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Background Although some retrospective studies have suggested the value of adjuvant therapy, no recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer. Methods This was a randomized phase III trial. Patients with resected bile duct cancer were assigned randomly to gemcitabine and observation groups, which were balanced with respect to lymph node status, residual tumour status and tumour location. Gemcitabine was given intravenously at a dose of 1000 mg/m2, administered on days 1, 8 and 15 every 4 weeks for six cycles. The primary endpoint was overall survival, and secondary endpoints were relapse-free survival, subgroup analysis and toxicity. Results Some 225 patients were included (117 gemcitabine, 108 observation). Baseline characteristics were well balanced between the gemcitabine and observation groups. There were no significant differences in overall survival (median 62·3 versus 63·8 months respectively; hazard ratio 1·01, 95 per cent c.i. 0·70 to 1·45; P = 0·964) and relapse-free survival (median 36·0 versus 39·9 months; hazard ratio 0·93, 0·66 to 1·32; P = 0·693). There were no survival differences between the two groups in subsets stratified by lymph node status and margin status. Although haematological toxicity occurred frequently in the gemcitabine group, most toxicities were transient, and grade 3/4 non-haematological toxicity was rare. Conclusion The survival probability in patients with resected bile duct cancer was not significantly different between the gemcitabine adjuvant chemotherapy group and the observation group. Registration number: UMIN 000000820 (http://www.umin.ac.jp/).

Secondary hyperparathyroidism (SHPT) is a serious major complication in hemodialysis patients with chronic kidney disease. Long-term maintenance of serum phosphate, calcium, and parathyroid hormone (PTH) levels in appropriate ranges in these patients is a major challenge. We investigated the efficacy and safety of long-term treatment with etelcalcetide, a novel intravenous calcimimetic, in Japanese SHPT patients on long-term hemodialysis. This study was a multicenter open-label study. A total of 191 hemodialysis patients with serum intact PTH (iPTH) > 240 pg/mL were enrolled. Etelcalcetide was administered thrice weekly for 52 weeks, with an initial dose of 5 mg and flexibility to adjust the dose between 2.5 and 15 mg and to adjust the dosing of concomitant medications for SHPT. The efficacy endpoint was the proportion of patients with serum iPTH decreased to the target range (60–240 pg/mL). Serum iPTH levels decreased immediately after etelcalcetide was started. At the end of the study, 87.5% (95% confidence interval 81.4–92.2; 140/160 patients) of patients achieved target serum iPTH levels, with control of serum calcium and phosphate levels. Adverse events, mostly mild to moderate, were reported by 96.8% of patients and led to study discontinuation in 7.4% of patients. Nausea, vomiting, and symptomatic hypocalcemia were found in 4.7, 9.5, and 1.1%, with 0.5, 1.1, and 1.1% considered treatment-related. Etelcalcetide effectively maintained serum iPTH, calcium, and phosphate levels in appropriate ranges with concomitant medications for SHPT for 52 weeks in Japanese hemodialysis patients, and was safe and well tolerated. JapicCTI-142665.

Previously, we used dual immunofluorescent analysis and showed that the thyroid gland from patients with Graves' disease had a reduced number of CD4+CD45RA+ cells, but an increased number of complementary CD4+CDw29+ cells. An immunohistochemical study, however, produced opposite results; interstitial lymphocytes predominantly expressed the CD45RA+ rather than the CDw29+ phenotype. Because the difference in findings may be due to differences in the techniques used, we did the following experiments: Mononuclear cells were treated with various amounts of collagenase (50-1000 mg/l) which had no effect on the cell surface antigens CD3, CD4 and CD45RA. A dual immunofluoresent study showed that the numbers of CD4+CD45RA+ and CD8+CD45RA+ cell population among CD45RA+ cell population were markedly decreased in the thyroid tissue, and that the CD45RA antigen on the intrathyroidal mononuclear cells was mainly expressed on the CD20+ cells. As the thyroid section had been fixed with acetone before immunohistochemical staining, CD45RA− cells were treated with acetone and stained with anti-CD45RA monoclonal antibody using an avidin-biotin peroxidase complex method. The results of this experiment suggest that there are cell surface molecules which react with anti-CD45RA monoclonal antibody after treatment with acetone in CD45RA− cells. The above findings confirm our previous results which showed that the thyroid glands of patients with Graves' disease have decreased numbers of suppressor-inducer T cells. Also, several problems exist in the detection of CD45RA+ cells when using an immunohistochemical method.

