bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided cisplatin-based two-drug chemotherapy in unresectable non-small cell lung cancer
Authors: Moon Y. W. , Kim Y. T. , Sohn J. H. , Chang J. , Kim S. K. , Park M. S. , Chung K. Y. , Choi S. H. , Yang J. Y. , Kim J. H. 
Published: March 2020

7118 Background: Heterogeneity of tumor response to chemotherapy is a big obstacle in cancer treatment. The aim of this study was to investigate correlations of ATP-CRA and clinical outcome after ATP-TCA-guided cisplatin-based chemotherapy in unresectable NSCLC. Methods: From Sep. 2003 to Oct. 2005, ATP-CRA was done in tumor tissue specimen obtained from patients with suspected lung malignancy. ATP-CRA tested sensitivities of anticancer drugs used widely in advanced NSCLC such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabin, and vinorelbine. The cell death rate was determined by measuring the intracellular ATP levels of untreated controls and drug exposed cells. A sensitive drug was defined as a drug producing 30% or more reduction of ATP compared to untreated controls. Test-guided cisplatin-based two-drug chemotherapy was given to pathologically confirmed NSCLC. Results: 31 patients were enrolled and their median follow-up duration was 13.3 months. Response rate was 48.3%. Median progression-free and overall survivals were 4.4 months and 11.2 months, respectively. Patients were dichotomized into platinum-sensitive (S) and resistant (R) groups. S-group (19) contained cases sensitive to platinum alone (6) or both drugs (13). R-group (12) contained cases sensitive to none (9) or the other drug alone (3). Clinical response rate was higher in S-group (75.0% vs 35.3% in R-group; p = 0.0635). Considering correlations of test results and clinical response, positive/negative predictive values were 64.7% / 75.0% with the predictive accuracy of 69.0%. Although without significant differences in histology, stage, and performance status, S-group had longer progression-free (5.0 vs 2.4 months in R-group; p = 0.056) and overall (21.8 vs 9.7 months in R-group; p = 0.018) survivals. Conclusions: In vitro chemosensitivity test, ATP-CRA results and clinical outcome were correlated well after test-guided cisplatin-based two-drug chemotherapy in unresectable NSCLC, presenting favorable response and survival in platinum-sensitive versus resistant group. [Table: see text]
Identifying patients with non-small cell lung cancer (NSCLC) unlikely to benefit from erlotinib: An exploratory analysis of National Cancer of Institute of Canada Clinical Trials Group BR.21
Authors: Florescu M. , Hasan B. , Shepherd F. A. , Seymour L. , Ding K. , Pater J. 
Published: March 2020

7161 Background: Despite a 9% response rate, BR.21 demonstrated significant survival benefit for patients receiving erlotinib as 2nd/3rd line therapy for NSCLC. We undertook to characterize, by exploratory subset analysis, patients less likely to benefit from erlotinib. To identify factors for consideration, we first identified baseline characteristics associated with early progression by eight wks and early death by 3 mos. Methods: Using stratification factors and potential prognostic factors from BR.21, the Cox regression model with stepwise selection was used to establish a prognostic model to separate erlotinib patients into 4 risk categories based on the 10th, 50th & 90th percentiles of prognostic index scores. 7 variables (smoking history, PS, weight loss, anemia, high LDH, response to prior chemo and time from diagnosis to randomization) were used in the final model. The hypothesis was that the characteristics of the treated patients in the highest risk group would also be predictive of lack of benefit from erlotinib when erlotinib and placebo patients with the same characteristics were compared. Results: Factors associated with PD by 8 wks were: PS2–3 (p = 0.009), weight loss (p = 0.0004), anemia (p = 0.008), PD to prior chemo (p = 0.006), non-Asian (p = 0.047), EGFR IHC-negative (p = 0.005), Factors associated with survival < 3 mos were: PS2–3 (p < 0.0001), weight loss (p < 0.0001), anemia (p < 0.0001), PD to prior chemo (p < 0.0001), non-Asian (p = 0.008), high LDH (p < 0.0001), time to randomization <12 mos (p = 0.0003). Comparison of overall survival for the 4 risk groups derived from prognostic index score as follows: high benefit (HR = 0.41, p = 0.007), 2 intermediate benefit (HR 0.79, p = 0.09; HR 0.80; p = 0.09); no benefit (HR 1.23; p = 0.42). Median survivals for erlotinib (placebo) patients in each group were 17.3 (8.3), 9.7 (7.5), 4.1 (3.7), 1.9 (2.7) mos. Conclusions: By establishing a prognostic model, we identified a small group of patients who are unlikely to benefit from 2nd/3rd line erlotinib therapy. This model requires prospective validation to confirm that it is both prognostic and predictive of outcome from treatment. [Table: see text]
Erlotinib as first-line treatment for untreated advance stage NSCLC with good prognosis
Authors: Akerley W. L. 
Published: March 2020

