Multidisciplinary management of locally recurrent rectal cancer with carbon ion radiotherapy followed by prophylactic removal of the irradiated bowel: a case report.

BACKGROUND: Locally recurrent rectal cancer (LRRC) involving the upper sacrum is typically incurable, and palliative treatment is the only option for most patients, resulting in a poor prognosis and reduced quality of life. Carbon ion radiotherapy (CIRT) has emerged as a promising modality for treating LRRC. This report presents a case of LRRC with sacral involvement that was managed via multidisciplinary therapy incorporating CIRT. CASE PRESENTATION: A 55-year-old male was diagnosed with an anastomotic recurrence of rectal cancer 15 months after undergoing anterior resection. Computed tomography (CT) suggested that the lesion was at an anastomosis site and broadly adherent to the upper sacrum, and colonoscopy confirmed the diagnosis of LRRC. Histopathological examination of the biopsy specimens revealed adenocarcinoma cells and that lesion was genetically RAS-wild. Induction chemotherapy with mFOLFOX6 and panitumumab was used as the first treatment. The recurrent lesion shrank and no signs of distant metastasis were observed after 11 cycles, although the range of the lesions attached to the sacrum remained unchanged. Therefore, we provided CIRT for this inoperable lesion and prophylactically removed the radiation-exposed bowel including the recurrent lesion, because radiation-induced ulcers can cause bleeding and perforation. Despite the presence of considerable fibrosis in the irradiated region, the operation was successful and the postoperative course had no untoward incidents. He is still recurrence-free 24 months following surgery, despite the lack of adjuvant chemotherapy. This is the first report of CIRT followed by CIRT-irradiated bowel removal for an unresectable anastomosis recurrent lesion. CONCLUSIONS: The clinical course of this case suggests that CIRT could be a potentially effective therapeutic option for LRRC involving the bowel, as long as the prophylactic removal of the irradiated bowel is performed at the optimal time. Further research involving larger sample sizes is warranted to validate the findings and conclusions of this case report.

Regulatory T cells and M2-polarized tumour-associated macrophages are associated with the oncogenesis and progression of oral squamous cell carcinoma.

Regulatory T cells (Tregs) and tumour-associated macrophages (TAMs) contribute to the tumour microenvironment by inhibiting anti-tumour immune responses. This study was performed to investigate the roles of Tregs and TAMs in oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPL). The expression of Treg markers CD25 and FoxP3 and TAM markers CD163 and CD204 was investigated in 82 OSCC and 45 OEPL specimens, and their associations with clinicopathological parameters were analyzed. Correlations were found among CD25, FoxP3, CD163, and CD204 levels (P < 0.001), and these targets were up-regulated in OSCC compared to OEPL (P < 0.001). In OSCC, infiltration of Tregs and/or M2 TAMs was associated with sex and clinicopathological features, such as tumour size, nodal metastasis, tissue differentiation, stromal reaction, invasive behaviour, and invasive depth. In OEPL, CD25, FoxP3, CD163, and CD204 immunoreactivities were significantly associated with sex, postoperative recurrence, and cancerization to OSCC. This study is novel in showing that the infiltration of Tregs and M2 TAMs is significantly associated with the progression of premalignant lesions to OSCC. This suggests that these cells represent prognostic biomarkers for premalignant lesion progression and that immunotherapeutic approaches to control Treg/M2 TAM numbers could protect against progression to malignancy.

Continuous cell culture monitoring using a compact microplate reader with a silicone optical technology-based spatial filter.

Continuous cell monitoring is very important for the maintenance and control of cell multiplication and differentiation. This paper presents a compact microplate reader that is able to continuously measure a 24-well microplate (6 × 4 wells) using the optical absorption measurement method. The 24-channel plate reader consisted of a spatial filter, light emitting diode light source, and color sensors and was similarly sized with the cell culture microwell plates. A spatial filter was previously fabricated by our group using silicone optical technology (SOT). This SOT-based spatial filter has an excellent noise reduction effect. Light reflection at the optical path interface can be absorbed and only forward light can be transmitted; accordingly, a larger S/N ratio than that of conventional optical systems is expected. The fabricated 24-channel plate reader permits real-time cell monitoring during cultivation on the clean bench and in cell culture conditions by incorporating the SOT spatial filter. Using the device, it was possible to continuously evaluate the concentration and pH of reagents in the 24 wells in real time. Moreover, cell activity and protein production were detectable using the device. These results suggest that the newly fabricated device is a promising tool for the evaluation of cell behaviors for cell management.

