The distribution of a live attenuated herpes simplex virus (βH1)-mediated gene delivery into the central nervous system (CNS) was regulated by growth inhibition with ganciclovir (GCV) and the effect ...of this transgene expression system on the physiologic response was characterized by the acoustic startle response and its prepulse inhibition. We inoculated βH1 expressing β-galactosidase (β-gal) driven by the latency associated transcripts promoter into the right caudate putamen of rats. Histochemical analysis demonstrated that the inoculation of βH1 in the right caudate putamen resulted in a high level of β-gal expression in the neurons of the area projecting to the inoculation site. On 14 days after inoculation without GCV-treatment, β-gal activity localized in the anterior olfactory nucleus, frontal, insular, orbital, parietal, perirhinal, piriform cortices and the temporal region including the amygdala. In contrast, the distribution of β-gal activity was regulated by the interval between virus inoculation and GCV-treatment and maintained after its cessation without significant alteration. The whole process of transgene expression did not influence the emotional behavior, indicating that this vector system is a suitable model for analyzing the transgene function or applying the gene therapy for the CNS diseases.
The effects of 1,3-dioleoyl-2-palmitoyl glycerol (OPO) on lymph chylomicron transport, composition and size in rats were investigated in comparison with 1,2-dioleoyl-3-palmitoyl glycerol (OOP). The ...OPO and OOP were prepared by enzymatic transesterification reactions. The concentrations of OPO and OOP in the preparations were 65.7 g/100 g, and the composition of fatty acids was similar for each. The OPO preparation contained triacylglycerols with 76.6% of the palmitic acid in the sn-2 position, whereas 100% of the oleic acid was esterified to the sn-2 position in the OOP preparation. Rats were infused with lipid emulsion containing 150 g/L of OPO or OOP via a stomach catheter. Lymph was collected through the mesenteric lymphatic trunk at 1-h intervals for 12 h. Collected lymph chylomicrons were analyzed for triacylglycerol, fatty acids, apolipoprotein A-I and particle size. The maximum transport rates of triacylglycerols in the OPO group were higher than those in the OOP group. The overall absorption of triacylglycerols, palmitic acid and oleic acid in the OPO group was also higher than that in the OOP group. In the chylomicrons, 60-70% of the fatty acids at the sn-2 position of the infused triacylglycerol was transported at the original position. The transport rates of diolecyl-palmitoyl glycerol in the OPO group were higher than those in the OOP group. The transport rates of apolipoprotein A-I did not differ between groups, whereas the mean diameter of the chylomicrons in the OPO group was larger than that in the OOP group. These results indicate that OPO is absorbed and transported more effectively than OOP
Current guidelines define primary and secondary endocrine resistance according to the periods of adjuvant endocrine therapy (adj-ET); however, the relationship between adj-ET period and endocrine ...resistance remains unclear.
We examined progression-free survival (PFS) after primary ET for recurrent hormone receptor-positive/HER2-negative breast cancer, and evaluated the relationship between endocrine resistance and the periods of adj-ET.
We assessed PFS among 183 patients who received ET as primary treatment for the first recurrence, according to the period of adj-ET (adj-ET < 1 year, 1-2 years, ≥2 years, and completion).
Patients who relapsed during the first year of adj-ET had the significantly shortest PFS. PFS did not significantly differ between patients who relapsed at 1-2 years of adj-ET and patients who relapsed while on adj-ET but after the first 2 years.
