bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDM2 polymorphism and recurrence-free and overall survival in early stage non-small cell lung cancer (NSCLC)
Authors: Suk Heist R. , Zhou W. , Cogan-Drew T. , Liu G. , Su L. , Neuberg D. , Lynch T. J. , Wain J. C. , Christiani D. C. 
Published: March 2020

7221 Background: MDM2 is a negative regulator of p53. A T->G polymorphism in the promoter region of MDM2 has been described, where the G/G genotype is associated with higher MDM2 mRNA and protein levels. Overexpression of MDM2 is thought to interfere with p53-mediated apoptosis and growth inhibition, leading to cancer progression. We hypothesized that the MDM2 G/G genotype may be associated with worse survival outcomes in early stage lung cancer. Methods: We evaluated the relationship between MDM2 polymorphism status and overall survival (OS) and recurrence-free survival (RFS) among 385 Stage I and II NSCLC patients treated with surgical resection at Massachusetts General Hospital from 1992 to 2000. The MDM2 polymorphism was genotyped using the 5’-nuclease assay (Taqman). Kaplan-Meier methods and the log-rank test were used to compare survival by polymorphism status. Cox proportional hazards models were used to adjust for possible confounding variables. Results: Median age was 69, and 48% were female. 52% were Stage IA, 29% Stage IB, 4% Stage IIA, and 15% Stage IIB. 49% had adenocarcinoma, 29% squamous cell, 12% BAC, and 10% other NSCLC. The genotype frequencies for the MDM2 polymorphism were: T/T 161 (42%), T/G 156 (40%), G/G 68 (18%). Genotype was not associated with age, sex, stage, histology, or smoking status. Median follow-up time was 5.79 years. After adjusting for age, sex, stage, histology, and pack-yrs of smoking, the G/G genotype appeared to be associated with worse RFS and OS (AHR 1.60 (95% CI 1.10–2.34), p = 0.01; AHR 1.56 (95% CI 1.03–2.38), p = 0.04; respectively). In subset analysis, patients with squamous cell cancer and current-smokers had significantly worse survival with the G/G genotype, while there was no significant difference by genotype among adenocarcinomas and non-current smokers. (For squamous cell, 5-yr OS for T/T 59%, T/G 52%, G/G 7%, p = 0.0001; for current smokers, 5-yr OS for T/T 67%, T/G 49%, G/G 27%, p = 0.04). Conclusions: Our findings suggest that the G/G genotype of the MDM2 polymorphism is associated with worse survival among early stage NSCLC patients, particularly those with squamous cell histology and current smokers. Supported by NIH grants CA074386, CA092824, CA090578, FAMRI Young Clinical Scientist Award, Doris Duke Foundation. [Table: see text]
FDG uptake as a predictor of outcome in stage I non-small cell lung cancer
Authors: Viswanathan A. K. , Pillot G. , Goodgame B. , Yang Z. , Shriki J. , Gao F. , Dehdashti F. , Siegel B. A. , Govindan R. 
