Hitoshi Ishikawa

Carbon-ion radiation therapy for prostate cancer

In 1994, carbon‐ion radiotherapy was started at the National Institute of Radiological Sciences using the Heavy‐Ion Medical Accelerator in Chiba. Between June 1995 and March 2000, two phaseu2003I/II dose escalation studies (protocols 9402 and 9703) of hypofractionated carbon‐ion radiotherapy for both early‐ and advance‐stage prostate cancer patients had been carried out to establish radiotherapy technique and to determine the optimal radiation dose. To validate the feasibility and efficacy of hypofractionated carbon‐ion radiotherapy, a phaseu2003II study (9904) was initiated in April 2000 using the shrinking field technique and the recommended dose fractionation (66 gray equivalents in 20 fractions over 5u2003weeks) obtained from the phaseu2003I/II studies, and was successfully completed in October 2003. The data from 175 patients in the phaseu2003II study showed the importance of an appropriate use of androgen deprivation therapy according to tumor risk group. Since November 2003, carbon‐ion radiotherapy for prostate cancer was approved as “Highly Advanced Medical Technology” from the Ministry of Health, Labor, and Welfare, and since then approximately 1100 patients have received carbon‐ion radiotherapy as of July 2011. In this review, we introduce our steps thorough three clinical trials carried out at National Institute of Radiological Sciences, and show the updated data of carbon‐ion radiotherapy obtained from approximately 1000 prostate cancer patients. In addition, our recent challenge and future direction will be also described.

Influence of Multiple Genetic Polymorphisms on Genitourinary Morbidity After Carbon Ion Radiotherapy for Prostate Cancer

PURPOSEnTo investigate the genetic risk of late urinary morbidity after carbon ion radiotherapy in prostate cancer patients.nnnMETHODS AND MATERIALSnA total of 197 prostate cancer patients who had undergone carbon ion radiotherapy were evaluated for urinary morbidity. The distribution of patients with dysuria was as follows: Grade 0, 165; Grade 1, 28; and Grade 2, 4 patients. The patients were divided (2:1) consecutively into the training and test sets and then categorized into control (Grade 0) and case (Grade 1 or greater) groups. First, 450 single nucleotide polymorphisms (SNPs) in 118 candidate genes were genotyped in the training set. The associations between the SNP genotypes and urinary morbidity were assessed using Fishers exact test. Then, various combinations of the markers were tested for their ability to maximize the area under the receiver operating characteristics (AUC-ROC) curve analysis results. Finally, the test set was validated for the selected markers.nnnRESULTSnWhen the SNP markers in the SART1, ID3, EPDR1, PAH, and XRCC6 genes in the training set were subjected to AUC-ROC curve analysis, the AUC-ROC curve reached a maximum of 0.86. The AUC-ROC curve of these markers in the test set was 0.77. The SNPs in these five genes were defined as risk genotypes. Approximately 90% of patients in the case group (Grade 1 or greater) had three or more risk genotypes.nnnCONCLUSIONSnOur results have shown that patients with late urinary morbidity after carbon ion radiotherapy can be stratified according to the total number of risk genotypes they harbor.

Intraocular pressure lowering effect of brinzolamide 1.0% as adjunctive therapy to latanoprost 0.005% in patients with open angle glaucoma or ocular hypertension: an uncontrolled, open-label study.