7178 Background: Erlotinib demonstrated improved survival in previously treated NSCLC, but did not affect survival in untreated NSCLC when used with concurrent chemotherapy. A potential hypothesis for this paradox is erlotinib may be more effective for patients with less aggressive tumors (i.e. those still surviving after multiple chemotherapy treatments). The current trial was designed to evaluate erlotinib before initial chemotherapy in a population of patients with less aggressive tumors based on clinical criteria. Methods: Eligibility criteria included stage IIIB/IV or recurrent NSCLC, no prior chemotherapy for systemic disease, PS = 0–1, weight loss less than 10%, and no urgent symptoms. Patients received erlotinib 150 mg po/day until objective or symptomatic progression before they were switched to chemotherapy. The 10 endpoint was time-to-progression after 1st chemotherapy. Results: 40 patients have been accrued. The median age was 65, 35 had PS = 1, 8 were never-smoker, and 23 were former smokers. Histologies were: Adeno 20, BAC 2, Sq 6, NSCLC 11, Other 1. The major toxicity was rash (Gr0 in 4, Gr1in 15, Gr2 in 14, Gr3 in 3, 4 too early. Other toxicity included liver (Gr 1 in 2, Gr2 in 1), mucositis (Gr1 in 1, Gr2 in 1) and diarrhea (liver (Gr1 in 10, Gr2 in 1, Gr3 in 2). 34 have been followed long enough for response evaluation, which identified 4 (12%) with PR (median 37 wks), 8 with stable (median 20 wk) and 22 with progression. At progression only 2 patients were too ill to start chemotherapy due to inadequate performance status. The median time on erlotinib was 8 wks overall: for rash Gr 0–1 8 wks, Gr 2–3=43 wks (p = 0.03). The median and 6-month PFS for chemotherapy are 22 wks and 45% with17 still on treatment. The median and 1-yr survivals are 50 wks and 47% with 24 pts still alive. Conclusions: Mid-term safety analyses exceeded expectations. Rash predicts duration of erlotinib effectiveness. Preliminary results suggest single agent, erlotinib may be as effective (PFS and survival) as initial chemotherapy with less toxicity and merits randomized testing as first treatment for advanced lung cancer. No significant financial relationships to disclose.
Elevated osteopontin (OPN) plasma levels are highly prognostic in advanced non-small cell lung cancer (NSCLC): Analysis of SWOG S0003
Authors: Mack P. C. , Redman M. W. , Chansky K. , Williamson S. K. , Farneth N. , Lara P. N. , Le Q. , Gumerlock P. H. , Crowley J. J. , Gandara D. R. 
Published: March 2020

7198 Background: OPN is a secreted glycoprotein with a diverse array of functions, including induction of uPA & increased cell migration. OPN has been shown to be elevated in a number of tumor types, & its downregulation reduces tumorigenicity & metastasis in tumor models. High levels have also been associated with tumor hypoxia/angiogenesis, as are vascular endothelial growth factor (VEGF) & plasminogen activator inhibitor (PAI-1). We hypothesized that secreted levels of these biomarkers would correlate with clinical outcome after treatment. Methods: Plasma concentrations of OPN, VEGF & PAI-1 were measured by ELISA in 160 NSCLC patients enrolled on the Southwest Oncology Group (SWOG) trial S0003 (paclitaxel/carboplatin ± the hypoxic cytotoxin tirapazamine). Post-treatment plasma samples were available in 56 patients. Results: Baseline OPN plasma levels correlated significantly with patient overall survival (OS). High interpatient variability was observed, with levels ranging from undetectable to 2560 ng/ml, (median: 606.5 ng/ml). When dichotomized, median OS was 11 months for patients below median OPN levels & 7 months for those above (p = 0.004). Survival decreases with increasing OPN concentration. Furthermore, OPN levels correlated with response rate (RR) (median responders: 497; median non-responders: 698 ng/ml. Wilcoxon rank-sum p = 0.03). No association between baseline levels of either VEGF or PAI-1 with RR or OS was observed. However, plasma levels of both PAI-1 & VEGF were significantly inter-related & trended together (p < 0.0001), & both decreased significantly after treatment (p = 0.0004 & 0.04, respectively). Median decrease: OPN: 17%, PAI: 44%, VEGF: 42%. No significant differences were observed between study arms, suggesting that OPN is prognostic in NSCLC, but not predictive for response to tirapazamine. Conclusions: 1) There is a great need for development of tumor biomarkers which can be serially assessed pre- & post-therapy. 2) High OPN plasma levels were significantly associated with reduced RR & OS for patients on this trial. OPN is a strong candidate for inclusion in a panel of prognostic (& perhaps predictive) markers for NSCLC. Supported by the Hope Foundation & R01-CA107228. No significant financial relationships to disclose.
The impact of FLIPI on outcome of frontline treatment with single-agent I-131 tositumomab for follicular lymphoma (FL)
Authors: Kaminski M. S. , Hamstra D. , Estes J. , Wahl R. 
Published: March 2020