Published: March 2020

7224 Background: Lung cancer is the leading cause of cancer-related mortality in both men and women in the United States. Over 80% of patients are diagnosed with non-small cell lung cancer (NSCLC) and approximately 30% of patients with NSCLC present with resectable disease. Nearly 40–50% of patients with resected stage I NSCLC develop recurrent disease. Currently there are no clinical, radiological, or molecular markers to predict outcomes following surgery in early stage NSCLC. Positron emission tomography (PET) with 2-[18F] fluoro-2-deoxy-D-glucose (FDG-PET) is used commonly in the staging work up of NSCLC. The standardized uptake value (SUV) is a semiquantitive measure of FDG uptake that correlates with tumor doubling time. We studied the relationship between the maximum preoperative tumor SUV (SUVmax) for FDG and disease-free survival (DFS) in patients with resected stage I NSCLC. Methods: We identified 153 consecutive patients diagnosed with stage I NSCLC between 1999 and 2003 who had undergone FDG-PET before curative surgical resection. Data were collected regarding stage distribution, histology, recurrence and survival. No patient in this cohort received adjuvant chemotherapy or radiotherapy. SUVmax above and below the median was correlated with DFS. Results: Of 153 patients with stage I NSCLC, 90 (59%) had T1 and 63 (41%) had T2 tumors. The mean and median follow-up time for the cohort was 2.9 and 3.1 years respectively. The mean and median SUVs were 7.0 and 6.0 respectively. The 5-year DFS categorized by SUVmax < 6 vs. SUVmax ≥ 6 was 62% vs. 46 (p = 0.0036) for the entire cohort; 64% vs. 54% (p = 0.20) for the T1 subset; and 60% vs. 40% (p = 0.07) for the T2 subset. Conclusions: High SUVmax (≥ 6) on preoperative FDG-PET is a predictor of poor outcome in resectable stage I NSCLC. [Table: see text]
Increased risk of thrombosis with lenalidomide in combination with dexamethasone and erythropoietin
Authors: Niesvizky R. , Spencer A. , Wang M. , Weber D. , Chen C. , Dimopoulos M. A. , Yu Z. , Yu Z. , Delap R. , Zeldis J. , Knight R. D. 
Published: March 2020

7506 Background: Lenalidomide (Len) is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against multiple myeloma (MM) and additive effects when combined with dexamethasone (Dex). At the interim analysis of MM-009/010, lenalidomide/dexamethasone achieved a significant benefit over dexamethasone, providing a longer median time to progression (TTP), higher response rates, and higher CR rates. Aim: This subgroup analysis of MM-009/010 was performed to evaluate thrombosis in patients receiving Len/Dex vs Dex. Thrombotic events included the following adverse event terms: thrombosis, deep venous thrombosis, thromboembolism, and pulmonary embolism. Methods: Patients (pts) with relapsed or refractory MM were randomized to either receive oral Len (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. Results: Thrombotic events were reported in 39 (11.3%) of 346 pts treated with Len/Dex compared to 13 (3.8%) of 346 pts treated with Dex alone (p < 0.001). Multivariate analysis identified Len/Dex treatment and erythropoietic treatment to be independently correlated with thrombosis (Table). Older age, lower plasma cell percentage in marrow, and better ECOG performance status had a weaker association with thrombosis. Thrombosis occurred more frequently among pts with prior history of thrombosis, although that was not a significant predictor in the multivariate anlaysis. None of 23 pts who used aspirin or salicylate during the first month of treatment developed thrombosis and all events occurred in pts with rising M-paraprotein levels at baseline. Conclusions: The current study findings suggest that the administration of erythropoietic agents should be minimized in MM pts receiving Len/Dex. Prophylactic antithrombotic therapy should also be considered. [Table: see text] [Table: see text]
High CR and near-CR rate with bortezomib incorporated into up-front therapy of multiple myeloma with tandem transplants
Authors: Barlogie B. , Anaissie E. , Bolejack V. , Zangari M. , Van Rhee F. , Shaughnessy J. , Hollmig K. , Pineda-Roman M. , Crowley J. , Tricot G. 