Effect of pregnancy on lower limb lymphedema in patients treated with multisite lymphaticovenular anastomoses (MLVAS).

Lymphaticovenular anastomosis (LVA) using supermicrosurgical techniques is effective for treating and preventing progression of lymphedema. We analyzed the influence of pregnancy on LVA in five patients from a total 2179 LVA cases. Previous studies offer conflicting reports on whether pregnancy worsens pre-existing lymphedema. This is the first report on the influence of pregnancy on lower limb lymphedema previously treated by multisite LVA (mLVA). Five patients with primary (n=4) and secondary (n=1) lower leg lymphedema were analyzed for this study. Patient age ranged from 18 to 31 (average 22.6) years old with 4 right and 1 left extremities involved. Duration of symptoms ranged from one to 19 (average 7.4) years and the periods of compression therapy were from 1 to 19 years (6.6 years). Four patients had single pregnancies and one patient was multiparous with 3 pregnancies. Final follow-up ranged from 5.8 to 18 years (average 8.9 years) after the primary mLVA. All patients had normal pregnancy, birth, and no serious complications after surgeries. Following pregnancy three patients had complete functional recovery (limb volume reduction and no compression requirement), one with functional improvement (limb volume reduction but required compression), and one with no change in symptoms (not worse and continued need for compression). There were no occurrences of infection following pregnancy. Based on this case series, it is suggested that pregnancy does not worsen the pre-existing lymphedema in patients who had previously undergone mLVA. Further studies with larger number of patients are needed to confirm these results.

Effects of in ovo feeding of L-leucine on amino acids metabolism and heat-shock protein-70, and -90 mRNA expression in heat-exposed chicks.

Recently, we found that in ovo feeding of L-leucine (L-Leu) stimulated the metabolism of lipids and afforded thermotolerance in male Chunky broiler chicks. In this study, we investigated the effects of feeding L-Leu in ovo on the metabolism of amino acids and on the cellular stress response mainly in the central and peripheral tissues in neonatal male broiler chicks and partly in embryonic tissues. Chicks (9 d old) were exposed to high ambient temperature (HT: 35 ± 1°C) or control thermoneutral temperature (CT: 28 ± 1°C) for 180 min. The ambient temperatures were based on our recent reports and the recommendation of the Chunky broiler manual in which 28°C has been suggested as a normal ambient temperature for 5 to 9-d-old broiler chicks. In ovo feeding of L-Leu caused a significant (P < 0.05) decline in diencephalic arginine concentrations but it increased the diencephalic and plasma lysine concentrations when compared with the control chicks under HT. Notably, in ovo feeding of L-Leu significantly (P < 0.05) attenuated the increment of hepatic arginine compared with the control chicks under HT. Interestingly, in ovo feeding of L-Leu significantly (P < 0.05) attenuated the diencephalic gene expression of heat-shock protein (HSP) -70 and -90 in heat-exposed chicks. The gene expressions of mammalian target of rapamycin (mTOR) and its downstream genes (ribosomal protein S6 kinase (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1)) in the central and peripheral tissues were not influenced in the chicks under heat stress. We found that the gene expressions of mTOR, S6K1, and 4E-BP1 were significantly (P < 0.05) stimulated only in the embryonic breast muscle, and not in the other embryonic tissues, by in ovo feeding of L-Leu. In conclusion, in ovo feeding of L-Leu caused a change in the metabolism of amino acids in response to heat stress in broiler chicks. Attenuated gene expressions of HSP-70 and -90 under heat stress further suggests that in ovo feeding of L-Leu may afford thermotolerance in broilers.

Pathological changes of adipose tissue in secondary lymphoedema.