7509 Background: The FLIPI is potentially useful in predicting clinical outcome and comparing treatment results among clinical studies in FL. We recently reported the results of I-131 tositumomab as frontline treatment in 76 pts with advanced-stage FL (NEJM 325:441, 2005). A single 1-week course resulted in a 95% and a 75% overall and complete response (CR) rate, respectively, and at a median follow-up of 5.1 years median progression-free survival (PFS) was 6.1 yrs. In multivariate analyses, bone marrow involvement was the only baseline variable that had a significant effect on PFS. Methods: To evaluate whether baseline FLIPI scores in this study could predict outcome and to compare this pt population with that in other frontline studies, the records of all 76 patients were reviewed. Results: FLIPI scores were available for 74 of the 76 pts: 11 pts (15%) low risk, 37 (50%) intermediate risk, and 26 (35%) high risk. CR rates for each risk group were 82%, 73%, and 73%, respectively. 5-yr PFS were 63% (35–92%, 95% CI), 63% (47–78%), and 52% (33–71%), respectively, p = 0.322. Grouping low + intermediate risk vs. high for PFS: p = 0.134. 5-yr overall survival (OS) rates were 100%, 95% (87–100%), 78% (62– 93%), respectively, p = 0.072, but grouping low + intermediate risk vs. high p = 0.028. A comparison to other frontline studies is below. Conclusions: The FLIPI did not predict for PFS or OS in FL pts treated with single-agent I-131 Tositumomab. However, an OS difference was seen when low + intermediate risk pts were grouped and compared with high risk pts. The distribution of FLIPI scores amongst pts in this study is similar to that observed in other front-line FL studies. Further studies exploring single-agent radioimmunotherapy vs. chemo/radioimmunotherapy combinations are warranted. [Table: see text] [Table: see text]
Incidence of secondary leukemia/myelodysplasia (AML/MDS) in Hodgkin’s disease (HD) with three generations of therapy at Stanford University
Authors: Advani R. H. , Hoppe R. T. , Rosenberg S. A. , Horning S. J. 
Published: March 2020

7516 Background: Long term HD survivors have an increased risk of therapy-related AML/MDS that peaks about 5 years (yr) after alkylating agent (AA)-based chemotherapy (CT). Successive generations of Stanford studies limited AA exposure to address this risk. Methods: Patients (pt) treated with CT from 1974–2003 (RT only excluded) were retrospectively analyzed. S study pt received AA-based CT (MOPP or PAVE) alone (6%), with involved (IF) (21%) or extended field (EF) radiotherapy (RT) (73%); C pt received AA-based CT alone (26%) or with RT (37%) or non-AA-based CT (VBM or ABVD) + IFRT (37%); G pt received VBM + IFRT (12%) or the Stanford V + RT regimen (88%). Results: 21 (3.3%) of 639 pt developed AML/MDS: 13 after primary and 8 after secondary CT. AML/MDS incidence was significantly less in G pt (0.3%) compared to S (6.7%) and C pt (4.5%), p < 0.0001 and remained significant when pt followed <5 yr (18%) were excluded, p = 0.001. Secondary therapy was required more often for S (29%) and C (28%) pt than G (11%) pt. Number and Percent of AML/MDS in Three Eras Conclusion: AML/MDS was rare in the current Stanford V regimen era, indicating that limiting the cumulative dose of AA CT in combination with lesser RT volumes have significantly reduced the incidence of leukemia and the need for secondary CT. Longer follow-up is required to assess the impact of the Stanford V regimen on solid tumor and cardio-vascular risks. [Table: see text] No significant financial relationships to disclose.
Stanford V regimen in 59 patients (pts) with HD and HIV Infection (HD-HIV): A very effective approach in the long-term analysis
Authors: Spina M. , Gabarre J. , Fasan M. , Re A. , Schiantarelli C. , Talamini R. , Talamini R. , Vaccher E. , Tirelli U. 
Published: March 2020

