bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arterial blood carboxyhemoglobin as a predictor for response after chemotherapy in patients with lung cancer
Authors: Nakayama K. , Yasuda H. , Sasaki T. , Suzuki T. , Asada M. , Okinaga S. , Yamaya M. 
Published: March 2020

20029 Background: It is desirable to predict the response to chemotherapy in patients with lung cancer using a simple and reliable method. Arterial blood carboxyhemoglobin concentration (Hb-CO) is a useful biomarker for severity in inflammatory pulmonary diseases and is associated with cancer tissue volume in operable NSCLC. However, arterial Hb-CO as a predictor for response to chemotherapy in advanced lung cancer has not been reported. Methods: We enrolled 35 patients with SCLC and 66 ones with NSCLC in stage III or stage IV, treated with chemotherapy between October 2000 and December 2002. All patients with SCLC were treated with PE (cisplatin 80 mg/m2, day 1 and etoposide 100 mg/m2, day 1-day 3) every 3 weeks. The patients with NSCLC were treated with either VC (vinorelbine 25 mg/m2, day 1 and 8 plus cisplatin 80 mg/m2, day 1) or DG (gemcitabine 1100 mg/m2, day 1 and day 8 plus docetaxel 60 mg/m2, day 1) every 3 weeks. Arterial Hb-CO were examined before and at during chemotherapy and the response rate were studied. The patients with either a partial response (PR) or a complete response (CR) were categorized as responder, whereas patients with no change (NC) or progressive disease (PD) were as non-responders. According to the analysis in aterial Hb-CO, the patients were divided into two subgroups, patients with high (≥0.3%) or low (<0.3%) maximum changes in the Hb-CO (ΔHb-CO) during chemotherapy. Results: The response rate was 80% in SCLC and 38% in NSCLC. In responder patients with SCLC or NSCLC, the arterial Hb-CO significantly increased and reached maximum at day 4 of the 1st cycle of chemotherapy. In contrast, in non-responder patients, the Hb-CO did not increase during the chemotherapy. The response rate in patients with high ΔHb-CO was significantly higher than that with low ΔHb-CO in SCLC (26/26 vs 2/9, P < .001) and NSCLC (24/24 vs 1/42, P < .001). The high ΔHb-CO at day 4 of the 1st chemotherapy cycle was significantly associated with the response to the chemotherapy in SCLC (Odd ratio, OR = 12.5 [95% CI: 3.13–50, P < .001]) and in NSCLC (OR = 25 [95% CI: 3.23–100, P < .01]) (logistic regression analysis). Conclusions: Increases in arterial Hb-CO at day 4 of the 1st chemotherapy cycle in SCLC and SCLC may be a predictor of response to chemotherapy. No significant financial relationships to disclose.
Effects of PKC beta inhibitor enzastaurin on parental and chemoresistant ovarian cancer cell lines
Authors: Meinhold-Heerlein I. , Bauerschlag D. O. , Bräutigam K. , Maass N. , Mundhenke C. , Hilpert F. , Kaisenberg von C. , Jonat W. , Bauknecht T. , Arnold N. 