Published: March 2020

7519 Background: Tandem autotransplants have increased complete response (CR) rates and extended event-free survival (EFS) and overall survival (OS) in multiple myeloma (MM). Because of its remarkable efficacy in end-stage disease and to further increase CR and thereby improving EFS and OS, bortezomib (Velcade, V) was incorporated into Total Therapy 3 (TT3), both with DT-PACE combination chemotherapy (dex, thalidomide, cis-platin, adriamycin, cyclophosphamide, etoposide) as induction prior to and consolidation after transplant. Methods: TT3 has accrued 247 of a target population of 300 patients; median follow-up is 16 months. Twenty-seven percent of patients were 65 yr and older; cytogenetic abnormalities (CA) were present in 31% and inter-phase FISH-based deletion 13 in 42%. Results: Median times to 1st and 2nd transplants were 3 mo and 5 mo, with projected completion rates of 95% and 82%. The cumulative frequency of CR plus near-CR was 50% at 6 mo, 75% at 12 mo, reaching 80% at 18 mo. Blood stem cells were readily procured, yielding ≥20 million CD34 cells/kg in > 95%. At 12 mo, 91% are alive and 89% event-free. Relapse has occurred in 29 patients, whose distinguishing features included age ≥ 65 yr (48% vs 24%, p = .005), abnormal cytogenetics (CA, 48% vs. 29%, p = .03) and LDH > ULN (48% vs 23%, p = .004). Among 21 deaths, baseline features were: creatinine >4 mg/dL in 4; age ≥ 65 yr in 11; PS > 3 in 5 and PS > 2 in 4; CRP > 10 mg/L in 9 patients. Conclusions: Introducing V in TT3 as part of combination chemotherapy is safe, permits robust stem cell collection and induces remarkably high CR plus near-CR rates. High-risk MM features such as CA and LDH, defined in Total Therapies 1 and 2, also appeared detrimental with TT3. [Table: see text]
Comparison of lenalidomide in combination with dexamethasone to dexamethasone alone in patients who have received prior thalidomide in relapsed or refractory multiple myeloma
Authors: Wang M. , Knight R. , Dimopoulos M. , Siegel D. , Rajkumar S. V. , Facon T. , Yu Z. , Zeldis J. , Olesnyckyj M. , Weber D. M. 
Published: March 2020

7522 Background: Lenalidomide (len), an analog of thalidomide (thal) is a novel, oral immunomodulatory agent that is effective against multiple myeloma (MM). Two randomized, Phase III trials (MM009 and MM010) have recently demonstrated superior responses and overall survival (OS) for patients (pts) treated with len and dexamethasone (dex) in comparison with dex-placebo. This is a prospective subgroup analysis to assess the impact of prior therapy with thal on the sensitivity of MM to subsequent lenalidomide. Methods: We evaluated 692 pts from both trials (MM009 and MM010). The pts had relapsed/refractory MM, were not refractory to dex and were randomized to receive either len (25 mg daily for 3 weeks (wks) every 4 wks) plus dex (40 mg on days 1–4, 9–12, 17–20 every 4 wks for 4 cycles, then 40 mg on days 1–4 every subsequent cycle) or placebo plus dex. Standard criteria were used to evaluate response and TTP. Results: Pooled data from 692 pts showed superior median TTP (48.1 vs 20.1 wks) and OR (59.2% vs 22.5%) in pts treated with len/dex compared to dex-placebo (p <0.001). Although subgroup analysis of pts with prior thal therapy revealed that pts who received len/dex had significantly improved OR, PR CR and median TTP than pts who received dex-placebo, OR, CR and TTP were highest in len/dex pts not previously treated with thal. Multivariate analysis indicates that after controlling for the treatment factor and baseline disease characteristics, whether or not pt had prior exposure to thal is a marginally significant variable to predict TTP. The risk of deep venous thrombosis and pulmonary embolism in these subgroups will be updated on further analysis. Conclusions: Lenalidomide in combination with dexamethasone is more effective than dexamethasone-placebo regardless of prior thalidomide in relapsed/refractory multiple myeloma. [Table: see text] [Table: see text]
A phase II trial of lenalidomide for patients with AL amyloidosis
Authors: Sanchorawala V. , Wright D. G. , Rosenzweig M. , Finn K. T. , Skinner M. , Seldin D. C. 