7583 Background: The introduction of HAART has significantly improved the outcome of pts with HD-HIV. However there are no data on the long-term follow-up of HD-HIV pts treated with conventional chemotherapy (CT) regimens and concomitant HAART. In 2002, we reported the results of a prospective phase II study with the intensive 12-week CT with adjuvant radiotherapy (Stanford V) and concomitant HAART in 59 pts with HD-HIV, a well-known unfavorable subgroup of HD (Spina et al. Blood 2002; 100:1984–1988). Methods: To analyze the long-term outcome of patients included in the Stanford V and HAART protocol. Results: The median follow-up is 53 months (range 3–104 months The overall survival (OS) is 59%, the freedom from progression (FFP) is 62% and the disease free survival (DFS) is 72%. The 5-year probability of OS was significantly different in pts with an international prognostic score (IPS) <3 in comparison to that of pts with an IPS >2 (84% vs 36%, p = 0.001). Similarly, the percentages of FFP at 5 years in these groups were 72% and 45% (p = 0.03). No significant side effects have been observed so far. Conclusions: After a median follow-up of 4.5 years, 72% of pts with this unfavorable subgroup and IPS <3 is free from progression, superimposable to that observed in the general population with comparable adverse prognostic factors. Therefore, Stanford V is a very effective regimen in pts with HD-HIV in the long-term analysis. Supported by AIRC and ISS grants. No significant financial relationships to disclose.
Anti-CD74-doxorubicin immunoconjugate (IMMU-110) is cytotoxic in non-Hodgkin’s lymphoma (NHL) models and overcomes MDR
Authors: Blumenthal R. , Stein R. , Michell R. , Goldenberg D. M. 
Published: March 2020

7598 Background: The internalizing LL1 anti-CD74 antibody is an optimal agent for delivering drugs, toxins, or radionuclides to CD74+ cancer cells. Here, we investigated the efficacy of IMMU-110 (Immunomedics, Inc.) in common follicular and aggressive types of NHL cells and in two disseminated non-Burkitt NHL models. Methods: CD74, MDR and MRP expression on NHL cell lines was determined by flow cytometry. In vitro cytotoxicity was assessed by cell cycle analysis of propidium iodide (PI)-stained cells and by measuring apoptotic cells using FITC-Annexin V and PI. In vivo therapy of a single 350-μg dose of IMMU-110 was evaluated in disseminated SUDHL4 and FSCCL. Results: Raji and Daudi Burkitt lines express similar amounts of CD74 (>93% positive cells and a MCF=35), yet a 3-day treatment with 0.8 μg/ml of IMMU-110 results is 18.4% of Raji and 67.9% of Daudi cells in Sub-Go. Aside from Daudi cells that respond with cells shifting into Sub-Go, most other NHL cell lines experience a G2/M block (44%-82% of cells) in response to a 3-day exposure to IMMU-110. Both MDR- and MDR+ NHL cells responded to IMMU-110. Kaplan Meier analysis showed a significant increase in survival of both SUDHL4 (MDR-/MRP-)- and FSCCL (MDR+/MRP+)-bearing SCID mice (P < 0.025) with 100% survival of treated mice vs. 38% survival of untreated mice at 70–77 days post cell implantation. Conclusions: IMMU-110 is cytotoxic in non-Burkitt and in Burkitt NHL cell lines. The magnitude of the cytotoxic response is not related to the amount of CD74 expressed on the cell surface. IMMU-110 is therapeutic in drug-sensitive (SUDHL4) and drug-resistant (FSCCL) NHL models, suggesting that antibody targeting can bypass the MDR drug efflux system that prevents free doxorubicin from being therapeutic. [Table: see text] [Table: see text]
Lenalidomide (Len) in combination with dexamethasone (Dex) is more effective than Dex alone at first relapse and provides better outcomes when used early rather than as later salvage therapy in relapsed multiple myeloma (MM)
Authors: Stadtmauer E. A. , Weber D. , Dimopoulos M. A. , Borrello I. , San-Miguel J. F. , Hellmann A. , Marta Olesnyckyj M. , Yu Z. , Zeldis J. B. , Knight R. D. 
Published: March 2020