Depression is well known as one of the psychiatric complications of interferon (IFN) therapy in patients with chronic active hepatitis C. We compared the psychiatric status during interferon therapy between patients with renal cell cancer (RCC) and those with chronic active hepatitis C.The psychiatric status of 40 patients with renal cell cancer, 36 who were subjected to radical nephrectomy and 4 who were not because of the presence of distant metastasis and other complicated underlying diseases, was assessed by psychiatrists before and at 2, 4, 12 and 24 weeks after the start of IFN therapy according to the major depressive episode diagnostic criteria listed in the DSM-III-R and the Hamilton Depression Scale (HDS). The mental aspect was measured using the Eysenk Personality Questionnaire (EPQ) before IFN therapy, and the results were compared with those obtained in 85 hepatitis C patients evaluated according to the same protocol for psychiatric assessment.Eight of the 40 patients were diagnosed as having depression before IFN therapy and 5 of them became even more depressed 2 weeks after the start of IFN therapy. Nine patients were found to be depressed after the start of IFN therapy, 7 of them were diagnosed before 4 weeks of therapy. All the patients needed treatment for depression: discontinuation of IFN therapy in 4, decrement of the IFN dose in 8, and psychiatric drug medication in 13. The patients who suffered from depression had significantly higher scores in neuroticism (EPQ) before IFN therapy than those who did not become depressed. There was no difference in age, sex or cancer stage between the two groups. The occurrence of depression in RCC patients was the same as that observed in hepatitis C patients receiving IFN therapy. But in RCC patients the depressive state was diagnosed earlier and was more severe than that observed in hepatitis C patients.Urologists should be aware of the psychiatric symptoms of RCC patients under IFN therapy just as in hepatitis patients. The depression in RCC patients was considered to be related to the cancerous disease itself which may explain its higher degree of severity, as compared to hepatitis C patients.

Helicobacter pylori and nonsteroidal antiinflammatory drugs (NSAIDs) are considered the major causes of peptic ulcer. If ulcers are not attributable to H. pylori, most are thought to be attributable to NSAIDs. We have previously reported that rheumatoid arthritis (RA) patients taking NSAIDs long term (NSAIDs group) are more likely to develop gastric ulcers, which commonly occur in the gastric antrum. In addition, the morphology of gastric ulcers in the NSAIDs group differs from that in the non-NSAIDs group (control group), in whom NSAIDs are not involved in the occurrence of gastric ulcers. In this study, we compared gastric ulcers in the NSAIDs group with those in the control group in terms of H. pylori infection. The positive rate of H. pylori in gastric ulcers was significantly lower in the NSAIDs group than in control group (53.6% vs 91.5%). At the ulcer site they were seen significantly less often in the antrum than in either the angle or body of the stomach (35% vs 100%) in the NSAIDs group. On the other hand, the H. pylori-positive rate for ulcers in the antrum did not differ significantly from that in the angle and body of the stomach (81.8% vs 93.8%) in the control group. These findings suggest that H. pylori plays little role in antral ulcers in those taking NSAIDs.

Patients who survive partial hepatectomy sometimes have unsatisfactory liver regeneration and restoration of liver function. Although the extent of resection should be adjusted to attain favorable liver regeneration and restoration of liver function, a guiding principle for this has not been established.Seventy patients with hepatic tumors associated with liver disorders of various severity who underwent hepatectomy were studied. We calculated the removal rate of the liver and the regeneration rate of the remnant liver using computed tomography. The liver function was investigated using ICG R-15 (retention rate of indocyanine green). Liver disorder was classified into 4 groups, according to the severity of fibrosis.The regeneration rates of the remnant liver indicated a significant decline in patients with severe fibrosis. In the no fibrosis and mild fibrosis groups, an increased removal rate was associated with increased regeneration rate, and post-operative ICG R-15 improved with time. However, in the moderate fibrosis and severe fibrosis groups, an increased removal rate was not associated with increased regeneration rate, and post-operative ICG R-15 showed no change or became worse with time.Severe fibrosis of the liver parenchyma is associated with poorer regeneration of the remnant liver leading to poor restoration of post-operative liver function. The severity of fibrosis is useful as a predictive factor for liver regeneration and restoration of liver function after partial hepatectomy.

