bluuebunny/crossref_metadata_2025_split huggingface dataset:
Somatically mutated immunoglobulin VH genes without intraclonal heterogeneity indicate a post germinal center origin of primary intraocular diffuse large B-cell lymphomas
Authors: Malumbres R. , Davis J. , Ruiz P. , Lossos I. S. 
Published: March 2020

8072 Background: Primary intraocular lymphoma (PIOL) is a very rare high grade malignant non-Hodgkin lymphoma, usually of the diffuse large B cell lymphoma (DLBCL) type, which presents in the vitreous, retina and/or the optic nerve. Sixty to 80% of patients with PIOL eventually disseminate to the brain, whereas up to 15% of primary central nervous system lymphoma (PCNSL) patients exhibit ocular involvement. For these reasons, PIOL is regarded as a subtype of PCNSL. Analysis of the immunoglobulin heavy chain (VH) sequences in PCNSL tumors demonstrated biased overrepresentation of the VH4–34 gene and indicated derivation of these tumors from highly mutated germinal center (GC) B cells with ongoing mutational activity. Whether PIOL tumors are of similar or different origin is presently unknown. Methods: Immunoglobulin VH genes were examined in vitrectomy specimens of 4 PIOL patients, 1 patient with concomitant PCNSL and 1 patient with systemic DLBCL involving the eye. The extracted DNA was amplified by PCR using VH family specific primers, cloned and sequenced. Results: Seven clonal VH rearrangements belonging to the VH4, VH3 and VH1 families were cloned from the analyzed cases. In concordance with previous reports, the lymphomatous eye infiltrate from the PCNSL patient revealed a mutated clonal VH4–34 gene with intraclonal heterogeneity -a manifestation of active ongoing mutational activity. All the PIOL clonal VH rearrangements also exhibited mutated sequences with homology to the germline sequences ranging between 76 to 95%. However, in contrast to PCNSL, 3 out of 4 PIOL cases exhibited no intraclonal heterogeneity while the remaining case demonstrated ongoing somatic mutations in one of the 2 clonal VH rearrangements detected in this tumor. Interestingly, the clinical course of this patient was highly unusual, since he exhibited systemic dissemination during follow-up. Conclusions: Analysis of VH gene sequences from PIOL tumors indicate a post- GC derivation and suggest that they belong to the activated B cell (ABC)-like subtype of DLBCL. This is in contrast to the GC-origin of closely related PCNSL. No significant financial relationships to disclose.
Improved outcome after sequential brief induction conventional chemotherapy, concurrent chemoradiation (cCRT), consolidation high-dose chemotherapy (HDCT) or further conventional chemotherapy for early stage CD56+ natural killer (NK)/T-cell lymphoma
Authors: Yiu H. , Ngan R. K. , Cheng H. , Wong K. , Cheung M. , Lau W. 
Published: March 2020

8075 Background: Nasal NK/T lymphoma is uncommon but prognosis is universally poor even in early stage disease. Chemotherapy is often added to radiation for improving outcome although its role has not been well defined. Methods: Since 1998, an intensive protocol has been introduced for pts with stage I or II disease, which consists of 3 cycles of anthracycline-based (CHOP or ProMACE-CytaBOM) chemotherapy to be followed by cCRT (50–54Gy radiotherapy with weekly cisplatin at 40mg/m2) for pts with adequate renal function, and then consolidation HDCT. Cyclophosphamide, BCNU & Etoposide HDCT was offered to pts <60 years with adequate organ functions. Otherwise, 3 more cycles of conventional chemotherapy were given. Results: Out of the 27 pts recruited into the intensive protocol up till 2005, 23 completed cCRT & 14 received HDCT. Six pts had failed either locally or systemically, among whom 2 local failures were salvaged by further local radiotherapy. Eight patients had died with 4 related to lymphoma progression, 3 due to treatment complications and 1 died of prevailing medical illness. A preceding cohort of 35 pts intended to be treated with combined sequential conventional chemotherapy and radiotherapy only (sCRT: n=35) from 1986 to 1997 was also analyzed and compared with the current cohort (cCRT: n=27). Pts in both groups had similar characteristics. The type of intended treatment was a statistically significant factor for 6-year failure-free survival (sCRT 22.9%, cCRT 65.9%; p=0.0049, log-rank test) and overall survival (sCRT 36.4%, cCRT 69.8%; p=0.05, log-rank test), so are B symptoms (present Vs absent) and stage (I Vs II). Conclusions: The intensive protocol with sequential brief induction conventional chemotherapy, cCRT, and consolidation HDCT / conventional chemotherapy in appropriate pts was feasible, leading to better outcome than the combination of sequential conventional chemotherapy and radiation alone. The relative contributions of cCRT and HDCT to the improved outcome should be further explored. No significant financial relationships to disclose.
A phase IB safety and pharmacokinetic (PK) study of recombinant human Apo2L/TRAIL in combination with rituximab in patients with low-grade non-Hodgkin lymphoma
Authors: Yee L. , Fanale M. , Dimick K. , Calvert S. , Robins C. , Ing J. , Ling J. , Novotny W. , Ashkenazi A. , Burris H. 
Published: March 2020

