Search

It has been proposed that 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which activates glucocorticoids, plays a role in chronic inflammatory diseases including metabolic diseases, rheumatoid arthritis, and ulcerative colitis. We have recently reported that the expression of 11β-HSD1 is increased in the gingiva of patients with chronic periodontitis and in that of rats with ligature-induced periodontitis. In this study, to further demonstrate the involvement of 11β-HSD1 in chronic periodontitis, the expression of 11β-HSD1 was investigated in another rat model of experimental periodontitis induced by intragingival injection of lipopolysaccharide from Porphyromonas gingivalis (LPS-PG). Alveolar bone loss was observed two weeks after intragingival injection of LPS-PG. The level of 11β-HSD1 mRNA assessed by real-time reverse transcriptase-polymerase chain reaction was significantly elevated in LPS-PG-induced periodontitis compared with controls. The expression of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates glucocorticoids, was not significantly different between control and LPS-PG-induced periodontitis. The expression of 11β-HSD1 was significantly correlated with that of TNF in LPS-PG-induced periodontitis. The increased expression of 11β-HSD1 protein in LPS-PG-induced periodontitis was confirmed by immunohistochemistry using anti-11β-HSD1 antibody. These results further suggest a role for 11β-HSD1 in the pathogenesis of chronic periodontitis.

Background Although rituximab added to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) is the standard chemotherapy for untreated DLBCL, its therapeutic effect is limited in younger patients with high-intermediate risk or high-risk disease according to the age-adjusted international prognostic index. In fact, the efficacy and safety of HDT plus rituximab followed by ASCT for such patients remain unclear. Patients and Methods We retrospectively investigated the safety and effectiveness of HDT/ASCT in patients with untreated DLBCL. Twenty-two patients, aged 60 years and younger, with untreated DLBCL (classified as high-intermediate [n = 14 (64%)] or high [n = 8 (32%)] risk) underwent upfront HDT/ASCT between January 2004 and December 2008, achieving either a complete response (CR; n = 15 (68%)) or a partial response (PR; n = 7 (32%)). Results The 5-year overall survival rate was 81.0% and the progression-free survival rate was 73.0%, with no significant difference between risk groups based on the international prognostic index. The most common nonhematologic toxicity was febrile neutropenia [n = 9 (41%)]. The cause of all 3 fatalities was exacerbation of the underlying disease, and no treatment-related mortality was observed. No variables with a significant influence on overall survival were identified, but a correlation of the treatment response before transplanation with progression-free survival was suggested (CR vs. PR: 92% vs. 30%, P = .002). Conclusion These results suggest that adding rituximab to upfront HDT/ASCT is feasible and can improve the outcome in untreated patients with poor-prognosis DLBCL. In the future, upfront HDT/ASCT should be more extensively evaluated in clinical trials.

Sinusoidal obstruction syndrome (SOS) is one of the severe complications of hematopoietic stem cell transplantation (HSCT). Systemic management including respiratory and circulatory support is necessary. In addition, abdominal paracentesis is often needed for pain relief and to reduce the pressure of tense ascites. Concentrated ascites reinfusion therapy (CART) involves the filtration, concentration, and reinfusion of drained ascites, which contributes to reuse of autologous proteins. CART has been reported as supportive therapy for patients with liver cirrhosis and cancer. We retrospectively reviewed the efficacy and safety of CART in three patients (two with acute myelogenous leukemia and one with chronic myeloid leukemia) who developed SOS after allo-HSCT. They all had symptomatic, tense, and diuretic-refractory ascites with right costal pain and marked weight gain. Two patients showed immediate improvement after CART. However, one patient experienced four CARTs with slow recovery. All patients are now alive and are being monitored as outpatients over 2 years with remission. No severe adverse event was observed related to CART, and 25.2-98.0 (median 30.2) grams of albumin was collected and reinfused. CART after paracentesis reduces protein loss in ascites by reinfusion of autologous protein instead of exogenous albumin preparations. Although transient fever is reported as a frequent adverse event, no events like severe bleeding or infection were observed. While its safety has not been fully established in patients with hematological disease after HSCT, CART may be a considerable supportive therapy for SOS with tense ascites.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone to active cortisol, has been reported to play an important role in metabolic diseases as well as chronic inflammatory diseases. The involvement of 11β-HSD1 in chronic periodontitis was investigated in the present study. The relationship between the levels of 11β-HSD1, chronic periodontitis, and body mass index (BMI) was analyzed. The expression of 11β-HSD1 mRNA was significantly higher in the chronic periodontitis group than in the control group. Since the expression of 11β-HSD2, which converts active cortisol to inactive cortisone, was slightly lower in the chronic periodontitis group than in the controls, the ratio of 11β-HSD1 versus 11β-HSD2 was significantly higher in the chronic periodontitis group than in the controls. A correlation was not observed between BMI and the level of 11β-HSD1 or between BMI and the ratio of 11β-HSD1 versus 11β-HSD2. These results suggested that an increase in the ratio of 11β-HSD1 versus 11β-HSD2 was associated with chronic periodontitis irrespective of obesity.