We conducted corticectomy in twenty-five patients with intractable partial epilepsy due to focal cortical dysplasia (FCD). MRI could not detect FCDs in three patients, interictal SPECT, however, revealed hypoperfusion corresponding to FCDs in two of these patients, while the FCD in one remaining patient was histologically identified in a resected specimen. The location of FCDs was as follows: the frontal lobe in sixteen patients, the temporal in five, the occipital in two, fronto-parietal in one, and the temporo-parietal in one. Prior to the surgery, twenty-one patients underwent invasive long-term intracranial EEG/CCTV monitoring. Of the fourteen patients who were tracked for longer than 2 years following surgery, eleven belonged to Class I according to Engel's criteria, two to Class II, and one to Class III. We compared intracranial EEG findings (interictal and ictal) between these twenty-one patients and eight patients with frontal lobe epilepsy resulting from different lesions. The results of this comparison, together with the seizure outcome following surgery, indicated that FCD is intrinsically epileptogenic. The invasive long-term monitoring should, as a rule, be performed in all patients with FCDs prior to the corticectomy.

The number of patients treated with interferon (IFN) has increased markedly in Japan since 1992, when the Health and Welfare Ministry approved the use of IFN for treating chronic active hepatitis C. It is important to identify and treat depression, which is one of the psychiatric complications of IFN therapy and often leads to discontinuation of the therapy, in patients with chronic hepatitis C. In this study we prospectively investigated the incidence of depression during IFN therapy in patients with chronic active hepatitis C. The psychiatric status of 85 patients (53 men, 32 women; mean age 49.1 years) with chronic active hepatitis C who began receiving IFN at Showa University Hospital was assessed before and 2, 4, 12 and 24 weeks after the start of IFN therapy, using the major depressive episode diagnostic criteria listed in the DSM-III-R and the Hamilton Depression Scale HDS). All of the patients provided informed consent prior to participation in this study. IFN therapy was discontinued in 5 cases (5.9%) because of physical side effects and in 4 cases (4.7%) because of depression. Two, 11, 14, 25 and 16 patients were diagnosed as having major depressive episodes before and 2, 4, 12 and 24 weeks after the start of IFN therapy, respectively. The number of patients who were asymptomatic before the start of IFN therapy but were diagnosed as having a major depressive episode at least once during IFN therapy was 31 (31/83 = 37.3%). The mean HDS scores at 2, 4, 12 and 24 weeks (5.4, 6.0, 8.8 and 6.6) were significantly higher than that before the start of IFN therapy (3.0). The patients whose first diagnosed major depressive episodes occurred more than 4 weeks after the start of IFN therapy tended to be more severely depressed than those in whom it occurred less than 4 weeks after the start of IFN therapy. Compared to the 47 patients who completed 24 weeks of IFN therapy without experiencing depression, the 31 patients who were diagnosed as experiencing major depressive episodes during IFN therapy had significantly higher neuroticism scores determined using the Eysenck Personality Questionnaire, showed a more severely depressed mood and experienced more severe sleep disturbances before the start of IFN therapy. The latter group of patients also tended to have comorbid chronic physical disorders such as hypertension or diabetes mellitus and the histories of mental disorders before the IFN therapy; however these differences were not statistically significant. There were no differences between the two groups in patient age or sex, the severity of hepatitis before the IFN therapy, the type of IFN used in the therapy or the efficacy of IFN in the treatment of the hepatitis C. Our results indicate that the decision as to whether to treat chronic active hepatitis C with IFN should be made carefully and that early intervention and careful monitoring of depression are required during IFN therapy in the treatment of chronic active hepatitis C.

Twenty-eight patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were clinically studied for the effectiveness of the time-difference combination use of netilmicin (NTL) and minocycline (MINO). The patients were treated with NTL 100 mg and two hours later, with MINO 100 mg intravenously, twice daily, in the morning and evening for 14 days. Of 26 patients, MRSA was eradicated in 16 (61.5%), decreased in one, and unchanged in nine. Superinfections occurred with Serratia marcescens and Pseudomonas aeruginosa in two patients. The clinical efficacies were assessed in two patients with septicemia, 16 with pneumonia, and eight with chronic bronchitis. The obtained results were excellent in four patients, good in 15, fair in six, and poor in one patient. The rate of effectiveness was 73.1% (19/26). The overall clinical effectiveness judged by the committee was good in 19, fair in five, and poor in two patients. The efficacy rate was also 73.1% (19/26). Coagulase type II of MRSA was found in 23 patients, and coagulase type III in three patients, with overall clinical efficacy rates of 73.9% (17/23) and 66.7% (2/3), respectively. A side effect of eruption was observed in one patient, and its incidence was 3.6% (1/28). Abnormal laboratory test results were observed in 16 patients (57.1%), including abnormal liver function in 14 patients, abnormal kidney function in three, and increased eosinophils in three. Laboratory abnormalities occurred twelve of 16 bedridden patients, and this rate was higher than that in non bedridden patients. However, these abnormalities were all mild, transient, and immediately recovered after the treatment. In conclusion, the time-difference combination therapy using NTL and MINO was effective in the treatment of MRSA infections.