8078 Background: Recombinant human Apo2L/TRAIL (rhApo2L/TRAIL) induces apoptosis (programmed cell death) through binding to the pro-apoptotic receptors DR4 and DR5. Preclinical studies show that rhApo2L/TRAIL selectively induces apoptosis in many cancer cell lines derived from various malignancies including NHL, while sparing most normal cells. In vivo, rhApo2L/TRAIL and Rituximab cooperate to shrink or attenuate the growth of various NHL tumor xenografts in SCID mice. RhApo2L/TRAIL is being co-developed by Genentech and Amgen as a targeted therapy for solid tumors and hematologic malignancies. Methods: Subjects were eligible to participate if they had CD20+ follicular NHL or small lymphocytic lymphoma or marginal zone B-cell lymphoma that had progressed following stable disease or an objective response lasting > 6 months duration to the most recent rituximab-contain regimen. RhApo2L/TRAIL is administered intravenously over 1 hour for 5 consecutive days every three weeks up to 4 cycles at dose levels of 4 and 8 mg/kg. Rituximab is administered intravenously at 375 mg/m2 weekly for up to eight doses. Results: Six subjects with low grade NHL (4 with follicular NHL and 2 with small cell NHL) have been enrolled and treated with 4 mg/kg rhApo2L/TRAIL and rituximab, and one subject (with follicular NHL) has been enrolled and treated with 8 mg/kg rhApo2L/TRAIL and rituximab. The enrolled subjects range in age from 39–82 years; there are 6 male and 1 females. The number of prior therapies for NHL range from 1–8. Four subjects have received all protocol specified therapy. There have been no DLTs or SAEs or Grade 3/4 adverse events reported to date. To date, five subjects have undergone tumor response assessment: there have been 2 patients with complete response, 1 with partial response and 2 with stable disease. Conclusion: The combination of rhApo2L/TRAIL at 4 mg/kg/day and rituximab appears safe and shows evidence of activity in subjects with low grade NHL that has relapsed following previous rituximab-containing therapy. Enrollment is continuing to test rhApo2L/TRAIL at 8 mg/kg plus rituximab for expanded safety data and further dose optimization. No significant financial relationships to disclose.
Cost-effectiveness of tositumomab and iodine I-131 tositumomab (Bexxar therapeutic regimen (BTR)), in treatment of non- Hodgkin lymphoma (NHL)
Authors: Flowers C. R. , Sambrook J. C. , Briggs A. , Osenenko K. , Wang H. , Dalal M. R. 
Published: March 2020

