bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics (PK) and pharmacodynamics (PD) of rituximab administered by faster infusion in patients with previously untreated diffuse large B-cell (DLBCL) or follicular lymphoma (FL).
Authors: Brewster Michael , Hurst Deborah , Chai Akiko , Lee Edward James , Upadhyaya Gargi H. , Dakhil Shaker R. 
Published: March 2020

6591 Background: Faster infusion of rituximab (R) can improve patient (pt) convenience and reduce strain on oncology unit resources. To assess the safety, PK and PD of a 90-min infusion rate for R in NHL pts, a prospective, open-label, phase III, multicenter, single-arm trial (RATE) was conducted. Safety results have been previously presented (ASH 2011). Methods: Pts (≥18 yrs old) with untreated DLBCL or FL, without clinically significant cardiovascular disease, received R-chemotherapy. R (375 mg/m2) was given at the standard infusion rate (4–6 h) in Cycle 1. Pts who did not experience Grade 3/4 infusion-related reactions (IRRs) and who had circulating lymphocyte counts ≤ 5000/µl before Cycle 2, received subsequent R (375 mg/m2) infusions at a 90-min rate: 20% over 30 min then 80% over the next 60 min. Pts (n=14) who completed all cycles at the 90-min infusion rate gave further serum samples up to 16 wks after the last cycle for determination of PK parameters, including R terminal half-life (t½), maximum serum concentration (Cmax), systemic clearance (CL) and volume of distribution (V). Results: For pts (n=365) that received the 90-min infusion rate at Cycle 2, serum R concentrations increased over the course of the study. Estimated median values were: CL, 107 ml/d; V at steady state, 3830 ml; t½, 24.6 d. At Cycle 2, 50.5% of pts had undetectable CD19+ levels; this percentage increased during the study (68.3% Cycle 6, 87.5% Cycle 8). Conclusions: Peak R levels were higher than seen in published data of q3w R regimens but comparable with levels seen for q1w R regimens. The estimated median values for CL, V, t½ and B cell (CD19+) depletion with the 90-min infusion rate were similar to previously reported estimates for infusions at the standard rate. These results, in combination with the safety profile previously reported, show that a faster infusion of R can be an acceptable option for selected NHL pts who tolerated the standard infusion rate at Cycle 1 without a severe IRR. [Table: see text]
Azacitidine as induction therapy of elderly patients with acute myelogenous leukemia.
Authors: Khan Cyrus , Rossetti James M. , Hilton Christie , Sadhashiv Santhosh , Khalid Sanaullah , Abid Arifa , Fischer Victoria , Fazal Salman , Sahovic Entezam A. , Shadduck Richard K. , Lister John 
Published: March 2020

6620 Background: Effective alternative treatment of elderly patients (aged ≥ 60 years) with acute myelogenous leukemia (AML) remains challenging. Elderly patients with AML respond poorly to standard induction regimens and have high treatment related mortality. In a prior retrospective analysis of elderly patients with AML performed at our institution, azacitidine (AZA) showed an overall response rate (ORR) of 60% with limited toxicity. Methods: This is a prospective, phase II open-label study using AZA in patients ≥60 years with AML. Inclusion criteria: Newly-diagnosed non-M3 AML and ECOG ≤ 2. Patients with circulating blast count ≥30,000/mcl were treated with hydroxyurea until < 30,000/mcl. AZA was administered at 100 mg/m2 subcutaneously for 5 consecutive days every 28 days until disease progression or significant toxicity. Results: In all, 15 patients were enrolled last follow-up being 8/2/11. The mean age of patients is 74 years (range: 64–82). Mean ECOG score was 1. Mean baseline bone marrow blast count was 52% (range: 25–92%). ORR was 46% (n=7) with complete response (CR) in 3 (20%) patients and partial response (PR) in 2 (13%) patients according to NCI response criteria, and hematologic improvement (HI) in 2 (13%) patients according to IWG response criteria. The mean number of days on treatment was 198 (range: 13–724). The mean time to best response among responders was 95 days (range: 44-279). The mean number of days hospitalized for diagnosis plus treatment or disease-related complication was 19 (range: 5–56), with the majority of therapy administered in an outpatient setting. Mean overall survival (OS) from diagnosis for all patients was 355 days (range: 13–908) and mean OS for responders was 532 days (range: 120–908). Non-hematological toxicity was limited to mild injection site skin reaction and fatigue in 73% (11/15). No treatment-related deaths were observed. The dose and schedule of AZA remained constant in a majority of the patients. Conclusions: This study suggests that a 5-day schedule of SC AZA at 100 mg/m2 to elderly patients with newly-diagnosed AML is a feasible, well-tolerated and effective alternative to standard induction chemotherapy.
Association of cytokine levels and reductions in spleen size in COMFORT-II, a phase III study comparing ruxolitinib to best available therapy (BAT).
Authors: Harrison Claire N , Kiladjian Jean-Jacques , Gisslinger Heinz , Passamonti Francesco , Sirulnik L. Andres , Wang Ling , Squires Matthew , Knoops Laurent , Barosi Giovanni , Barbui Tiziano , Cervantes Francisco 
Published: March 2020