ABSTRACT Purpose: A prospective study was conducted to evaluate the intraocular pressure (IOP) lowering effect of brinzolamide 1.0% ophthalmic suspension as an adjunctive therapy with latanoprost 0.005% ophthalmic solution in patients with open angle glaucoma or ocular hypertension. Patients and methods: Fourteen patients with open angle glaucoma (OAG) or ocular hypertension (OH) who had been using latanoprost 0.005% for more than 6 months were initiated on adjunctive brinzolamide therapy. The IOP values at 1 month, 2 months, and 3 months were compared with those measured immediately before adding brinzolamide to the regimen (baseline). The incidence of adverse events such as conjunctival hyperemia and corneal epithelial defect were also examined. Results: The baseline IOP was 21.1 ± 4.8u2009mmHg (mean ± standard deviation). After 1 month, 2 months, and 3 months of therapy IOP was 16.9 ± 4.5u2009mmHg, 16.6 ± 4.0u2009mmHg, and 15.9 ± 3.1u2009mmHg, respectively, showing significant reductions in IOP at all the measuring time-points during the study compared with the baseline value (u2009p < 0.01). Conjunctival hyperemia developed in one patient after 1 month and in another after 2 months; however, both were mild, and therapy was continued. Corneal epithelium defect was observed in 3 patients. One of them had mild defect before brinzolamide was added to the regimen. Increase of eye discharge was seen in one patient. No serious side effects were otherwise observed. Conclusion: The addition of brinzolamide to a latanoprost 0.005% regimen may further lower intraocular pressure in patients with open angle glaucoma or ocular hypertension.

Quantitative measurement of ocular dominance using binocular rivalry induced by retinometers

PURPOSE: To develop a new method using binocular rivalry and retinometers to quantitatively examine ocular dominance and to investigate the magnitude of ocular dominance in cataract patients preoperatively and postoperatively. SETTING: Eye Clinic, Kitasato University School of Medicine Hospital, Sagamihara, Kanagawa, Japan. METHODS: The duration of exclusive visibility of the dominant and nondominant eye target in binocular rivalry were measured in 60 healthy volunteers (study 1) and preoperatively and postoperatively in 10 cataract patients (study 2). Rivalry targets were presented directly to the retina of each eye using 2 retinometers. Subjects reported the exclusive visibility of 1 eye target, and the total duration of exclusive visibility for each eye in dominant and nondominant eye trials was evaluated. RESULTS: In study 1, the magnitude of ocular dominance was quantitatively assessed with 4 grades based on differences in total duration of exclusive visibility between dominant and nondominant eyes. In study 2, magnitude of ocular dominance could be evaluated in all cataract patients regardless of refractive and cataract conditions. Magnitude of ocular dominance displayed significant correlations between preoperative and postoperative conditions (simple regression, P<.001). CONCLUSIONS: Ocular dominance can be quantitatively evaluated using this new method based on binocular rivalry and retinometers, particularly in cataract patients. Magnitude of ocular dominance may indicate preoperatively whether a patient with cataracts will have sufficient ocular dominance to adjust to monovision correction.

Dose-Volume Histogram Parameters and Clinical Factors Associated With Pleural Effusion After Chemoradiotherapy in Esophageal Cancer Patients

PURPOSEnTo investigate the dose-volume histogram parameters and clinical factors as predictors of pleural effusion in esophageal cancer patients treated with concurrent chemoradiotherapy (CRT).nnnMETHODS AND MATERIALSnForty-three esophageal cancer patients treated with definitive CRT from January 2001 to March 2007 were reviewed retrospectively on the basis of the following criteria: pathologically confirmed esophageal cancer, available computed tomography scan for treatment planning, 6-month follow-up after CRT, and radiation dose ≥ 50 Gy. Exclusion criteria were lung metastasis, malignant pleural effusion, and surgery. Mean heart dose, mean total lung dose, and percentages of heart or total lung volume receiving ≥ 10-60 Gy (Heart-V(10) to V(60) and Lung-V(10) to V(60), respectively) were analyzed in relation to pleural effusion.nnnRESULTSnThe median follow-up time was 26.9 months (range, 6.7-70.2) after CRT. Of the 43 patients, 15 (35%) developed pleural effusion. By univariate analysis, mean heart dose, Heart-V(10) to V(60), and Lung-V(50) to V(60) were significantly associated with pleural effusion. Poor performance status, primary tumor of the distal esophagus, and age ≥ 65 years were significantly related with pleural effusion. Multivariate analysis identified Heart-V(50) as the strongest predictive factor for pleural effusion (p = 0.01). Patients with Heart-V(50) <20%, 20%≤ Heart-V(50) <40%, and Heart-V(50) ≥ 40% had 6%, 44%, and 64% of pleural effusion, respectively (p < 0.01).nnnCONCLUSIONnHeart-V(50) is a useful parameter for assessing the risk of pleural effusion and should be reduced to avoid pleural effusion.

