Pathogenicity of functionally activated PD-1+CD8+ cells and counterattacks by muscular PD-L1 through IFNγ in myositis.

Programmed-cell-death 1 (PD-1) expression is associated not only with T-cell activation but with exhaustion. Specifically, PD-1+ T cells present an exhausted phenotype in conditions of chronic antigen exposure, such as tumor microenvironments and chronic viral infection. However, the immune status regarding exhaustion of PD-1+CD8+ T cells in chronic autoimmune diseases including idiopathic inflammatory myopathies (IIMs) remains unclear. We aimed to clarify the role of PD-1+CD8+ T cells and PD-1 ligand (PD-L1) in IIMs. We showed that PD-1+ cells infiltrated into PD-L1-expressing muscles in patients with IIMs and immune checkpoint inhibitor-related myopathy. According to the peripheral blood immunophenotyping, the PD-1+CD8+ cell proportions were comparable between the active and inactive patients. Of note, PD-1+CD8+ cells in the active patients highly expressed cytolytic molecules, indicating their activation, while PD-1-CD8+ cells expressed low levels of cytolytic molecules in the active and inactive patients. A part of PD-1+CD8+ cells expressed the HMG-box transcription factor TOX highly and presented the exhausted phenotype in the active patients. Among PD-1+CD4+ T cells, PD-1highCXCR5-CD45RO+CD4+ peripheral helper T cells were increased in the active patients. PD-L1-deficient mice developed severer C-protein-induced myositis (CIM), a model of polymyositis, with abundant infiltration of PD-1+CD8+ cells expressing cytolytic molecules than wild-type mice, indicating pathogenicity of the PD-1+CD8+ cells and the protective role of PD-L1. The deficiency of IFNγ, a general PD-L1-inducer, impaired muscular PD-L1 expression and exacerbated CIM, indicating IFNγ-dependent muscular PD-L1 regulation. IFNγ-induced PD-L1 on myotubes was protective in an established muscle injury model. In conclusion, PD-1+CD8+ T cells rather than PD-1-CD8+ T cells were a pathogenic subset of IIMs. Muscular PD-L1 was regulated by IFNγ and exerted protective properties in IIMs.

Development of organ-specific autoimmunity by dysregulated Aire expression.

Deficiency for AIRE/Aire in both humans and mice results in the development of organ-specific autoimmune disease. We tested whether augmented and/or dysregulated AIRE/Aire expression might be also prone to the breakdown of self-tolerance. To define the effect of augmented Aire expression on the development of autoimmunity, antigen-specific clonal deletion and production of clonotypic regulatory T cells (Tregs) in the thymus were examined using mice expressing two additional copies of Aire in a heterozygous state (3xAire-knockin mice: 3xAire-KI). We found that both clonal deletion of autoreactive T cells and production of clonotypic Tregs in the thymus from 3xAire-KI were impaired in a T-cell receptor-transgenic system. Furthermore, 3xAire-KI females showed higher scores of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein than wild-type littermates, suggesting that augmented Aire expression exacerbates organ-specific autoimmunity under disease-prone conditions. In humans, we found that one patient with amyopathic dermatomyositis showed CD3- CD19- cells expressing AIRE in the peripheral blood before the treatment but not during the remission phase treated with immunosuppressive drugs. Thus, not only loss of function of AIRE/Aire but also augmented and/or dysregulated expression of AIRE/Aire should be considered for the pathogenesis of organ-specific autoimmunity. We suggest that further analyses should be pursued to establish a novel link between organ-specific autoimmune disease and dysregulated AIRE expression in clinical settings.

Factors associated with impaired physical function in elderly rheumatoid arthritis patients who had achieved low disease activity.

OBJECTIVE: We aimed to investigate factors associated with impaired physical function (defined as HAQ Disability Index [HAQ-DI] >0.5) of old-old (aged 75-84) patients with rheumatoid arthritis (RA). METHODS: Data from 15,185 RA patients in the National Database of Rheumatic Disease in Japan were extracted from 2017 to 2018. We enrolled 3,708 patients aged 55-84 in simplified disease activity index (SDAI) ≤11 and Steinbrocker stage I/II. Factors associated with HAQ-DI >0.5 were analyzed by multivariable logistic regression. RESULTS: About half of the old-old patients received methotrexate, which was lower than middle-aged (55-64) and young-old patients (65-74). The proportion of glucocorticoids in the old-old patients was highest among the three groups, and biological disease-modifying anti-rheumatic drugs were similarly used. The prevalence of HAQ-DI >0.5 was significantly higher in old-old patients with low disease activity than in those with remission. The same was true in the middle-aged and young-old patients. Multivariable analysis showed age, higher SDAI, glucocorticoid use, and methotrexate non-use were significantly associated with HAQ-DI >0.5 in the old-old patients. CONCLUSIONS: SDAI remission was an ideal goal for old-old patients in terms of physical function. Glucocorticoids and a low proportion of methotrexate use may influence the physical function of old-old patients.

