bluuebunny/crossref_metadata_2025_split huggingface dataset:
HER-2/neu expression in glioblastoma multiforme (GBM)
Authors: Gupta S. , Sheikh H. , Schneider C. , Zhang X. , Padmanabhan A. , Ali A. 
Published: August 2020

e13035 Background: Glioblastoma multiforme (GBM) is a disease in which very few cytotoxic chemotherapy agents have been shown to have activity. This is partly due to their inability to cross the blood brain barrier. Trials with bevacizumab, a VEGF inhibitor that disrupts tumor angiogenesis, have demonstrated activity against this otherwise chemotherapy resistant disease. This has led to interest in other biologic agents that target angiogenic pathways for the treatment of GBM. Over-expression of HER-2/neu by human tumor cells is closely associated with increased angiogenesis and expression of VEGF. Lapatinib is a recently available low molecular weight immunotherapeutic agent that targets HER-2/neu proteins. In a recent study, breast cancer patients treated with lapatinib and capcitabine had decreased brain metastases indicating that lapatinib may cross the blood brain barrier and thus have potential in the treatment of malignant gliomas. Limited studies have evaluated HER-2/neu gene expression in GBM and the results are inconsistent. We evaluated the expression of Her-2/neu protein in 41 consecutive GBM cases to explore the potential utility of targeting this pathway. Methods: Archival histopathologic sections from 41 patients (age 26–89 years) with a diagnosis of GBM from 2004–2008 were reviewed. The diagnosis was confirmed and optimal sections were selected. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections using the primary antibody against HER-2/neu (clone 4B5, Ventana). The results were evaluated by three independent investigators. Interpretation was performed using the semi-quantitative criteria (Score 0 to 3+) currently used for primary breast carcinomas. Results: 38 out of 41 cases showed no immunohistochemical staining with HER-2/neu antibody (score 0). Three cases demonstrated weak, incomplete membrane staining of rare tumor cells (score 1+) and were interpreted as negative. The positive and negative controls worked properly. Conclusions: Our study indicates that there is no significant immunohistochemical over-expression of HER-2/neu protein in GBM. This suggests that HER-2/neu over-expression is not a significant oncogenic pathway in GBM, and therefore may not be a potential therapeutic target in this disease. No significant financial relationships to disclose.
Treatment of glioblastoma in Venezuela: Limitations using the current standard of care
Authors: Arbona-Roche E. I. , Sucre C. , Vera-Gimón R. , Vera-Gimón A. , Vera-Vera R. , Gutierrez E. , Urdaneta N. , Gutierrez M. , Somaza S. , Tremont-Lukats I. W. 
Published: August 2020

e13036 Background: The EORTC/NCIC phase III clinical trial using chemoirradiation with temozolomide (TMZ) 75 mg m-2 x 42d, followed by adyuvant TMZ 150–200 mg m-2 daily x 5d q28d x six cycles set a new standard of care for newly diagnosed glioblastoma (GBM). The applicability of this regimen in developing countries can be problematic. Objectives: To review our experience in Venezuela, contrasting overall survival (OS), 6-month progression-free survival (6PFS), and toxicity in our patients with corresponding outcomes from the EORTC/NCIC trial. Methods: We treated 30 patients with this regimen from March 2001 through July 2004. Results: The median age was 51 years; 17 (60%) were men; 27 (90%) had biopsy or partial resection; 27 (90%) took prophylactic anticonvulsants; and 23 (77%) had prophylaxis against P. jiroveci. Most patients (83%) took the full TMZ treatment during radiation, 7% interrupted TMZ during RT, and 10% could not afford the drug. One patient had Stevens-Johnson syndrome and did not complete RT. Twelve (40%) patients had stereotactic radiosurgery for recurrent disease during the adjuvant phase. The 24-month OS was 30%, median OS was 7.5 months, median PFS was 5 months, and 6PFS was 41%. SRS did not have any effect on OS (p = 0.17, logrank). Grade 3–4 hematologic toxicity was seen in two patients (7%). Conclusions: Except for differences in median OS (7.1 mo) and in 6-PFS (12.6 percentage points) all other measures were reasonably close to the EORTC/NCIC trial. Of concern is the high rate of anticonvulsant prophylaxis using enzyme-inducing drugs and the difficult access to TMZ. No significant financial relationships to disclose.
Preliminary results of a phase I trial of sorafenib combined with cisplatin/etoposide (CE) or carboplatin/pemetrexed (CbP) in solid tumor patients (pts)
Authors: Dhruva N. S. , Stinchcombe T. E. , Walko C. M. , Socinski M. A. , Bernard S. , Kim W. Y. , Keller K. , Hilbun L. R. , Dees E. C. 
Published: August 2020