Published: March 2020

20037 Background: Enzastaurin (LY317615.HCl), a selective inhibitor of protein kinase C beta (PKCβ), inhibits induction of angiogenesis and apoptosis. Activation of PKCβ has been correlated with tumor cell proliferation and invasiveness. The impact of Enzastaurin was investigated in an ovarian cancer tissue culture model utilizing the parental cell line HEY and resistant subclones against different cytostatic drugs. Methods: The ovarian cancer cell line HEY was used to develop subclones with selective resistance against Cisplatin, Etoposide, Docetaxel and Paclitaxel, respectively. The ovarian cell line IGROV-1 with high expression of PKC beta served as control. All cell lines were stimulated with 5 μM Enzastaurin for up to four hours. Immunoblotting analyses determined the expression of GSK3β, a target of PKCβ. Proliferation and apoptosis induction after Enzastaurin treatment was analysed by a proliferation assay and DAPI staining. Results: All cell lines showed phosphorylation of GSK3β, the highest expression level was found in parental and Cisplatin-resistant HEY cells as well as in IGROV-1 cells. Phosphorylation decreased after stimulation with 5 μM Enzastaurin for 30 minutes, most obvious detectable in parental and Cisplatin-resistent HEY cells and also IGROV-1 cells. Proliferation and apoptosis assays demonstrated the Paclitaxel- and Docetaxel-resistant HEY cells as the most sensitive cell lines for Enzastaurin treatment. In contrast, Cisplatin-resistant HEY cells and IGROV-1 cells exhibited the highest resistance against Enzastaurin. Conclusion: The results indicate that ovarian cell lines with a high expression level of active PKCβ like Cisplatin-resistant HEY cells and IGROV-1 cells display also strong phosphorylation of GSK3β. Though in these cell lines the inhibitory effect of Enzastaurin is most prominent, the cell proliferation is hardly affected, nor apoptosis is accelerated when Enzastaurin concentrations up to 10–15 μM were used. Compared to the Cisplatin-resistant variants the normal HEY cells are more sensitive to the inhibitor. Taxane-resistant cells seem to respond to low concentrations of Enzastaurin. Therefore, Enzastaurin may become an effectful drug to treat ovarian carcinomas with resistance to Taxane-based chemotherapies. [Table: see text]
Never-smoking history predicts long-term survival in patients with non-small cell lung cancer with postoperative recurrence
Authors: Fujiwara Y. , Kiura K. , Toyooka S. , Hotta K. , Tabata M. , Takigawa N. , Kozuki T. , Ohashi K. , Matsuo K. , Tanimoto M. 
Published: March 2020

20047 Background: Factors affecting long-term survival after postoperative recurrence in non-small cell lung cancer (NSCLC) patients have not been fully understood. Furthermore, molecular features of them also have remained undetermined. The aim of this study was to identify these possible factors and to investigate their association with epidermal growth factor receptor (EGFR) mutation. Methods: Fifty-eight patients with postoperative recurrent NSCLC treated at Okayama University Hospital between January 1999 and December 2003 were retrospectively analyzed. We defined those surviving for 2 years or longer after postoperative recurrence as long-term survivors. Tumor samples for EGFR mutation analysis were available in 32 (55%) patients and were examined in exons 18 to 21 of EGFR using direct sequence method. Results: Demographics of 58 patients were as follows: median age 65 years (range, 33–85 years), male/female, 69%/31%; adenocarcinoma/others, 69%/31%; ever/never-smokers, 66%/34% and local/local and distant/distant recurrence; 29%/10%/61%. Median survival time and 1-year survival rate for 58 patients were 22.7 months and 79%, respectively, with a minimum follow-up time of 2 years. Half of 28 long-term survivors did not have any smoking history, whereas only 6 never-smokers were included in the remaining 30 patients who died within 2 years, indicating that never-smoking history is significantly associated with long-term survival (p=0.016). In multivariate analysis, never-smoking history was a significant predictive factor for long-term survival (Odds ratio 4.90, 95% confidence interval: 1.26–19.00, p=0.022). Among 32 patients analyzed for EGFR mutation, patients harboring EGFR mutation in ever-smokers and in never-smokers were 10% and 82%, respectively. Seven (47%) of 15 long-term survivors analyzed had EGFR mutation; however, only 4 (24%) of 17 patients who died within 2 years did (p = 0.169). Conclusions: Our data suggest that never-smoking history might have a favorable effect on long-term survival in postoperative recurrent NSCLC patients, and long-term survivors tend to have EGFR mutation. No significant financial relationships to disclose.
Polymorphisms of the thiopurine S-methyl transferase gene (TMPT) in a Mexican population
Authors: Candelaria M. , Taja-Chayeb L. , Vidal S. , Gutiérrez O. , Ostrosky P. , Duenas-Gonzalez A. 
