Pharmacogenomic study of gemcitabine efficacy in patients with metastatic pancreatic cancer: A multicenter, prospective, observational cohort study (GENESECT study).

BACKGROUND: Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy. METHODS: This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%. RESULTS: In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p = .007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p = .019). CONCLUSIONS: Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS.

Switching from concomitant therapy to tafluprost/timolol fixed combination.

PURPOSE: To evaluate the efficacy and safety of tafluprost/timolol fixed combination (TTFC). STUDY DESIGN: A prospective clinical study. METHODS: Twenty-eight patients (28 eyes) with primary open-angle glaucoma, who had used tafluprost and timolol gel for at least 3 months with good adherence, were enrolled. Concomitant administration of tafluprost and timolol was switched to TTFC without a washout period. The intraocular pressure (IOP), blood pressure, pulse rate, and ocular signs were compared between before switching (baseline), and 4 and 8 weeks after switching. A questionnaire survey was also performed 4 weeks after switching to investigate ocular comfort and patient preferences. RESULTS: The IOP showed no significant change after switching to TTFC (14.8 ± 2.8, 14.6 ± 3.4, and 14.8 ± 3.7 mmHg at baseline, Week 4, and Week 8, respectively). The pulse rate and systolic blood pressure showed no changes, but diastolic blood pressure was significantly lower at Week 8. At baseline, fluorescein staining revealed corneal abnormalities in 3 patients, which resolved by Week 8 in 1 patient. Hyperemia was noted in 2 patients at baseline, and this also resolved by Week 8 in 1 patient. Three patients discontinued study treatment for the following reasons (1 patient each): blurred vision; ocular irritation, eyelid erythema, and asthenopia; and loss to follow-up from Week 8. The questionnaire survey revealed no significant differences between the 2 treatments, although more patients preferred TTFC. CONCLUSION: Among 28 patients enrolled, only 2 patients discontinued the study treatment due to adverse reactions. In patients whose adherence was considered relatively good to concomitant therapy, switching to TTFC achieved similar IOP control with good safety and a high level of patient acceptance.

Efficacy and safety of a switch to latanoprost 0.005% + timolol maleate 0.5% fixed combination eyedrops from latanoprost 0.005% monotherapy.

BACKGROUND: The purpose of this prospective study was to investigate the intraocular pressure (IOP)-lowering effect and safety of latanoprost 0.005% + timolol maleate 0.5% fixed combination eyedrops, now available in Japan. MATERIALS AND METHODS: Thirty-one patients diagnosed with primary open-angle glaucoma who had an insufficient intraocular pressure (IOP) decrease with latanoprost 0.005% eyedrop monotherapy were enrolled. The latanoprost 0.005% eyedrops were discontinued, and administration of latanoprost 0.005%/timolol maleate 0.5% fixed combination eyedrops was initiated without any washout period. IOP was compared before and at months 1, 3, and 6 after the switch. The incidence of adverse reactions was investigated at every follow-up visit. RESULTS: Mean IOP was 17.3 ± 2.7 mmHg before the switch, 15.5 ± 2.6 mmHg one month after the switch, 14.9 ± 2.4 mmHg 3 months after the switch, and 15.1 ± 2.2 mmHg 6 months after the switch, indicating that IOP decreased significantly after the change. The IOP reduction rate was 9.9% ± 11.5% after one month, 13.1% ± 10.9% after 3 months, and 11.2% ± 11.8% after 6 months. Two patients (6.5%) discontinued therapy due to adverse reactions (one case each of itchiness and bradycardia). CONCLUSION: When latanoprost 0.005% eyedrop monotherapy was replaced by latanoprost 0.005% + timolol maleate 0.5% fixed combination eyedrops, IOP decreased significantly without increasing the frequency of administration, and safety was satisfactory.

Ocular hypotensive effect and safety of travoprost 0.004%/timolol maleate 0.5% fixed combination after change of treatment regimen from ß-blockers and prostaglandin analogs.

INTRODUCTION: Travoprost 0.004%/timolol maleate 0.5% fixed combination eye drops are available in Japan. We prospectively investigated the intraocular pressure (IOP)-decreasing effect of travoprost 0.004%/timolol maleate 0.5% fixed combination eye drops and the adherence of patients to the administration protocol. MATERIALS AND METHODS: We studied 43 eyes from 43 patients diagnosed with primary open- angle glaucoma, who were using prostaglandin analogs and ß-blockers. The prostaglandin analogs and ß-blockers were discontinued, and the treatment regimen was changed to travoprost 0.004%/timolol maleate 0.5% fixed combination eye drops without any washout period. IOP before and at 1 month, 3 months, and 6 months after the treatment change was evaluated and compared. A questionnaire about protocol adherence was administered 1 month after the treatment change. RESULTS: IOP was 15.7 ± 2.9 mmHg before the change, 15.5 ± 2.7 mmHg at 1 month after the change, 15.3 ± 3.6 mmHg at 3 months after the change, and 15.8 ± 3.2 mmHg at 6 months after the change, and none of the differences were significant (P = 0.191). The responses to the questionnaire showed that cases where eye drop administration was forgotten decreased after the treatment change. Moreover, because of changes in eye drops, 19.0% of patients had irritation. More than half (54.8%) of the patients preferred travoprost 0.004%/timolol maleate 0.5% fixed combination eye drops. Seven patients (16.3%) discontinued eye drop use because of adverse reactions within 6 months after the change. CONCLUSION: When the treatment regimen was changed from prostaglandin analogs and ß-blockers to travoprost 0.004%/timolol maleate 0.5% fixed combination eye drops, administration protocol adherence increased and IOP was preserved; however, adverse reactions appeared in about 16% of the cases.