8089 Background: BTR has demonstrated efficacy in NHL patients and it has potential to prolong time to progression (TTP) in relapsed/refractory, low grade, follicular, or transformed NHL. This study assessed effectiveness and cost-effectiveness of BTR compared to alternative therapies in first, second, and third line NHL therapy. Methods: Time-to-event models were constructed with 2 events: progression and death. Patient data from 8 BTR clinical trials were combined to fit Weibull models for TTP and overall survival (OS) by including FLIPI covariates. Estimates for BTR were compared with estimates for alternatives from Weibull models fitted to published TTP and BTR OS data by lines of therapy and measured in life-years (LY). Estimated pre-progression costs included drug costs, lab tests, monitoring, and adverse events; post progression costs included NHL costs until death, all valued in 2006 $US and discounted at 3%. Indirect comparisons yielded incremental cost-effectiveness ratios (ICER=Δ cost/Δ LYs) in each line of therapy. Results: As observed in the table , cost of care estimates in BTR were often comparable with alternative therapies, but typically LY gain favored BTR. Mostly in first and third line, a BTR strategy had an ICER less than the cost-effectiveness threshold of $50,000 per LY gained. Conclusion: Overall, a BTR strategy has a favorable cost-effectiveness profile to alternative strategies including rituximab maintenance (RXM) in first, second, and third line NHL therapy. Results imply both a possible survival gain with early BTR use, and the cost-effectiveness of BTR. This modeling approach can aid in clinical decision making regarding the sequence and timing of therapy for patients with follicular NHL. No significant financial relationships to disclose. [Table: see text]
Contribution of constitutive activation of Akt to the pathogenesis of mantle cell lymphoma (MCL) independent of PTEN protein expression
Authors: Economopoulou C. , Psyrri A. , Liakata E. , Papageorgiou S. , Economopoulou P. , Kontsioti F. , Pappa V. , Economopoulos T. 
Published: March 2020

8101 Background: To determine whether the PI3K/Akt signaling pathway is involved in the pathogenesis of mantle cell lymphoma (MCL), we investigated the phosphorylation status of Akt in primary MCL cases and cell lines. We also sought to determine whether loss of the phosphatase PTEN is the mechanism of Akt activation in MCL. Methods: We evaluated the protein levels of Akt, phosphorylated Akt and PTEN in 15 primary MCL cases and 2 cell lines by immunoblotting Results: Akt was phosphorylated in 3 of 15 MCL cases and in 2 of 2 mantle cell lymphoma cell lines. PTEN protein was expressed in 15 of 15 primary mantle cell lymphoma cases and in 2 of 2 MCL cell lines. Conclusions: We conclude that constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis of MCL. Loss of PTEN protein expression is not the responsible mechanism for Akt activation. Alternative mechanisms of Akt activation are being evaluated to identify markers predictive for response to PI3K/Akt inhibitors in MCL. No significant financial relationships to disclose.
The effect of induction therapy with novel agents on stem cell mobilization in multiple myeloma
Authors: Mazumder A. , Jagannath S. , Vesole D. 
Published: March 2020

8102 Background: Thalidomide or bortezomib combined with dexamethasone (TD or BD respectively) are now being increasingly used as induction regimens for newly diagnosed multiple myeloma. There are conflicting reports on the effects of T on stem cell mobilization. Since we have used both these regimens at our center, we performed a retrospective analysis of stem cell mobilization after induction therapy with either TD (n = 22) or BD (n = 18). Methods: The patients were balanced with respect to initial Durie-Salmon stage, median number of cycles of induction therapy prior to collection, response to induction therapy, bone marrow cellularity and involvement, and time from end of therapy to collection. All patients were mobilized with G-CSF 10mcg/kg and collected in a large volume pheresis, with a goal of at least 6x10(6) CD34+ cells/kg (for tandem transplant). Results: To achieve our stem cell goal, the number of patients who required 3 or more phereses in the TD group was 17/22 whereas it was only 4/18 in the BD group. (p<0.005). 3/3 patients who had received lenalidomide also required 3 or more phereses. Also, the number of CD34+ cells/kg obtained in the TD group was less–mean of 2.8x10(6) per pheresis, as compared to a mean of 5.2x10(6) per pheresis in the BD group (p<0.01). Time to neutrophil engraftment was similar in both groups. However in the TD group there was a 1 day delay in platelets > 20,000/ul (p<0.05). Conclusions: Thus, thalidomide induction led to a lower yield of stem cells when compared to bortezomib. Differences in stem cell markers are being investigated. This may become especially important when limiting numbers of stem cells are available from elderly patients, those with prior radiation or bulk disease and when used for in vitro manipulation. It is possible that agents such as bortezomib may alter the bone marrow microenviroment differently from imids such as thalidomide. No significant financial relationships to disclose.
Risk of renal failure associated with IV bisphosphonate use in patients with multiple myeloma
Authors: Joyce A. T. , Harrison D. J. , Jun S. , Feliu A. L. , Anthony M. 
Published: March 2020