Relapse at 1-2 years after adj-ET initiation might be better classified as secondary endocrine resistance rather than primary endocrine resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Varicella skin test antigen has been developed based on the induction of delayed-type hypersensitivity (DTH) to varicella-zoster virus (VZV). The booster immune response to Oka varicella vaccine was ...assessed by cutaneous reactivity to purified VZV glycoprotein complexes, gB, gE:gI, gH:gL, and varicella skin test antigen. Skin tests with these antigens significantly augmented antibody production to glycoproteins and VZV antigen resulting in no further augmentation by the subsequent vaccination. All glycoprotein complexes induced the cutaneous reaction similarly to varicella skin test antigen. Cutaneous reaction to glycoproteins and varicella skin test antigen was boosted after vaccination. However, the magnitude of cutaneous reaction to each glycoprotein complex before and after vaccination was rich in variety. These results indicated that skin test with varicella skin test antigen is a more suitable indicator in monitoring cell-mediated immunity to VZV than that using purified glycoproteins.
We previously identified 18 genes that correlated with ER positivity by adapter‐tagged competitive‐PCR analysis of 2412 genes in human breast cancer tissues. The aim of the present study was to ...determine the prognostic significance of these genes. mRNA expression levels of 12 of the above 18 genes were quantified in breast cancer tissues by real‐time PCR assay, and their association with patients' prognosis (n=110) was studied according to hormone receptor (HR) status. In addition, the genes found to influence prognosis were further investigated to examine whether their mRNA expression could be induced by estrogen in MCF‐7 cells in vitro. Of the 12 genes, mRNA expression levels of two α1‐antichymotrypsin (ACT) and stanniocalcin 2 (STC2) were significantly (P=0.002 and P=0.007, respectively) associated with good prognosis in HR‐positive (ER and/or PR positive) breast cancer patients treated with adjuvant hormone therapy. Multivariate analysis showed that ACT mRNA level, but not STC2 mRNA level, in HR‐positive patients, was a significant prognostic factor (P=0.042), which was independent of tumor size and lymph node metastases. On the other hand, mRNA expressions of ACT and STC2 were not significantly associated with prognosis in HR‐negative patients. Estradiol treatment resulted in a significant increase in the mRNA levels of both ACT and STC2 in MCF‐7 cells. The mRNA level of ACT, which is an estrogen‐inducible gene, is a significant predictor of good prognosis in HR‐positive, but not HR‐negative, patients with breast cancers. Since HR‐positive patients were treated with adjuvant hormone therapy, we suggest that ACT mRNA level could potentially be used as a predictor of response to hormone therapy, rather than a prognostic factor (predictor of metastatic potential).
We have characterized the differential actions of acyclovir and penciclovir against varicella-zoster virus (VZV) in cell culture by comparing the frequency of appearance of resistant viruses followed ...by their characterization. Cells were infected with cell-free virus and the cultures were successively treated with increasing concentrations of acyclovir or penciclovir. Drug-resistant viruses were selected in the presence of 6 μg/ml of acyclovir or penciclovir. The emergence frequency of resistant viruses was significantly higher following acyclovir exposure than following penciclovir exposure (Fisher’s exact test,
P<0.0001), possibly reflecting virus growth differences under these experimental conditions. Based on antiviral drug susceptibility and thymidine kinase (TK) activity assays, 11 acyclovir-resistant variants from seven experiments using three virus strains (Kawaguchi strain, Oka varicella vaccine strain and a clinical isolate from a zoster patient) were found to be TK-deficient. Sequence analysis of TK-deficient variants of the Kawaguchi strain revealed deletions that caused frameshifts, resulting in premature termination in the TK gene.
Purpose
This phase I trial assessed afatinib, an irreversible ErbB family blocker, plus vinorelbine in Japanese patients with advanced solid tumors not amenable to standard treatment.
Methods
Primary ...objectives were evaluation of safety and the maximum tolerated dose (MTD) of once-daily (QD) afatinib plus weekly intravenous vinorelbine. Secondary objectives included pharmacokinetic assessments and preliminary efficacy. Dose finding utilized a 3 + 3 design, with a starting dose of afatinib 20 mg QD plus vinorelbine 25 mg/m
2
weekly.