Published: March 2020

7524 Introduction: A phase II trial was designed to evaluate the toxicity and response rate of lenalidomide (Revlimid, CC-5013), alone and in combination with dexamethasone in patients with AL amyloidosis. Patients with this plasma cell disorder have organ dysfunction that makes them more susceptible to drug toxicity. Methods: Planned enrollment, 35 patients. Regimen: 3 cycles of lenalidomide at 25 mg/d for 21d, with dexamethasone 10 mg bid for 4 days, 3 times a month, every other month, for those patients not responding to lenalidomide alone. Toxicity and responses were evaluated after 1, 3, 6, 9, and 12 months of treatment. Hematologic responses were based upon qualitative and quantitative measures of clonal plasma cell disease. Organ responses were scored according to published criteria. Results: 24 patients have been enrolled to date, age range is 47–76, M:F 18:6, κ:λ 7:17. Organ involvement: 75% renal, 38% cardiac, 18% hepatic or gastrointestinal, 17% neuropathy, 13% soft tissue or lymph node. 22 had been treated previously, and 12 had undergone treatment with HDM/SCT. After none of the first 6 patients tolerated 3 treatment cycles at 25 mg/day, the starting dose was reduced to 15 mg/day. A total of 112 cycles have been administered (1–14 cycles per patient). 2 patients were removed from study because of rashes; one because of gout and severe fatigue; one by choice; and one patient died in the first treatment cycle, apparently due to complications of the underlying disease. Grade 3 toxicities observed included fatigue (33%), hypoalbuminemia (29%), worsening performance status (29%), neutropenia (21%), rash (21%), dizziness (13%), gout (13%), dyspnea (8%), muscle weakness (8%), and pneumonia (8%). One patient (4%) had a DVT on lenalidomide and dexamethasone. 8 out of 13 have had a measureable hematologic response, of which 3 were complete or near complete. 8 patients had elevated free light chains (FLC) with a skewed κ:λ ratio, and 4 of these had ≥50% reduction in FLC level. 4 of 14 patients with proteinuria improved. Conclusion: Lenalidomide is reasonably well-tolerated in patients with AL amyloidosis, and alone or in combination with dexamethasone, can induce excellent hematologic responses and improvement in organ disease. No significant financial relationships to disclose.
Phase I/II results of a second-generation humanized anti-CD20 antibody, IMMU-106 (hA20), in NHL
Authors: Morshhauser F. , Leonard J. P. , Coiffier B. , Petillon M. , Coleman M. , Bahkti A. , Teoh N. , Wegener W. A. , Goldenberg D. M. 
Published: March 2020

7530 Background: The humanized anti-CD20 antibody, IMMU-106 (hA20), has similar murine CDRs to rituximab, but the remaining framework is identical to humanized anti-CD22 IgG1 antibody, epratuzumab, whose safety and short infusion times have been reported. Methods: An open-label, multicenter, phase I/II, dose escalation study was conducted in adult patients with recurrent NHL to establish the safety, tolerance, PK, and immunogenicity (HAHA) of hA20 administered weekly x 4. Thirty-four patients have now received hA20 at 120 (n = 7), 200 (n = 6), 375 (n = 18) or 750 mg/m2 (n = 3). These were predominantly stage III/IV patients (n = 27) with follicular lymphoma (N = 23) who received 1–7 prior treatments (median, 2), including 1 (N = 22) or more (N = 9) rituximab regimens (without progression within 6 months). Results: Thirty-three patients completed all 4 hA20 infusions. Median infusion times at 375 mg/m2 were 3.1 h for 1st infusion, 2.0–2.3 h for subsequent infusions, and were generally shorter at lower doses. Fourteen patients (14%) had transient events, predominantly grade 1–2 events at 1st infusion. Antibody levels increased with hA20 dose; at 375 mg/m2, mean serum half-lives after 1st and 4th infusions were 3.4 ± 1.7 and 12.3 ± 3.9 days, respectively. With median follow-up now 3–6 months, peripheral blood B-cell depletion persists, HAHA evaluations are negative, and 14/23 patients (61%) with response assessments have objective responses by Cheson criteria. All 6 CR/CRu’s (23%) were in follicular lymphoma, occurred at all dose levels even at 120 mg/m2 (including patients with 2–4 prior rituximab-containing regimens ), and with 5/6 continuing. Conclusions: The tolerability, relatively short infusion times, and CR/CRu’s in patients with follicular lymphoma who relapsed after rituximab-containing regimens is encouraging. This study is continuing to assess response durability and to determine the optimal hA20 dose for subsequent studies. [Table: see text]
Bi-weekly dosing preserves the efficacy of rituximab in elderly patients with poor-prognosis DLBCL: Results from the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study group (DSHNHL)
Authors: Schubert J. , Reiser M. , Wenger M. , Kloess M. , Lengfelder E. , Franke A. , Steinhauer H. B. , Clemens M. , Schmitz N. , Loeffler M. , Pfreundschuh M. 
