Early Clinical Remission Is a Predictor of Long-Term Remission with the Use of Vedolizumab for Ulcerative Colitis.

Vedolizumab (VDZ) is an α4ß7 integrin-antibody used to manage refractory ulcerative colitis (UC). This retrospective multicenter study aimed to identify predictors of efficacy or the time points when evaluation of VDZ therapy for UC would be most useful. We compiled data on 87 patients with moderate to severe active UC that was treated with VDZ. Overall clinical remission (CR) rates at 6 weeks and 52 weeks after VDZ administration were 44.4% (bio-naïve 44.2%, bio-failure 44.8%) and 52.8% (bio-naïve 53.5%, bio-failure 51.7%) respectively. Also, 83.3% (bio-naïve 81.3%, bio-failure 85.7%) of patients achieved mucosal healing at week 52. Among patients with a CR at week 52, 73.3% had a CR at week 6. In contrast, of patients who discontinued VDZ, 82.4% had not reached a CR at week 6. Our study demonstrated that VDZ was effective in a large percentage of UC patients, with a high mucosal healing rate even after prior biological exposures. This suggests that VDZ can be a treatment option even in bio-failure cases. Additionally, it was considered that early CR can predict long-term remission and that week 6 can be a helpful evaluation point for treatment decisions when using VDZ for UC.

Fasting plasma glucose reference values among young Japanese women requiring 75g oral glucose tolerance tests.

OBJECTIVE: Currently there are various discussions on the upper limit of FPG (Fasting Plasma Glucose) levels. In Japan, when abnormal levels of FPG are detected at general health checkups or complete physical examinations, 75g Oral Glucose Tolerance Tests (75g OGTT) are often conducted in follow-up examinations. Therefore we investigated the appropriate upper limit of FPG levels to decide whether 75g OGTT are actually necessary. RESEARCH DESIGN AND METHODS: Based on the FPG levels of 256,309 women with an age range of 20 to 79, we established the upper limits of FPG levels by 5-year intervals, using a method equivalent to the National Committee for Clinical Laboratory Standards (NCCLS) used in the U. S. [4]. We also obtained the ROC curve from the 75g OGTT results from 160 women aged 20 to 39. We then divided those 160 women into four categories based on their 75g OGTT results, and compared the abnormal rates of their 2-hour post-75g OGTT glucose levels, HOMA-R and Insulin Index using the Kruskal-Wallis test. RESULTS: The upper limits of FPG levels were 99 mg/dl in the 20-29 age range, 101 mg/dl in the 30-34 age range, and 104 mg/dl in the 35-39 age range. The upper limits of the FPG reference intervals increased almost proportionally up to the age 50, and showed little difference thereafter. The point on the ROC curve where the total value of sensitivity plus specificity reached the highest had an FPG level of 99.5 mg/dl. For 2-hour post-75g OGTT glucose levels and HOMA-R, there was a significant difference in abnormal rates between the categories of FPG ≤ 99 mg/dl and 100 ≤ FPG ≤ 109 mg/dl, but not in Insulin Index. CONCLUSIONS: We believe that 75g OGTT are necessary for Japanese women aged 20 to 39 with FPG levels of 100 mg/dl or above.

Favorable genetic polymorphisms predictive of clinical outcome of chemoradiotherapy for stage II/III esophageal squamous cell carcinoma in Japanese.

OBJECTIVES: This study was performed to find the genetic factors predictive of clinical outcome to a 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT) in Japanese patients with locally advanced esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Thirty-one patients with stage I-IVa ESCC (I/II/III/IVa = 7/7/14/3) were enrolled in this study. One course of treatment consisted of protracted venous infusions (PVIs) of 5-FU (400 mg/m2/24 hours for days 1-5 and 8-12), CDDP (40 mg/m2/3 hours on days 1 and 8) and radiation (2 Gy/d on days 1-5, 8-12, and 15-19), and a 2nd course was successively repeated after a 2-week interval. A total of 8 measurements of the plasma concentration of 5-FU were made using high performance liquid chromatography. Genetic polymorphisms examined herein included those in the genes coding thymidylate synthase (TS), glutathione S-transferase P1 (GSTP1), multidrug resistant transporter MDR1/P-glycoprotein, and intercellular adhesion molecule-1, and in a circadian rhythm-relating gene, CLOCK. RESULTS: The CR rate depended on stage (P = 0.001), but the analysis was not sufficiently powered to reach a level of statistical significance for the 2-year survival rate (P = 0.061). For stage II/III patients, to have 2 or 3 polymorphisms of 3R/3R of 5'-TSER, a 6 bp of 3'-TSUTR, and GSTP1-Ile105Val resulted in an extensively longer survival (P = 0.020), although no difference was found between 2 groups, with respect to the plasma concentrations of 5-FU and clinicopathologic characteristics. CONCLUSIONS: The prognostic index may allow predictions of the clinical outcome of a 5-FU/CDDP-based CRT in stage II/III ESCC patients.