e13521 Background: Sorafenib had demonstrated single agent activity in non-small cell and small cell lung cancer. Methods: A non-comparative, two arm phase I trial escalating sorafenib in combination with fixed doses of CE or CbP was performed. A 3-patient cohort design was utilized to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Dose level 0 for all pts was a sorafenib dose of 200 mg po BID continuously. Pts on arm A received C (60 mg/m2) on day 1 and E 120 mg/m2 on days 1,2,3 every 3 weeks with escalating doses of sorafenib. On arm B, pts received treatment with Cb (AUC=6) and P 500 mg/m2 every 3 weeks with escalating doses of sorafenib. However, excessive toxicity was observed on arm B, therefore the trial was amended such that Cb dose was lowered to AUC=5 (arm C). DLT were assessed in the 1st cycle and defined as grade (gr.) 4 anemia or thrombocytopenia, gr. 4 neutropenia lasting > 7 days, gr. ≥ 3 non-hematologic toxicity (except nausea, vomiting, and alopecia) and > 2 week dose delay. Response was assessed every 2 cycles according to RECIST, and best response was recorded. Results: Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 47–73), male/female: 12/8, PS of 0/1: 6/14, and median number of prior therapies 2 (range 1–4). The most common tumor types were NSCLC (n=8), SCLC (n=4) and head/neck (n=2). At dose level 0 arm A (200 mg BID), 2 of 4 patients experienced DLT (gr.4 thrombocytopenia, gr.3 fatigue, febrile neutropenia and gr.4 neutropenia for > 7 days, gr.3 febrile neutropenia, diarrhea, hypokalemia, hyponatremia); 2 pts have been enrolled at dose level -1 (200 mg po QD) without DLT. Two of 3 patients enrolled on arm B at dose level 0 had gr.4 thrombocytopenia. On arm C at dose level 0 (200 mg po BID), 1/6 pts experienced DLT (gr.3 hyponatremia, dehydration, hypoglycemia). Enrollment continued at dose level 1 (400 mg po BID), but 2/5 pts experienced a DLT (both gr. 3 fatigue/anorexia). Responses observed were: PR (n=3) (all arm C), and SD (n=6). Conclusions: The MTD of sorafenib in combination with carboplatin (AUC=5) and pemetrexed 500 mg every 3 weeks is 200 mg po BID. The MTD of sorafenib in combination with cisplatin/etoposide has yet to be determined and is currently accruing at dose level -1. [Table: see text]
Antitumor activity of NK012 combined with cisplatin against small-cell lung cancer and intestinal mucosal changes in tumor-bearing mouse after treatment
Authors: Nagano T. , Yasunaga M. , Goto K. , Koga Y. , Kuroda J. , Nishimura Y. , Sugino T. , Nishiwaki Y. , Matsumura Y. 
Published: August 2020

e13522 Background: The novel SN-38-incorporating polymeric micelles NK012 has been shown to have significant antitumor activity against several cancer mouse models compared with CPT-11. The phase I study demonstrated that patients treated with NK012 did not develop grade 3/4 diarrhea, one of the major adverse effects of CPT-11. The aim of this study is to investigate the advantages of NK012 combined with cisplatin (cis-dichlorodiammineplatinum (II): CDDP) over CPT-11/CDDP, one of the most active regimens against small-cell and non-small-cell lung cancers in the clinic, in mice bearing a small-cell lung cancer (SCLC) xenograft in terms of antitumor activity and toxicity, particularly intestinal toxicity. Methods: Cytotoxic effects were evaluated in human SCLC cell lines (H69, H82, vascular endothelial growth factor [VEGF]-secreting cells, SBC-3/VEGF and its mock transfectant SBC-3/Neo). In vivo antitumor effects were evaluated in SBC-3/Neo-and SBC-3/VEGF-bearing mice after NK012/CDDP or CPT-11/CDDP administration on days 0, 7, and 14. Drug distribution was analyzed by high-performance liquid chromatography or fluorescence microscopy, and the small intestine was pathologically examined. Results: The in vitro growth inhibitory effects of NK012 were 198- to 532-fold more potent than those of CPT-11. A significant difference in the relative tumor volume on day 30 was found between NK012/CDDP and CPT- 11/CDDP treatments (P=0.0058). Inflammatory changes in the small intestinal mucosa were rare in all NK012-treated mice, but were commonly observed in CPT-11-treated mice. Moreover, a large amount of CPT-11 was excreted into the feces and high CPT-11 concentration was detected in the small intestinal epithelium. On the other hand, a small amount of NK012 was found in the feces and NK012 was weakly and uniformly distributed in the mucosal interstitium. Conclusions: NK012/CDDP combination may be a promising candidate regimen against lung cancer without severe diarrhea toxicity, and therefore warrants further clinical evaluation. No significant financial relationships to disclose.
Phase I study of imatinib in combination with gemcitabine and capecitabine
Authors: Ramaekers R. C. , Elkahwaji J. , Reed E. , Ganti A. , Wang J. , Grem J. , Baranowska-Kortylewicz J. , Hauke R. 
Published: August 2020