6625^ Background: Ruxolitinib is a potent and selective oral JAK1/2 inhibitor that has been approved for the treatment of myelofibrosis (MF). Ruxolitinib has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms and quality of life (QoL) in 2 phase 3 studies (COMFORT-I and –II) in patients (pts) with primary MF (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). This analysis evaluated associations between cytokine levels and spleen size reductions in the COMFORT-II study. Methods: COMFORT-II is a randomized (2:1), open-label, phase 3 study comparing the safety and efficacy of ruxolitinib with BAT. Spleen volume was measured by MRI every 12 weeks and spleen length by palpation at each study visit. Plasma samples were analyzed using Rules Based Medicines Human MAP v1.6; 89 cytokines were measured at BL and wks 4, 24, and 48. Simple linear regression was used to evaluate the correlation between BL or change from BL in cytokine levels with % change of spleen size. Results: In the ruxolitinib arm, association was found between changes in TNF-α and leptin levels and % spleen volume reduction at wk 24 (TNF-α: N = 93; correlation coefficient [R] = 0.43; false discovery rate adjusted P value [P] < .01; leptin: N = 96; R = -0.28; P = .09) and wk 48 (TNF-α: N = 86; R = 0.43; P < .01; leptin: N = 87; R = -0.34; P = .02) that was not observed with BAT and was independent of JAK2V617F status. For ruxolitinib-treated JAK2V617F+ pts, higher leptin levels at BL were associated with greater % spleen length reductions at wk 48 (N = 45; R = -0.44; P = .11). A clear trend was observed for increased leptin levels that preceded weight gain on ruxolitinib treatment. For ruxolitinib-treated JAK2V617F+ pts, decreased IL-8 at wk 4 was associated with % spleen volume reductions at wk 24 (N = 68; R = 0.28; P = .24) and wk 48 (N = 60; R = 0.38; P = .15). Conclusions: This analysis has shown statistically significant associations between changes in cytokine levels and spleen size reductions. Further analysis is in progress to determine associations between cytokine levels and QoL or symptoms and to confirm these observations in an independent data set.
History of autoimmunity to predict clinical response to DNA methyltransferase inhibitors (DNMTI) in myelodysplastic syndromes (MDS), and MDS-derived acute myeloid leukemias (AML).
Authors: Emadi Ashkan , Sadrzadeh Hossein , Patal Payal , Burns Kathleen H. , Duffield Amy , Ballen Karen K. , Amrein Philip C. , Attar Eyal C. , Smith B. Douglas , Fathi Amir Tahmasb 
Published: March 2020

6629 Background: MDS is comprised of a heterogeneous group of clonal myeloid disorders. Chronic immune stimulation has been reported as a trigger for the development of a subset of MDS, with increased autoreactive cytotoxic T cells present in the bone marrow. Autoimmunity has been associated with MDS and other marrow failures. DNMTIs, 5-azacytidine and decitabine, are approved for the treatment of MDS. In addition to epigenetic impacts, these agents may have immunomodulatory effects, including augmentation of MAGE-related anti-tumor response. These reports and clinical observations led us to hypothesize that MDS patients with a history of autoimmunity may be more responsive to DNMTIs. Methods: To identify patients with MDS, a retrospective database review (2007-2011) was performed at Johns Hopkins Hospital (JHH) and Massachusetts General Hospital (MGH). The MGH data also included those with AML whose disease had progressed from MDS. Past medical history of autoimmune disorders, diagnosis, blood counts, flow cytometry and cytogenetics were reviewed. Patients with aplastic anemia, paroxysmal nocturnal hemoglobinuria or non-malignant etiologies of cytopenia were excluded. Patients with MDS were further studied if they were treated with DNMTI. Results: Of 137 patients with MDS or MDS/AML, 23 had a documented history of autoimmunity in the medical record. Of these, 15 (65.2%) experienced a response to therapy as defined by the International Working Group. Of 114 patients without a documented history of autoimmunity, 34 (29.8%) achieved a response during therapy, a significantly lower percentage as compared to those with autoimmune conditions (p-value 0.002, t-test). The majority of responding patients with a history of autoimmunity displayed a normal karyotype (9 of 15 patients). Conclusions: A history or co-presence of an autoimmune disorder may predict a high likelihood of achieving a clinical response to DNMTIs. Correlative studies in this unique population of patients with MDS and MDS/AML and prospective clinical studies are needed to improve our understanding of the possible mechanism of action of DNMTIs in these patients.
Phase III trial of concurrent thoracic radiotherapy (TRT) with either the first cycle or the third cycle of cisplatin and etoposide chemotherapy to determine the optimal timing of TRT for limited-disease small cell lung cancer.
Authors: Park Keunchil , Sun Jong-Mu , Kim Sang-We , Ahn Myung-ju , Ahn Jin Seok , Lee Dae Ho , Suh Cheolwon , Ahn Yong Chan , Pyo Hongryull , Choi Eun Kyung , Song Si Yeol , Lee Se-Hoon , Lee Jung Shin 
Published: March 2020