To evaluate ocular surface molecules after transconjunctival pars plana vitrectomy (PPV).A total of 28 eyes of 28 patients who received PPV were examined. Tears (10μl) were collected before and after 20-gauge PPV or 23-gauge PPV. The concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70 and tumour necrosis factor (TNF)-α were measured. The concentrations of each cytokine before and after surgery were compared. The change ratios of each cytokine (post-/presurgery) between 20-gauge and 23-gauge PPV were compared.IL-1β, IL-6, IL-8 increased after PPV (Wilcoxon rank sum test; IL-1 β, p=0.009; IL-6, p0.001; IL-8, p0.001), while the other cytokines did not. Among them, only IL-8 increased significantly in 20-gauge PPV than in 23-gauge PPV (p=0.01, Mann-Whitney U test). Multivariate analysis showed that 20-gauge PPV was a significant factor behind the increase in postoperative IL-8 (OR 5.21, 95% CI (1.46 to 18.55), p=0.018), but surgical time and simultaneous cataract surgery were not significant factors.The increase in inflammatory cytokine IL-8 in tear was significantly less after 23-gauge PPV than 20-gauge PPV, indicating that transconjunctival PPV is less invasive from the viewpoint of the ocular surface molecular biology. This information may be important when deciding the method of PPV.

A series of novel liquid crystalline compounds with a tetrahydropyrane ring were synthesized, and the physical properties have been measured. The compounds showed peculiar dependency of the dielect...

We sought to determine the frequency of primary extranodal lymphoma (ENL) and its characteristics in Kanagawa, a human T-cell leukemia virus type 1 (HTLV-1) nonendemic area in Japan. Subjects were 847 newly diagnosed patients with malignant lymphoma at the Yokohama City University Hospital and 8 affiliated hospitals mainly located in Kanagawa prefecture from 1999 to 2005. We compared the clinicopathological characteristics of primary ENL with primary nodal lymphoma (NL). Histological specimens were evaluated according to the World Health Organization classifications. A total of 395 (46.6%) and 452 (53.4%) patients had primary ENL and primary NL, respectively. The frequency of primary ENL increased with age. Primary extranodal sites included the gastrointestinal tract (30.4%), Waldeyer's ring (17.8%), orbits (7.0%), soft tissue and subcutaneous tissue (5.2%), bone (4.6%), skin (4.3%), thyroid gland (4.3%), testis and prostate (3.3%), bone marrow (3.3%), nasal and paranasal cavities (2.6%), salivary glands (2.3%), lung and pleura (2.0%), breast (1.8%), central nervous system (1.0%), uterus and ovary (0.5%), and others (9.8%). Among the 395 cases of primary ENL, diffuse large B-cell lymphoma (61.2%) was most frequently diagnosed, followed by extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (13.3%) and follicular lymphoma (5.6%). The frequency of primary ENL is approximately 50% of the total lymphoma cases in Kanagawa, an HTLV-1 nonendemic area in Japan. This frequency appears to be higher than that in Western countries.

A 47-year-old woman with primary biliary cirrhosis and scleroderma was examined at our hospital for a 1-week history of non-resolving fever, arthralgia, myalgia, muscle weakness and fatigue. A diagnosis of systemic lupus erythematosus was made based on arthralgia, low leukocyte count, low lymphocyte count, low serum concentration of complements, positive anti-nuclear antibody and positive anti-double-strand-DNA antibody. She was negative for anti-U1RNP antibody, but positive for anti-Jo1 antibody, and her initial serum concentration of creatine phosphokinase was elevated. We diagnosed her as having overlap syndrome with scleroderma, systemic lupus erythematosus and possible polymyositis associated with primary biliary cirrhosis. Prednisolone rapidly improved her symptoms. Lobulated leukocytes were observed in her peripheral blood specimen. She was positive for anti-HTLV-1 antibody, but Southern blot hybridization did not confirm monoclonal integration of HTLV-I proviral DNA in her peripheral blood. This suggests the possibility of a relationship between HTLV-1 infection and various autoimmune disorders including primary biliary cirrhosis.