MDR1 haplotype frequencies in Japanese and Caucasian, and in Japanese patients with colorectal cancer and esophageal cancer.

The genotype frequencies of MDR1 T-129C, C1236T, G2677A,T and C3435T SNPs were compared in 154 healthy Japanese and 100 healthy Caucasians to provide basic information on the inter-ethnic differences of pharmacotherapeutic outcome. The variants were found at allelic frequencies of 5.5%, 65.6%, 16.6%, 40.6% and 40.6%, for T-129C, C1236T, G2677A, G2677T and C3435T, respectively, in Japanese, and at 5.1%, 45.9%, 3.6%, 46.4% and 56.6%, respectively, in Caucasians, with a statistically significant difference for C1236T, G2677A,T and C3435T (p<0.001). G2677A was about 5-fold more frequent in Japanese than Caucasians. These genotype frequencies were also investigated in 95 Japanese patients with colorectal cancer (CRC) and esophageal squamous cell carcinoma (ESCC), but no significant difference was detected, when compared with healthy Japanese subjects. The haplotype frequency reached a total of about 85% in Japanese with the following 4 major haplotypes; T(-129)-T1236-T2677-T3435 (36.1%), T(-129)-T1236-G2677-C3435 (22.5%), T(-129)-C1236-G2677-C3435 (14.2%) and T(-129)-C1236-A2677-C3435 (13.3%). The second and fourth haplotypes were hardly inferred in Caucasian, whereas T(-129)-C1236-G2677-T3435 (12.8%) was found to be Caucasian-specific. There was a tendency for higher frequencies of the T(-129)/C-(129)-C1236-A2677-C3435 haplotype in Japanese CRC patients and T(-129)-T1236-T2677-T3435 haplotype in Japanese ESCC patients, compared with that in healthy Japanese subjects.

MDR1 C3435T polymorphism is predictive of later onset of ulcerative colitis in Japanese.

Recently, a silent polymorphism of C3435T of the MDR1 gene, encoding the multidrug resistant transporter MDR1/P-glycoprotein, has been found to be associated with susceptibility to ulcerative colitis (UC), but this remains controversial. This study was conducted to find a possible reason for the discrepancies, and it was suggested that the age of onset was important for the association, namely, C3435T was predictive of susceptibility to later onset UC, but not for early onset UC. Linkage disequilibrium of C3435T with T-129C, C1236T and G2677A, T was suggested to be altered in UC, but the analysis of their haplotype provided no advantage in terms of prediction over that with only C3435T. The effect of C3435T on susceptibility could not be explained by that on mRNA expression in rectal mucosa, but it was greater in the C(3435)-noncarriers in the early onset group, allowing the individualization of steroid-based pharmacotherapy.

Two cases of reversible posterior leukoencephalopathy syndrome, one with and the other without pre-eclampsia.

Two cases of reversible posterior leukoencephalopathy syndrome (RPLS) are reported. One was a 26-year-old woman, who had pre-eclampsia and developed cortical blindness and subsequent eclampsia at 28 weeks' gestation. The other was a 27-year-old woman, who had no pre-eclampsia and developed loss of consciousness and subsequent systemic convulsion at 36 weeks' gestation. On brain magnetic resonance imaging, they both had high signal intensity on T2-weighted and fluid-attenuated inversion recovery images, and normal signal intensity on diffusion-weighted image of the posterior lobe, which almost disappeared with the amelioration of clinical symptoms thereafter. RPLS is considered to be the result of vasogenic brain edema caused by hypertension. Two hypotheses are conceived to explain the emergence of RPLS without hypertension. The first suggests that an immunotolerant condition such as pregnancy can easily cause vasogenic edema without the elevation of blood pressure. The second suggests that hypertension exists but cannot be detected because it is extremely acute and transient.

[Dilution index as a candidate parameter reflecting dialysis dose in combined peritoneal dialysis and hemodialysis therapy].