7004 Background: Concurrent thoracic radiotherapy (TRT) with chemotherapy has been regarded as optimal treatment for limited-disease small cell lung cancer (SCLC). However, the issue on how early TRT should be commenced is not yet defined. Methods: A total of 219 patients with limited-disease SCLC, who were enrolled from July 2003 to June 2010, received four cycles of cisplatin plus etoposide (cisplatin 70 mg/m2 on day 1 and etoposide 100 mg/m2 on days 1 to 3 every 3 weeks). We randomly assigned these patients to receive concurrent TRT, beginning with the first cycle (initial arm) or the third cycle (delayed arm) of chemotherapy. In both arms, patients received 2.1 Gy once-daily in 25 fractions over a period of five weeks, with a total dose of 52.5 Gy. Patients with partial or complete response were recommended to receive prophylactic cranial irradiation (PCI). Results: Approximately 82% of patients completed planned four cycles of chemotherapy with 52.5 Gy TRT (81.1% and 82.4% in the initial and delayed arm, respectively). After a median follow-up of 4.9 years (range, 1.2 – 8.1 years), the median overall survivals were 24.1 and 26.8 months (P=0.60) in the initial and delayed arm, respectively. Progression-free survival and complete response rates were 12.2 vs. 12.1 months (P=0.94) and 36.0% vs. 38.0% (P=0.77) in the initial and delayed arms, respectively. PCI was given to 49.5% and 55.6% of patients in the initial and delayed arms, respectively (P = 0.37). Febrile neutropenia was significantly more frequent with the initial arm, occurring in 21.6% of patients, as compared with 10.2% in the delayed arm (P = 0.02). All grade esophagitis occurred in 45.0% and 37.0% of the initial and delayed arms, respectively (p = 0.23). Conclusions: TRT (52.5 Gy, once daily) beginning with the third cycle of chemotherapy showed comparable survival outcomes and complete response rates with TRT beginning with the first cycle of chemotherapy, with a lower frequency of febrile neutropenia.
Prognostic and predictive effects of KRAS mutation subtype in completely resected non-small cell lung cancer (NSCLC): A LACE-bio study.
Authors: Shepherd Frances A. , Bourredjem Abderrahmane , Brambilla Elisabeth , Domerg Caroline , Douillard Jean-Yves , Filipits Martin , Graziano Stephen L. , Hainaut Pierre , Janne Pasi Antero , Le Chevalier Thierry , Le Teuff Gwenael , Pignon Jean-Pierre , Pirker Robert , Seymour Lesley , Soria Jean-Charles , Taron Miquel , Tsao Ming Sound ,   LACE-Bio Collaborative Research Group
Published: March 2020

