lymphoma xenografts. We are conducting a phase II study to determine the efficacy and toxicity of GNS plus RIT in recurrent B-cell NHL and to evaluate the effects of this combination on the level of Bcl-2 expression, correlating this with clinical and molecular response. Methods: Pts are required to have recurrent B-cell NHL, absolute neutrophil count of ≥ 1000, platelet count of ≥ 75,000, and serum creatinine ≤ 1.8 mg/dL. GNS (3mg/kg/d) is administered as continuous IV infusion for 7 days in weeks 1, 3, and 5 (days1–7, 15–21, 29–35). Rituximab (375mg/m2) is given weekly for 6 doses (days 3,8,15,22,29). Results: Twenty-one pts have been entered to date (median age: 63 y, range 37–82; median no. prior treatments: 2, range 1–3). Eight pts had follicular lymphoma (FL), 6 small lymphocytic lymphoma (SLL), 2 mucosa- associated lymphoid tissue (MALT) lymphoma, 3 mantle cell lymphoma (MCL), and 2 large cell lymphoma (LCL). Fifteen pts are evaluable. The overall response rate is 33%. One pt with MALT achieved a CR (6%), four pts (3 FL, 1 MCL) achieved a PR (26%), one pt (FL) had minimal response (6%), and 7 had stable disease (46%). Two responders had a relapse within 6 months of the prior therapy and one response occurred in a RIT-refractory patient. Common grade 3–4 toxicities included: reversible neutropenia in 7 pts (36%), thrombocytopenia in 2 pts (10%), and non-neutropenic fever in 4 pts (21%), Conclusions: Combined therapy with GNS and RIT is feasible and has clinical activity in both aggressive and indolent recurrent NHL. Accrual is ongoing and additional data is needed to better define the activity of this regimen. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genta Genta Genta
Genomic profiles of low-grade murine gliomas evolve during progression to glioblastoma
Authors: Mark Vitucci, David M Irvin, Robert S McNeill, Ralf S Schmid, Jeremy M Simon, Harshil D Dhruv, Marni B Siegel, Andrea M Werneke, Ryan E Bash, Seungchan Kim, Michael E Berens, C Ryan Miller
Journal: Neuro-Oncology (2017)

Gliomas are diverse neoplasms with multiple molecular subtypes. How tumor-initiating mutations relate to molecular subtypes as these tumors evolve during malignant progression remains unclear.We used genetically engineered mouse models, histopathology, genetic lineage tracing, expression profiling, and copy number analyses to examine how genomic tumor diversity evolves during the course of malignant progression from low- to high-grade disease.Knockout of all 3 retinoblastoma (Rb) family proteins was required to initiate low-grade tumors in adult mouse astrocytes. Mutations activating mitogen-activated protein kinase signaling, specifically KrasG12D, potentiated Rb-mediated tumorigenesis. Low-grade tumors showed mutant Kras-specific transcriptome profiles but lacked copy number mutations. These tumors stochastically progressed to high-grade, in part through acquisition of copy number mutations. High-grade tumor transcriptomes were heterogeneous and consisted of 3 subtypes that mimicked human mesenchymal, proneural, and neural glioblastomas. Subtypes were confirmed in validation sets of high-grade mouse tumors initiated by different driver mutations as well as human patient-derived xenograft models and glioblastoma tumors.These results suggest that oncogenic driver mutations influence the genomic profiles of low-grade tumors and that these, as well as progression-acquired mutations, contribute strongly to the genomic heterogeneity across high-grade tumors.
18F-Fluorocholine, 18F-FDG, and 18F-Fluoroethyl Tyrosine PET/CT in Parathyroid Cancer
Authors: Margit Hatzl, Julia C. Röper-Kelmayr, Franz A. Fellner, Michael Gabriel
Journal: Clinical Nuclear Medicine (2017)

We report on a 71-year-old woman presenting with biochemical features indicating recurrent disease in long-term follow-up of left-sided parathyroid carcinoma. She had undergone several surgical procedures including total thyroidectomy, partial resection of the esophageal wall, and curative neck radiation 12 years previously. PET/CT using 18F-fluorocholine revealed high uptake in local relapse in the lower neck, comparable to 18F-FDG, whereas only faint uptake was observed with 18F-fluoroethyl tyrosine. As shown in this case, imaging with FDG and 18F-fluorocholine is feasible in (recurrent) parathyroid carcinoma and clearly superior to 18F-fluoroethyl tyrosine.
Open to options: A cancer clinical trials education pilot study
Authors: E. H. Weiss, M. Golant, A. Thornton, V. Kennedy, E. Stovall, M. Michaels, J. Taylor, K. Brintzenhofeszoc
Journal: Journal of Clinical Oncology (2004)