Published: March 2020

20049 Background: Polymorphisms at the thiopurine S-methyltransferase coding gene (TPMT) determine enzyme activity and as a consequence the development of toxicity of thiopurine drugs. Methods: To test the frequency of polymorphisms of TPMT gene in Mexican population. 36 DNA samples from volunteer donors were analyzed. Genomic DNA from peripheral leukocytes was isolated by standard methods. Known (wild type and polymorphic) sequenced PCR fragments of the TPMT gene were used used as controls. PCR amplification: Fragments of the TPMT gene were amplified using the following oligonucleotides primers: Exon 5: 5′-CTGCATGTTCTTTGAAACCCTATGAA-3′ and 5′-CTTGAGGACAGAGAGGCTTTGACCTC-3′; exon 7: 5′-CTCCACACCCAGGTCC-ACACATT-3′ and 5′-GTATAGTACTAAAAAATTAAGACAGCTAAAC-3′; exon 10: 5′-AATCCTGATGTCATTCTTCATAGTATTT-3′ and 5′-CATCCATTACATTTTCAGG-CTTTAGCATAAT-3′. PCR products were then analyzed by denaturating high performance liquid chromatography (DHPLC) for the most frequent mutant TPMT alleles, according to the method developed by Schaeffeler et al (Clin Chem 2001; 47: 548) on an analysis system from Transgenomics Results: A high frequency of gene polymorphisms was identified, particularly in the exon 7 (14/36 = 38%), followed by exon 10 (3/36 = 8.3%) and 5 (2/36 = 5.5%). After analysing the three exons, the presence of mutations discriminating for TPMT alleles showed that 7/36 (19.4 %) were silent and located at T474C, in exon 7 (*1S) and 7/36 (19.4 %) were functional, and located in TPMT alleles *2 (2/36 = 5.5%), *3B (2/36 = 5.5%), *4 (2/36 = 5.5%) and *3B/4 (1/36= 2.7%). Conclusions: This is the first analysis of the polymorphisms at this gene in a Mexican population. The frequency of known silent polymorphisms was higher than those reported in other world regions but the frequency of functional polymorphism is within the range found in other reports. DHPLC is a highly sensitive, rapid and efficient method to identify relevant TPMT gene mutations which allows the screening for genetic variability in the TPMT gene . This trial was supported by a grant of CONACYT. No significant financial relationships to disclose.
Expression of metastasis suppressor gene maspin in breast cancer brain metastases
Authors: Schem C. , Stark A. M. , Mehdorn H. M. , Jonat W. , Maass N. 
Published: March 2020

20057 Background: Recently our demonstrated that the expression of several Metastasis Suppressor Genes (MSG) is reduced in breast cancer brain metastases. Current data suggest that MSG Maspin (serpin B5) is a promising candidate for further treatment options. So, we examined the mRNA and protein expression of Maspin in normal breast tissue, breast cancer primaries, -brain metastases and breast cancer cell lines. Methods: Maspin mRNA expression was examined by real time reverse transcription polymerase chain reaction (RT-PCR) in fresh frozen samples from normal breast tissue, breast cancer primaries and -brain metastases. Furthermore maspin was examined in poorly invasive and non-metastatic breast cancer cell lines MCF-7, T47-D, in highly invasive and metastatic MDA-MB-231 breast cancer cells (231-parental) and in brain- and bone-selective metastatic clones (231-brain, 231-bone). Maspin protein was detected by immunohistochemistry in paraffin-embedded sections from 16 patients with breast cancer primaries and brain metastases using a specific monoclonal mouse antibody. Results: In relation to normal breast tissue, maspin mRNA expression was decreased in primary tumors and again decreased in brain metastases. Normalized ΔCT values were 1 (normal tissue), 0.3 (primary tumors) and 0.13 (brain metastases). Immunohistochemistry revealed the same tendency. 3 of 16 (19%) breast cancer primaries were positive whereas none of the brain metastases showed positive maspin staining. In comparison to poorly invasive breast cancer cell lines, maspin mRNA expression was decreased in 231-parental, increased in 231-brain and not detectable in 231-bone. Conclusions: Maspin expression is reduced in breast cancer brain metastases. It is differentially expressed in brain- and bone-selective metastatic cell lines. These results suggest an important role for maspin in breast cancer brain metastasis. No significant financial relationships to disclose.
O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and relation to 1p/19q loss in low grade gliomas: A GICNO study
Authors: Nicolardi L. , Bertorelle R. , Bonaldi L. , Compostella A. , Roma A. , Tebaldi E. , Pession A. , Reni M. , Franceschi E. , Ghimenton C. 
