bluuebunny/crossref_metadata_2025_split huggingface dataset:
New prognostic loci related to the survival of patients with advanced non-small cell lung cancer receiving chemotherapy: A genome-wide association study.
Authors: Lee Young Joo , Yoon Kyong-Ah , Joo Jungnam , Lee Donghoon , Han Ji-Youn , Lee Jin Soo 
Published: March 2020

e18119 Background: We investigated prognostic significance of genetic variants identified by genome-wide association study (GWAS) for the patients with advanced non-small cell lung cancer (NSCLC). Methods: Among the patients included in our previous GWAS paper for lung cancer risk, we selected 348 patients with stage IV NSCLC, who had started chemotherapy in May 2002 through December 2005 at the National Cancer Center Hospital, and had the follow-up data available. After applying quality control criteria, the association of 271,817 genotyped SNPs with overall survival was analyzed by the Cox proportional hazard regression model adjusted with known prognostic factors using the bootstrap resampling procedure. Results: Overall, the median age of patients was 56 years, 64.9% were female, 67.2% were never smokers, and 80.4% had adenocarcinoma; 73.0% received platinum-based chemotherapy and 73.6 % received EGFR-TKIs. The median survival time (MST) for all patients was 25 months. A total of 23 SNPs with MAF of >0.05 were selected using a cut-off minimum p-value of <5x10-5 (either in additive or dominant models) in at least 70% of a thousand bootstrap samples. Those SNPs were known to be located in the genomic coding region of the FAM154A, EGF, NCOA2, CDH8, ANKS1A, DLST, VGCNL1, SLC35D2, and THSD7B. Carrying a variant genotype of rs1571228 SNP located on the FAM154A, for example, was significantly associated with better overall survival with MST of 29.6 months for those with AG/GG (n=144/30) genotypes vs. 21.5 months for those with AA (n=173) genotype under the dominant model (hazard ratio of 0.52 [95% CI, 0.42-0.67], p = 2.03 x 10-7). This association remained consistent in a subgroup of patients who received platinum-based chemotherapy (n= 254, p = 1.69 x 10-6) or EGFR-TKIs (n = 256, p = 9.04 x 10-6). Conclusions: Genetic variants at multiple loci were found to be prognostically important for patients with advanced NSCLC, which warrants further investigation into its biological relevance and clinical implication.
DNA repair components modulating the function of breast cancer susceptibility gene 1 (BRCA1) in advanced non-small cell lung cancer (NSCLC) patients (p) treated with platinum-based chemotherapy.
Authors: Bonanno Laura , Costa Carlota , Majem Margarita , Sanchez Jose Javier , Gimenez Capitan Ana , Vergnenegre Alain , Massuti Bartomeu , Mayo Clara , Molina-Vila Miguel Angel , Favaretto Adolfo G. , Pallares Cinta , Benlloch Susana , Rugge Massimo , Taron Miquel , Rosell Rafael 
Published: March 2020

e18130 Background: The standard first-line treatment for advanced NSCLC p with wild-type epidermal growth factor receptor (EGFR) is platinum-based chemotherapy, but median overall survival (OS) is about 12 months, with great heterogeneity in terms of efficacy and tolerability. Low BRCA1 mRNA expression has been correlated with sensitivity to cisplatin, but BRCA1 function is modulated by other DNA repair components. For example, AEG1 can induce BRCA1 expression, and CASPASE 3 cleaves the mediator of DNA damage checkpoint 1 (MDC1) preventing the activation of the DDR pathway Methods: Paraffin-embedded samples were collected from 115 advanced NSCLC p treated with first-line platinum-based chemotherapy (not including taxanes and vinca alkaloids). Samples were screened for EGFR, KRAS and p53 mutations, and gene expression levels of BRCA1, RAP80, AEG1, MDC1, CASPASE 3, 53BP1, MMSET, PIAS4, UBC9, UBC13, NPM1 and HERC2 were quantified by real-time PCR. Results: Gene expression levels were significantly higher in squamous tumors, and the correlation among genes confirmed the biological model. Median OS was 11 months and median progression free survival (PFS) was 7.1 months. In p with low levels of both BRCA1 and RAP80, PFS was 12 months and OS was not reached, while in p with high level of both genes, PFS was 5.1 months and OS was 6.2 months and in p with other combinations, PFS was 7.4 months and OS was 10.9 months (P=0.02). Increased levels of AEG1 increased the risk of death (HR: 1.3; P=0.01) and of progression (HR: 1.2; P=0.04). When CASPASE 3 levels were divided into tertiles, intermediate levels were associated with improved PFS (P=0.005) and OS (P=0.05). The multivariate analysis confirmed the role of BRCA1 (P=0.02) and CASPASE 3 (P=0.008). Conclusions: The study showed the predictive value of combined BRCA1 and RAP80 mRNA levels. In addition, AEG1 and CASPASE 3 have emerged as potential predictive markers.
A retrospective study analyzing activity of ofatumumab in blastic variant mantle cell lymphoma.
Authors: Ghai Vikas , Sharma Kamal , Hasanali Zainul , Shimko Sara , Stuart August , Liao Jason , Epner Elliot E 
Published: March 2020