BACKGROUND: The pathophysiology of lymphoedema is poorly understood. Current treatment options include compression therapy, resection, liposuction and lymphatic microsurgery, but determining the optimal treatment approach for each patient remains challenging. OBJECTIVES: We characterized skin and adipose tissue alterations in the setting of secondary lymphoedema. METHODS: Morphological and histopathological evaluations were conducted for 70 specimens collected from 26 female patients with lower-extremity secondary lymphoedema following surgical intervention for gynaecological cancers. Indocyanine green lymphography was performed for each patient to assess lymphoedema severity. RESULTS: Macroscopic and ultrasound findings revealed that lymphoedema adipose tissue had larger lobules of adipose tissue, with these lobules surrounded by thick collagen fibres and interstitial lymphatic fluid. In lymphoedema specimens, adipocytes displayed hypertrophic changes and more collagen fibre deposits when examined using electron microscopy, whole-mount staining and immunohistochemistry. The number of capillary lymphatic channels was also found to be increased in the dermis of lymphoedema limbs. Crown-like structures (dead adipocytes surrounded by M1 macrophages) were less frequently seen in lymphoedema samples. Flow cytometry revealed that, among the cellular components of adipose tissue, adipose-derived stem/stromal cells and M2 macrophages were decreased in number in lymphoedema adipose tissue compared with normal controls. CONCLUSIONS: These findings suggest that long-term lymphatic volume overload can induce chronic tissue inflammation, progressive fibrosis, impaired homeostasis, altered remodelling of adipose tissue, impaired regenerative capacity and immunological dysfunction. Further elucidation of the pathophysiological mechanisms underlying lymphoedema will lead to more reliable therapeutic strategies.

Chymase inhibition attenuates monocrotaline-induced sinusoidal obstruction syndrome in hamsters.

Chymase stored in mast cells activates matrix metalloproteinase (MMP)-9, which may relate to the progression of sinusoidal obstruction syndrome (SOS). We investigated the preventive effect of a chymase inhibitor, TY-51469, on monocrotaline-induced SOS in hamsters. Hamsters were orally administrated with a single dose of monocrotaline (120 mg/kg) to induce SOS. Treatment with TY-51469 (1 mg/kg per day) or placebo had started 3 days before the monocrotaline administration. Two days after the monocrotaline administration, significant increases in aspartate aminotransferase, alanine aminotransferase and total bilirubin and a significant reduction of albumin were observed in plasma, but their changes were significantly attenuated by treatment with TY-51469. The numerous hepatic necrosis areas were observed in the placebo-treated group, but the ratio of necrotic area to total area in liver had been significantly reduced by treatment with TY-51469. Both chymase activity and MMP-9 level in liver were significantly augmented in the placebo-treated group. Furthermore, tumor necrosis factor (TNF)-α level in liver was also augmented in the placebo-treated group. However, the chymase activity and levels of MMP-9 and TNF-α were significantly attenuated in the TY-51469-treated group. Until 14 days after monocrotaline administration, survival rates in the placebo- and TY-51469-treated groups were 25% and 70%, respectively, and a significant difference was observed. In conclusion, chymase inhibition by TY-51469 may prevent the accelerating of severity in monocrotaline-induced SOS in hamsters.

Development and validation of a tuberculosis prognostic score for smear-positive in-patients in Japan.

BACKGROUND: No scoring system has ever been used to estimate the prognosis of individual tuberculosis (TB) patients. OBJECTIVE: To develop and validate a tuberculosis prognostic score. METHODS: This retrospective cohort study conducted in Japan comprised the development (n = 179; mean age 65.9 ± 18.8 years) and validation (n = 244; mean age 64.3 ± 20.1 years) of a tuberculosis prognostic score among patients with newly diagnosed smear-positive non-multidrug-resistant pulmonary tuberculosis without human immunodeficiency virus infection. The score (raw score) was defined by modifying a logistic regression formula using known risk factors as independent variables and in-patient death as a dependent variable. RESULTS: The raw score was calculated as follows: age (years) + (oxygen requirement, 10 points) - 20 × albumin (g/dl) + (activity of daily living: independent, 0 point; semi-dependent, 5 points; totally dependent, 10 points). The raw scores were grouped into risk groups 1 (raw score < -30) to 5 (raw score ≥ 60) using 30-point intervals. Every increase in risk group was equivalent to a 7.3-fold increase in the odds ratio for in-hospital death (P < 0.001). The area under the receiver operating characteristics curve by risk group for in-patient death was 0.875 (P < 0.001). CONCLUSIONS: In this study we were able to develop and validate a tuberculosis prognostic score.

Gene expression analysis of rheumatoid arthritis synovial lining regions by cDNA microarray combined with laser microdissection: up-regulation of inflammation-associated STAT1, IRF1, CXCL9, CXCL10, and CCL5.

