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To evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients. Patients who had completed 24 weeks of TCZ‐SC (162 mg/2 weeks) or TCZ‐IV (8 mg/kg/4 weeks) monotherapy in the double‐blind period of the MUSASHI study were enrolled in an 84‐week open‐label extension period. All received TCZ‐SC (162 mg/2 weeks) monotherapy. Effects of the IV to SC switch were evaluated at week 36 (12 weeks after switching). Overall, 319 patients received ≥1 dose of TCZ‐SC during the open‐label extension period; 160 switched from TCZ‐IV to TCZ‐SC (TCZ IV/SC) and 159 continued TCZ‐SC (TCZ SC/SC). Disease Activity Score in 28 joints using the erythrocyte sedimentation rate clinical remission rates were 62.5% (100 of 160) for TCZ IV/SC and 50.0% (79 of 158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100 of 160) and 57.0% (90 of 158), respectively, at week 36. In the TCZ IV/SC group, 9% of patients (9 of 100) who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing ≥70 kg, the percentage with a sufficient serum TCZ concentration (≥1 μg/ml) decreased from 90.9% (10 of 11) at week 24 to 45.5% (5 of 11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC. Efficacy is adequately maintained in most patients switching from TCZ‐IV (8 mg/kg/4 weeks) to TCZ‐SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ‐IV can switch to TCZ‐SC without serious safety concerns. Clinical efficacy may be reduced after switching in some patients with high body weight.

ABSTRACTForty-six Helicobacter cinaediisolates from the same hospital were analyzed by multilocus sequence typing. Most H. cinaediisolates exhibited clonal complex 9 and were mainly isolated from immunocompromised patients in the same ward. Three Helicobacter fennelliaeisolates were obtained from the same ward and exhibited the same pulsed-field gel electrophoresis patterns. All isolates were resistant to clarithromycin and ciprofloxacin. H. cinaediand H. fennelliaemust be carefully monitored to prevent nosocomial infection.

Abstract: Increased glucose metabolism has been reported to occur in association with colorectal cancer. As positron emission tomography (PET) using [18F]fluorodeoxyglucose is able to depict hypermetabolic sites, it can therefore be used to detect colorectal cancer. A 69-year-old male patient with a recurrent solitary liver metastasis from colon cancer underwent whole-body PET which revealed high [18F]fluorodeoxyglucose uptake in the lesion. Furthermore, PET revealed peritoneal metastases that had not been detected by conventional imaging methods. Consequently, PET proved useful in helping us to avoid performing unnecessary treatment for the liver metastasis. Although it is uncertain whether early identification of recurrence can prolong survival, it may help to prevent unnecessary treatments being carried out. Thus, the application of PET in carefully selected patients could be beneficial to the management of recurrent colorectal cancer.

Abstract: Background. Intraoperative radiation therapy (IORT) has been performed to prevent local recurrence of rectal cancer only when positive margins are suspected. To further reduce local recurrence, we attempted to develop a new IORT irradiation method in which electron beam irradiation is administered as uniformly as possible to the intrapelvic dissection surfaces. Methods. Low anterior resection and abdominoperineal resection were performed in one male and one female cadaver. Electron beam irradiation was administered by four different methods, and absorbed doses were measured at 15 sites within the pelvis. We also attempted to measure absorbed doses at nine sites within the pelvis in 14 patients treated with IORT. Results. The cadaver study revealed low absorbed doses in the lateral walls of the pelvis when a single irradiation was delivered from the anterior. When the lateral walls of the pelvis were irradiated twice, once each time on the right and left, the absorbed doses were low in the central pelvis and presacrum. Relatively high absorbed doses were achieved in all of these areas by a technique that combined these two methods. Adequate absorbed doses were not achieved by a single irradiation administered from the perineum. Conclusion. This study suggests that electron beam irradiation administered three times to the dissected surfaces in the pelvis after resection of rectal cancer (i.e., to the central pelvis and presacrum from the anterior, and to the left and right lateral walls of the pelvis) is the most suitable method for achieving adequate absorbed doses.

Abstract: A 61-year-old women had been treated with methotrexate (MTX) since May 1993 for rheumatoid arthritis. She developed a high fever on 1 July 1997 and was diagnosed as havingListeria monocytogenes sepsis and meningoencephalitis. The encephalitis progressed inexorably and she died on 12 July. Although MTX is used as a first-line disease modifying anti-rheumatic drug, listeriosis should be remembered as a potentially fatal adverse effect.

