bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II safety study of bevacizumab in patients with multiple recurrent or progressive malignant gliomas
Authors: Raizer J. J. , Gallot L. , Cohn R. , Chandler J. , Levy R. , Getch C. , Batjer H. , Marymont M. , Tellez C. , Mellot A. , Newman S. 
Published: March 2020

2079 Introduction: Available treatment options for patients with recurrent MG are few. Recent trends have used target specific agents but none has been effective to date. A single agent trial was designed to determine the safety and efficacy of bevacizumab in patients with recurrent MG. Recently, bevacizumab and CPT-11 in combination have shown response rates of approximately 60%. Patients and Methods: All patients (pts) had to sign an IRB informed consent. All pts had to have at least two relapses. Pts had to be > 18 year of age with Karnofsky performance status of > 60. Adequate bone marrow, liver and renal function was required, as well as normal urine protein and creatinine. Patients were required to be on a non-enzyme inducing anti-convulsants. An MRI with perfusion was done at baseline (if patient consented) and then every 6 weeks. Patients continued on trial as long as they did not have tumor progression. Patients received bevacizumab 15 mg/kg every 3 weeks as a 60–90 minute infusion. Results: To date, 16 pts with recurrent MG have been treated. 14 pts had a glioblastoma (GBM) and 2 had an anaplastic oligodendroglioma (AO). Median number of doses given was 3 (range 1–12). No patient had an intracranial hemorrhage and the only significant toxicity was a DVT in a patient with prior DVT. Best responses per McDonald criteria were: PR in 2 pts, SD in 4 pts, PD in 3 pts and non-evaluable in 7 pts: 4 follow up imaging not done, 1 each with stable MRI after 2 doses but WD for non-compliance, clinical decline and patient’s choice. Results: Bevacizumab as a single agent given every 3 weeks at 15 mg/kg is safe. Partial responses and stable disease were seen in about 30 % of patients with follow up imaging but many patients are early in treatment. Our response rates to date are lower then previous reports of patients treated with CPT-11 and bevacizumab; this maybe due to the increased number of prior therapies, a different schedule of bevacizumab or the omission of CPT-11. Updated response rates, time to progression and overall survival will be presented. [Table: see text] No significant financial relationships to disclose.
PCR of immunoglobulin heavy-chain (IgH) complementary determining region III (CDRIII) for diagnosis of meningeal dissemination (MD) in primary CNS lymphoma (PCNSL): A prospective evaluation
Authors: Korfel A. , Fischer L. , Gleissner B. , Martus P. , Novrousian M. , Krümpelmann U. , Klasen H. , Kirchen H. , Thiel E. 
Published: March 2020

2082 Background: The prognostic impact of MD in PCNSL is unclear. Cytomorphological examination of cerebrospinal fluid (CSF) cells is the gold standard for detection of MD. PCR for detection of a clonal B-cell population may represent a more sensitive and specific method for MD detection. Methods: CSF was collected by lumbar puncture before treatment in patients with newly diagnosed PCNSL of B cell type, histologically proven. CSF cytomorphological examination was performed by an experienced hematopathologist or neurologist immediately after sampling at the treating institution. A sample of native CSF was sent for PCR examination to our central moleculargenetic laboratory. Here, DNA from CSF cell pellets was extracted using commercially available kits. A seminested PCR of the IgH chain CDR III region was performed using the primers LJH in the first, VLJH in the second and FR3A in both PCR reactions. PCR products were subjected to an automated fluorescent fragment analysis (ALF) to detect a monoclonal vs. polyclonal pattern, and results were compared to conventional cytology. Results: From January 2001 to August 2006 CSF from 215 patients was collected. Here, data from the first 146 patients examined is presented ( Table ). MD was detected in 15 of 106 examined patients (14%) by cytomorphological evaluation and in 17 of 146 patients (11.6%) using PCR. In 8 patients with negative cytology the PCR product was monoclonal, and in 7 patients with positive cytology a polyclonal PCR product was found. Conclusion: The frequency of MD in PCNSL detected by PCR of the IgH CDR III region is low and comparable to that detected by cytomorphological evaluation. However, discordant PCR and cytology results are frequent. Thus, PCR analysis appears to be an important adjunct for MD diagnosis. [Table: see text] No significant financial relationships to disclose.
A clinical trial of autologous formalin-fixed tumor vaccine (AFTV) for patients with glioblastoma multiforme
Authors: Tsuboi K. , Ishikawa E. , Yamamoto T. , Takano S. , Matsumura A. , Ohno T. 
Published: March 2020