Published: March 2020

20064 Background: 1p and 19q deletions have been associated with a favorable response to chemotherapy and a good prognosis in patients (pts) with oligodendroglioma. MGMT promoter methylation has been associated with a longer survival in pts with glioblastoma who receive alkylating agents. As yet, there are no data on the expression of MGMT, and on the relationship between 1p/19q deletions and MGMT promoter methylation in low grade glioma (LGG). Methods: Pts that received a first line chemotherapy regimen with temozolomide for progressive LGG were enrolled in the study, designed to investigate the correlation between MGMT methylation status and 1p/19q deletions in this setting. 1p/19q deletions were analysed by FISH, and MGMT promoter methylation by methylation specific PCR (MSP). Results: Seventy-five pts (26 females, 49 males; median age 42 years: range 22–68 years) were accrued. Of these, 48 (64%) had oligodendrogliomas (O), 19 (25.3%) astrocytomas (A), and 8 (10.6%) oligoastrocytomas (OA); 44 (58.7%) had a history of epilepsy, 41 (54.7%) had a frontal tumor localization, 27 (36%) had MRI contrast enhancing lesions, and 35 (46.7%) had been pre-treated with radiotherapy. 1p/19q deletions, evaluable in 58 pts (77.3%), were both present in 36 pts (62%), (3 being A and 2 OA); 18 pts (31%) had no loss; 1 pt (1.7%) had 1p loss; 3 pts (5.2%) 19q loss. Combined 1p and 19q loss was not correlated with a frontal localization (p = 0.12), median age (0.47) and/or gender (0.62). MGMT promoter methylation, present in 17 (56.6%) of 30 assessable cases, was significantly associated with combined 1p/19q deletions (p = 0.03). MGMT promoter methylation was not significantly associated with age (p = 0.46), gender (p = 0.2), tumor localization (p = 0.12) and/or histology (0.37). Conclusions: 1p/19q deletions are strictly correlated to histology and to MGMT promoter methylation; further prospective trials are required to clarify the impact of these molecular signatures on clinical outcome. No significant financial relationships to disclose.
Analysis of serum HER-2/neu levels (S-HER2) in breast cancer (BC) patients (pts)
Authors: Palmeri S. , Mangiameli A. , Vaglica M. , Allegro R. , Macaluso M. C. , Bongiovanni A. , Di Noto L. , Vasta D. , Raciti L. , Lio D. 
Published: March 2020

20092 Background: Circulating serum levels of the extracellular domain of the HER-2/neu receptor have been described in up to 15–30% of pre-surgical BC pts and 45% of metastatic BC (MBC) pts. S-HER2 has been reported to have a potential prognostic and predictive role in BC pts. Methods: We conducted a prospective evaluation of the S-HER2 levels in BC pts with the aim of studying its prognostic role and correlation with the clinical situation.The S-HER-2 levels were measured by an ELISA immunometric test (cut-off 13 ng/ml) at the first visit and then every 3 months.All pts gave a written informed consent. Results: From Jan ‘05 97 consecutive BC pts [68 st I-III; 29 (1 male) st.IV; median age at entry: 60y (28–83)] have been accrued and a total of 196 serum samples have been tested for S-HER2 (mean = 2/pt).Preliminary results are reported.Elevated S-HER2 levels at the first dosage (bS-HER2) were present in 25% of primary and 52% of MBC pts.In 68 primary BC pts the tumor HER2 status was 0/1+ in 54% (bS-HER2 >13 ng/ml = 22%) and 2+/3+ in 22% (bS-HER2 >13 ng/ml = 27%); there was no correlation between bS-HER2 with tumor HER2 status, size,axillary nodes, ER status, grading according to the Fisher’s exact test. In 29 MBC pts the tumor HER2 status was 0/1+ in 24% (bS-HER2 >13 ng/ml = 24%) and 2+/3+ in 48% (bS-HER2 >13 ng/ml = 21%); there was no correlation between S-HER2 and sites of metastases/n.of sites even if the S-HER2 median value was 18 and 12.5 ng/ml in visceral vs no visceral metastases.We also observed in 35% of MBC pts experiencing progression of disease that S-HER2 sequential values increased from baseline;in 21% of MBC pts that experienced complete remission the S-HER2 values decreased <13 from baseline. Conclusions: This analysis showed no definite association between bS-HER-2 and clinical parameters.Further evaluations in a larger group of pts and association with response,survival and changes of S-HER2 status will be conducted. No significant financial relationships to disclose.