Nonequilibrium and relaxation in deeply supercooled liquid of isopropylbenzene obtained through glass transition from vapor-deposited glass.

Change in the light interference in film samples of isopropylbenzene was studied in the supercooled liquid (SCL) state. Samples were originally formed as glass by vapor deposition on a cold substrate and the intensity of laser light reflection from them was monitored as the temperature was raised with a constant rate up to the region of the SCL state above the glass-transition temperature. Two types of periodic changes in the light intensity were observed in the SCL state. One was attributed to the interference condition change accompanying the structural relaxation from the low-density SCL to the equilibrium SCL state, and the other was due to the gradual expansion of the high-density SCL. Analysis of the latter change revealed that the initial density of the high-density glass was larger than that estimated in our previous paper.

[Applicability of the 3D-VIBE sequence to whole brain imaging].

The VIBE method has been developed imaging also holds its breath in an abdomen, and to do three-dimensional T1WI in possible time in gradient echo sequence, and applied to dynamic study mainly and planning for time reduction using an interpolation and partial fourier. We considered the condition for imaging to do whole brain as high resolution image using VIBE. Even if base matrix was maintained when an interpolation and partial fourier were used too much excessively by Phantom experiment, the resolution of MPR image fell. There was a limit of the interpolation therefore to maintain the resolution as voxel. SNR fell by FA increase by the applicability to the head, and peak existed in about 15 degrees in CNR of white matter and gray matter. Therefore by it's clinical and optimizing the imaging condition of VIBE, whole brain, it was imaging possible in about 3 minutes as high resolution image.

[Analysis of dot-like hemosiderin spots using brain dock system].

BACKGROUND AND PURPOSE: Dot-like low intensity spots (a dot-like hemosiderin spot: dotHS) on T2*-weighted MR images (T2*WI), which is regarded as a sensitive method for hemosiderin detection, have been histologically diagnosed as old microbleeds associated with microangiopathies. The clinical significance of the dotHS, however, is still under debate. Therefore, we investigated the factors associated with dotHS. METHODS: We investigated 209 healthy volunteers in our hospital (sex: 106 males, 103 females; age: 38 to 78 years old, mean age: 56.4 +/- 8.3 years old) using "Brain Dock", a formalized screening system for asymptomatic brain diseases. The Odds ratio (OR) was estimated from multiple logistic regression analyses using the dotHS and variables. RESULTS: T2*WI demonstrated dotHS in 7.7% of volunteers, and the mean number of dotHS was 0.16 +/- 0.78. The hemosiderin was preferentially deposited in the basal ganglia and thalamus. Age > or = 65 years old (OR: 5.9; 95% confidence interval [CI]: 1.4-25.9; p = 0.02), hypertension (OR: 7.0; 95% CI: 1.4-34.7; p = 0.02), and headache (OR: 5.8; 95% CI: 1.4-24.6; p = 0.02) were all found to be independently associated with dotHS. CONCLUSIONS: The dotHS was significantly associated with several factors, including age, hypertension and headache.

[Dynamic changes in magnetic resonance diffusion-weighted and fluid-attenuated images of cerebral fat embolism: a case report].

Cerebral fat embolism (CFE) is serious complication of a long-bone fracture. We reported magnetic resonance (MR) diffusion-weighted (DWI) and fluid attenuated inversion recovery (FLAIR) images in a patient suffered with CFE. A 26-year-old man with a right femoral bone fracture lapsed into a semicoma eight hours later. Eighteen hours after the depressed consciousness, DWI and FLAIR images on MR imaging showed multiple high-intensity spots in corona radiata, basal ganglia, thalamus, corpus callosum, brain stem and cerebellum. Thereby, he was diagnosed as CFE. These multiple lesions were more detectable on FLAIR images than DWI, particularly in posterior fossa. Eight days after the onset, follow-up DWI, FLAIR, and T 2-weighted MR image (T 2 WI) showed most of the lesions disappeared or shrunk. The resolution of the lesions suggests that most of the lesions were brain edema as a result of the unique pathophysiological condition of CFE. The remained lesions were diagnosed as cerebral infarctions. The consciousness of the patient improved alert. Three months later, follow-up MRI showed almost complete resolution of the abnormal intensities. Follow up DWI and FLAIR images observed in the patient indicated that many small lesions occurs throughout the whole brain without a preferential region, and many of the lesions can subside or attenuate in CFE.