2085 Background: This clinical pilot study is to investigate the safety, feasibility, plus clinical response of autologous formalin- fixed tumor vaccine (ATFV) in primary glioblastoma multiforme (GBM) patients. Methods: Eleven (8 recurrent and 3 initially treated) primary GBM patients were evaluated. AFTV was prepared from formalin-fixed tumor tissue or paraffin-embedded tissue and premixed with original adjuvant materials. A delayed-type hypersensitivity test (DTH) was performed before and after each course of ATFV treatment that comprised 3 vaccinations at a 5-site intradermal inoculation. In addition, immunohistochemical analysis of MIB-1, p53, and MHC class-I complex was performed on the tumor tissue to analyze the difference in the response to the treatment. Results: The treatment was well tolerated with only local induration and low-grade fever. Among the 11 patients, the best responses were 1 complete remission, 2 partial response, 1 no change, and 7 progressive disease. In this series, the median survival period was 7 months from the initiation of the AFTV treatment, and 3 of the 4 responders survived for more than 20 months after AFTV inoculation. DTH reactions, immunohistological analysis of p53 and MHC class-I complex, and patient status may be useful to predict the efficacy of this therapy. Conclusion: This study demonstrated that AFTV treatment is safe, feasible, and potentially beneficial. Further clinical investigation is highly desirable in order to improve the outcome of GBM patients. No significant financial relationships to disclose.
Recurrent primary central nervous system lymphoma (PCNSL) treated with pemetrexed
Authors: Altman J. K. , Gallot L. , Cohn R. , Chandler J. , Levy R. , Getch C. , Marymont M. , Tellez C. , Raizer J. J. 
Published: March 2020

2086 Introduction: Untreated, survival in PCNSL is approximately 2 months. However using high dose methotrexate based regimens, median survival is up to 60 months. A significant number of patients relapse. There is currently no standard therapy, but many regimens have been used with variable results. Pemetrexed is a multi-targeted anti-folate agent approved for first line treatment of malignant pleural mesothelioma and second-line for locally advanced or metastatic non-small cell lung cancer. A phase II trial was initiated for patients with recurrent gliomas, PCNSL or brain metastases. Pemetrexed, in addition to inhibiting dihydrofolate reductase, targets other sites of inhibition, giving it a broader spectrum of activty. This suggests that pemetrexed could be effective in PCNSL. Patients and Methods: The dose of pemetrexed used was 900 mg/m2 every 3 weeks; based on phase I data where the MTD was 800 mg/m2 in heavily pretreated patients and not reached in lightly pretreated patients. Patients received dexamethasone 4 mg twice daily on the day before, the day of, and the day after each infusion of pemetrexed and supplemental folic acid and B12. Eligibility criteria for PCNSL patients included failure of at least one prior chemotherapy regimen. Patients had to be > 18 year of age with KPS status of > 60. Adequate bone marrow, liver, and renal function were required. An MRI was done every 6 weeks and for patients who attained a CR, a maximum of six doses was given. Results: To date, five patients with recurrent PCNSL have been treated on this trial after signing IRB approved consent. Patient Characteristics Discussion: We report our experience of pemetrexed in 5 patients with recurrent PCNSL. Toxicity has been minimal except in the one patient who was heavily pretreated (including a stem cell transplant). Activity was seen in all patients but transient in two. Pemetrexed is active in relapsed PCNSL. The optimal dose and schedule need to be determined, as well as activity in a larger group of patients. We continue to enroll patients in this study. [Table: see text] No significant financial relationships to disclose.
Antitumor activity and biological effects of primary endocrine therapy with GnRH analog and letrozole in premenopausal women with locally advanced operable ER and PgR positive breast cancer
Authors: Torrisi R. , Ghisini R. , D'Alessandro C. , Bagnardi V. , Bottiglieri L. , Peruzzotti G. , Rocca A. , Goldhirsch A. , Colleoni M. 
Published: March 2020