6116 Background: The Wellness Community (TWC), NCCS, NCI, and ASCO present pilot data to assess the effectiveness of cancer clinical trials education. We tested three methods of delivering existing education materials to evaluate effectiveness and determine if education reduces barriers to participation and affects treatment decisions. Method: Standardized cancer clinical trials education materials from NCI and TWC were used in three interventions: 1) a physician-led workshop (Los Angeles), 2) an Internet course (Boston), and 3) a mailed home-study course (St. Louis). At each site, participants completed pre- and post-intervention surveys. We measured changes in knowledge (test-based and perceived), willingness to participate, willingness to seek more information, and anxiety. A telephone survey occurred 30–45 days later to further assess satisfaction, attitudes, and behavior changes. Results: Of 203 participants, 158 completed pre- and post-intervention surveys. In the primarily white (93%), female (80%) sample, 75% had cancer (60% in active treatment), and 18% were caregivers. Overall, test-based knowledge about cancer clinical trials increased significantly following all interventions (p< .001), with independent significance for the home-study group only (p< .001). Perceived knowledge increased significantly following participation, both overall and for each group (p< .001); as did willingness to participate in a clinical trial (p< .001). Following the intervention, participants rated a high likelihood to seek more information, and the majority (58%) of participants reported reduced anxiety. Conclusion: Results of this pilot study suggest that education about cancer clinical trials is associated with increased knowledge about trials (actual test-based and perceived), increased interest to learn more about trials, increased willingness to participate, and decreased anxiety about trials. Given the small sample size and non-randomization, causal inferences must be limited; but results suggest that existing NCI Clinical Trials Education materials with TWC's informational brochure may be valuable tools in many formats for oncology practitioners and patients. No significant financial relationships to disclose.
Pharmacokinetics of gimatecan, and orally administered camptothecin analogue, in patients with malignant gliomas
Authors: J. G. Supko, L. Alderson, P. Wen, K. Cassidy, S. Pace, M. Obrocea, F. Hochberg
Journal: Journal of Clinical Oncology (2004)

2039 Background: Gimatecan (GTN) is a lipophilic camptothecin analogue with excellent activity against in vivo tumor models when given orally (p.o.). This report describes the pharmacokinetics (PK) of GTN in a phase I trial in adults with recurrent malignant gliomas. Methods: GTN was given p.o. once a day for 5 days every 4 weeks. The dose was independently escalated in patients based upon whether or not enzyme inducing antiseizure drugs (EIASDs) were used concurrently. At least 3 patients were evaluated at each dose level. Sampling to define GTN plasma profiles for first and fifth daily doses was performed during cycle 1. Total GTN (intact lactone + carboxylate forms) was measured in plasma by HPLC with fluorescence detection (limit of detection, 1.0 ng/ml). PK parameters were estimated by noncompartmental methods and are reported as mean ± SD values. Results: PK data are available at 4 doses ranging from 0.33–1.23 mg/m2/day in 14 non-EIASD patients and from 0.33–1.60 mg/m2/day in 12 patients receiving EIASDs. There has been no dose limiting toxicity. GTN reached a peak concentration in plasma (Cmax) within 2 h for 90% of all doses (N = 51). In the non-EIASD group, GTN had a long terminal half-life of 57 ± 22 h and an apparent clearance (CL/f) of 1.2 ± 0.9 L/h. CL/f was not significantly associated with body surface area suggesting that flat dosing may be appropriate. In patients receiving 1.23 mg/m2/day (N= 5), there was only a 5-fold difference between the trough concentration 24 h after dose 1 (16 ± 5 ng/ml) and the Cmax for dose 5 (76 ± 21 ng/ml). The mean drug accumulation factor was 2.7 ± 0.6 based upon the 24 h area under the curve for doses 1 and 5. EIASDs had a marked effect on GTN PK, increasing CL/f by a factor of 2–10 and decreasing the apparent half-life to a similar extent. Conclusions: Treatment with well tolerated doses of GTN p.o. on a daily x 5 schedule provides prolonged systemic exposure to potentially effective drug levels. As with other anticancer agents, EIASDs significantly increased the clearance of GTN; greater doses will be required to achieve plasma levels that are comparable to patients not taking EIASDs. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sigma-Tau Research Sigma-Tau Research
Influence of insurance type on survival in patients with acute myeloblastic leukemia.
Authors: Dianne Pulte, Hermann Brenner, Lina Jansen
Journal: Journal of Clinical Oncology (2015)