8104 Background: IV Bisphosphonates including zoledronic acid (ZA) and pamidroniate are frequently used to delay time to skeletal related events in patients with multiple myeloma. The risk of renal toxicity with these agents is well known and regular monitoring of kidney function is required. Despite regular monitoring of creatinine, patients taking IV bisphosphonates may experience decreased renal functioning and renal failure. The purpose of this study was to determine the relative risk of renal failure in patients with multiple myeloma treated with ZA or pamidronate relative to patients whose lytic lesions remained untreated with medications. Methods: Commercially insured adults newly diagnosed with multiple myeloma 7/1/2002–6/2006 were identified using ICD-9 codes within the PHARMetrics Integrated Outcomes Database. Patients were stratified based on evidence of IV bisphosphonate use (treated) or no such evidence (untreated) following initial qualifying diagnosis. For treated patients, the date of first administration of an IV bisphosphonate was the patient's index date. Treated patients were matched to untreated patients based on use of radiation therapy or chemotherapy, year of cancer diagnosis, and health plan enrollment duration.The incidence rate (IR) for renal failure defined using ICD-9 codes was based on number of incident cases identified among the total person-years at risk and expressed as a rate per patient year. IRs and incidence rate ratios (IRR) (comparing the treated to untreated cohorts), with corresponding 95% confidence intervals are reported. Results: Treated (n=401) and untreated (n=431) patients were similar with respect to age (mean 56 years in both cohorts), but treated patients were more likely to be female (54% vs. 47%; p = 0.04) and less likely to have a history of anemia (48% vs. 51%; p=0.002). IV bisphosphonate use was associated with an 8.5% incidence of developing renal failure per patient year versus 4.9% in the untreated cohort (IRR 1.72; 95% CI 1.22–2.42). The risk was similar whether patients were treated with ZA or pamidronate. Conclusions: IV bisphosphonate use was associated with a significantly increased risk (72%) of developing renal failure in patients with multiple myeloma. No significant financial relationships to disclose.
An analysis of erythropoietin (EPO) and venous thromboembolic events (VTE) in multiple myeloma (MM) patients (pts) treated with anthracycline-based chemotherapy and the immunomodulator agent thalidomide
Authors: Baz R. C. , Walker E. , Kelly M. , Hussein M. A. 
Published: March 2020

8107 Background: The use of EPO has recently been reported to be associated with higher rates of VTE in MM pts receiving lenalidomide or thalidomide and dexamethasone (Knight et al. NEJM 2006). Uncontrolled erythrocytosis, a recognized risk factor for VTE, may complicate therapy with EPO when the hemoglobin is not carefully monitored. Other risk factors such as renal failure in this pt population might contribute to hypercoagulability. We sought to evaluate the contribution of EPO use to the development of VTEs in pts with MM treated with the immunomodulator agent thalidomide in combination with chemotherapy. Methods: We retrospectively reviewed records of 105 pts enrolled on a clinical trial for newly diagnosed or relapsed MM pts with pegylated liposomal doxorubicin, vincristine, dexamethasone and thalidomide (DVd-T). In this study pts pts were aggressively monitored for VTE as previously described (Hussein et al Mayo Clin.Proc. 81 (7):889–895, 2006). Demographic variables, aspirin therapy (on intent to treat basis), EPO therapy, as well as the occurrence of VTEs were extracted. Results: The median age was 63 years and 62 (59%) received EPO in conjunction with their MM therapy. VTE prophylaxis with aspirin (81mg daily) was administered to all but 21 pts. Of the 62 pts receiving EPO, 15 (24%) had a VTE compared to 11 (26%) who did not receive EPO (OR 0.928, 95% CI 0.38 - 2.3). Among the 21 pts who did not receive aspirin as VTE prophylaxis, 11 (52%) experienced a VTE compared to 18% (15/84) in those who did receive aspirin as VTE prophylaxis (OR 5.1, 95% CI 1.8 - 14). In the subgroup of 62 pts that received EPO, 54% (7/13) of pts who did not receive aspirin developed a VTE compared to 16% (8/49) who received aspirin and developed a VTE (OR 6, 95% CI 1.6 - 22.6), which is comparable to the overall study population. Conclusions: These results do not indicate an association between EPO use and VTE in MM pts receiving anthracycline-based chemotherapy with the immunomodulator thalidomide and on intent to treat basis low dose aspirin is effective in reducing the incidence of VTE with this complex regimen. [Table: see text]
ZIO-101 (S-dimethylarsino-glutathione): Phase I/II trials in advanced/progressive multiple myeloma
Authors: Berenson J. R. , Jaganath S. , Reece D. , Boccia R. , Soebel R. , Belch A. , Schwartz B. , Gale R. P. , Hussein M. 
Published: March 2020