Purpose To describe the incidence and clinical management of corneal infections with methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). Methods The incidence of methicillin-resistant Staphylococcus (MRS) at the Department of Ophthalmology, Kyoto Prefectural University of Medicine, was reviewed during the 5-year period from January 1996 to December 2000. Clinical aspects of MRS colonization or infection in the eye were investigated. Results Methicillin-resistant S. aureus or MRSE was detected from 30 eyes with ocular diseases; post-keratoplasty (11 eyes), ocular surface disorders without operation (9 eyes), and others (10 eyes). Among the 30 eyes, 12 manifested keratitis. Eight cases (8 eyes) occurred after keratoplasty, including four postoperative cases in patients with Stevens-Johnson syndrome, and two bilateral cases (4 eyes) in patients with acute-phase Stevens-Johnson syndrome. The degree of MRS keratitis was classified into 4 groups: asymptomatic carrier or conjunctivitis, intraepithelial infiltrations, superficial keratitis, and severe keratitis leading to corneal perforation. All cases of keratitis were treated successfully with topical ofloxacin (OFLX), vancomycin (VCM), or arbekacin (ABK). Conclusion Factors associated with ocular MRS colonization were long-term use of antibiotics and/or steroids, and hospitalization. Patients who had undergone keratoplasty or who had Stevens-Johnson syndrome were at increased risk of MRS keratitis. Superficial stromal infiltrations, minimal melting, and minimal stromal scarring are characteristic of MRS keratitis. Therapy for MRS keratitis is summarized. Ofloxacin, VCM, and ABK are effective in the treatment of MRS keratitis. Vancomycin eye ointment is effective as the final choice in serious cases.

Sinusoidal obstruction syndrome (SOS) is one of the severe complications of hematopoietic stem cell transplantation (HSCT). Systemic management including respiratory and circulatory support is necessary. In addition, abdominal paracentesis is often needed for pain relief and to reduce the pressure of tense ascites. Concentrated ascites reinfusion therapy (CART) involves the filtration, concentration, and reinfusion of drained ascites, which contributes to reuse of autologous proteins. CART has been reported as supportive therapy for patients with liver cirrhosis and cancer. We retrospectively reviewed the efficacy and safety of CART in three patients (two with acute myelogenous leukemia and one with chronic myeloid leukemia) who developed SOS after allo-HSCT. They all had symptomatic, tense, and diuretic-refractory ascites with right costal pain and marked weight gain. Two patients showed immediate improvement after CART. However, one patient experienced four CARTs with slow recovery. All patients are now alive and are being monitored as outpatients over 2 years with remission. No severe adverse event was observed related to CART, and 25.2-98.0 (median 30.2) grams of albumin was collected and reinfused. CART after paracentesis reduces protein loss in ascites by reinfusion of autologous protein instead of exogenous albumin preparations. Although transient fever is reported as a frequent adverse event, no events like severe bleeding or infection were observed. While its safety has not been fully established in patients with hematological disease after HSCT, CART may be a considerable supportive therapy for SOS with tense ascites.

Summary Long-term observation has identified a pattern of continuing relapse in limited stage diffuse large B-cell lymphoma (DLBCL) treated by three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved-field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R-CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5-year progression-free survival and 5-year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the ‘standard’ strategy of three cycles of R-CHOP followed by involved-field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R-CHOP alone.

Novel series of liquid crystalline compounds having an enyne unit, 1-(4-alkylphenyl)-4-(trans-4-alkylcyclohexyl)-but-3-en-1-yne and 1-(4-alkoxyphenyl)-4-(trans-4-alkylcyclohexyl)-but-3-en-1-yne are presented. The synthetic methods, mesomorphic phases, and some physical properties of these series are reported.

Human herpesvirus-6 (HHV-6) encephalitis is recognized as a relatively rare, but sometimes lethal, complication of allogeneic hematopoietic stem cell transplantation (HSCT). Although the development of new diagnostic techniques and antiviral therapy has improved, the prognosis of encephalitis is still unclear. We surveyed 197 patients who underwent allogeneic HSCT between January 2004 and March 2008 at our institution, and 8 (4.0%) were diagnosed as having HHV-6 encephalitis. Five were male and 3 were female, with a median age of 40.5 years. The median onset of HHV-6 encephalitis was 18 days after HSCT, and the median duration of antiviral therapy was 41 days. The median survival time from the onset of encephalitis was 23.1 months (range: 2.7-66.7), and 3 patients died of unrelated causes (sepsis in 2 and gastrointestinal tract bleeding in 1). Cord blood transplantation was identified as the only independent risk factor (relative risk [RR] = 4.98; P = .049) by multivariate analysis. There was no statistical significance of survival after HSCT between the patients with HHV-6 encephalitis and those without HHV-6 encephalitis (the 2-year survival rate was 60% and 52.6%, respectively; P = .617). Four of the 5 surviving patients were unable to return to society because of neuropsychological disorders, including anterograde amnesia and seizures with prominent hippocampal atrophy. Although HHV-6 encephalitis occurring after HSCT is now becoming a curable complication, its sequelae, such as neuropsychological disorders, have a marked influence on the quality of life of long-term survivors. Accordingly, it is necessary to identify risk factors for HHV-6 encephalitis and establish methods for prevention of this complication.