OBJECTIVES: The main histological change in rheumatoid arthritis (RA) is the villous proliferation of synovial lining cells, an important source of cytokines and chemokines, which are associated with inflammation. The aim of this study was to evaluate gene expression in the microdissected synovial lining cells of RA patients, using those of osteoarthritis (OA) patients as the control. METHODS: Samples were obtained during total joint replacement from 11 RA and five OA patients. Total RNA from the synovial lining cells was derived from selected specimens by laser microdissection (LMD) for subsequent cDNA microarray analysis. In addition, the expression of significant genes was confirmed immunohistochemically. RESULTS: The 14 519 genes detected by cDNA microarray were used to compare gene expression levels in synovial lining cells from RA with those from OA patients. Cluster analysis indicated that RA cells, including low- and high-expression subgroups, and OA cells were stored in two main clusters. The molecular activity of RA was statistically consistent with its clinical and histological activity. Expression levels of signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 1 (IRF1), and the chemokines CXCL9, CXCL10, and CCL5 were statistically significantly higher in the synovium of RA than in that of OA. Immunohistochemically, the lining synovium of RA, but not that of OA, clearly expressed STAT1, IRF1, and chemokines, as was seen in microarray analysis combined with LMD. CONCLUSIONS: Our findings indicate an important role for lining synovial cells in the inflammatory and proliferative processes of RA. Further understanding of the local signalling in structural components is important in rheumatology.

Evaluation of nondigested carbohydrates in hydroxypropylated tapioca starch.

In vitro and in vivo digestibilities of hydroxypropyl starch were investigated to determine an appropriate nondigested carbohydrate assaying method for hydroxypropyl starch. Hydroxypropyl tapioca starch (HPTS), with a 0.338 degree of substitution, was used as a hydroxypropyl starch source. Practically all nondigested carbohydrate in HPTS was low molecular weight and was not precipitated in 78% ethanol. The contents of nondigested carbohydrate in HPTS and in effluents of ileorectomized rats fed the HPTS diet obtained by the AOAC 2001.03 (enzyme-gravimetric-HPLC method) were almost the same, 56% and 59%, respectively. The recovery of hydroxypropyl groups from ileorectomy effluents was 98%. The AOAC 2001.03 method is suggested to be appropriate in determining the content of nondigested carbohydrates in hydroxypropyl starch.

Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob.

Fiber-substituted adenovirus (Ad) vectors containing fibers of Ad serotype 35 (AdF35) efficiently transduce a variety of human cells because their receptor, human CD46, is ubiquitously expressed on almost all nucleated cells. However, the ubiquitous expression of CD46 might lead to unexpected transduction in untargeted organs. In this study, we developed fiber-modified AdF35 vectors with an integrin-binding Arg-Gly-Asn (RGD) peptide incorporated into the FG, HI or IJ loop, which have been identified as important regions for binding to CD46. Incorporation of foreign peptides into these loops does not inhibit trimerization of the fibers. In CD46-negative cells, fiber-mutant AdF35 vectors containing an RGD peptide in the FG or HI loop showed 6- to 30-fold higher transduction efficiencies in an RGD-peptide-dependent manner than the unmodified AdF35 vectors. In contrast, in CD46-positive cells, insertion of foreign peptides markedly reduced the transduction efficiencies of the AdF35 vectors, indicating that insertion of foreign peptides significantly inhibits binding to CD46. In particular, CD46-mediated transduction was completely diminished by insertion of foreign peptides into the HI loop. Our findings indicate that HI loop is the most suitable domain to mediate a foreign peptide-dependent and CD46-independent transduction by incorporation of foreign peptides into the Ad35 fiber knob.

Impact of FDG-PET/CT fused imaging on tumor volume assessment of head-and-neck squamous cell carcinoma: intermethod and interobserver variations.

BACKGROUND: Although gross tumor volume (GTV) at the primary site can predict local control of head-and-neck squamous cell carcinoma (SCC) in patients who are treated with organ-preservation therapy, GTV assessment does not eliminate substantial interobserver variation. PURPOSE: To evaluate whether F-18-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) fused imaging provides additional information for GTV assessment. MATERIAL AND METHODS: We obtained FDG-PET/CT fused images on 20 patients with head-and-neck SCC. All had undergone preoperative conventional workup, including contrast-enhanced CT and magnetic resonance imaging (MRI). The GTV of the primary tumors was designed by two independent observers who used routine clinical data. Observer A was a radiologist and observer B a radiation oncologist. GTV1 and GTV2 were designed without and with FDG-PET/CT, respectively. For geometric interobserver comparison, we calculated the concordance rate as the ratio of the intersection (AxB) of the GTVs to their union (AxB). Intermethod (GTV1 vs. GTV2) and interobserver (A vs. B) differences in the GTVs were assessed by Bland-Altman analysis and the Spearman rank-correlation test. The interobserver concordance rates for GTV1 and GTV2 were compared using a two-tailed paired-samples t test. RESULTS: On FDG-PET/CT, all primary tumors were visualized. There was no systemic trend for a volume difference between GTV1 and GTV2. Although the 95% limits of agreement were wider for interobserver than intermethod differences, the 95% limits of interobserver agreement were narrower for GTV2 than GTV1. The mean interobserver concordance rate for GTV2 was higher than for GTV1 (54.5% vs. 39.1%, P=0.0002). CONCLUSION: FDG-PET/CT is a useful modality for consistent GTV assessment, which should not be used as a single modality but rather to obtain supplemental information in patients with head-and-neck SCC.