[Richter syndrome successfully treated with ibrutinib monotherapy: two case reports].

The Richter syndrome (RS) is defined as a histologically diagnosed diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. A standard treatment for RS has not yet been established. Most patients with RS are treated with combination chemotherapy regimens used for de novo DLBCL or HL. Recently, the Bruton's tyrosine kinase inhibitor, ibrutinib (IBR), has shown remarkable efficacy in CLL; however, limited evidence exists regarding its single agent efficacy in RS. We encountered two patients with RS in whom CLL transformed to DLBCL, confirmed by G-banding/spectral karyotyping analysis. Both patients achieved durable responses for 12 and 10 months, with IBR alone. Hemorrhagic cystitis due to adenovirus occurred in one patient at an initial dose of 420 mg/day, but a dose reduction to 280 mg/day made long-term continuation of IBR possible. Interestingly, retreatment with IBR alone achieved disease control again for 5.5 and 2 months, after these patients underwent salvage chemotherapies for aggressive relapse.

Current diagnosis and treatment of polymyositis and dermatomyositis.

Idiopathic inflammatory myopathies (IIMs) are heterogeneous disorders that affect the skeletal muscles. Polymyositis, dermatomyositis, and inclusion body myositis are major IIM subsets. Immune-mediated necrotizing myopathy became recognized as a potentially new IIM subset. Since the new classification criteria published by the International Myositis Classification Criteria Project have higher sensitivity and specificity for IIM classification and subclassification than the previous criteria, they should help precise diagnosis. It should be noted that several tests available in current clinical practice, such as electromyography, magnetic resonance imaging, and other myositis-specific autoantibodies than anti-Jo-1 antibodies, were not included in the new criteria. As for treatment, glucocorticoids are used empirically as the first-line treatment despite their various adverse effects. Concomitant treatment with steroid-sparing immunosuppressive agents, including methotrexate, azathioprine, calcineurin inhibitors, mycophenolate mofetil, and cyclophosphamide, reduces successfully initial glucocorticoid doses for the remission induction, the relapse risk during glucocorticoid tapering, and adverse effects of glucocorticoids. Treatment with biologics, including rituximab and abatacept, seems promising in some IIM patients. Multi-target treatment with glucocorticoids and several steroid-sparing immunosuppressive agents is effective in refractory IIM patients. Considering proven steroid-sparing efficacy and tolerability of multi-target treatment in patients with other autoimmune diseases, it should be a good therapeutic option for IIMs.

Poncet's disease with high titers of rheumatoid factor and anti-citrullinated peptide antibodies mimicking rheumatoid arthritis.

Reactive arthritis accompanying tuberculosis (TB), also known as Poncet's disease, is a rare condition. In the present report, we describe the case of a patient with Poncet's disease, who presented with high titers of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA), which mimicked rheumatoid arthritis (RA). A 69-year-old man with a childhood history of chronic left gonitis suffered from right knee arthritis for 3 years. Chronic monoarthritis in his right knee and positive results obtained on interferon-gamma release assay were suggestive of tuberculous arthritis. However, there was no evidence of TB infection. Moreover, the high titers of RF and ACPA suggested a diagnosis of RA. Surprisingly, the culture of a small sample from his bony ankylosed left knee that had no focal signs of infection, exhibited a positive result for TB infection. Thus, based on these findings, the patient was diagnosed with Poncet's disease. His symptoms improved after initiation of anti-TB therapy, which supported the accuracy of the diagnosis. In addition, we analyzed the characteristics of Poncet's disease by conducting a literature review, and identified that the presence of extra-articular manifestation and negative results for RF and ACPA tests were the features that facilitated distinguishing between typical Poncet's disease and RA; however, since tuberculous patients occasionally exhibit positive results for ACPA tests, the differential diagnosis is essential in ACPA-positive arthritic patients.

Clinical role of a modified seton technique for the treatment of trans-sphincteric and supra-sphincteric anal fistulas.

PURPOSES: We have devised a modified seton technique that resects the external fistula tract while preserving the anal sphincter muscle. This study assessed the technique when used for the management of complex anal fistulas. METHODS: Between January 2006 and December 2007, 239 patients (208 males and 31 females, median age: 41 years) underwent surgery for complex anal fistulas using the technique. Of the 239 patients, 198 patients had trans-sphincteric fistula and 41 patients had supra-sphincteric fistula. RESULTS: The durations of the surgeries were 17 min (47, 13) [median (range, interquartile range)] for trans-sphincteric fistulas and 38 (44, 16) for supra-sphincteric fistulas. The durations of the surgeries were significantly (P < 0.05) longer for supra-sphincteric fistula than trans-sphincteric fistula. The hospital stays were 4 (13, 2) days and 5 (14, 3) days, respectively, for trans- and supra-sphincteric fistulas. The durations of seton placement until the spontaneous dropping of the seton were 42 (121, 48) and 141 (171, 55) days respectively. The recurrence rate was 0 % in patients with trans-sphincteric fistulas and 4.9 % (2 of 41) in patients with supra-sphincteric fistulas (P < 0.01). Serious incontinence was not observed. CONCLUSIONS: The technique provided favorable results for the treatment of complex anal fistulas and could be safely applied while preserving the sphincter function and conserving fecal continence.