Our study was undertaken to investigate the effects of gold sodium thiomalate (GSTM) on the proliferation and HLA-DR antigen expression of human umbilical vein endothelial cells (EC). The proliferation of the EC was determined by 3H-thymidine incorporation into the EC. The expression of HLA-DR antigen on the surface of the EC was detected by an indirect immunofluorescent method using a fluorescent flow cytometer. When GSTM was added at the start of the EC culture, GSTM at a low concentration could inhibit the proliferative response of the EC to endothelial cell growth supplement. Furthermore, when the EC were cultured with recombinant interferon-gamma (rIFN-gamma) and GSTM, GSTM was also able to suppress the HLA-DR antigen expression on the surface of EC induced by rIFN-gamma. On the time-kinetic study of the effects of GSTM on the HLA-DR antigen expression induced by rIFN-gamma, the pretreatment of GSTM was able to suppress the HLA-DR antigen expression, whereas GSTM did not affect the HLA-DR antigen expression already induced by rIFN-gamma. Our findings suggest that the therapeutic effects of gold compounds in patients with rheumatoid arthritis may be attributed to the interference of the proliferation and HLA-DR antigen expression of the EC.

The phenotypic markers of mononuclear cells in synovial tissue from 19 patients with active rheumatoid arthritis (RA) were identified by a dual immunofluorescent method. The mononuclear cells were isolated from synovial tissue by mechanical disaggregation and an enzymatic digestion technique. The results revealed a marked reduction in CD4+2H4+ cells (suppressor inducer T cells) and an increment in CD4+4B4+ cells (helper T cells) among CD4+ cells in synovial tissue. The percentage of CD8+CD11b+ cells (suppressor effector T cells) was significantly lower in synovial tissue than in peripheral blood from patients with RA, resulting in an increased percentage of CD8+CD11b-- cells (cytotoxic T cells). The synovial tissue had higher percentages of pan B cells (B1+ cells), differentiated B cells (B1+B2-- cells) and plasma cells (PCA-1+ cells). These findings suggest that a combination of the increment in helper T cells, the reduction in suppressor T cells, and the increment in differentiated B cells may lead to excessive production of autoantibodies.

We investigated the incidence and characteristics of an elevated tumor associated antigen CA 19-9 in patients with rheumatic diseases. Serum concentration of CA 19-9 was increased in 13 of 39 patients (33.3%) with definite or classical rheumatoid arthritis (RA), in 6 of 19 patients (31.6%) with systemic lupus erythematosus (SLE), in 3 of 9 patients (33.3%) with progressive systemic sclerosis (PSS) and in 9 of the other 35 patients (25.7%). Malignant neoplasm was not detected in any of the patients with rheumatic diseases. Pretreatment of mouse serum with patients' sera did not reduce the measured CA 19-9 values obtained by the conventional assay. The CA 19-9 antigen found in sera from patients with RA was present in a non-IgG fraction, and had the same molecular weight as that in one patient with pancreatic cancer, as determined by gel filtration. These results demonstrated that serum CA 19-9 levels were increased in some patients with rheumatic diseases.

Recently it was demonstrated that the Tal antigen is a marker for activated T cells and the population of Tal+ cells includes memory T cells. Our study was undertaken to analyze Tal+ cells in peripheral blood from patients with rheumatoid arthritis (RA) and examine the correlation between the proportion of Tal+ cells and disease activity. Using a dual immunofluorescent method, T cell subsets were analyzed in peripheral blood from 46 patients with RA, 10 patients with osteoarthritis (OA) and 10 healthy subjects. Patients with RA had a significantly higher percentage of T cells bearing the Tal antigen than patients with OA and healthy subjects. Furthermore, the percentage of CD3+Tal+ cells in peripheral blood from patients with RA was significantly correlated with disease activity including erythrocyte sedimentation rate, morning stiffness and the Lansbury index, whereas CD3+ HLA-DR+ cells did not correlate. In serial observations in patients with RA, the percentage of CD3+ Tal+ cells decreased in accordance with the improvement of disease activity. Thus, we suggest that the percentage of Tal+ cells may be a marker of the disease activity in patients with RA.