7600 Background: High-dose Dex remains a standard therapy for relapsed or refractory MM. Lenalidomide is a novel, oral, immunomodulatory drug (IMiD) that has activity against MM with additive effects when combined with Dex. At the interim analysis of MM-009/010, Len/Dex achieved a significant benefit over Dex, providing a longer median TTP, higher response rates, and higher CR rates. Aim: This prospective subgroup analysis was performed to determine the potential benefit of starting Len/Dex at first relapse by analyzing outcomes versus Dex among patients (pts) who had received only 1 versus >1 prior line of therapy. Methods: Pts who had received 1–3 prior treatments and were not refractory to Dex were randomized to either oral lenalidomide (25 mg daily for 3 weeks every 4 weeks) plus Dex (40 mg on Days 1–4, 9–12, 17–20 every 4 weeks for 4 months, then 40 mg on Days 1–4 every cycle thereafter) or placebo plus Dex. The EBMT criteria were used for response. Randomization was stratified at entry by number of prior therapies (1 versus > 1). Results: Of 692 randomized pts, 241 pts (34%) received only 1 prior therapy. Those receiving 2nd-line Len/Dex had a significantly longer median TTP (66 vs. 20 wks) and a higher RR (CR + PR); (63% vs. 26%) versus those receiving 2nd-line Dex. After a median follow-up of 12.1 mos for all pts, 2nd-line Len/Dex provided significantly improved overall survival (OS) (hazard ratio 1.85, P = 0.03) versus 2nd-line Dex. Among the 451 pts who had received > 1 prior line of therapy, the median TTP (44 vs. 20 wks), RR (57% vs. 20%), and OS (hazard ratio 1.50, P = 0.03) were higher with Len/Dex vs. Dex. Response to Len/Dex was superior to that of Dex regardless of the type of prior therapy. Comparing pts who received Len/Dex as 2nd-line versus later salvage therapy, the median TTP was longer and response rates higher in pts treated in second-line. Conclusions: Len/Dex provided higher response rates and improved TTP compared with Dex at first relapse and beyond. TTP and response rates were superior when Len/Dex was administered earlier at first relapse compared with its use as later salvage therapy. These data support the use of Len/Dex for pts as 2nd-line therapy for relapsed MM. [Table: see text]
Pharmacodynamic relationships between asparagine INPUT (Imax) post asparaginase (ASNase) therapy and outcome in SR ALL patients (CCG-1962)
Authors: Avramis V. I. , Panosyan E. H. , Avramis I. A. , Dorey F. , Gaynon P. 
Published: March 2020

9025 Background: ASNase is an important agent in the treatment of childhood acute lymphoblastic leukemia. Most other chemotherapeutic agents require entry into cells and some variety of activation. ASNase acts unmodulated and totally outside of cells, targeting extracellular ASN and glutamine. Several investigators have described a relationship between ASNase activity and ASN. In vivo, the equilibrium asparagine level depends on the input rate of ASN derived from the nutrients plus the de novo biosynthesis minus its deamination from the serum ASNase activity. Imax is a pharmacodynamic (PD) parameter developed in 1980’s representing the cumulative input of ASN from nutrients and de novo biosynthesis. Of note, glutamine is the amino group source for the synthesis of ASN from aspartate. In Enzyme-substrate relationships a sigmoid relationship exists that reaches a maximum product formation (Imax). We reported a link between Day 14 ASN depletion - not ASNase activity - and response for children with ALL in first marrow relapse (Jarrar et al, 2006). Methods: On CCG-1962, 117 children with standard risk ALL were randomly allocated to native or pegylated ASNase. Relevant PK-PD parameters have been reported (Avramis et al, Blood 2002). ASNase activity was not predictive of EFS. Induction (IND) Day 3 - 24 serum ASN levels were fitted into a PD model and the Imax values were evaluated for 112 patients. Results: The median Imax values were 1E-6 nmoles/ml/min in all 112 (range 2.0E-2 to 1.0E-7) and in the native or PEG-ASNase randomized patients. The mean values were 1.1E-3.1±3E-3 in 112 patients and 1.5E-3±4.0E-3 & 1.1E-3±3.0E-3 nmoles/ml/min in the native or PEG-ASNase randomized patients. We examined EFS by Imax values in lifetable analyses. High Imax values predicted statistically poorer outcome (p<0.00001) with various cut-off values (e.g., Imax ≥1x 10−3 or Imax ≥5 × 10−4 nmoles/ml/min. The effect was similar in the native and pegylated ASNase subsets. ASNase activity was not prognostic. Conclusions: Hence, ASN Imax in serum is a treatment-independent PD prognostic factor in a subset of children with standard risk ALL. Strategies to provide uniform therapeutic effect among patients with differing Imax are under consideration. No significant financial relationships to disclose.