Vasodilatory mechanism of unoprostone isopropyl on isolated rabbit ciliary artery.

Purpose. To clarify the vasodilatory mechanism of unoprostone isopropyl (unoprostone), a PG F2a related compound used for treatment of glaucoma, we have investigated the effect of this drug and its metabolites on isolated rabbit ciliary artery in vitro. Methods. Under the dissecting microscope, ciliary arteries were prepared from albino rabbit eyes and mounted in a myograph system. The effects of unoprostone isopropyl and other agents were investigated using isometric tension recording methods. Results. Unoprostone induced a dose-dependent relaxation in ciliary arteries that were pre-contracted with high-K solution, 10µM histamine or 10µM PG F2a. Neither unoprostone metabolite M1 or M2 had a relaxant effect on the precontracted vessels. Relaxation was unaffected by inhibition of adenylyl cyclase with SQ 22536, guanylyl cyclase with ODQ, or maxi-K channels with iberiotoxin. Pretreatment with unoprostone did not affect histamine-induced transient contractions in Ca 2+ -free solution. However, SKF96365, a general Ca 2+ channel blocker, evoked relaxation similar to unoprostone with respect to amplitude and rate of onset. Conclusions. Unoprostone, but not its metabolites M1 and M2, relaxed pre-contracted rabbit ciliary artery. The mechanism of vascular smooth muscle relaxation by unoprostone differs from that of IOP reduction and does not depend on adenylyl cyclase, guanylyl cyclase, or maxi-K channels. Relaxation may be mediated by inhibition of Ca 2+ entry, possibly through capacitative Ca 2+ channels.

Short‐cycle periodic alternating (ping‐pong) gaze

Periodic a l t e rna t ing horizontal-gaze deviat ions may exhibit long or short In the long cycle, the eyes remain tonically deviated for 1 to 2 minutes before shifting to the opposite side; the rhythmicity is similar to that of periodic alternating nystagmus (PAN), prompting the presumption that the gaze deviation represents PAN without the fast p h a s e s . ’ ~ ~ , ~ In the shor t cycle, the eyes change directions immedia t e ly o r a f t e r a few seconds delay.3,6-1s Senelick7 designated this phenomenon as “pingpong gaze.” Most reports of this abnormality are descriptive and lack oculographic documentation of the slow eye movement waveform. We repor t a patient in whom we obtained oculography and a p o s t m o r t e m e x a m i n a t i o n , and review the 18 patients described in the literature.

Genetic Variants of NPAT-ATM and AURKA are Associated With an Early Adverse Reaction in the Gastrointestinal Tract of Patients With Cervical Cancer Treated With Pelvic Radiation Therapy

PURPOSEnThis study sought to associate polymorphisms in genes related to cell cycle regulation or genome maintenance with radiotherapy (RT)-induced an early adverse reaction (EAR) in patients with cervical cancer.nnnMETHODS AND MATERIALSnThis study enrolled 243 cervical cancer patients who were treated with pelvic RT. An early gastrointestinal reaction was graded using the National Cancer Institute Common Toxicity Criteria, version 2. Clinical factors of the enrolled patients were analyzed, and 208 patients were grouped for genetic analysis according to their EAR (Grade ≤1, n = 150; Grade ≥2, n = 58). Genomic DNA was genotyped, and association with the risk of EAR for 44 functional single-nucleotide polymorphisms (SNPs) of 19 candidate genes was assessed by single-locus, haplotype, and multilocus analyses.nnnRESULTSnOur analysis revealed two haplotypes to be associated with an increased risk of EAR. The first, comprising rs625120C, rs189037T, rs228589A, and rs183460G, is located between the 5 ends of NPAT and ATM (OR = 1.86; 95% CI, 1.21-2.87), whereas the second is located in the AURKA gene and comprises rs2273535A and rs1047972G (OR = 1.75; 95% CI, 1.10-2.78). A third haplotype, rs2273535T and rs1047972A in AURKA, was associated with a reduced EAR risk (OR = 0.42; 95% CI, 0.20-0.89). The risk of EAR was significantly higher among patients with both risk diplotypes than in those possessing the other diplotypes (OR = 3.24; 95% CI, 1.52-6.92).nnnCONCLUSIONSnIndividual radiosensitivity of intestine may be determined by haplotypes in the NPAT-ATM and AURKA genes. These variants should be explored in larger association studies in cervical cancer patients.