7007 Background: We reported previously that KRAS is weakly prognostic and not significantly predictive of benefit from adjuvant chemotherapy (ACT) in NSCLC (Tsao et al. Proc ESMO 2012, Abst 4217). In colorectal cancer (CRC), KRAS mutation predicts resistance to EGFR monoclonal antibodies, but recent reports suggest that this may not be true for all mutation subtypes (De Roock et al. JAMA 2010). Smoking-related KRAS mutations in NSCLC differ from those of CRC. To explore the influence of KRAS mutation subtype, we undertook an analysis of KRAS subtype in LACE-Bio. Methods: KRAS mutation was determined in blinded fashion in 3 laboratories by direct sequencing. Exploratory analyses were performed to identify relationships between mutation status and subtype, overall (OS) and disease-free survival (DFS) using a Cox model stratified by trial and adjusted for covariates. Results: KRAS subtype was available in 1,532 patients (756 observation [OBS], 776 ACT). There were 300 mutations (275 codon 12, 24 codon 13, 1 codon 14). In the OBS arm, there was no difference in prognosis for OS for codon 12 (Hazard Ratio [HR] mutation v wild-type [WT] KRAS 1.04, CI .77-1.4) or codon 13 (HR 1.01, CI 0.47-2.17) mutations. A trend for benefit from ACT was observed in WT (HR ACT v OBS 0.89 CI 0.76-1.04, p=0.15) but not in patients with codon 12 mutations (HR 0.95, CI .67-1.35, p=0.77). In patients with codon 13 mutations, chemotherapy was deleterious (HR 5.78, CI 2.06-16.2, p<0.001), test for equality among 3 HRs p=0.002. Results were similar for DFS. Among codon 12 mutations, there was no prognostic effect based on specific amino acid substitution. Patients with G12A or G12R mutations appeared to derive greater benefit from ACT (HR 0.66 p=0.48) compared to those with G12C or G12V (HR 0.94 p=0.77) or G12D or G12S (HR 1.39 p=0.48) or WT, but the differences were not significant (comparison of 4 HRs p=0.76). Conclusions: In this study, patients with KRAS codon 13 mutations had significantly poorer outcomes with ACT. These results require further confirmation and should be interpreted with caution in view of the small number of patients with codon 13 mutations. Supported by unrestricted grants from Sanofi Aventis and LNCC.
Pilot SCAT trial: Spanish customized adjuvant chemotherapy (CT) based on BRCA1 mRNA expression levels (l) in resected stage II-IIIA non-small cell lung cancer (NSCLC) patients (p).
Authors: Sanchez Jose Miguel , Cobo Manuel , Arrabal Rafael , Massuti Bartomeu , Rodriguez Paniagua Jose Manuel , Moran Teresa , Astudillo Julio , Jimenez Ulpiano , Pun Yat Wa , Aguiar Bujanda David , Freixenet Jorge , Gonzalez-Larriba Jose-Luis , Hernando-Trancho Florentino , Gómez-Codina Jose , Penalver Juan-Carlos , Martinez Banaclocha Natividad , Lopez-Vivanco Guillermo , Pac Joaquin , Taron Miquel , Rosell Rafael ,   Spanish Lung Cancer Group
Published: March 2020

7011 Background: Surgical resection is the standard treatment in early stages of NSCLC. Nonetheless, long-term survival rate even after surgical resection is disappointing. Several randomized trials and meta-analyses confirmed the survival benefit of adjuvant cisplatin-based CT for stage II and IIIA. BRCA1 is a component of multiple DNA repair pathways, functions as a molecular determinant of response to cytotoxic chemotherapeutics agents, and is an independent prognostic variable in resected p. Since BRCA1 mRNA expression has been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 expression may provide additional information for customizing adjuvant CT. Methods: Completely resected p with pathological lymph node involvement (N1, N2) received 4 cycles of customized adjuvant CT according BRCA1 l. Low l: gemcitabine-cisplatin, intermediate l: docetaxel-cisplatin, high l: docetaxel. Overall survival (OS) was the primary endpoint. Multivariate analysis for time to relapse (TTR) and survival was performed. Results: Eighty-three p were elegible. Most of the patients were male (83%). Type of surgery: 23% pneumonectomy, and 77% lobectomy or bilobectomy. Fifty-three per cent had low BRCA1 l, 33,7% intermediate l, and 13,3% expressed high l. Most of the tumors with adenocarcinoma histology had low l (71%). With a median follow-up of 41.6 months (m), median TTP for the whole group was 22.9 m (13.4-32.5): 20.3 m for low l, 56.5 m for intermediate l, and 51.9 m for high l (P=0.31). Median OS for the whole group was 63.6 m (33.3-93.9): 55 m for low l, and not reached for intermediate and high l (P=0.58). Forty-three p (51.8%) are still alive. Conclusions: Selection of customized CT based on BRCA1 expression l is feasible and could increase time to relapse and survival in resected N1-N2 p. No statistical differences for survival: 55 months for gemcitabine-cisplatin, and not reached for docetaxel-cisplatin and for docetaxel as single agent. Randomized phase III SCAT trial with the addition of a non-pharmacogenomic control arm is ongoing (372 patients included).
Comparison between diameters of the whole nodule and solid area and the proportion of GGO in the tumor shadow on HRCT in predicting less-invasive lung cancer and recurrence after complete resection in patients with clinical N0 NSCLC.
Authors: Matsuguma Haruhisa , Nakahara Rie , Suzuki Haruko , Kasai Takashi , Kamiyama Yukari , Igarashi Seiji , Mori Kiyoshi , Kodama Tetsuro , Yokoi Kohei 
Published: March 2020