e13523 Background: Imatinib-mediated inhibition of platelet-derived growth factor receptor lowers tumor interstitial pressure allowing for improved intratumoral antineoplastic drug concentration. A phase I study of imatinib (Im) with the synergistic combination of gemcitabine (Gem) and capecitabine (Cape) was undertaken. Methods: Eligibility requirements included refractory solid tumors, ECOG 0/1 and adequate organ function. A 3-week treatment cycle was used with the dose levels (DL) 0 and -1 as outlined in the table. Dose limiting toxicity (DLT) was defined as occurring within the first 2 cycles of therapy. Patients remained on therapy unless DLT occurred or disease progression. Results: Twelve patients with a median age of 59.5 (range 44 - 77) were evaluable. Baseline characteristics included ECOG PS 0/1: 6/6; prior systemic therapies: median 3 (range 1–6); tumor types: renal (4), melanoma (2), prostate, esophageal, pancreatic, small cell lung, breast, unknown primary. At DL 0, 2 of 6 patients experienced DLT (gr. 3 thrombocytopenia; gr. 4 leucopenia). At DL -1, 1 of 6 patients experienced DLT (gr. 3 thrombocytopenia). No patient missed a dose; one patient in DL -1 completed only 1 cycle. Median cycles administered was 2 (range, 1 - 19). At cycle 2 evaluation, 7 pts had stable disease, 4 had progressive disease and 1 was not evaluable. Grade 3 or 4 toxicity included thrombocytopenia, leucopenia, hyperglycemia and weakness. All hematologic grade 3/4 toxicity was seen in patients having received ≥3 cytotoxic regimens previously. Most common grade 1/2 toxicities included anemia, nausea/emesis and fatigue. One patient with renal cell had stable disease (SD) for 15 cycles and one patient with melanoma had SD for 19 cycles. Conclusions: Im in combination with Gem and Cape is well tolerated in patients without extensive exposure to cytotoxic therapy. Activity is seen in various tumor types particularly melanoma and renal cell. The suggested dose for phase II studies is Im 400 mg/d, Gem 400 mg/m2 and Cape 400 mg/m2 in the dose schedule as described above. [Table: see text] [Table: see text]
Tolerability and efficacy of indigenously developed nanoparticle paclitaxel in Indian patients
Authors: Deshmukh C. D. , Hingmire S. S. , Bakshi A. V. , Kelkar D. S. 
Published: August 2020

e13533 Background: Nanoparticle paclitaxel ([N]), India's first cremaphor free water-soluble paclitaxel is based on the principles of nanotechnology. The present study evaluates the safety and efficacy of this formulation in an Indian population. Methods: A prospective observational study over 18 months between April 2007 and December 2008 was done using N in a dose of 220 mg/m2 infused over 1 hour. Safety parameters were based on self reported adverse events while efficacy was monitored as per the RECIST criteria. Results: Fifty-four patients were included. The average age was 56 years (21–72 years). Ten patients (18.52%) had stage III and 23 (42.59%) had stage IV disease. Over 70% of patients were suffering from ovarian cancer, gastric cancer and non small-cell lung cancer (39 of 54 patients). The overall efficacy results across all tumour types were comparable to the published literature with 19 (35.19%) patients showing partial response, 3 (5.56%) showing complete response, stable disease in 11 (20.37%) patients while progressive disease in 12 (22.22%) patients. The efficacy results in the 3 most common tumour types are shown in the table below. In the cohort, 22 (40.74%) patients did not experience any side effects. The most common side effect was body ache (Grade III-NCI CTC v3.0) in 17 (31.5%) patients, neutropenia (Grade II -7, grade III and grade IV -1 each) in 9 (16.67%) cases, 3 (5.56%) cases each experienced neuropathy (Grade III -2 and grade IV-1), nausea, and weakness. Two patients (3.70%) experienced grade III thrombocytopenia and 1 (1.85%) patient developed grade II anemia. Conclusions: Our observations confirm the safety of nanoparticle paclitaxel (N) in an Indian population. This formulation obviates the need for cremaphor thereby allowing shorter infusion duration and eradicating the need of premedication, reduced incidence and severity of adverse effects. Nanoparticle based paclitaxel offers a major advancement in paclitaxel administration. [Table: see text] No significant financial relationships to disclose.
Reduced folat carrier gene status in colorectal, gastric, and pancreatic cancer
Authors: Cil T. , Tuzun A. Y. , Altintas A. , Batum S. , Isikdogan A. , Yurt M. 
Published: August 2020