Combined peritoneal dialysis and hemodialysis therapy (combined therapy) is recognized as an effective alternate in peritoneal dialysis patients with insufficient water and solute removal, but there is no appropriate index for dialysis dose, as two distinct dialysis procedures are utilized in the same patient. Among several candidate parameters, the dilution index proposed and defined by Yamada, et al as the solute generation rate divided by the distribution volume and time-averaged concentration of the solute might be applicable, because it is unrelated to the method of solute removal. Among 11 patients undergoing combined therapy at Toride Kyodo General Hospital, six patients who had transferred from peritoneal dialysis alone to combined therapy were recruited. All patients received peritoneal dialysis therapy for five consecutive days followed by one day off dialysis before a hemodialysis session on the seventh day every week. Total weekly creatinine and urea removal by residual renal function, peritoneal dialysis, and hemodialysis were measured, and their solute removal on the last(5th) day under peritoneal dialysis was ascertained and correlated with the averaged daily removal of solutes. Hence the value of solute removal obtained on the last day under peritoneal dialysis was multiplied seven times and defined as the weekly solute generation. The distribution volumes of creatinine and urea were defined as 58% of body weight. The time-averaged concentration was obtained from the mean level of a solute before and after a hemodialysis session. During the period followed solely by peritoneal dialysis, the dilution indices for creatinine and urea were 1.22 +/- 0.14 and 1.85 +/- 0.14, respectively. The dilution index after transferring to combined therapy, calculated by the above-mentioned method was increased to 1.72 +/- 0.29 and 2.28 +/- 0.31, respectively. Hence the dilution index may be useful for reflecting dialysis doses even in combined therapy.

Improvement of gastric atrophy after Helicobacter pylori eradication therapy.

BACKGROUND: It remains controversial whether gastric atrophy is reversible after Helicobacter pylori eradication therapy. AIM: To clarify whether gastric atrophy improves after H. pylori eradication therapy using a histologic approach. METHODS: Subjects were 87 H. pylori infection-cured patients (treatment group) and 29 continuously H. pylori-infected patients (control group). The subjects in the treatment and control groups were followed for 10-49 months (mean, 22 months) and 11-50 months (mean, 22 months), respectively. Biopsy specimens were obtained from the greater curvature of the antrum and corpus at the beginning and end of the observation period; histologic analyses of these specimens were performed for detection of activity, inflammation, atrophy, and intestinal metaplasia. Results were scored without any clinical information according to the Sydney system. RESULTS: In the treatment group, the histologic score for atrophy was improved in the corpus but not in the antrum. Intestinal metaplasia was not improved in either the antrum or the corpus. There were no significant differences during the follow-up in gastric atrophy and intestinal metaplasia in the control group. CONCLUSION: Gastric atrophy was improved in the corpus approximately 2 years after H. pylori eradication therapy.

[Phase II study of combination therapy with paclitaxel and carboplatin against postoperative small residual disease in patients with stage I c-IV ovarian cancer--KCOG 989 trial].

The tolerability and feasibility of combination therapy with paclitaxel (TXL) and carboplatin (CBDCA) against small residual disease following first-line optimal debulking of stage I c-IV ovarian cancer were evaluated in a multicenter dose-finding study. Eligibility criteria included histologically diagnosed stage I c-IV epithelial ovarian cancer with a postoperative residual lesion < or = 10 mm in diameter, no prior chemotherapy, and written informed consent of the patient and his/her family members to the chemotherapy. Twenty-two patients were enrolled and 20 of them were eligible. The patients were to receive 5 courses of TXL (175 mg/m2) and CBDCA (AUC 5) every 3 weeks. Hematological toxicities occurred in the form of grade 3 leukopenia during 25.7% of all courses, grade 3 neutropenia during 32.0% of all courses, and grade 4 neutropenia during 56.0% of all courses. No courses were associated with grade 4 leukopenia. G-CSF support was needed during 48 of 109 courses (44%) and caused normalization of the leukocyte count from a nadir of 1,921 +/- 434/mm3 after a mean time of 6 +/- 3.1 days, compared with 6 +/- 3.6 days needed for recovery from a nadir of 2, 357 +/- 360/mm3 without G-CSF support. This indicates similarly rapid recovery from severe leukopenia with the use of G-CSF. All eligible patients completed at least 5 courses of the chemotherapy. Some courses were given at a reduced dose or delayed due to toxicity but these dosage modifications were thought to be acceptable for both TXL and CBDCA. Five courses of TXL combined with CBDCA were tolerated well in this patient population.