Idiopathic thrombocytopenic purpura (ITP) commonly affects women of childbearing age. We studied the clinical characteristics of pregnant women with ITP to estimate their risks of bleeding. A retrospective chart review was performed for all obstetric patients with ITP who had delivery at our hospital, from 1 March 2000 to 31 March 2008. Twenty women with ITP delivered 24 children in 23 pregnancies. In all, eight women were treated with corticosteroid during their pregnancy period, and there was only one non-responder. There was no correlation between the maternal platelet count and the amount of blood loss at delivery. Two infants were revealed to have had platelet counts lower than 30 × 109/L, and were treated with high-dose IV IgG. One of them also received corticosteroid therapy. There was no relationship between maternal platelet count at delivery and infant platelet count at birth. Overall, no serious bleeding event was seen in either of the mothers or infants. For most women with ITP, pregnancy is uncomplicated, and even those with severe thrombocytopenia during pregnancy have good outcomes when under the strict care of a hematologist and gynecologist.

The prognosis of diffuse large B-cell lymphoma (DLBCL) has improved markedly in recent years of rituximab era. The prognosis of de novo CD5-positive DLBCL is reported to be poor, but the effect of rituximab on this type of lymphoma remains unclear. To investigate the effect of rituximab on CD5-positive DLBCL, we collected DLBCL patients and analysed prognostic factors. A total of 157 patients with DLBCL who were immunophenotyped with flow-cytometry (FCM) and treated with chemotherapy were subjected to analysis. Those treated with radiotherapy alone or with supportive therapy only were not included. Patients diagnosed in 2003 or later were treated with rituximab combined chemotherapy. There were 95 males and 62 females. Their age ranged from 20 to 91 years old, and the median was 65 years. Nineteen patients were diagnosed as having de novo CD5-positive DLBCL. Rituximab was given alongside chemotherapy in 85 patients. Of these, 11 were positive for CD5 and 74 were negative. The addition of rituximab improved the overall survival (OS) of DLBCL patients (2-year OS: 82% vs. 70%, p = 0.01). For CD5-negative DLBCL, patients treated with rituximab showed 2-year OS of 84%, which was significantly better than those treated without rituximab (70%, p = 0.008). However, for CD5-positive DLBCL, the prognosis was not statistically different between the patients treated with and without rituximab (59% vs. 50%, p = 0.72). Although rituximab improved the prognosis of DLBCL, such improvement was restricted to the CD5-negative group. Further investigation is required to improve the prognosis of patients with CD5-positive DLBCL.

A 42-year-old woman was admitted to our hospital with acute myelogenous leukemia. We conducted blood-type examination, and her serum showed strong agglutination with all B cells but questionable agglutination with A1 cells, which became stronger with incubation. We considered her blood type as O, but her previously assessed blood type was A. After receiving one cycle of induction therapy, she achieved complete remission and blood group A antigen was proven on her red blood cells. Anti-A1 in her serum disappeared after induction therapy. We should be aware that blood group antigens are not entirely independent of the environment and are occasionally modified by disease.

To evaluate the Visual Function 14(VF-14) index of functional visual impairment in patients with corneal disease treated by phototherapeutic keratectomy (PTK).Seventy-two patients with corneal disease who were treated by PTK participated in this study between March 1999 and September 2002. Demographic, ocular history, best-corrected visual acuity, and detailed ocular examination data were collected. Functional visual impairment information was obtained by questionnaire covering the following: VF-14, Cataract Symptom Score, and satisfaction with vision.The mean best-corrected visual acuity of the eye scheduled for PTK was 0.67+/-0.63(mean +/- standard deviation) the logarithm of the minimum angle resolution (logMAR) whereas that of the post-operated eye was 0.34+/-0.38 logMAR. The mean VF-14 score, Cataract Symptom Score, and satisfaction with vision were improved significantly after the treatment. The satisfaction with vision was correlated with the VF-14 score and the Cataract Symptom Score. The VF-14 scores of all of the patients whose pre-PTK VF-14 scores were under 50 were improved after PTK.The VF-14 is a valid measure of functional visual impairment in patients with corneal disease treated by PTK.

A homologous series of various compounds with polar terminal groups conjugated with carbon-carbon double bonds: thecyanoethylene, cyanobutadiene, and fluorocyanoethylene groups were prepared. These derivatives have very wide mesomorphictemperature ranges. Moreover, by measuring physical properties, the mixtures containing this series were found to have largedielectric anisotropies (ic) and appropriate birefringence values (in). The X-ray diffraction measurement of the cyanoethylenederivatives supports an anti parallel dimer conformation in their smectic phases. A fluorine atom at the a position of thecyano group prevents the formation of such electrostatic dimers. It is concluded that the wide mesomorphic temperature rangeof these derivatives was caused by the stronger molecular interaction. Moreover, the derivatives which can form dlimerstructures showed the wider mesomorphic temperature ranges.Key words: Cyanoethylene Cyanobutadiene Fluorocyanoethylene Anti parallel dimerization Conjugated terminal group