Phase 1 study of CPX-1, a fixed ratio formulation of irinotecan (IRI) and floxuridine (FLOX), in patients with advanced solid tumors
Authors: Batist G. , Chi K. , Miller W. , Chia S. , Hasanbasic F. , Fisic A. , Mayer L. , Swenson C. , Janoff A. , Gelmon K. 
Published: March 2020

2014 Background: In vitro studies have shown that varying the ratio of individual agents in drug combinations can result in synergistic, additive or antagonistic activity against tumor cells. CPX-1 is a liposomal formulation of IRI and FLOX in a fixed 1:1 molar ratio which was selected as optimal in vitro and confirmed to be synergistic in vivo in preclinical tumor models. CPX-1 overcomes the dissimilar pharmacokinetics (PK) of the individual drugs, enables sustained maintenance of this ratio after IV administration, and was evaluated in a Phase I open-label, dose-escalation study. Methods: Starting dose was 30 U/m2 (1 Unit of CPX-1 contains 1 mg IRI + 0.36 mg FLOX) given on day 1 and 15 of each 28-day cycle. Dose escalation was by modified Fibonacci with 4 subjects/cohort. Eligibility included: ≥ 18 yo; advanced solid tumor; ECOG PS ≤ 2; adequate bone marrow/liver/renal function. PK analysis was done on day 1 and 15 of the first cycle. Results: 26 subjects (16M:10F), median age 54.5 y (21–72), all with prior therapy, enrolled in 6 cohorts with the 5th cohort expanded to 6 subjects. Diagnoses: 8 colorectal, 3 pancreatic, 3 ovarian, 2 breast, 2 gastric, 2 esophageal, 2 sarcomas, 1 renal cell, 1 prostate, 1 NSCLC and 1 sphenoid sinus. Response: 20 subjects evaluable: 2 confirmed PRs (NSCLC 8+ wks; Colon 13+ wks, in a patient with prior IRI exposure) and 13 with SD (8–24+wks). Safety: DLTs were observed at the 6th dose level: 4 subjects with DLTs: 3 diarrhea (one resulting in death due to dehydration/ARF) and one neutropenia. Other possibly related grade 3 and 4 events included one each of: grade 3 diarrhea, grade 3 vomiting, grade 3 neutropenia, grade 3 fatigue, grade 3 compression fracture and arthralgia and pulmonary embolism grade 4. PK: In all 14 subjects analyzed to date the 1:1 molar ratio of IRI to FLOX was maintained for 24 hours and metabolites 5-FU and SN-38 were present in the plasma. Conclusions: CPX-1 represents a new approach to developing drug combinations in which drug ratios are pre-selected in vitro based on optimal antitumor activity and maintained systemically through pharmacokinetic control. Phase 2 studies are planned with a recommended dose of 210U/m2 of CPX-1. [Table: see text]
Concentrations of the DNA methyltransferase inhibitor 5-fluoro-2’-deoxycyticine (FdCyd) & its metabolites 5-fluoro-2’-deoxyuridine (FdUrd), 5-fluorouracil (FU), 5-fluorouridine (FUrd), & 5-fluorocytosine (FC) in plasma of patients treated with FdCyd
Authors: Beumer J. H. , Parise R. A. , Newman E. M. , Doroshow J. H. , Synold T. W. , Lenz H. , Egorin M. J. 