e18500 Background: The blastic variant (BV) form of mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin's lymphoma (NHL) for which no standard of care exists. Ofatumumab is a CD20-directed monoclonal antibody (mAb) FDA approved for the treatment of patients with CLL. We retrospectively studied relapsed BV of MCL in patients treated with regimens containing ofatumumab and previous or concurrent epigenetic therapy (cladribine (2-CdaA) and vorinostat). Methods: BV was confirmed by histopathological patterns, ki-67 proliferation index, immunophenotyping, and t(11;14) by FISH and/or cyclin D1 overexpression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression free survival and complete response. Correlative studies to support the hypothesis that epigenetic modulation of multiple genes in multiple pathways can potentiate the activity of mAbs were performed. Results: Ofatumumab administered to 5 Stage IV BV of MCL patients (Table). 3/5 patients had a radiological complete response, lasting 21.1, 13.4 and 12 months, The other 2 patients had partial response and are on the maintenance. Observed PFS in this cohort is a median 13 months (2.7-20.7). Correlative studies following epigenetic therapy found upregulation of the following genes by RT-PCR: NOXA1 (3/5 patients), CEBP1 (2/5) and EZH2 (2/5). Conclusions: Epigenetic drugs can augment the activity of mAbs. In this case, a more potent mAb improves response in MCL. Correlative studies to support the hypothesis that epigenetic modulation of multiple genes in multiple pathways can potentiate activity of mAbs. The combination of 2-CdA and vorinostat synergistically activates genes silenced by histone deacetylation, histone methylation and DNA methylation and enhances the activity of the mAb ofatumumab. [Table: see text]
Unusual primary presentations of mantle cell lymphoma in the urinary tract and testes.
Authors: Peker Deniz , Kubal Timothy Edward , Sotomayor Eduardo M. , Sokol Lubomir , Cultrera Jennifer L. , Bello Celeste M. , Chervenick Paul A. , Sagatys Elizabeth , Naghashpour Mojdeh , Zhang Ling , Moscinski Lynn , Shah Bijal D. 
Published: March 2020

e18503 Background: The initial clinical presentation of Mantle Cell Lymphoma is protean, ranging from single sites of indolent disease followed for years without therapy to aggressive disseminated disease that requires treatment within weeks of diagnosis. While many cases of Mantle Cell Lymphoma present with disseminated disease, other patients may present with symptoms related to a primary extranodal site of disease. The majority of these primary extranodal cases are diagnosed in the gastrointestinal tract, other cases have been noted in the skin, conjunctiva, testes and male genitourinary tract. Methods: Database review of 204 patients diagnosed with Mantle Cell Lymphoma at Moffitt Cancer Center between May 1992 and December 2010. Results: Three cases of Mantle Cell Lymphoma presented with symptoms related to primary extranodal sites in the urinary tract and male genital organs. Two cases of testicular involvement presented with gradual enlargement of the testes. In patient 1, the orchiectomy specimen harbored both seminoma and mantle cell lymphoma. Low level bone marrow involvement by mantle cell lymphoma was present and in the presence of indolent features he was treated for his primary seminoma and followed expectantly for mantle cell lymphoma. In patient 2, orchiectomy revealed a pleomorphic variant of mantle cell lymphoma with no other sites of disease on staging workup. He was treated with 6 cycles of R-CHOP and prophylactic IT methotrexate with a complete remission. A third patient presented with obstructive urinary symptoms and was found to have mantle cell lymphoma of the prostate. Additional staging revealed diffuse lymphadenopathy, colon and bone marrow involvement. A complete remission was obtained with 6 cycles of R-CHOP. None of these three patients was found to have evidence of CNS involvement at diagnosis or in followup with only the second patient receiving intrathecal prophylaxis. Conclusions: Mantle Cell Lymphoma may present with unusual extranodal involvement at diagnosis including sites and symptoms related to the genitourinary tract and testes. Diagnostic lumbar puncture and intrathecal prophylaxis should be considered in these patients.
Positron emission tomography scan (PET) in human T-cell lymphotropic virus-1 (HTLV) associated adult T-cell leukemia lymphoma (ATLL): Single center experience.
Authors: Sidhu Gurinder Singh , Preet Mohan , Latif Rabia , Axiotis Constantine A , Braverman Albert S. 
Published: March 2020