Time Course of Accommodation After Implantable Collamer Lens Implantation

PURPOSEnTo assess the time course of accommodative function after Implantable Collamer Lens (ICL) implantation and to investigate the relationship between patient age and accommodation in ICL-implanted eyes.nnnDESIGNnProspective, nonrandomized clinical trial.nnnMETHODSnWe prospectively examined 69 eyes of 40 consecutive patients with myopic refractive errors of -3.25 to -22.75 diopters (D) who were undergoing ICL implantation. We assessed the amplitude of accommodation using an accommodometer before and one, three, six, and 12 months after surgery. We also investigated its relationship with patient age.nnnRESULTSnThe accommodation was 6.36 +/- 3.94 D (mean +/- standard deviation) before surgery and 4.89 +/- 2.72 D, 4.98 +/- 2.67 D, 5.16 +/- 2.72 D, and 5.72 +/- 2.85 D at one, three, six, and 12 months after surgery, respectively. The variance of data was statistically significant (P = .02, repeated-measures analysis of variance). Multiple comparisons demonstrated significant differences between measurements made before surgery and at one month after (P = .004, Fisher least significant difference test), before surgery and at three months after (P = .007), and before surgery and at six months after (P = .01). There was a significant correlation between patient age and accommodation before (Pearson correlation coefficient, r = -0.665; P < .001) and one year after (r = -0.803; P < .001) ICL implantation.nnnCONCLUSIONSnAccommodation was impaired transiently in the early postoperative periods, and then recovered gradually over time, indicating that transient dysfunction of the ciliary muscles by ICL fixation may occur after ICL implantation even if the crystalline lens remained intact. As patients aged, the amplitude of accommodation became significantly smaller not only in normal eyes but also in ICL-implanted eyes.

New approach for the glaucoma detection with pupil perimetry

Objective: To calculate the pattern deviation for identifying abnormal points of pupil perimetry, and also to evaluate the grayscale display for distinguishing glaucomatous pupil field loss (abnormal test points) from normal pupil field (normal test points). Methods: Fourteen patients ranging in age from 51 to 80 years, who had normal-tension glaucoma (6 eyes) and primary open-angle glaucoma (8 eyes) were tested. Pupil perimetry (Kowa & Hamamatsu, Japan) was used to objectively measure the visual field. Also, to obtain a subjective visual field, the analysis was performed with a Humphrey Field Analyzer (30-2, Full threshold program, Carl Zeiss Meditec, Dublin). Of the 76 test points, the 22 surrounding points and the 3 points corresponding to the blind spot are excluded; and among the remaining 51 points, the 85th percentile value of pupil perimetry was calculated. The abnormal and normal test points were recorded, and the amount of positive or negative deviation of each test point from the normal median value for the corresponding test points was determined. We also used this technique to identify the value for distinguishing glaucomatous pupil field loss from the normal pupil field. Results: This study could be improved by calculating the sensitivity and specificity of a certain cut-off value between the normative data and the glaucoma patients. The value for identifying both abnormal and normal test points was a negative deviation of −4. Based on these results, pupil perimetry gray scales were determined: white (< −3), 25% gray (from −4 to −8), 50% gray (from −9 to −13), 75% gray (from −14 to −18) and black (> −19). Glaucomatous pupil field losses were generally distinguished from the normal pupil field by use of a gray scale. Conclusion: Our studies demonstrated that, when a deviation of > −4 was regarded as an abnormal value, the detection of pupil perimetry exhibited improvement in glaucoma patients.