8109 Background: ZIO-101(S-dimethylarsino-glutathione), a novel organic arsenic, is active against multiple cancers including myeloma in vitro and in animal models. In vitro, it is active at low concentrations in cancers resistant to arsenic trioxide. Anti-cancer activity is multifaceted and is mediated by disrupted mitochondrial function, increased reactive oxygen species (ROS) production, modified signal transduction and anti-angiogenesis. Methods: (1) Phase I/II study to determine maximum tolerated dose (MTD), dose- limiting toxicity (DLT), safety-profile and preliminary efficacy in patients with advanced/progressive myeloma receiving ZIO-101 daily for 5 consecutive d every 4 w; (2) comparison of this schedule at MTD with a schedule of 420 mg/me2/d twice/w for 3 w every 4 w. Results: (1) phase I/ II: 19 patients have been treated so far. Median age is 61 y (range, 41–84 y). Median N prior therapies was 8 (range, 4–10). ZIO-101 was well-tolerated; MTD was 420 mg/me2/d for the 5 d schedule, and DLT was transient confusion /ataxia. No clinically- important biochemical, bone marrow, or cardiac toxicities were seen and there was neither neuropathy nor QTc-prolongation. Pain during peripheral infusion was reported in some patients. Anemia was the only adverse event = grade-3 in 25% of subjects. 6 of 14 evaluable subjects had stable disease (SD) =8 w and 2, SD > 6 mo. Accrual to the phase II portion continues. Conclusions: ZIO-101 was well- tolerated. In the daily for 5 consecutive d every 4 w schedule, the MTD is 420 mg/me2/d and DLT, transient confusion /ataxia. There was SD in 43% of patients with advanced/progressive myeloma, of whom half are beyond 6 months. Accrual into the phase II part of this study continues. No significant financial relationships to disclose.
Expression and immunogenicity of the cancer-testis antigen CT7 (MAGE-C1) in patients with multiple myeloma
Authors: Curioni Fontecedro A. , Knights A. J. , Tinguely M. , de la Rosa O. , Lopes B. , Moch H. , Renner C. , Zippelius A. , Knuth A. 
Published: March 2020

8112 Introduction: CT7 (MAGE-C1) is an antigen with restricted expression in cancer and testis (CT antigen). It has been demonstrated to be expressed in more than 55% of Multiple Myeloma (MM) bone marrow biopsies (BMB). CT7 immunogenicity was so far unknown. Thus we aimed to analyse the immune response of MM patients towards CT7. Moreover, we evaluated correlations between CT7 expression and prognostic features. Methods: The CT7 gene was cloned from a MM cell line by RT-PCR; the protein has been expressed in E. coli, purified by affinity FPLC and analysed by Mass Spectrometry. MM patients’ sera (1:200 dilution) were analysed towards the CT7 full length protein by Western Blot (WB) and against truncated CT7 by WB and ELISA. BMB were analyzed by immunohistochemistry (IC) for CT7 expression and for proliferation/differentiation markers. Specific chromosomal aberrations were investigated by FISH analysis. Results: Both full-length and truncated proteins have been produced and fully sequenced. Out of 55 patients’ sera 12 typed positive for the full length protein by WB analysis. Ten of sixteen (62.5%) BMB were positive for CT7. So far no correlation with prognostic features was established. Conclusions: For the first time the in vivo immunogenicity of CT7 was demonstrated. Our preliminary data indicate that spontaneous anti-CT7 humoral responses occur in a significant proportion of MM patients. All detectable humoral responses observed to date are in patients with advanced disease. Characterization of antibody-binding sites and specific CD8/CD4 T cell responses in MM patients is on-going. Our data support the broad and strong expression of CT7 in patients with MM. To date CT7 represent the most immunogenic cancer testis antigen in MM. No significant financial relationships to disclose.