21008 Background: Aromatase inhibitors (AIs) in combination with GnRH analog (A) were never systematically studied in premenopausal women with hormone receptor positive locally advanced operable breast cancer. Methods: We investigated in a two stage phase II trial, the activity of GnRH A plus letrozole (LT), added when E2 levels were in the postmenopausal range, in premenopausal women with T2-T4b N0-N2, endocrine responsive (ER and PgR ≥ 10% of the cells) breast cancer. We also investigated at baseline and at surgery the expression of ERβ, MAPkinases (MAPKs), ERa, EGFR, Her-2/neu, either normal or phosphorylated (p). Results: Thirty-nine patients (pts) were enrolled and 35 (ER >50%, 29 (90%) ; Ki 67 = 20%, 17 (53%); cT2/3, 24/5) are evaluable for response (3 of whom did not receive LT for refusal or failure of achievement of ovarian suppression). There were 16 objective responders (46%, 95% CI 29.5- 62.5), 1 of whom had pCR (3%). Nineteen pts (50%) were stable. Breast conserving surgery became possible for 42% of the patients. Side effects were mild. Endocrine therapy was correlated with grade 2 hot-flashes and arthralgia in 43% and 6% of the patients, respectively. Molecular analysis was performed in 27 pts (13 responders and 14 non responders). Treatment induced a significant decrease of pERa an upregulation of ER-β, which were independent of response. No overexpression of EGFR and HER-2 was registered at baseline and after treatment. Conclusions: The combination of LT and GnRH A is feasible and effective in premenopausal women with locally advanced endocrine responsive operable breast cancer. A biological response to estrogen suppression was observed. Tailored endocrine therapy of longer duration merits further investigations in the preoperative setting. No significant financial relationships to disclose.
Molecular identification of carcinoma of unknown primary (CUP) with gene expression profiling
Authors: Qu K. Z. , Li H. , Whetstone J. D. , Sferruzza A. D. , Bender R. A. 
Published: March 2020

21024 Background: We previously reported a method for determining the site of tumor origin for CUP by comparing a 92- gene expression profile to that in a database created from 600 primary and metastatic tumor bank specimens of known origin. K-nearest neighbor analysis was used to determine the likelihood of an unknown patient specimen originating from a particular site with the likelihood assigned as a confidence level and reported as high, medium, low, or unclassified. Herein, we report the analysis of the gene expression profiling results from our initial series of clinical CUP specimens. Methods: We reviewed the results of 76 consecutive de-identified patient samples submitted to our laboratory for routine CUP testing. RNA was extracted from the formalin-fixed, paraffin-embedded (FFPE) tissue blocks and cDNA products used in a semi-quantitative real-time PCR to detect 87 tumor-associated genes and 5 reference genes. Gene expression data were then compared with our database and k-nearest neighbor analysis used to identify the 5 closest neighbors. If all 5 or 4/5 were the same, the result was classified as “high likelihood”, 3/5 = “moderate likelihood”, 2/5 = “low likelihood” and none matching was “unclassifiable”. Results: For the 76 clinical CUP samples tested, gene profiling analysis yielded high-likelihood predictions for 34 (45%), moderate for 12 (16%), low for 12 (16%), and unclassified for 14 (18%); amplification was inadequate for 4 (5%) samples. Overall, gene profiling analysis yielded classifiable predictions in 58 (76%) of clinical CUP samples. An occult carcinoid, metastatic melanoma and adenocarcinoma of the endocervix were identified and then found clinically using this assay. Conclusions: Our previous findings indicate that gene expression profiling can correctly identify the site of tumor origin in a high percentage of tumor bank samples. Data from the present study suggests that this approach can identify a primary site of tumor origin in 76% of actual clinical specimens from pathologist-submitted CUP cases. No significant financial relationships to disclose.
Fas-670 polymorphism and prostate cancer
Authors: Lima L. , Calais da Silva F. M. , Calais da Silva F. E. , Morais A. , Lobo F. , Medeiros R. 
Published: March 2020

21028 Background: The FAS/FASL system is one of the major pathways in apoptosis and is important to regulate cell proliferation and tumor cell growth. Functional promoter polymorphisms of FAS gene (FAS -670 A/G) alter the transcriptional activity. The role of FAS polymorphisms in prostate cancer has not been studied. Methods: DNA extracted from peripheral blood from 529 prostate cancer patients and from 247 healthy controls was analysed by Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) for FAS gene locus -670 genotypes. Results: We found that the AG and GG genotypes represent significantly protection (OR=0.41; confidence interval (CI): 0.26–0.65 and OR=0.39; CI: 0.21–0.74, respectively) for extracapsular invasion. Taken this genotypes together, a significantly protection was found for G allele carriers (OR=0.41; CI: 0.27–0.63). Conclusions: It is well known that G allele reduces the transcriptional activity of FAS gene. Fas exist as membrane bound and soluble forms and with opposite roles. They derive from the same gene by alternative splicing. Membrane Fas receptor trigger apoptosis and in other hand soluble Fas (sFas), which lacks transmembrane domain, binds to Fas ligand antagonizing Fas-Fas ligand apoptotic pathway. It is reported that serum sFas is elevated in prostate cancer and associated with advanced disease. Our results suggest that G allele may reduce sFas levels preventing the apoptotic inhibition caused by the soluble form. No significant financial relationships to disclose.
CYP3A5*3 genotypes and advanced non-small cell lung cancer development
Authors: Nogal A. , Coelho A. , Araújo A. , Azevedo I. , Faria A. , Soares M. , Catarino R. , Medeiros R. 
Published: March 2020