Abstract 1574 Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma (NHL), with a highly variable natural history ranging from an indolent disease to a rapidly progressive one such as its transformation to aggressive NHL. We have used the Follicular Lymphoma International Prognostic Index (FLIPI) that uses patient- or tumor-specific characteristics for the risk-stratification of patients with FL at the time of diagnosis. The tumor microenvironment, including variable monocyte-derived cell infiltration, has recently shown to play an important role in the clinical course of FL patients. Wilcox et al. showed that an elevated absolute monocyte count (AMC) is associated with inferior overall survival of FL patients receiving varying treatment strategies (Wilcox RA, et al. Leuk Lymphoma 2012). We retrospectively evaluated the prognostic changes in AMC at diagnosis in FL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy alone. This study included 157 consecutive FL patients treated with the R-CHOP therapy at 1 of the 7 participating hospitals between 2001 and 2009. Since 2001, the Yokohama City University Hematology Group in Japan uniformly and curatively treated patients with FL, except for those with stage 1 FL; the patients were treated with 6 cycles of standard R-CHOP therapy for 21 days. Patients who showed partial response (PR) after the initial 4 cycles were administered a total of 8 R-CHOP cycles, and those who did not show PR after the initial 4 cycles or patients in whom the disease progressed at any given time received salvage therapy. Patients who had bulky masses at diagnosis received involved field radiation following 6—8 cycles of R-CHOP therapy. Patients for whom the doses had to be reduced by more than 20% were excluded from the study. The study included 80 men and 77 women, with a median age of 63 years at diagnosis (range, 18—80 years). The FL of the 157 patients were classified as grade 1 (n = 65), grade 2 (n = 60), grade 3a (n = 20), and grade 3b (n = 12) according to the World Health Organization (WHO) scheme. The median AMC at diagnosis was 349 cells/μL (range, 10—1110 cells/μL). The median observation period for surviving patients was 45 months. The 5-year progression-free survival (PFS) estimated for the entire cohort was at 71.3%. The differences in the PFS when patients were stratified according to their AMCs were not significant. The effect of the following variables on PFS were assessed: (1) AMC > 390 cells/μL; (2) age > 60 years; (3) hemoglobin level < 120 g/L; (4) elevation of serum lactate dehydrogenase levels; (5) nodal areas > 4; and (6) advancement of clinical stage. In the univariate analysis, the presence of more than 4 nodal areas (hazard ratio [HR] = 2.65, 95% CI, 1.58—4.47, P < 0.001) and advanced clinical stage (HR = 2.75, 95% CI, 1.26—6.03, P= 0.01) were associated with inferior PFS. However, in the multivariate analysis, the association between the presence of more than 4 nodal areas and survival was found to be significant (HR = 2.33, 95% CI, 1.28—4.24, P = 0.006). Therefore, both univariate and multivariate analyses indicate that AMC was not a prognostic factor for PFS. There was no statistically significant correlation between AMC and FL patients' clinical outcome. AMC is not a prognostic factor in FL patients treated by R-CHOP. Disclosures: No relevant conflicts of interest to declare.

Abstract 1620 Few randomized prospective studies have been conducted on patients with localized DLBCL in the rituximab era. The SWOG 0014 study examined DLBCL patients treated with 3 cycles of R-CHOP followed by involved-field radiotherapy. Each of the patients had at least 1 of the 4 risk factors (nonbulky stage II, over 60 years of age, WHO performance status [PS] of 2, or elevated LDH), but showed 4-year progression-free survival (PFS) and 4-year overall survival (OS) rates of 88% and 92%, respectively. However, long-term observations showed that the PFS and OS curves did not plateau (Persky DO, et al. J Clin Oncol 2008). We retrospectively analyzed a series of patients with localized DLBCL treated with R-CHOP therapy alone. This study included 190 consecutive, untreated patients with localized DLBCL seen between 2003 and 2009 in 1 of the 7 participating hospitals. All the patients were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP in 1 of the hospitals. Patients who required a dose reduction of more than 20% were excluded from the study, as were patients with special forms of DLBCL, such as intravascular lymphoma, primary mediastinal large B-cell lymphoma, and T-cell-rich B-cell lymphoma. Patients who achieved partial remission (PR) after the 4 initial cycles underwent a total of 8 R-CHOP cycles. Patients who did not achieve PR after the 4 initial cycles or those with disease progression at any time during the study underwent salvage therapy, and that time point was designated as the point at which the disease progression began. Additional local irradiation was allowed in patients with PR. Patients who received additional radiotherapy following CR in the decision of attending physicians were excluded from this study. Patients who achieved CR but who were initially at risk of central nervous system (CNS) involvement received 4 intrathecal doses of methotrexate (15 mg) and hydrocortisone (25 mg) for CNS prophylaxis. Central pathological reviews were not performed; only the individual institutional diagnoses were used. The study included 111 men and 79 women, with a median age at diagnosis of 63 years (range, 18–80 years). According to the IPI, 133 patients were classified as L; 49, as LI; 5, as HI; and 3, as H. Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. CNS prophylaxis was performed in 15 patients who had an initial CNS risk and achieved CR. The median observation period for the living patients was 52 months. The responses to therapy were 180 CR, 8 PR, and 2 progression of disease (PD). The 5-year PFS and 5-year OS rates were 84% and 90%, respectively, and both plateaued (Figure 1). None of the patients experienced PD after 4 years of observation. Multivariate analysis revealed that the presence of bulky mass, which was evident in 18 patients, was an independent risk factor for PFS (P = 0.007, relative risk [RR] 3.5) and OS (P = 0.003, RR 5.8), along with poor performance status. During the observation period, 29 patients experienced PD. The progression sites included the primary sites in 15 patients, outside the primary sites in 10, and undetermined in 4. There were 16 deaths, 14 of which were due to the lymphoma. In 149 patients with at least one of the 4 risk factors used in the SWOG 0014 study, the 5-year PFS and 5-year OS rates were 86% and 94%, respectively. Six cycles of R-CHOP therapy alone were observed to be highly effective in attaining good survival results with plateaus. These results suggest that the “standard” strategy of 3 cycles of R-CHOP followed by involved-field radiotherapy for localized DLBCL should be replaced by R-CHOP alone. Disclosures: No relevant conflicts of interest to declare.