Background:The conventional classification of the degree of hemorrhoids does not consider the severity of hemorrhage. The purpose of this study was to establish a new objective method for evaluating hemorrhoids in close relation to the main symptoms, hemorrhage and prolapse, as observed through a retroflexed colonoscope in the rectum. Methods:The subjects were 531 consecutive patients who complained of symptoms related to the rectum or the anus. The degree of mucosal elevation of the rectal columns, changes in color (the existence and degree of red color sign, dilated vein, and white area), and the existence and size of hypertrophied anal papillae were evaluated by colonoscopy. Results:Red color sign was the finding closely related to hemorrhage (p< 0.0001). Dilated vein, white area, and a large hypertrophied anal papilla were related to prolapse (p< 0.0001). The degree of mucosal elevation of the rectal columns was related to both hemorrhage and prolapse (p< 0.0005, p< 0.05). Conclusion:Retroflexing the colonoscope intrarectally facilitated identification of findings in the anal canal related to hemorrhage and prolapse, which are the clinical manifestations of hemorrhoids. (Gastrointest Endosc 1998;48:272-5.)

The Stoffel fragment of Taq DNA polymerase lacks the 5′to 3′exonuclease activity that hydrolyzes potentially blocking DNA strands during primer extension. We therefore asked whether by using this fragment in the PCR, non-extendable, base-paired oligonucleotides could inhibit amplification in a sequence-dependent manner. Model targets were chosen from the partially conserved ribosomal 16S rDNA of three bacterial species: E. coli, Bacillus subtilisand Neisseria gonorrhoea. A single pair of primers was capable of amplifying a homologous 240-bp region from all three. Two nonextendable “blocking” oligonucleotides were synthesized with sequences complementary to the inter-primer regions of E. coliand B. subtilis, respectively. Both blockers were shown specifically to prevent amplification of their complementary targets, but not of the reciprocal control targets or of the non-complementary N. gonorrhea. Specificity was further confirmed by an internal positive control. Similar inhibition was seen with mixtures of targets in a single reaction. With intact TaqDNA polymerase, no blocking was observed. Primers and blockers targeting specific regions of N. gonorrhoearDNA were used to confirm the requirement that blockers be directed to the inter-primer region. Sequence-dependent amplification inhibition, such as that demonstrated here, would be applicable to PCR-related strategies using primers capable of using multiple targets, where such selective inhibition could be useful.

Abstract: The indications for laparoscopic colon resection and the associated complications are discussed herein. This procedure was indicated for patients with benign disease or malignant disease with invasion limited to the submucosal layer. The subjects consisted of 14 cases with submucosal tumor invasion diagnosed preoperative, three with submucosal invasion clarified by endoscopic polypectomy, three with adenomas larger than 2 cm in diameter strongly suspected of being focal submucosal tumor invasion considered unsuitable for endoscopic mucosal resection and one with Crohn's disease with ileus. Two cases in whom laparoscopic surgery was not appropriate were included in this series. In one case with a superficial elevated lesion (Ma type), 15 mm in diameter, a diagnosis of moderately differentiated adenocarcinoma of the cecum was made preoperatively, but subserosal tumor invasion of the colonic wall with negative lymph node metastasis (nO) was revealed by examination of the resected specimen. The histology of the second superficial elevated lesion (Ha+lie type), which had a central depression, 13 mm in diameter and located above Bauhin's valve, was a well differentiated adenocarcinoma of which the cancerous portion invaded the proper muscle with positive lymph node metastasis (n1). Complications occurred in four cases. There were two cases of intraoperative vascular injury necessitating conversion to a standard laparotomy. One case with complete transection of the left ureter by End‐GIA later underwent reoperation. The other case with minor leakage at the anastomotic site was managed with conservative therapy. In both of these cases the depth of tumor invasion had been incorrectly assessed as representing small elevated lesions, 15 mm in diameter, in the right colon. Furthermore, the cases who experienced complications had left colonic lesions. These results suggest that preoperative ultrasonic‐endoscopy should be conducted as extensively as possible and that a good bloodless visual field appears to be necessary to avoid injuring adjacent organs.