e18504 Background: Serologic positivity for HTLV and ATLL are endemic amongst Caribbean populations. Kings County and University Hospital of Brooklyn serve population with large number of immigrants from this region. ATLL in this population is mostly of aggressive (leukemia/lymphomatous) type. Responses to chemotherapy (CT) are brief, and 90% succumb to ATLLwithin 18 months (m) of presentation. Lactic dehydrogenase (LDH) levels are high, but PET is not used in routine staging. Methods: Records of all patients with ATLL presenting to these institutions between 2001-11 were reviewed. The results of PET, including maximum standard uptake value (SUVmx) were recorded for scans obtained before (12) and after (19) initial CT, and at relapse (13). Results: Of 95 T cell lymphoma patients, 73 had ATLL. PET was performed in 26 of the 73 patients; 20 of the 26 had ATLL, 5 had other T cell lymphomas. Infusional etoposide, vincristine, doxorubicin and prednisone (EPOCH) was the CT of 17 of the 20 ATLL patients; relapse occurred after a median of 9.5 m, often followed by salvage CT. Of the 6 male and 6 female patients scanned pre-CT, the median SUVmx was 9.9; range 2.9-33. Their initial median LDH level was 390 (321-683). The median overall survival (OS) was 11.5 (1-24 m). Thirteen patients had 19 post-CT scans, with a median SUVmx of 3.0; only one SUVmx was elevated (8.4); that patient had progressive disease, but the others variously displayed complete and partial remissions, or progression. Their median OS was 13 m (range 4-39 m). Their median LDH at presentation was 523. Eight patients had 13 scans at relapse, with a median SUVmx of 10.6, range 3.7-21. Their median OS was 17 m (range 12-21). OS and SUVmx were not correlated. Conclusions: Like Hodgkin’s and large B cell lymphomas, the pre-CT PET SUVmx levels of ATLL patients were significantly elevated; most fell to normal or slightly elevated levels after CT. PET is thus likely to have some value in staging ATTL. Our results suggest that PET response of ATLL patients to CT correlates poorly with durable relapse-free survival. The latter parameter is probably dependent on factors other than proliferative rate or control of aerobic glycolysis.
Anaplastic large cell lymphoma (ALCL) ALK positive and ALCL ALK negative uniformly treated with intensive alternating chemotherapy at a single institution.
Authors: Romejko-Jarosinska Joanna , Domanska-Czyz Katarzyna , Ostrowska Beata , Paszkiewicz-Kozik Ewa , Poplawska Lidia , Rymkiewicz Grzegorz , Walewski Jan Andrzej 
Published: March 2020

e18512 Background: Anaplastic large cell lymphoma ALK positive (ALCL ALK+) is frequently referred to as easily curable disease, however, patients with more than 1 IPI risk factors have a poor outcome. ALCL ALK negative (ALCL ALK-) have usually higher IPI score and there is no general consensus on what treatment is the optimal. We evaluated data on 26 consecutive patients with ALCL ALK+ and ALCL ALK- treated uniformly at our institution between July 2004 and April 2011. Methods: 26 patients with ALCL ALK+ or ALCL ALK- were treated according to GMALL B-ALL/NHL 2002 protocol (Hoelzer D et al. Blood 2007; 110: Abstr. 518) without rituximab. Kaplan-Meier method and Cox’s model were used to analyze overall survival time and progression free survival time. Results: ALK protein expression was tested in 26 patients, 19(73%) were positive, 5(27%) were negative. Median age was 33 years (range 16-53). 14 pts (54%) were male, 20 (77%) were in clinical stage (CS) III or IV, 16 (61,5%) had B symptoms, 10(38,5%) had bulky disease, 10 (38,5%) had LDH > N, and 20 (77%) had IPI score >1. The overall response rate (ORR) was evaluated in 23 of 26 patients. The ORR was 87% (20/23 patients). After median follow up of 26 months (range; 6-90) overall (OS) and progression free survival (PFS) at 2 years was 67%: 95% C.I.=[48%, 86%] and 65%: 95% C.I.=[48%, 82%], respectively. On multivariate analysis none of factors: CS III and IV, B symptoms, bulky disease, IPI score>2, LDH>N, ALK expression influenced OS and PFS. The major toxicity was reversible myelosuppression: grade 4 neutropenia occurred after every cycle. Other complications included mucositis and infection. Two toxic deaths (7,6%) from sepsis occurred during neutropenia after first cycle of treatment. Conclusions: These results suggest that GMALL- B-ALL/NHL 2002 protocol is an effective treatment for both ALCL ALK + and ALCL ALK-, however, toxicity is remarkable, with neutropenia and infection being most frequent complications.
Prevalence of autoimmune conditions in patients with marginal zone lymphoma: Exploratory analysis of a series of consecutive patients.
Authors: Grabska Joanna , Bockorny Bruno , Codreanu Ion , Mewawalla Prerna , Dasanu Constantin , Silver Joel 
Published: March 2020