Positive and negative regulation of adenovirus infection by CAR-like soluble protein, CLSP.

Coxsackievirus and adenovirus receptor (CAR) is a member of the immunoglobulin (Ig) superfamily and a component of epithelial tight junction. CAR also functions as a primary receptor for coxsackievirus B and adenovirus (Ad) infection. In this study, we report the identification of a novel protein, CAR-like soluble protein (CLSP), which is closely related to CAR. Mouse CLSP (mCLSP) was composed of 390 amino acids, including three Ig domains, and showed strong homology to the IgV domain of CAR. Interestingly, mCLSP lacks a transmembrane domain, indicating that this is a soluble protein. mCLSP mRNA was detected primarily in the brain and ovary. When mCLSP cDNA was introduced into SK HEP-1 cells, which were known to be CAR positive and easily infected with Ad vector, the infection with Ad vector was severely inhibited. On the other hand, mCLSP promoted the infection with Ad vector in CAR-negative NIH3T3 cells. Furthermore, recombinant CLSP directly bound to Ad and inhibited the Ad vector-mediated transduction in SK HEP-1 cells. Computational analysis for a genome database showed that the CLSP gene is rodent-specific, and that human and bovine lack this gene. These results suggest that CLSP may play a role in the antiviral defense of the host in rodent animals.

Fiber-modified adenovirus vectors containing the TAT peptide derived from HIV-1 in the fiber knob have efficient gene transfer activity.

The interaction between viral capsid proteins and specific molecules exposed on the plasma membrane of the cells is involved in the viral tropism. A human adenovirus (Ad) belonging to subgroups A, C, D, E and F infects cells via the interaction between the fiber knob and the primary receptor, the coxsackievirus and adenovirus receptor (CAR). Conventional human adenovirus type 5 (hAd5) vectors show efficient transduction in CAR-positive cells; in contrast, hAd5 vector application is limited by poor transduction into cells lacking CAR expression. In the present study, to broaden the tropism of hAd5 vectors, we generated hAd5 vectors containing the TAT peptide, which is a protein transduction domain derived from human immunodeficiency virus, in the HI loop of the fiber knob (Ad-TAT(HI)-L2) or the C-terminus of the fiber knob (Ad-TAT(C)-L2). In CAR-negative adherent cells, Ad-TAT(HI)-L2 and Ad-TAT(C)-L2 showed approximately 50- to 500-fold higher gene expression than the conventional hAd5 vector (Ad-L2). Ad-TAT(HI)-L2 was also more efficient than Ad-L2 in blood cell lines and in two types of primary cultured human vascular smooth muscle cells, which are almost refractory to Ad-L2. Furthermore, Ad-TAT(HI)-L2 was more efficient than other types of fiber-modified Ad vectors, which harbor an RGD (Arg-Gly-Asp) or a poly-lysine (KKKKKKK;K7) peptide in the HI loop or the C-terminus of the fiber knob, respectively. Ad-TAT(HI)-L2 efficiently transduced the organs in levels and patterns that were roughly similar to those of Ad-L2 after being systemically injected into mice. To the best of our knowledge, this study is the first report showing that hAd5 vectors containing the TAT peptide in the fiber knob could efficiently transduce cells independently of CAR. These Ad vectors should be useful for gene functional analysis and gene therapy.

TAK1 represses transcription of the human telomerase reverse transcriptase gene.