e13540 Background: Folates play a key role in one-carbon metabolism essential for the biosynthesis of purines, thymidylate and hence DNA replication. Folates and antifolates which cannot traverse membranes must use specific transport systems for their cellular uptake. Antifolates such as raltitrexed and pemetrexed which will be used for gastrointestinal system cancer patients treatment are divalent anions which predominantly use the reduced folate carrier (RFC) for their cellular uptake. The aim of this prospective study; was documenting RFC gene status in gastric, colorectal and pancreatic cancers in southeast region of Turkey. Methods: We were evaluated homozygote, heterozygote mutations of RFC (SLC19A1) and wild type of RFC in new diagnosis gastric, colorectal and pancreas cancer patients who presented at the medical oncology and gastroenterology divisions of the Dicle University Hospital in Turkey between the dates August 2007 and October 2008 in southeast region of Turkey. Results: We were evaluated gene status of RFC in 62 (50%) colorectal, 45 (36.3%) gastric and 17 (13.7%) pancreatic cancer patients. In colorectal cancer patients group; 28 (45.9%), 19 (31.1%), 14 (23%), in gastric cancer 29 (64.4%), 7 (15.6%), 9 (20%), in pancreatic cancer 11 (64.7%), 2 (11.8%), 4 (23.5%) heterozygote, homozygote and wild type gene status, respectively. These results have no statistically significant (p=0.209) in three different gastrointestinal cancer types. Conclusions: New generation antifolat chemotherapeutic drugs such as pemetrexed which is multitargeted antifolat and enters the cells via the RFC system has demonstrated activity in gastrointestinal cancers. We think that antifolat drugs will be used in colorectal, gastric and pancreatic cancer patients in standard treatment protocols and RFC gene status will be an important of antifolat drugs activity in these tumors. No significant financial relationships to disclose.
Paclitaxel and cisplatin versus paclitaxel and cisplatin plus all-trans retinoic acid for the prevention of chemotherapy-induced neuropathy: A randomized phase II trial
Authors: Rios Trejo M. A. , Ceron Lizarraga T. , Fernández González M. C. , Ordoñez G. , Martinez Barrera L. , Astorga Ramos A. , Mendoza D. , Sotelo J. , Arrieta O. 
Published: August 2020

e14506 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event, similar to that of diabetes where there is reduction of the expression and transport of Neural Growth Factor (NGF). Retinoic acid regulates genes related to cellular proliferation and NGF expression. We conducted this clinical trial to determine the effect of all-trans retinoic acid (ATRA) on the development of CIPN with paclitaxel and cisplatin in patients with advanced non-small cell lung cancer (NSCLC). Methods: Ninety five patients with advanced NSCLC were included to receive chemotherapy based on paclitaxel 175 mg/m2 and cisplatin 80 mg/m2 every 3 weeks for a maximum of 6 cycles. The patients were randomized to receive ATRA 20 mg/day or placebo 1 week before treatment until after completing 2 cycles. Prior to chemotherapy and after 2 cycles of treatment neurophysiology tests, clinical exam and serum NGF levels (34 patients) were performed. Results: There were no differences in general characteristics of the patients between groups. NGF serum levels were lower in the placebo group 4.89 pg/ml baseline and 4.6 pg/ml 2C (p = 0.007) versus ATRA 4.8 pg/ml and 4.7 pg/ml (p=0.107). The electrophysiological studies showed a greater degree of motor axonal damage in the right (p=0.003) and left (p=0.013) tibial nerves in the placebo group after 2C. In the ATRA group there were no significant differences baseline and after chemotherapy. Conclusions: ATRA might have a neuroprotective effect in patients with NSCLC treated with paclitaxel and cisplatin. A phase III trial is needed to confirm these findings. No significant financial relationships to disclose.
A pilot study evaluating surrogates of response to short-term vorinostat in women with newly diagnosed breast cancer
Authors: Stearns V. , Jacobs L. K. , Tsangaris T. N. , Briest S. , Lange J. R. , Slater S. , Fackler M. , Sugar E. , Gabrielson E. , Davidson N. E. 
Published: August 2020