We compare the mesogenic properties of two-ring compounds, substituted at one end with n-alkyl groups and at the other end with alkyl, alkyloxy, ω-fluorinated alkyloxy, methylenoxy-alkyl and acyloxy groups. The different groups have different effect on the mesogeneity, and their effect is different when they are attached at benzene resp. cyclohexane rings. In order to find out rational reasons for this behaviour we performed quantum chemical calculations on the density functional theory and ab initio level. Contrary to existing opinions, in cyclohexane derivatives the calculated axial conformers were proven to have so low stability that in the thermal equilibrium they do not play a role. In alkyloxy compounds gauche conformers were found to be more stable than the most elongated all-trans conformers.

A series of chemically stable novel liquid crystalline four ring chain compounds (1a–1c) having a difluoromethyleneoxy (CF2O) linkage moiety have been designed and prepared, and their properties have been thoroughly investigated. The novel compounds intrinsically possess much higher positive Δϵ (>32) and Δn (>0.190), relatively low viscosity, wider nematic phase temperature ranges and significantly higher clearing temperatures in comparison to the analogous three ring chain CF2O compound (2) that is currently applied in almost all the latest TN-TFT monitors, notebook PCs and IPS-TVs.

A series of novel liquid crystal compounds with five-ring framework having a –CF2O- linkage group (1a–1e) has been synthesized and their physical properties were measured. These compounds are characterized to have higher nematic-isotropic liquid transition temperatures and broader mesophase temperature range. As for the anisotropic properties, this series is categorized as compounds having large Δϵ and Δn. Although these compounds possess five rings in their structures, they exhibit high miscibility caused by the rotately non-symmetric structures including the lateral fluorine substituted phenylene rings. One of the novel compounds exhibits SmF phase and shows the second-order phase transition of SmA to SmC. The compounds are effective to improve the response property of the mixtures due to their high elastic constants. These five-ring compounds possess diversified properties and of high potential materials for improving the LCD performances.

We synthesized new low polar derivatives of tetrahydropyran with nematic and smectic behaviour. Quantum chemical calculations show, that the most elongated conformers of the cyclohexane and tetrahy...

Effect of a new anti-inflammatory drug which has a little ulcer inducing property on gastrointestinal tract, TA-60 (2-[4-(3-methyl-2-butenyl) phenyl] propionic acid), on the prostaglandin (PG) metabolism was investigated. TA-60 inhibited the PGE2 biosynthesis of the bovine seminal vesicle microsome dose-dependently. The inhibition constant (Ki) of TA-60 was approximately 8 microM. The potency of TA-60 was approximately the same and two times that of ibuprofen (IP) and phenylbutazone (PBZ), respectively. TA-60 did not show the time dependent inhibition of the PGE2 biosynthesis unlikely to indomethacin (IM). The decrease in the PGE2 contents in the stomach of the rats by TA-60 reached a plateau and the content was not decreased to less than a certain level. The PGE2 content of the intestine was not changed by TA-60. TA-60 did not inhibit the activity of the PG degradating enzyme, 15-hydroxy PG dehydrogenase (15-OH-PG-DH) of the gastric mucosa like the other non-steroidal anti-inflammatory drugs (NSAIDs): IP, PBZ and IM. These results suggest that the slight ulcerating effect of TA-60 on the gastrointestinal tract might be resulted from the small decreasing effect of TA-60 on the gastrointestinal level of PGE2.