e18543 Background: Recent literature suggests that an association exists between marginal zone lymphoma (MZL) and certain autoimmune conditions. Furthermore, MZL and autoimmune diseases may share same pathogenesis in these patients. The present study was set to identify the prevalence of autoimmune phenomena in MZL patients and compare it with same in general population. Methods: We conducted both retrospective and prospective analyses in a series of consecutive patients (n=24) with MZL that had been followed in outpatient setting. Median age was 71.8 years (range, 50-96). Records were reviewed for the presence of autoimmune abnormalities; length of the prospective analysis segment was ~24 months. Prevalence of autoimmune disorders in our cohort was compared to their respective prevalence in general population. Statistical analysis: The obtained values were tested for statistical significance using Fisher’s exact test for small number of observations (95% confidence); a p-value < 0.05 was considered significant. Results: A total of 50% patients included in our study had documented autoimmune conditions. Identified autoimmune disorders included Hashimoto thyroiditis (n=5), immune thrombocytopenia [ITP] (n=4), rheumatoid arthritis [RA] (n=1), Raynaud's phenomena (n=1), psoriasis (n=1), and autoimmune hemolytic anemia [AIHA] (n=1). Statistical analysis showed the following significance: Hashimoto thyroiditis (p=0.037), ITP (p<0.01), AIHA (p<0.01), RA(p=0.351), psoriasis (p=0.479), and Raynaud's phenomena (p=0.666). Conclusions: Circa half of MZL patients also have autoimmune conditions, thus significantly exceeding the overall prevalence in general population. Statistically significant differences in our MZL patients were recorded for Hashimoto thyroiditis, ITP, and AIHA. When compared to the prevalence in general population, the difference did not reach statistical significance for RA, psoriasis, and Raynaud's phenomena. However, this may be related to the relatively small size of the analyzed cohort. Therefore, larger studies would be useful before definitive conclusions can be drawn.
Patients with extramedullary manifestation of multiple myeloma: Prognostic factors and survival.
Authors: Wieczorek Agnieszka Anna , Balci Derya , Schmidt-Hieber Martin , Lohneis Philipp , Heider Ulrike , Pezzutto Antonio , Blau Igor Wolfgang 
Published: March 2020

e18552 Background: Multiple myeloma is a plasma cell dyscrasia that primarily involves bone marrow but also occurs in the soft tissues. While observing striking differences in clinical courses of patients with extramedullary plasmacytoma (EMP), solitary bone plasmacytoma (SBP), multifocal form of multiple myeloma (MFM) and multiple myeloma (MM), we wanted to assess prognostic factors and outcomes in those groups. This retrospective analysis was performed to evaluate response rate and overall survival (OS) of patients with extramedullary manifestations. Methods: We evaluated the data from 54 patients with MM (n=17), MFM (n=19), EMP (n=12) and SBP (n=6) treated at our institution from 1994-2012 and initially selected based on provided tissue samples. The MM control cohort was matched with regard to age, gender and prior treatment regimens. In 3 of 19 cases of MFM extramedullary locations were found at initial diagnosis. Two patients with EMP converted into MFM during the treatment. All EMP lesions arised in the upper aerodigestive tract. However extramedullary involvement in MFM was found in the head and neck (37%), chest (53%), abdomen (21%) and extremities (31%). Results: The 5-year OS rate was 92% in the patients with EMP. Whereas, 5-year OS rates of MM patients achieved 70.6%. MFM patients reached only 58% 5-year OS. The 5-year probability of progression was significantly higher in the group with MFM than EMP (89.5% vs 33%, p=0.0076, log rank test). Median progression free survival was 34 months for MM and 20 months for MFM (p=0.18). Conclusions: The 5-year progression free survival could be reached in 10 out of 12 patients with EMP. Two of the patients with primary EMP developed MFM. Moreover, the secondary development of extramedullary manifestation was associated with worse prognosis. Since the differences in the disease development cannot be easily predicted, there is an need of additional predictors that take into account different genetically determined risk status. Our retrospective analysis of genetic variations in this cohort of patients indicates the need of additional predictors in future randomized studies in these rare subtypes of MM.
Individualizing the starting dose for MPT therapy in elderly myeloma patients.
Authors: Blau Gary E , Orcun Seza , Lainez Jose Miguel , Reklaitis Gintaras V , Suvannasankha Attaya , Fausel Christopher A. , Kiel Patrick , Anaissie Elias J. 
Published: March 2020