Published: March 2020

7536 Background: The addition of rituximab (R) to 3-weekly CHOP-21 improved overall results in elderly patients with DLBCL, but was more effective in good-prognosis (g-p: IPI = 1,2) than poor-prognosis (p-p: IPI = 3,4,5) patients (JCO 23:4117, 2005). Similarly, addition of R to bi-weekly CHOP-14 in the RICOVER-60 trial resulted in improved time to treatment failure (TTF) in 828 elderly (61–80 years) DLBCL patients (Blood 106:9a, 2005). To study the effects of R when combined with CHOP-14 in different subgroups of elderly DLBCL patients. Methods: Intention-to-treat-analysis of the primary endpoint time-to-treatment-failure (TTF) and the secondary endpoint overall survival (OS) in the subgroup of g-p and p-p patients treated within the RICOVER trial which compared 6 and 8 cycles of CHOP-14, both with and without R. Results: Of 828 evaluable patients (61–80 years, stage I-IV), 503 had g-p (CHOP-14 = 252; R-CHOP-14 = 251) and 325 p-p (CHOP-14 = 161; R-CHOP-14 = 163). After a median observation of 26 months, there was no difference between 6 and 8 cycles in either subgroup. In contrast, addition of R resulted in a similar improvement of TTF in both g-p (67% vs. 81%, p = 0.001) and p-p (36% vs. 52%, p = 0.004) patients. The improvement of survival is not yet different in either group: g-p: 82% (CHOP-14) vs. 88% (R-CHOP-14), p = 0.458; p-p: 58% (CHOP-14) vs. 64% (R-CHOP-14), p = 0.146. Pharmacokinetic studies show a pronounced nadir of R levels after the first R-CHOP-14, with R levels increasing after each subsequent cycle. The R nadir after the first R-CHOP is expected to be even more pronounced in a 3-weekly schedule and might explain the small improvement reproted for 3-weekly R in elderly patients with p-p DLBCL. Conclusions: Our subgroup and pharmacokinetic analysis indicate that not only dose-dense chemotherapy, but also dose-dense rituximab contribute to the excellent results of the RICOVER-60 trial. Supported by Deutsche Krebshilfe. [Table: see text]
Weekly bortezomib in the treatment of patients (pts) with previously treated multiple myeloma: A phase II trial of the Minnie Pearl Cancer Research Network
Authors: Greco F. A. , Spigel D. R. , Barton J. H. , Farley C. , Schreeder M. T. , Hermann R. C. , Hainsworth J. D. 