7021 Background: Prediction of less-invasive lung cancer is important in selecting candidates for limited surgical resection. A greater proportion of ground-glass opacity (%GGO) is well-known to be strongly associated with less-invasive lung adenocarcinoma. Recently, the diameter of the solid area (SolidØ) has been reported to also be a simple and better marker for the same purpose compared to the diameter of the whole nodule (NoduleØ). The aim of this study was to confirm that SolidØ can completely replace %GGO in predicting less-invasive lung cancer. Methods: From 1987 to 2009, 433 patients with clinical T1a-2bN0 NSCLC underwent complete resection, and their preoperative HRCT images were preserved in DICOM format. NoduleØ and SolidØ were precisely measured using software. %GGO was calculated using the method we previously published (Eur J Cardiothorac Surg 25:1102-6, 2004). Less-invasive lung cancer was defined as having no vascular, lymphatic, nor pleural invasion. We compared the three parameters with regard to predicting less-invasive lung cancer and recurrence. Results: Among the 433 patients, 220 were male, 367 had an adenocarcinoma histology, and 58 experienced recurrence. Table shows percentages and numbers of non-less-invasive lung cancer cases. Among each category of SolidØ, greater %GGO is associated with less-invasive lung cancer. ROC analysis also showed that the area under the curve of %GGO was the highest (0.859, 95% CI 0.824 – 0.893), followed by SolidØ (0.806, 0.767 – 0.846), and NoduleØ (0.671, 0.620 – 0.721). Regardless of SolidØ, no patient with a greater %GGO (> 50%) experienced recurrence. Conclusions: Although SolidØ is a better prognostic indicator of non-invasiveness compared to NoduleØ, %GGO remains important. [Table: see text]
Use of a proliferation-based mRNA signature to predict outcome in early-stage non-small cell lung adenocarcinoma.
Authors: Behrens Carmen , Lombardi Francesca , Wagner Susanne , Fujimoto Junya , Raso Maria G , Spaggiari Lorenzo , Galetta Domenico , Huges Elisha , Reid Julia E. , Sangale Zaina , Swisher Stephen , Kalhor Neda , Moran Cesar , Gutin Alexander , Lanchbury Jerry S. , Kim Edward S. , Barberis Massimo , Wistuba Ignacio I. 
Published: March 2020

7023 Background: Adjuvant treatment of patients with early-stage lung adenocarcinoma is based on post-surgical pathological staging and patient performance status. Disparate outcomes within each staging group suggest that additional prognostic markers could improve our understanding of risk-benefit and potentially lead to better treatment decisions. A proliferation-based, mRNA expression profile was applied to public microarray data of surgically treated lung adenocarcinomas and a cohort of FFPE samples to test its potential prognostic utility. Methods: Public expression data (Director’s Consortium, DC) were derived from Affymetrix HG-U133A arrays. Clinical FFPE samples were assayed by quantitative PCR. A cell cycle progression (CCP) score was calculated from the expression average of 31 cell cycle genes normalized by 15 housekeeper genes. The prognostic value of the CCP score to predict stage I and II patient outcomes was evaluated by Cox proportional hazards analysis with disease-related death as the primary outcome measure. Results: In 256 DC cases, the CCP score was a significant predictor of death in univariate (p=0.0001) and multivariate analysis (p=0.001, HR 1.57, 95%CI 1.20-2.05) using age, stage, gender, smoking status and treatment as covariates. Similarly, in a second data set (GSE31210, n=204) the CCP score was highly associated with death (univariate, p=0.001; multivariate analysis, p=0.003, HR 1.81, 95% CI 1.24-2.66). Using quantitative PCR, the signature was applied to 381 FFPE samples with a median follow-up of 5 years collected at the MD Anderson Cancer Center and the European Institute for Oncology. In the presence of clinical covariates (as above and tumor size and pleural invasion), the CCP score remained the most significant predictor of death in univariate (p=0.0003) and multivariate analysis (p=0.007, HR 1.50, 95% CI 1.11-2.02). Conclusions: A 46 gene mRNA signature is a significant predictor of disease-related death in early-stage lung adenocarcinoma, providing independent prognostic value in the presence of clinical variables. This molecular predictor of cancer survival will be studied in additional cohorts for its ability to impact clinical treatment decisions.