We have studied cellular interactions among thyrocytes, intrathyroidal T cells and peripheral blood T cells from Graves' patients. In the autologous mixed lymphocyte reaction of Graves' patients, CD4+ cells were able to proliferate vigorously against autologous non-T cells, whereas CD8+ cells responded weakly to non-T cell stimulators. Furthermore, the proliferative response of the CD4+ 2H4+ suppressor-inducer T cell subset was increased like that of the CD4+ 2H4- helper T cell subset. In contrast to peripheral blood non-T cell stimulators, thyrocytes and intrathyroidal T cells had the ability to activate the CD4+ 2H4- helper T cell subset but were not able to cause proliferation both of CD4+ 2H4+ suppressor-inducer T cell and CD8+ suppressor/cytotoxic T cell subsets. The marked reduction in proliferative responses of CD4+ 2H4+ cells and CD8+ cells could not be attributed to a difference in kinetics or altered response to variable number of stimulator cells. On the basis of these findings, it is suggested that the concentration of the helper T cell subset may be progressively increased and suppressor circuits may be unable to be activated in thyroid tissues. These abnormalities in cellular interactions may induce the excessive production of autoantibodies.

We investigated the sensitivity of thyroid epithelial cells (thyrocytes) to IL-2 activated killer cells. The thyrocytes were lysed by autologous and allogeneic IL-2-activated killer cells; there were no differences in sensitivity to the killer cells between normal thyrocytes and thyrocytes from patients with Graves' disease. When thyrocytes were pretreated with recombinant interferon (rIFN) gamma or alpha, the IL-2-activated killer cell-mediated cytotoxicity was depressed and varied inversely with the cell surface expression of class I HLA gene products. The rIFN-gamma pretreatment did not alter the kinetics of thyrocytes lysis by IL-2-activated killer cells. Using cold target competition analysis, rIFN-gamma-pretreated thyrocytes clearly competed less effectively than did untreated cells for lysis of untreated target cells. These results suggest that rIFN-gamma or IFN-alpha pretreatment of thyrocytes may reduce their ability to be recognized by effector cells. These findings suggest that destruction of thyrocytes in autoimmune thyroiditis may be, in part, due to IL-2-activated killer cells and may be regulated by IFN.

A 37-year old man was suffered from Raynaud's phenomenon, sclerodactyly, and polyarthritis involving knees, shoulders, and hands. Recurrent skin ulcers were present in finger tips. Laboratory studies showed positive RA test, antinuclear antibody (nucleolar type), and anti-Scl 70 antibody. So diagnosis of progressive systemic sclerosis (PSS) was made. Progressed destructive arthritis with rheumatoid nodules developed in the patient. The joint destruction was severe and he was satisfied with the criteria of the American Rheumatism Association (ARA). This patient appears to be an overlapping case of PSS and rheumatoid arthritis (RA).

The present study utilized the anti-Ta1 mAb to characterize the cell surface phenotypes of peripheral blood and intrathyroidal lymphocytes in patients with Graves' disease. We found an increase in PBL bearing the Ta1 Ag in untreated patients. The euthyroid patients in remission, induced by antithyroidal drugs, radioisotope therapy, and subtotal thyroidectomy, had lower percentages of Ta1+ cells than did untreated patients. An increased percentage of Ta1+ cells in untreated patients was found in both CD4+ cells and CD8+ cells. The ratio of CD4+Ta1+ cells to CD8+Ta1+ cells in untreated patients was significantly higher than that of normal subjects. There was a positive correlation between the percentage of Ta1+ cells and the level of anti-TSH receptor antibody. In this prospective study, the proportion of Ta1+ cells was decreased in parallel with the reduction in anti-TSH receptor antibody and free T3 levels. In the chronically treated patients, the proportion of Ta1+ cells in the thyroid tissue was, yet similar to that in the peripheral blood, markedly increased in comparison to that of normal subjects. In contrast to Ta1+ cells, the thyroid tissue had a significantly higher percentage of HLA-DR+ T cells than did the paired peripheral blood. The proliferative responses of the Ta1+ cell-enriched population isolated from untreated patients toward thyroglobulin and microsomal Ag were markedly higher than those in a Ta1+ cell-depleted population, but both populations were able to respond equally to PHA. These results suggest that the Ta1+ cells may include Ag-triggered memory cells that are reactive with thyroid-specific Ag. Furthermore, monitoring such cells may provide an objective measure of abnormal immunologic activity.