The stress of immobilization in water caused a significant increase in the activity of choline acetyltransferase (CAT) and acetylcholinesterase (AChE), acetylcholine (ACh) content in the stomach and gastric acid secretion, but a decrease of choline content in rats. The increase in CAT activity began 1 h after the application of stress, peaked in 3 h and gradually decreased to normal within 7 h. Similar alterations in gastric acid secretion were observed. The ACh content in stomach tissue increased 30 min after the application of stress and remained elevated for 2.5 h. The content decreased to control levels after 5 h, and significantly increased again after 7 h. The choline content in stomach tissue significantly decreased 1 and 2 h after stress but returned to normal 3 h after the application. An increase in AChE activity was observed 2 and 7 h after the application of stress but normal levels were found after 4 h. Increases in CAT activity and acid output were also observed following administration of 2-deoxy-d-glucose (2-DG), but no changes in ACh and choline contents or AChE activity were observed. The increases in CAT activity and the acid secretion caused by stress and 2-DG administration were blocked by administration of hexamethonium. These results suggest that increases in gastric CAT, AChE activities and ACh content and a decrease of choline content in the early stages are results of increased vagus nerve activity, which influences gastric acid secretion. Furthermore, they suggest that alterations in ACh content and AChE activity at a later stage are less directly related to the increase in vagus nerve activity.

SU-88 [2′-carboxymethoxy-4,4′-bis(3-methyl-2-butenyloxy)chalcone] inhibited the activity of the prostaglandin (PG)-metabolizing enzyme, 15-hydroxy-PG-dehydrogenase (15-OH-PG-DH), in a cytoplasmic fraction of gastric mucosa. This compound had no effect on the PG synthetase of bovine seminal vesicle microsomes and lactate dehydrogenase in rat liver. The 15-OH-PG-DH activity of gastric mucosa was not influenced by a specific inhibitor of alcohol dehydrogenase, 4-methylpyrazole. Carbenoxolone (CBX) also inhibited 15-OH-PG-DH activity. The ic 50 values for SU-88 and CBX were approximately 20 and 40 μM respectively. SU-88 inhibited 15-OH-PG-DH activity uncompetitively or competitively according to whether PGE 1 or NAD was used as substrate. CBX inhibited competitively the activity of this enzyme for both substrates. After the addition of SU-88 or CBX to the incubation medium of gastric mucosa, the PGE 2 level of the medium was increased significantly while that of the tissue remained unchanged. These results indicate that SU-88 specificaly inhibited 15-OH-PG-DH activity and suggest that 15-OH-PG-DH activity regulates the level of PGs in gastric mucosa and may have an anti-ulcer influence.

The dissociation constant (Kd) and the maximum number of binding sites (Bmax) of 3H-nitrendipine (3H-NTD) were not altered by neuraminidase (NUase) treatment. The Kd and Bmax values were approximately 0.2 nM and 70 fmoles/mg protein, respectively. The influences of diltiazem on 3H-NTD bindings differed between NUase treated and untreated preparations. Diltiazem increased 3H-NTD (100 pM) binding dose-dependently with a 40% increase at about 10(-6) M in the untreated preparation. After treatment with NUase, a low dose of diltiazem decreased 3H-NTD (100 pM) binding, and the greatest effect was observed at 10(-9) M with a 50% decrease, while at a high dose of diltiazem (10(-6) M), 80% increase of the binding was observed. Scatchard plot analysis indicated that a high dose of diltiazem (10(-6) M) increased only the affinity of 3H-NTD to the binding site in both the NUase-treated and untreated preparations. In the untreated preparation, a low dose of diltiazem (10(-9) M) had no effect on 3H-NTD binding, but in the NUase-treated preparation, diltiazem (10(-9) M) showed opposing effects, namely, an increase and decrease of the binding at low and high concentrations of 3H-NTD, respectively. No straight line was obtained when a hill plot analysis of the effect of diltiazem on 3H-NTD binding was made. These results suggested that diltiazem allosterically regulates dihydropyridine derivative binding, and in this regulation, the concentration ratios between diltiazem and the dihydropyridine derivative is the most important factor. Furthermore, it is suggested that the sialic acid of the proteoglycan is involved in these interactions, especially in the effect of diltiazem on dihydropyridine binding.

Glucocorticoid binding to cytoplasmic and nuclear fractions and glucocorticoid-receptor complex binding to the nuclear fraction were investigated using rat liver. The glucocorticoid-receptor complex binding to the nuclear fraction was temperature-dependent, saturable, small in amount and of high affinity. The affinity and number of the glucocorticoid-receptor complex binding to the nuclear fraction were altered according to the glucocorticoid. Both the Bmax of nuclear glucocorticoid-receptor complex binding and the affinity of glucocorticoid to the cytoplasmic fraction were correlated with the relative anti-inflammatory potencies of glucocorticoids reported by Hynes and Murad (1980) and Fried et al. (1958). These results suggest that the number of nuclear binding sites of the glucocorticoid-receptor complex depends on the ligand steroid which is bound to the receptor of the cytoplasmic fraction and may be involved in physiological and pharmacological potencies of the glucocorticoid in addition to the affinity of the glucocorticoid to the receptor.