Published: March 2020

7547 Background: Bortezomib, administered on a twice-weekly schedule, is now a standard part of treatment for patients with multiple myeloma. Weekly bortezomib schedules have shown activity in other cancer types, and are more convenient than twice weekly schedules. In this multicenter, community-based phase II trial, we evaluate the feasibility, toxicity, and efficacy of weekly bortezomib in pts with previously treated multiple myeloma. Methods: Eligibility criteria included a diagnosis of multiple myeloma treated with 1 or 2 previous systemic regimens (only 1 if first-line therapy included high-dose therapy); ECOG PS 0–2; creatinine < 2.0 mg/dL; WBC ≥ 3000/μL; ANC > 1000/μL; platelets ≥ 50,000/μL; no peripheral neuropathy > grade 1; informed consent. All pts received bortezomib 1.6mg/m2 IV on days 1, 8, 15, and 22 of each 5-week cycle. Pts were reevaluated at 10-week intervals; treatment continued for 8 cycles (40 weeks) or until myeloma progression. Results: Between 5/04 and 12/05, 37 pts entered this trial. Pt characteristics: median age 70 years; male/female, 20/17; 24 pts (65%) had received 2 previous regimens (previous high dose therapy, 2 pts); elevated β-2 microglobulin, 27 pts (73%). Of 26 pts evaluated, 13 pts (50%) had major responses, 11 pts (42%) stable disease, and 2 pts (8%) had progression. After a median follow-up of 7 months, projected median PFS is 9.6 months; overall survival at 1 year is 81%. Weekly bortezomib was well tolerated by most pts. Grade 3/4 toxicities included fatigue (21%), diarrhea (11%), neutropenia (7%), thrombocytopenia (4%), all others < 5%. No grade 3/4 neuropathy occurred. Only 1 pt required bortezomib dose reduction during treatment, and 2 pts discontinued treatment because of toxicity (myelosuppression, 1; fatigue/dehydration, 1). Conclusions: Weekly bortezomib is a convenient, well tolerated treatment for pts with previously treated multiple myeloma. Overall response rates with this schedule are similar to those previously reported with the standard twice-weekly schedule. Further followup is necessary to better evaluate the duration of response and the incidence of cumulative toxicities. [Table: see text]
JC human polyomavirus (JCV) and Epstein-Barr virus (EBV) replicative activities are detected in Hodgkin/Reed Sternberg cells (HRS) and circulating lymphocytes (PBL) of Hodgkin lymphoma (HL) and associated with relapse, especially in younger patients
Authors: Carde P. , Andreoletti L. , Koscielny S. , Assaf E. , Girinsky T. , Bosq J. , Bernheim A. , Flamant S. , Violot D. , Parmentier C. , M’Kacher R. 
Published: March 2020

7551 Background: The HRS derive from germinal-center B-cells, potential sites for latency and reactivation of JCV in immunosuppressed individuals. Replication of human polyomaviruses (JC, BK, SV40) and EBV was assessed in Hodgkin (HL) and B cell non-Hodgkin (B-NHL) lymphomas. Methods: FISH, immunohistochemistry for oncogenic proteins, PCR and DNA sequencing to identify polyomaviruses and EBV on involved nodes and in PBL before, during and after treatment (N = 73 HL, 91 B-NHL). Controls were 30 healthy donors, 70 solid tumors and 14 acute leukemia patients. Results: using FISH, JCV and EBV DNA were detected in all lymphoma nodes. High genome copy number of JCV and EBV were present in 60% and 63%, respectively, in HL patients versus 11% and 14% in B-NHL patients (P < 10−6; P < 10−5). Using nest-PCR, JCV DNA sequencing after laser capture microdissection identified the presence and specificity of JCV sequences in HRS. T antigen and LMP1 co-expression, in 34% of HRS, was associated with early HL relapse (P < 10−4), particularly in young patients (P < 10−5). Only in HL patients PBL, genome copy number of JCV increased significantly during treatment (42%). Rogue cells (cultured lymphocytes with multiple complex chromosomal aberrations indicative of genomic instability) appeared in 40% of patients, and correlated with relapse (p < 10−4). The same JCV sequences were found in tumor cells and PBL of HL patients. Co-genomic replication of EBV and JCV was highly correlated in lymph nodes and in PBL in HL. Conclusions: JCV genomic replication was detected for the first time in HRS, and associated to rogue cell emergence in PBL. Co-detections of JCV and EBV genomic replication in HRS and PBL are associated with relapse, especially in young patients. HRS and PBL JCV/EBV infections are linked and worth further studies. No significant financial relationships to disclose.