e18555 Background: Many elderly or frail myeloma patients ineligible for autologous stem cell transplant (ASCT) receive non-myeloablative therapies such as the melphalan/prednisone/thalidomide (MPT) combination. These agents have variable pharmacokinetics (PK), and hence variable anti-tumor responses and toxicities. Yet, their dosing is uniform, partly because no convenient procedure exists to individualize dosage-schedules (costs and logistical difficulties with multiple blood samplings for a given patient). We herein propose a novel PK methodology that allows for individualized dosing of these agents. Methods: The MPT regimen is commonly used for older patients and consists of six cycles of 4mg/m2 M, 40mg/m2 P and 100mg T administered for seven days followed by a three-week rest period. To compare the peripheral blood concentrations between individuals, a marker combining the level and duration of exposure is the time weighted “average concentration” defined by CC=(Cumulative Area under the concentration time curve (AUC))/(Elapsed time from start of treatment). Using pattern recognition software, an individual’s PK profile was simulated from the population PK models using a single blood draw 2h after administration. The AUC for the individual is then used to adjust the starting dose to match the CC target profile based on the average population response. Results: Using PK data for the individual patients used to construct the PK population model, the simulated adjusted doses for initializing the therapy vary as follows: M 2.5-6mg/m2; P 12.5-140mg/m2; and T 76-130mg which is substantially different from the "standard" uniform dosing. Conclusions: The wide variability in dose levels obtained with the pattern recognition software may explain the marked differences in response and toxicities to the “standard” dosing protocol. An individualized starting dose can be applied using the proposed methodology which requires only a single blood draw after a lower “test dose” of these agents “prior” to commencing actual therapy.
Combinatorial treatment with CTO and temozolomide in sc-implanted human LOX 1MVI melanoma.
Authors: Karmali Rashida A. , Maxuitenko Yulia , Gorman Greg 
Published: March 2020

e19006 Background: Carboxyamidotriazole orotate (CTO) is the orotic acid salt of 5-amino-1.(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1, 2, 3-triazole-4-carboxamide. CTO possesses increased solubility. The antiproliferative and antimetastatic effects of CTO are related to inhibition of receptor –opertated calcium channel- mediated calcium influx. CTO can inhibit calcium sensitive signal transduction in the VEGF and the PI3K pathways, inhibition of FGF-2-induced tyrosine kinase, VEGF-mediated activation of phospholipase Cγ, generation of IP3 and nitric oxide synthase activation, and induction of apoptosis in imatinib mesylate resistant CML cells by downregulating bcr-abl. Methods: Different combinations of CTO and temozolomide (TEM) were first tested in female athymic NCr-nu/nu mice to evaluate tolerance of the combination. The tolerated combinations were then tested to evaluate the antitumor activity against subcutaneously –implanted human LOX 1MVI melanoma xenografts. Results: Oral CTO at doses of 513 or 342 mg/kg/dose Q1Dx14 resulted in inhibition of tumor growth (p<0.001 and p=0.004). Oral TEM at doses of 90 and 60mg/kg/dose Q4Dx3 resulted in dose-dependent inhibition of tumor growth (p<0.001 and p<0.001). Oral CTO at 513 or 342 mg/kg/dose in combination with TEM 90mg/kg/dose resulted in comparable tumor inhibition to TEM alone. However, oral CTO at 513mg/kg/dose in combination with TEM 60mg/kg/dose resulted in additive antitumor activity compared to each drug alone. Also, CTO at 342mg/kg/dose in combination with TEM 60mg/kg/dose had more than additive antitumor activity and was statistically different from the group treated with TEM 60mg/kg/dose alone (p=0.001). Conclusions: These results suggest that CTO enhances the sensitivity of TEM and may permit use of lower doses of TEM to obtain an optimum antitumor effect in combination therapy thus reducing toxicity of high TEM doses in this melanoma model.