e14508 Background: Epigenetic modifications contribute to breast cancer initiation and progression and may be reversible, thus representing an attractive area for new drug investigation. In preclinical breast cancer models, the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) induces cell cycle arrest, apoptosis and differentiation. Methods: We evaluated the safety and tolerability of short term vorinostat in women with a primary clinical stage I-III histologically confirmed carcinoma of the breast on a core needle biopsy. Participants received vorinostat 300 mg PO bid for a total of 6 doses, the last dose 2 hours prior to surgery or biopsy. Peripheral blood mononuclear cells were collected at baseline and following the last vorinostat dose to determine histone acetylation. Baseline and post-treatment tumor specimens were collected for analysis of histone acetylation, candidate gene methylation and expression. Tissues were also collected from untreated controls. Paired t-tests and Fisher's exact tests were used to evaluate changes from baseline for continuous and categorical data, respectively. Results: From March 2006 to October 2008, 25 women signed an informed consent and initiated study drug. Median age was 55 and 80% had hormone receptor positive tumors. Twenty-two women took all 6 prescribed doses. One participant took 4 and one 5 doses due to insurance clearance delay; one received a single dose due to fatigue and abdominal pain. Study-related surgical delays did not occur. Grade 1 toxicities included diarrhea (28%), low white blood cell count (24%), and fatigue, taste alterations and nausea (16% each). Tissue and blood samples were successfully collected. Tissue was also collected from 25 untreated controls. No significant change was observed in the proliferation marker Ki67 following 3 days of agent administration. Modulation of apoptosis, histone acetylation and gene methylation will be presented. Conclusions: Short-term administration of vorinostat is feasible, safe, and allows for studies of biomarker modulation. The results will be used to design future studies in which vorinostat will be administered in combination with other targeted therapies or with other epigenetic modifiers. [Table: see text]
Midostaurin: Review of pharmacokinetics (PK) and PK/pharmacodynamic (PD) relationship in AML/MDS patients
Authors: Dutreix C. , Huntsman Labed A. , Roesel J. , Lanza C. , Wang Y. 
Published: August 2020

e14540 Background: Midostaurin is a multi-tyrosine-kinases inhibitor targeting class III tyrosine-protein-kinases, including Fms-like tyrosine kinase-3 (FLT3), involved in hematopoiesis and leukemia. Oral midostaurin has been tested as a single agent and in combination therapy in >800 subjects. Methods: The two studies presented here involved patients with wild-type or FLT3-mutated de novo (phase Ib) or relapsed (phase II) AML or MDS. They covered a wide range of doses, given as monotherapy or in combination. Results: PK studies demonstrated that midostaurin was rapidly absorbed and metabolized into two major active metabolites: the demethylated compound, CGP62221 and the hydroxylated compound, CGP52421 . The relative potency of these metabolites (Midostaurin: CGP62221 : CGP52421 ) is approximately 1 : 1.4 : 0.1 in FLT3-based cellular assays. Following multiple oral daily single-agent doses, midostaurin and CGP62221 concentrations accumulated significantly in the first 3–5 days then declined by 40- 80% prior to a new steady state 2–3 weeks post-dose. CGP52421 concentrations accumulated continuously through day 28 and remained stable thereafter, roughly 7-times higher than the parent drug or CGP62221 . The time-dependent kinetics of midostaurin may reflect an induction of CYP3A4 by midostaurin and/or its metabolites, as already demonstrated in vitro, or alternatively a protein binding displacement mechanism. The blast response with monotherapy appeared to be correlated both with midostaurin plasma levels alone and summed together with its two major metabolites, corrected for their in vitro potency differences. PK/PD analyses showed sustained reduction (>90% from baseline) in peripheral blast (PB) counts in patients with a higher midostaurin plasma exposure at steady state (>2–3 μg/mL). However, evaluation of available bone marrow blast (BM) response data revealed that a much higher midostaurin plasma would be needed for a satisfactory BM response. Conclusions: Additional chemotherapy was required to achieve a clinical response, with particularly promising results for the FLT3-mutated patients. These results support the ongoing phase III AML study in AML FLT3-mutated patients with midostaurin given in combination with chemotherapy. No significant financial relationships to disclose.