21030 Background: Lung cancer is the most common cancer in Europe (381.500 new cases in 2004) and the third in the U.S.A (172.570 new cases in 2005). Smoking is one of the major causes of lung cancer: there are many procarcinogens present in tobacco smoke that, when activated, contribute to the development of this disease. The CYP3A subfamily represents a group of enzymes responsible for the metabolism of many currently used drugs, exogenous carcinogens and endogenous molecules such as steroids. Two of the major enzymes in this family, CYP3A4 and CYP3A5, activate polycyclic aromatic hydrocarbons such as benzo[a]pyrene and other procarcinogens present in tobacco smoke. Functional polymorphisms, such as CYP3A5*3 (associated with the lack of the CYP3A5 protein), could alter individual susceptibility to lung cancer. The aim of our study was to evaluate the influence of this polymorphism in the development of lung cancer. Methods: DNA samples were extracted from peripheral blood cells of 203 patients with non small cell lung cancer, including 42 non- smokers and 156 smokers or former smokers (no data available for the other 5 patients) and 162 blood donors. The CYP3A5*3 polymorphism was analysed through PCR-RFLP (SspI). Analysis of data was performed using the computer software SPSS for windows. The odds ratio (OR) and its 95% confidence interval (CI) were calculated as a measure of the association between CYP3A5*3 genotypes and NSCLC progression. Results: We found significant statistical differences between the control group and the patients with advanced stages (III and IV) of epidermoid and undifferentiated NSCLC (p=0.04; OR = 0.48; 95% CI = 0.232–0.977). Conclusions: Individual differences in the metabolism of carcinogens may influence the susceptibility to cancer development and behaviour. Our preliminary results suggest that the carriers CYP3A5*3 polymorphism are at lower risk of developing advanced lung cancer. This is probably due to a decreased activation of procarcinogens present in tobacco smoke in result of the lack of CYP3A5 caused by the CYP3A5*3 polymorphism. This is consistent with the hypothesis of a cumulative effect of carcinogens on the aggressive behaviour of the disease. No significant financial relationships to disclose.
Treatment-adjusted predisposition to second malignant neoplasms after a solid cancer in childhood: A case-control study
Authors: Guérin S. , Hawkins M. , Shamsaldin A. , Guibout C. , Diallo I. , Oberlin O. , Brugières L. , de Vathaire F. 
Published: March 2020

21031 Background: Previous therapy, genetic susceptibility and the type of the first cancer are known to be associated with the risk of a second malignant neoplasm (SMN) among patients treated for a childhood cancer. The aim of this study was to investigate the independent role of the type of first malignant neoplasm in the onset of any SMN taking into account treatment and family cancer syndromes. Methods: A case-control study nested in a European cohort of 4,581 patients, treated for a solid cancer during childhood was conducted. 146 cases with a SMN and 417 controls were matched according to sex, age at first cancer, chemotherapy, radiotherapy, the local radiation dose received at the site of the SMN for the case and at the same site for the matched controls and follow- up. Results: A significantly increased risk of developing any SMN was observed after Hodgkin's lymphoma, retinoblastoma, soft tissue sarcoma orand a malignant bone tumor as the first malignant neoplasm (FMN), independently of initial treatment and family cancer syndromes. A significantly increased risk of developing a sarcoma was observed among patients who had developed a retinoblastoma, OR=5.9 (95%CI : 1.0–34) a malignant bone tumor, OR=11.9 (95%CI : 1.5–95), or a soft tissue sarcoma, OR=5.1 (95%CI : 1.4–19) compared to patients with a Wilm's tumor as the FMN. Conclusions: Survivors of Hodgkin's lymphoma, retinoblastoma, soft tissue sarcoma or a malignant bone tumor are at increased risk of any SMN independently of initial treatment and genetic susceptibility. No significant financial relationships to disclose.
Single nucleotide polymorphisms in androgen-related genes and prostate cancer
Authors: Gos M. , Sadowska M. , Wiechno P. , Demkow T. , Janik P. 
Published: March 2020