A variety of β-hydroxyalkanoic acid derivatives were prepared by palladium catalyzed aerobic oxidative-carbonylations of terminal olefins at normal pressure of carbon monoxide and oxygen mixed gas.

The binding to a Ca-channel of a novel 1,4-dihydropyridine (DHP) Ca-antagonist, 2-nitratopropyl 3-nitratopropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (CD-349), was studied in rat myocardium and brain and hog coronary artery, and the binding was compared with that of other DHPs. In rat myocardium, the binding reaction of [3H]CD-349 was faster than that of nitrendipine (NTD). The association rate constant of [3H]CD-349 was about 10 times higher than that of [3H]NTD. The dissociation rate was also higher than that of [3H]NTD. Scatchard plot analysis of [3H]CD-349 binding showed one high affinity site for CD-349. The dissociation constant (Kd) and maximum number of binding sites (Bmax) were 333 pM and 286 fmoles/mg protein. They were almost the same as those for [3H]NTD. [3H]CD-349 and [3H]NTD bindings were dose dependently inhibited by 1,4-DHPs: nifedipine, nimodipine, nicardipine and CD-349. The order of the inhibitory potency of these drugs was CD-349 greater than nicardipine greater than nimodipine greater than nifedipine, when [3H]CD-349 and [3H]NTD were used as the ligands. Similar results were obtained for rat brain and hog coronary artery. [3H]CD-349 binding was not changed by alpha- or beta-adrenergic, cholinergic, histaminergic or serotonergic agents in rat myocardium. From these results, it is suggested that CD-349 binds to the Ca-channel reversibly with high affinity due to its high association rate for the site.

To investigate the affinity of glucocorticoid (GC) to its receptor, the binding of [3H]hydrocortisone 17-butyrate 21-propionate ([3H]HBP) and [3H]dexamethasone ([3H]DEX) in rat liver was analyzed kinetically. Scatchard analysis of [3H]hydrocortisone ([3H]HC) binding yielded a curvilinear plot with upward concavity with high and low affinities. The dissociation constant (Kd) value of high affinity was 1.9 nM and of low affinity 68.7 nM. A Scatchard plot of [3H]HBP binding showed a straight line with high affinity. The Kd value was 9.8 nM. The Kd values for the low affinity site of HC were in good agreement with the Ki values obtained from displacement experiments of [3H]DEX and [3H]HBP binding. The Ki values of HC for [3H]DEX and [3H]HBP were 51.9 and 42.3 nM respectively. The association rate constant for HBP to the GC receptor was 2.9 times lower than that for HC. The dissociation rate constant for HBP was 6.1 to 8.3 times lower than that for HC. The Kd values for [3H]HBP (9.5 nM) and [3H]HC (30.0 nM) obtained from the above two rate constants were approximately the same as the Ki and Kd values (in the case of HC, the value of the low affinity site). These results suggest that esterification of the hydroxyl group(s) in the side chain of GC by butyrate and propionate increased the affinity to the GC receptor, and that a decrease in the dissociation rate from the receptor caused the increase in the affinity to the GC receptor.

The characteristics of the time-dependency of nonsteroidal antiinflammatory drugs (NSAIDs) and their active sites in inhibiting cyclooxygenase activity were investigated using bovine seminal vesicle microsomal fraction. The Hill's coefficients of the inhibition curve of most NSAIDs were approximately 1.0, except for some drugs which had Hill's coefficients that were obviously more than 1.0. The values for indomethacin, diclofenac and flurbiprofen were approximately 1.5, 1.7 and 2.0, respectively. A time-dependent cyclooxygenase inhibiting effect was observed only with the NSAIDs in the group which had Hill's coefficients that were significantly more than 1.0. A time-dependent increase in inhibiting activity of these drugs was observed by the change in the inhibition curve. Time-dependently, the Hill's coefficient of the curve of the NSAIDs approached 1.0 from more than 1.0. With this change, the shift of the curve to the left was also observed time-dependently. These changes in the curve were no longer seen when the Hill's coefficient dropped to 1.0. These time-dependent effects were protected by salicylic acid, which did not have any effect on cyclooxygenase activity in vitro, in a dose-dependent manner. These results suggested that the two classes of NSAIDs, time-dependent and non-time-dependent, are clearly differentiated by the slope of the inhibition curve of NSAIDs. Furthermore, the present results indicate that the degree of time-dependence of the NSAIDs depends on the Hill's coefficient of the inhibition curve, and the value is important for the potency of the cyclooxygenase inhibition, in addition to the affinity for the catalytic site of the enzyme.

A variety of β-hydroxyalkanoic acid derivatives were prepared by palladium catalyzed aerobic oxidative-carbonylations of terminal olefins at normal pressure of carbon monoxide and oxygen mixed gas.