Results
Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m
2
) exceeded the MTD; dose-limiting toxicities (DLTs) were considered vinorelbine-related. Dose finding continued with modified dose levels; dose level 2a: afatinib 40 mg and a reduced dose of vinorelbine 20 mg/m
2
and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m
2
allowing omission of vinorelbine for grade ≥2 neutropenia/thrombocytopenia and afatinib dose modification for adverse events (AEs). At dose level 3, 1/6 patients had a DLT (upper abdominal pain requiring afatinib dose reduction). Overall, the most frequent treatment-related AEs (any/grade 3 and 4) were: neutropenia (100/71 %), leukopenia (100/59 %), diarrhea (94/0 %), anemia (71/12 %) and stomatitis (65/0 %). Two patients with breast cancer achieved a partial response; eight patients (various cancer indications) had stable disease. Pharmacokinetic analyses suggested no relevant drug–drug interactions.
Conclusions
Afatinib 40 mg QD plus vinorelbine 25 mg/m
2
weekly was tolerated in Japanese patients when dose modifications for known AEs for either compound were allowed. Tumor shrinkage was also observed. This dose schedule was recommended for phase II/III trials in Japanese patients.
Abstract
Background: Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and the ...combination of pertuzumab plus trastuzumab plus taxanes, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival (PFS). However, in the second and later line treatment of HER2-positive advanced or recurrent breast cancer, it has not settled whether it should be treated with pertuzumab plus trastuzumab plus chemotherapy or with trastuzumab plus chemotherapy. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that has been proved to prolong the overall survival of advanced or recurrent breast cancer patients compared with the treatment of physician's choice. The benefit of eribulin in combination with trastuzumab for patients with locally recurrent or metastatic HER2-positive breast cancer has been reported. However, the efficacy and safety of eribulin in combination with pertuzumab and trastuzumab for advanced or recurrent HER2-positive breast cancer patients has not been reported. The purpose of this study is to evaluate the efficacy and safety of eribulin in combination with pertuzumab and trastuzumab as second and later line therapy for patients with advanced or recurrent HER2-positive breast cancer.
Trial Design: This is a multicenter single arm phase 2 study for advanced or recurrent HER2-positive breast cancer patients who have experienced progression with anti-HER2 therapy. Patients received eribulin mesylate 1.4mg/m2 administered via intravenous (IV) infusion over 2 to 5 minutes on Days 1 and 8 each 21-day cycle and pertuzumab 840mg/kg IV and trastuzumab 8mg/kg IV over 90 minutes on Day 1 of Cycle 1. Thereafter eribulin mesylate 1.4mg/m2 and pertuzumab 420mg/kg and trastuzumab 6mg/kg was infused each 21-day cycle until disease progression or the appearance of toxic effects that could not be effectively managed. The primary endpoint is PFS of the combination therapy, based on local assessment of response using RECIST 1.1 criteria. Secondary endpoints are overall response rate (ORR), safety and tolerability. In addition, we examine PFS and safety according to the most recent treatment regimen. The study was conducted in accordance with the Declaration of Helsinki (2008), and the protocol and informed consent forms were submitted for approval to institutional review boards by the primary investigators. All patients provided written informed consent before undergoing any study-related procedures
Statistical Method: All efficacy analyses were based primarily on the full analysis set (FAS), which included all patients who received over 1 dose(s) of study treatment. The PFS and ORR were calculated 95% confidence intervals (CIs). Treatment of 39 evaluable patients with the identified phase 2 doses will detect this difference with a power of 80% and alpha=5% (one-sided test). Accounting for a 10% invaluable rate and lead-in patients, a total of 43 patients will be enrolled on the study. Clinical trial information UMIN000014107.
Citation Format: Hajime Abe, Shunji Kamigaki, Yoshifumi Komoike, Nobuki Matsunami, Yoshiaki Nakano, Kenji Tezuka, Junji Tsurutani, Jun Yamamura, Keiichi Yamazaki. A phase 2 study of eribulin in combination with pertuzumab and trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 (HER2)-positive breast cancer (SONG-02) abstract. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-04.
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