Abstract: Background: We evaluated a new dose-intensive schedule for oral UFT (tegafur and uracil in a molar ratio of 1:4) administered for 5 consecutive days followed by 2 drug-free days (weekly-5-method), in comparison with conventional daily administration (weekly-7 method), in Yoshida-sarcoma-bearing rats. Methods: The single dose of 20 mg/kg of UFT for rats corresponds to the human single dose when converted to dose per unit of body-surface area. The drug was administered 3 times a day for the weekly-5 method and twice a day for the weekly-7 method. A 7-day period was considered 1 course. The total doses per course were almost the same in both methods. Antitumor efficacy and survival effect were evaluated after 3 courses. Body weight changes and food consumption were also measured as indices of toxicity. The plasma pharmacokinetics were analyzed by simulating dosage patterns. Results: Significant tumor-growth inhibition was seen with both the weekly-5 and the weekly-7 methods as compared to the control. Moreover, the weekly-5 method showed higher tumor-growth inhibition and a better survival effect than the weekly-7 method. These results appear to be related to the duration of plasma concentrations of 5-FU being maintained above a certain concentration for a longer time with the weekly-5 method. Food consumption with the weekly-5 method recovered to the control level after the drug-free period, and body weight gain was also favorable. Conclusion: The results of this study suggest that the dose-intensive method of administering UFT orally for the weekly-5 method is a useful dosage schedule. Thus, this dosage schedule is recommended for use in clinical trials.

Rituximab (RT) has been proven to be very effective in depleting normal and malignant B lymphocytes in vivo and it is widely used for the treatment of B cell malignancies, particularly B cell non-Hodgkin’s lymphoma (NHL). RT alone does not appear to cause severe hypogammaglobulinemia according to initial clinical trials. However, recent studies revealed that patients who received RT as an adjuvant to stem cell transplantation (SCT) demonstrated an increased risk of developing severe hypogammaglobulinemia. We have found such hypogammaglobulinemia to be due to the delayed recovery of CD27 positive memory B cells and an impaired isotype expression. (Nishio et al. Eur J Haematol, 2006). This finding suggests that RT can influence not only the quantity, but also the quality of B-cell redistribution. Nevertheless, to our knowledge, precisely how the B-cell repertoire regenerates after anti-CD20-mediated transient B-cell depletion in patients with NHL remains to be elucidated. To clarify this, we performed a phenotypical analysis of B cells. A total of 22 patients with NHL who received RT combined with autologous SCT (n=17) or CHOP (n=5) were evaluated to identify their immunophenotype. The median period after the last administration of RT was 33.5 months (range from 12 to 56 months). We investigated the expression of various markers, including CD27, CD38, CD40, CD80, CD86 and CD95 on B cells by immunofluorescence staining with a flowcytometry analysis. A statistically significant difference was noted in three of the six surface antigens when the expressions of those antigens were compared with those in the healthy control populations (N=14). The most striking differences we found was the expression levels of CD27. The healthy control group had a much higher expression of CD27 in comparison to those of the patients treated with RT (28.1±14.1% vs 8.2±6.1%, p<0.001). In addition, significant differences in the expression of CD40 and CD80 were also noted. While the positive rates of CD80 and CD40 on B cells from healthy controls were 21.5±10.8% and 80.5±16.7%, those of patients treated with RT were 9.9±6.9% and 49.7±33.5%, respectively (p<0.01 and p<0.05). Since CD40-CD40L and CD80-CD28 pathways between B and T cells are necessary for the development of CD27 positive polyclonal B-cell activation and immunoglobulin production, we hypothesized that the B cells from patients treated with RT thus had a reduced ability to differentiate into plasma cells and immunoglobulin production in vitro. To test this hypothesis, we purified the B cells from ten patients with NHL treated with RT and then cultured them upon the engagement of immunoglobulin receptor and CD40 in the presence of IL-2 and IL-10. After eight days of stimulation, the supernatants of the culture were harvested and the concentrations of immunoglobulin were measured by ELISA. As a result, the IgG production was found to be significantly impaired in patients with NHL in comparison to those from the healthy controls. The observation of a delayed recovery of the memory B cells with an abnormal cell marker expression and function demonstrates that naive B cells may therefore be responsible for their failure to differentiate into plasma cells after RT therapy.

Rituximab (RT) has been proven to be very effective in depleting normal and malignant B lymphocytes in vivo and it is widely used for the treatment of B cell malignancies, particularly B cell non-Hodgkin's lymphoma (NHL). RT alone does not appear to cause severe hypogammaglobulinemia according to initial clinical trials. However, recent studies revealed that patients who received RT as an adjuvant to stem cell transplantation (SCT) demonstrated an increased risk of developing severe hypogammaglobulinemia. We have found such hypogammaglobulinemia to be due to the delayed recovery of CD27 positive memory B cells and an impaired isotype expression. (Nishio et al. Eur J Haematol, 2006). This finding suggests that RT can influence not only the quantity, but also the quality of B-cell redistribution. Nevertheless, to our knowledge, precisely how the B-cell repertoire regenerates after anti-CD20-mediated transient B-cell depletion in patients with NHL remains to be elucidated. To clarify this, we performed a phenotypical analysis of B cells.