Published: March 2020

2023 Background: The DNA methyltransferase inhibitor, FdCyd, is in phase I clinical trials. It is combined with tetrahydrouridine (THU), a cytidine deaminase inhibitor, to prevent rapid metabolism of FdCyd to the pharmacologically active metabolites FdUrd, FU, FUrd, & FC. We assessed the plasma levels of these active, yet undesired, metabolites in patients receiving FdCyd+THU. Methods: We developed a hydrophilic interaction chromatography LC-MS/MS assay capable of simultaneously quantitating FdCyd & metabolites. Patients were treated with 5 daily, 3-h infusions of FdCyd at doses of 5–80 mg/m2. Plasma was obtained before & at the end of infusions (EOI) on days 1 & 5. Results: The lower limits of quantitation for FU, FdUrd, FUrd, FC & FdCyd were 1, 1.5, 10, 3, & 10 ng/ml, respectively, & the assay for each analyte was linear over a 300–1000 fold range of concentrations. Plasma FdCyd increased with dose from 19–96 ng/ml at 5 mg/m2 to 1600–1728 ng/ml at 80 mg/m2, as previously described. FdUrd was not detectable in plasma of patients treated with FdCyd doses <20 mg/m2, & then increased from 2.31 ng/ml at 20 mg/m2 to 3.5–5.7 ng/ml at 80 mg/m2. FU was present in plasma of patients treated at all doses studied, & FU concentrations increased with dose. Inter-patient variability in concentrations was 1.5–3 fold (FdUrd) and 2–4 fold (FU). FUrd & FC were only present in the day 1 plasma sample of one patient, who was treated at 40 mg/m2, & were not present in the day 5 sample of that patient. No FdCyd or metabolite was detected in day 5 pretreatment plasma of the 2 patients treated with 80 mg/m2 of FdCyd. Conclusions: FdCyd administered with THU undergoes little catabolism. The EOI FU and FdUrd concentrations in plasma of patients treated with FdC+THU are <10% those observed after therapeutic continuous infusions of FU or FdUrd. Thus, selective inhibition of DNA methylation with FdCyd+THU is feasible. The LC-MS/MS assay developed will be a valuable tool to pharmacologically support continuing clinical development of FdCyd. Support: NO1-CM52202, P30CA47904, U01CA62505, & P30CA33572. No significant financial relationships to disclose.
Dosing of troxacitabine (Troxatyl [T], SGX-145) based on renal function
Authors: Kelner M. J. , Giles F. J. , Feldman E. J. , Roboz G. J. , Deangelo D. J. , Burley S. K. 
Published: March 2020

2025 Background: Troxacitabine (Troxatyl [T], SGX-145) is a novel L-configuration nucleoside analog anti-cancer agent with unique mechanistic/cytotoxic properties. T is clinically active against acute myelogenous leukemia (AML), chronic myeloid leukemia, myelodysplastic syndromes (MDS), renal cell carcinoma, and pancreatic cancer. A multi-center Phase 2/3 clinical trial is currently underway to evaluate the safety and efficacy of continuous IV infusion T treatment in second salvage AML. The major route of elimination of troxacitabine is renal excretion as unchanged drug (∼70%) and there is minimal protein binding. These results suggest that renal function may have a significant effect on steady-state troxacitabine plasma concentrations (Css). Methods: Pharmacokinetic and toxicity data from four AML clinical trials (>200 patients) are being analyzed to (1) Identify a minimum Css for therapeutic efficacy; (2) Define an upper limit of Css for adverse risk; and (3) Develop a mechanism to prospectively modify the troxacitabine dose based on renal function, which would avoid excessive toxicity while maintaining therapeutic blood levels. Results: Initial results from 41 patients indicate that to induce remission in AML patients, troxacitabine steady-state plasma concentrations (Css) must be ≥ 80 ng/mL. However, higher Css values correlate with increased toxicity and, thereby, increase the risks of the treatment for an individual patient, although an upper limit for adverse risk has not yet been defined. For patients with normal renal function (creatinine clearance ≥ 50 but ≤ 125 mL/min), a Calvert style formula, based on a patient’s estimated creatinine clearance, has been developed to define the dose required to achieve a therapeutic Css ≥ 80 ng/mL. Both linear and non-linear nomogram models are also being developed to adjust troxacitabine dosage for patients with moderate renal impairment (30 mL/min < creatinine clearance < 50 mL/min) or for patients with high GFR (creatinine clearance > 125 mL/min). Conclusion: A firm relationship exists between renal function, troxacitabine clearance, and Css values. This result indicates that a dosing strategy based on renal function may be warranted to obtain optimal troxacitabine Css values. [Table: see text]