In human cells, telomerase activity is tightly regulated by the expression of its catalytic subunit, namely, the human telomerase reverse transcriptase (hTERT). However, the molecular mechanisms involved in the regulation of hTERT expression have not been completely clarified. We have previously reported that transforming growth factor beta (TGF-beta) represses the expression of the hTERT gene. In the present study, we demonstrated that TGF-beta-activated kinase 1 (TAK1), originally identified as a mitogen-activated kinase kinase kinase, represses the hTERT core promoter activity in an E-box-independent manner, and it also represses the transcription of the hTERT gene in human lung adenocarcinoma cell line, A549 cells. This TAK1-induced repression was found to be caused by the recruitment of histone deacetylase to Sp1 at the hTERT promoter and a consequent reduction in the amount of acetylated histone H4 at the hTERT promoter. Finally, we demonstrated that TAK1 induces cellular senescence programs in normal human diploid cells. Thus, we assume that TAK1 triggers the repression mechanisms of the hTERT gene as a result of evoking cellular senescence programs. Considered together, TAK1 is thought to play a causative role in the determination of a finite replicative lifespan of normal and cancer cells.

Brain catecholamine alterations and pathological features with aging in Parkinson disease model rat induced by Japanese encephalitis virus.

We analyzed two disease model groups with rats infected by Japanese encephalitis virus (JEV), a 90-day group and a 180-day group after JEV infection. The time measured by the modified pole test showed that motor activities in these two groups were slower than those of age-matched control groups. Striatal dopamine (DA) levels were significantly decreased in all JEV-infected rats. Norepinephrine concentration in brain regions in the 180-day group was significantly decreased in the medulla oblongata and hypothalamus as compared with the control and 90-day group. Tyrosine hydroxylase-positive neurons were significantly decreased in both JEV-infected rat groups. These results suggest that DA decrease and pathological changes in JEV-infected model rats persist for a long time, at least up to 180 days, and this model will be useful for the evaluation of new anti-parkinsonian agents.

Isatin, an endogenous MAO inhibitor, and a rat model of Parkinson's disease induced by the Japanese encephalitis virus.

A single dose of isatin (indole-2,3-dione)(i.p.), an endogenous MAO inhibitor, significantly increased norepinephrine and 5-hydroxytryptamine concentrations in the rat brain and also significantly increased acetylcholine and dopamine (DA) levels in the rat striatum. Urinary isatin concentrations in patients with Parkinson's disease tend to increase according to the severity of disease. We have developed a rat model of Parkinson's disease induced by the Japanese encephalitis virus (JEV). The distribution of the pathological lesions of JEV-rats resemble those found in Parkinson's disease. Significant behavioral improvement was observed in JEV-rats after isatin, L-DOPA and selegiline administration using a pole test. Both isatin and selegiline prevented the decrease in striatum DA levels of JEV-rats. The increased turnover of DA (DOPAC/DA) induced by JEV was significantly inhibited by isatin, but not selegiline. These findings suggest that JEV-infected rats may serve as a model of Parkinson's disease and that exogenously administered isatin and selegiline can improve JEV-induced parkinsonism by increasing DA concentrations in the striatum.

Interferon beta-1b is effective in Japanese RRMS patients: a randomized, multicenter study.

OBJECTIVE: To assess the efficacy of interferon beta-1b (IFNB-1b) in Japanese patients with relapsing-remitting multiple sclerosis (RRMS). BACKGROUND: The effects of IFNB in RRMS have been assessed in study populations comprised predominantly of white patients. MS in Japanese patients is different from that in white patients in that there are two different presentations--classic MS (C-MS) and optic-spinal MS (OS-MS)--and chronic progressive forms are infrequent. METHODS: A total of 205 Japanese patients with RRMS were randomized to receive 50 microg or 250 microg (1.6 or 8.0 MIU) IFNB-1b administered SC every other day for up to 2 years. The primary endpoint was annual relapse rate. Secondary endpoints included further relapse-related and MRI outcome measures, as well as changes in Expanded Disability Status Scale and Neurologic Rating Scale. Efficacy was assessed in 188 patients, and safety was assessed in 192 patients. Supplemental ad hoc subgroup analyses were also performed for patients with OS-MS and those with C-MS. RESULTS: Annual relapse rates were 0.763 in the 250 microg group and 1.069 in the 50 microg group, a relative reduction of 28.6% (p = 0.047). Results for all secondary endpoints favored 250 microg IFNB-1b. Subgroup analyses suggested that the magnitude and direction of treatment effect in patients with OS-MS and C-MS was similar, albeit not significant due to small sample size. CONCLUSIONS: Interferon beta-1b (IFNB-1b) 250 microg significantly reduced relapse rates and change in MRI lesion area in Japanese patients with relapsing-remitting multiple sclerosis, and seemed to be comparably effective in optic-spinal multiple sclerosis (MS) and classic MS. The response to treatment with IFNB-1b in Japanese patients with MS suggests that a common pathogenesis and underlying genetic characteristics are shared with white patients.