e17612 Background: Acute myeloblastic leukemia (AML) is a potentially curable disease, but survival depends on the patient promptly receiving intensive chemotherapy and consolidation with further chemotherapy or hematopoietic stem cell transplant. Patients with no insurance or with Medicaid only may have difficulty accessing high quality care and therefore are at risk for poorer survival. Here, we evaluated survival for patients with AML by insurance type in the United States. Methods: Data were extracted from the Survival, Epidemiology, and End Results (SEER)-17 database. Patients with a diagnosis of AML of any type in 2007-2011 and mortality follow up to the end of 2011 were included. Complete analysis was used to determine 1-, 2-, and 3-year relative survival for patients overall and by insurance type. The association between overall survival and insurance status was estimated with Cox regression models with adjustment for age (15-44, 45-54, and 55-64 years at diagnosis), gender, and race (white, black, and other). Insurance types were categorized into none, Medicaid only, and other insurance. Because most patients over age 65 are eligible for Medicare, the analysis was restricted to ages 15-64. Results: After adjustment for race, gender, and age, mortality was higher for patients without insurance or with Medicaid compared to patients with non-Medicaid insurance, with hazard ratios of 1.46 (95% CI 1.28-1.67) for uninsured patients and 1.35 (1.24-1.47) for Medicaid only. Age standardized 3-year relative survival was 36.6% overall, 26.0% for uninsured patients, 27.5% for patients with Medicaid, and 39.3% for patients with other insurance (also see table). Conclusions: No insurance and Medicaid only are risk factors for poor outcome in patients with AML. Further research may be needed to isolate the reasons that survival is lower and to ensure that there are no preventable deaths from AML due to lack of access to health care. Age adjusted 1-, 2-, and 3-year relative survival for patients with AML by insurance type. Overall No insurance Medicaid Other Insurance 1-year 55.7% 46.0% 47.1% 58.5% 2-year 42.4% 33.3% 32.4% 45.4% 3-year 36.6% 26.0% 27.5% 39.3%
Bone marrow aspirate quality assessment.
Authors: Rachael A. Safyan, Matthen Mathew, Enrica Marchi, Melissa Kate Accordino
Journal: Journal of Clinical Oncology (2017)

76 Background: Bone marrow evaluation is the cornerstone of diagnosis, staging, and measurement of treatment response for many hematologic diseases. Aspirate adequacy is defined by whether the procedure results in a specimen of sufficient quality for pathologic review. Between July 1, 2014 and June 30, 2015, 49.3% of inpatient bone marrow aspirates performed by Hematology/Oncology fellows at Columbia University Medical Center were classified as suboptimal. Methods: We used the Plan-Do-Study-Act methodology to 1) understand the factors contributing to suboptimal aspirates, 2) evaluate the scope of the problem at both fellowship and institutional levels, 3) develop a training seminar to educate fellows on the procedure techniques, and 4) monitor for improvement post-intervention. We identified inpatient bone marrow biopsies performed by Hematology/Oncology fellows between July 1, 2015 and June 30, 2016 and tabulated aspirate adequacy as noted in the reports. A faculty-led educational seminar was held on February 1, 2016. Fellows completed a pre- and post-intervention survey to assess knowledge and experience with bone marrow aspirates. Bone marrow biopsy billing data was used as a surrogate marker for attending supervision. Results: All Hematology/Oncology fellows (n = 19) at Columbia University Medical Center participated. The pre-intervention survey (18 responses; 94.7%) revealed 76.5% of fellows had formal bone marrow aspirate training, 66.6% had supervision 25% to 75% of the time, and 52.9% were uncomfortable performing the procedure alone. Of the 43 aspirates from the pre-intervention period, 22 (51.2%) were adequate. 94.7% of fellows attended the training seminar. Post-intervention, 27 of 50 (54%) bone marrow aspirates were adequate. The post-intervention survey (16 responses; 84.2%) showed 93.3% of fellows were confident performing the procedure alone. There were fewer procedures billed in the post-intervention period (20.9% pre vs 8% post). Conclusions: A formal educational seminar on bone marrow aspirate technique increased fellow comfort with the procedure and trended toward improved aspirate adequacy. The next study phase will institute an annual training session for incoming fellows and create a bone marrow specimen preparation checklist.
Hepatitis C viral load, genotype, and increased risk of developing end‐stage renal disease: REVEAL‐HCV study
Authors: Tai‐Shuan Lai, Mei‐Hsuan Lee, Hwai‐I Yang, San‐Lin You, Sheng‐Nan Lu, Li‐Yu Wang, Yong Yuan, Gilbert L'Italien, Kuo‐Liong Chien, Chien‐Jen Chen
Journal: Hepatology (2017)