21033 Background: Single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in androgen metabolism were suggested to influence the individual prostate cancer susceptibility and clinical course of the disease. To examine this correlation in Polish population, we have developed a case-control study to analyze whether SNPs in CYP17 (+34T/C), SRD5A2 (V89L and A49T) and UGT2B15 (D85Y) genes may influence prostate cancer risk. These SNPs were also examined for their correlation with clinical features of prostate cancer at diagnosis and disease progression to hormone-refractory state. Methods: The genomic DNA was extracted from blood samples from 182 men with histologically confirmed prostate cancer and 217 healthy men, randomly chosen from population. SNPs analyses were performed with standard molecular methods. Results: The case-control study has revealed that 85YY and 85DY variants in UGT2B15 were more prevalent among patients (83%) than in the control group (73.3%; p=0.02; OR=1.78). The +34CC genotype in CYP17 was more frequent in patients with distant metastasis (30.4%) than in patients with organ confined (T1/T2) or locally advanced (T3/T4) disease (10.2% and 22.6%, respectively; p<0.05). This variant also correlated with higher PSA level at diagnosis. The 89LL variant in SRD5A2 was more common in patients with poorly differentiated prostate cancer (Gleason >6; 17.8%) than in men with well differentiated tumor (5.4%; p=0.033, OR=3.78). The 85YY variant in UGT2B15 was more prevalent in patients that developed hormone-refractory prostate cancer within two years from the beginning of androgen blockade (47.2% vs 23.3%, p=0.025, OR=2.95). Also the analysis of progression-free survival time on hormonal therapy for D85Y polymorphism yield significant results (p=0.041, Gehan's generalized Wilcoxon test). Conclusions: The D85Y polymorphism in UGT2B15 seems to influence prostate cancer risk in Polish population. The analyzed SNPs also correlated with clinical stage and PSA level at diagnosis (+34T/C in CYP17), tumor histological grade (V89L in SRD5A2) and response to hormonal therapy (D85Y in UGT2B15). No significant financial relationships to disclose.
Retrospective analysis of phosphorylation status of the estrogen receptor in patients with early stage disease
Authors: Swaby R. F. , Huang M. , Ruth K. J. , Ross E. A. , Gong Y. , Page R. E. , Freedman G. M. , Goldstein L. J. , Di Cristofano A. 
Published: March 2020

21034 Background: The AKT kinase, when phosphorylated to its activated form (pAKT), mediates many proliferative and survival effects of growth factor receptors such as members of the epidermal growth factor receptor (EGFR) family. Overexpression of AKT in breast neoplasms suggests that AKT activation is involved in breast cancer development and/or progression, and contributes to poor outcome. pAKT is frequently upregulated in Her-2/neu positive breast cancers. Activated AKT is able to phosphorylate in vitro serine 167 (pS167) of estrogen receptor alpha (ERa), resulting in ER-mediated transcriptional activity in the absence of estrogen and possibly contributing to tamoxifen resistance in ERa positive breast cancers. In addition, ERa is phosphorylated at S118 (pS118) by MAPK. Thus, it is possible that pAKT- mediated ERa phosphorylation is implicated in tumorigenesis and resistance to treatment with hormonal therapy in patients with breast cancer. Methods: Utilizing commercially available antibodies, IHC analysis of 125 paraffin-embedded, ERa positive, early breast cancer cases, stratified for stage, were tested for pAKT, PTEN, pS167, and pS118. Staining intensity and number of positive cells were assessed by 4 independent graders. Fisher's exact test was used to determine the significance of associations with a two-sided type I error of 5%. Results: Phosphorylation of AKT occurred in approximately one-half of cases. pS167 was phosphorylated in 66% of pAKT positive cases compared to 35% of pAKT negative cases (p<0.0001). When we analyzed nuclear pAKT staining, this association was more pronounced: 76% of pAKT(+) vs. 37% of pAKT(-) (p<0.0001). 69% of pS118(+) cases were pS167(+) compared to only 15% pS167(+) when pS118 was negative (p<0.0001). In approx. 32% of cases pAKT was present in both the cytoplasm and nucleus. 20% of samples had only cytoplasmic pAKT, while in 4% of cases pAKT was nuclear only, supporting the hypothesis that cytoplasmic phosphorylation of AKT may precede nuclear accumulation. Conclusions: Phosphorylation of pS167ERa is significantly associated with AKT activation (especially in the nucleus) in early breast cancer, supporting the hypothesis that these two events may be causally linked and contribute to breast cancer pathogenesis. No significant financial relationships to disclose.