The association between hepatitis C virus (HCV) infection and end-stage renal disease (ESRD) remains controversial without considering the role of HCV viral load and genotype. This study aimed to determine whether HCV RNA level and genotype affect the risk of developing ESRD. Between 1991 and 1992, 19,984 participants aged 30-65 years were enrolled in a community-based prospective cohort study in Taiwan. Chronic HCV infection was defined by detectable HCV viral load. ESRD was determined as the need for chronic dialysis or renal transplantation. Conventional Cox proportional hazard and competing risk models were used to determine the hazard ratio (HR) for ESRD. After a median follow-up of 16.8 years, 204 cases were detected during 319,474 person-years. The incidence rates of ESRD for nonchronically HCV-infected and chronically HCV-infected patients were 60.2 and 194.3 per 100,000 person-years, respectively. The multivariable HR was 2.33 (95% confidence interval [CI] 1.40-3.89) when comparing patients with and without chronic HCV infection. Patients with low and high HCV RNA levels were at higher risk of ESRD than those who were nonchronically HCV-infected (HR, 2.11, 95% CI 1.16-3.86, and HR, 3.06, 95% CI 1.23-7.58; Ptrend < 0.001). This association remained robust after taking pre-ESRD death as a competing event for ESRD. Patients with HCV genotype 1 tended to have a higher risk of developing ESRD (HR, 3.60 95% CI 1.83-7.07) compared with nonchronically HCV-infected subjects.This study reveals that chronic HCV infection is associated with an increased risk of developing ESRD and suggests that elevated serum levels of HCV RNA (>167,000 IU/mL) and HCV genotype 1 are strong predictors of ESRD, indicating clinical implications for the management of chronic HCV. (Hepatology 2017;66:784-793).
<scp>RN</scp>ase 7 downregulates <scp>TH</scp>2 cytokine production by activated human T cells
Authors: V. Kopfnagel, S. Wagenknecht, L. Brand, J. Zeitvogel, J. Harder, K. Hofmann, M. Kleine, T. Werfel
Journal: Allergy (2017)

The antimicrobial peptide (AMP) RNase 7 is constitutively expressed in the epidermis of healthy human skin and has been found to be upregulated in chronic inflammatory skin diseases such as atopic dermatitis and psoriasis. Activated T cells in lesional skin of patients with atopic dermatitis (AD) and psoriasis (PSO) might be directly exposed to RNase 7. In addition to their antimicrobial activity, immunoregulatory functions have been published for several AMPs. In this study, we investigated immunoregulatory effects of the antimicrobial peptide RNase 7 on activated T cells.Isolated human CD3+T cells were stimulated with RNase 7 and screened for possible effects by mRNA microarray analysis. The results of the mRNA microarray were confirmed in isolated CD4+T cells and in polarized TH2 cells using skin-derived native RNase 7 and a recombinant ribonuclease-inactive RNase 7 mutant. Activation of GATA3 was analysed by electrophoretic mobility shift assay.Treatment of activated human CD4+T cells and TH2 cells with RNase 7 selectively reduced the expression of TH2 cytokines (IL-13, IL-4 and IL-5). Experiments with a ribonuclease-inactive recombinant RNase 7 mutant showed that RNase 7 ribonuclease activity is dispensable for the observed regulatory effect. We further demonstrate that CD4+T cells from AD patients revealed a significantly less pronounced downregulation of IL-13 in response to RNase 7 compared to healthy control. Finally, we show that GATA3 activation was diminished upon cultivation of T cells with RNase 7.Our data indicate that RNase 7 has immunomodulatory functions on TH2 cells and decreases the production of TH2 cytokines in the skin.