Diagnostic clues of BCL2-negative, faint, or controversial follicular lymphomas: a study of 103 cases.

BCL2 positivity by immunohistochemistry is helpful for the diagnosis of follicular lymphoma (FL); however, a minority of FL cases are BCL2-negative, and the diagnosis is thus challenging. We retrospectively analyzed the incidence, morphology, immunophenotype, and genetic status of BCL21+ (weakly/focally positive by clone 124), BCL20 (negative), and BCL2controversial FLs compared with BCL22+ (strongly positive) FLs to clarify diagnostic clues. In 1068 FL cases, 103 (10%) with BCL21+ (37 cases, 4%), BCL20 (61 cases, 6%), or BCL2controversial (5 cases, 0.5%) were included in the final analysis. BCL21+ and BCL20 FLs tended to have limited stage disease, nodal disease, and grades 3A/3B histology and showed a higher complete response rate than BCL22+ FLs. Among 103 BCL20, BCL21+, or BCL2controversial FL cases, 34 (33%) had a diffuse area composed of CD20-positive small-to medium-sized lymphoid cells, a feature of low-grade B-cell lymphoma. Interfollicular dense CD20-positive cells and interfollicular clusters of CD10-positive cells were observed in 59% and 37% of cases, respectively. In remaining 13/40 cases (33%), BCL2 was converted to BCL22+ by other clones E17/SP66. CD23 and MUM1 were positive in 10/40 (25%) and 1/40 (3%) cases, respectively. IGH/BCL2 fusion and clonality were detected in 6/37 (16%) and 31/34 (91%) cases, respectively. In conclusion, morphological examination of the distribution of CD20-and/or CD10-positive cells and the presence of diffuse area could be used to diagnose FL in most cases. The majority of the remaining FL cases could be diagnosed using other BCL2 clones and clonality analyses.

Pathogenesis of Gastrointestinal Follicular Lymphomas: Consideration Based on Histopathology and Endoscopic Findings.

Gastrointestinal (GI) follicular lymphoma (FL) is the most frequently diagnosed extranodal FL; however, its pathogenesis is debatable. We investigated the distribution, endoscopic, and histopathologic findings of 366 GI FL samples obtained from 298 patients. FLs were most frequently observed in the small intestine (71%), including the duodenum (52%), but were also commonly found in the stomach (15%) and colon (12%). The proportion of granular lesions in the duodenum, terminal ileum, colon, and stomach was 74%, 39%, 24%, and 0%, respectively. Submucosal or ulcerated tumors were frequently observed in the stomach (48%) and colon (52%). Most GI FL showed grade 1 to 2 histology (89%) as well as CD10 + (93%) and BCL2 + (98%) positivity. There were no significant differences in the endoscopic or histologic findings between primary and secondary GI FLs. As known, the mucosa of the small intestine is thin and villous, while the mucosa of the stomach and colon is thicker and has a smooth surface. Granular lesions corresponding to very small FL were detected in the former but rarely in the latter. Nine (7%) patients with primary GI FL developed histologic transformation to diffuse large B-cell lymphoma (n=8) or high-grade B-cell lymphoma (n=1) 10 months to 14 years after the diagnosis of FL. Two patients died of lymphoma. In conclusion, the incidence and endoscopic findings differed, but the histopathology was similar in FLs in each site. These differences might be attributed to variations in each GI site's mucosal structure and the neoplastic follicles' size. Due to its characteristic structure, very small classic FLs might be detectable mainly in the small intestine.

CD3-and CD20-negative extramedullary non-Hodgkin leukemia/lymphoma: a histopathological study of 118 cases.

Histopathological diagnoses are challenging for rare CD3-and CD20-negative extramedullary leukemias/lymphomas. We report 118 cases of CD3- CD20-extramedullary leukemias/lymphomas (2.4% of 4977 cases). CD45 was positive in 68% of cases. Forty-nine (41%) cases were anaplastic large cell lymphomas. Thirty-five (30%) cases were large B-cell lymphomas/plasmablastic lymphomas positive for at least one of the following markers: CD79a, PAX5, CD19, CD138, and MUM1. Nine (8%) cases were peripheral T/NK-cell lymphomas, where at least CD43, CD45RO, or cytotoxic molecules were positive; 4, 3, and 2 cases were extranodal NK/T-cell lymphoma, nasal type, peripheral T-cell lymphoma-not otherwise specified, and adult T-cell leukemia/lymphoma, respectively. The remaining 25 (21%) cases included 11, 8, and 6 cases of myeloid sarcoma, blastic plasmacytoid dendritic cell neoplasm, and B- or NK-cell lymphoblastic leukemia/lymphoma, respectively. For large B-cell lymphoma/plasmablastic lymphoma diagnosis, MUM1 (92%) was the most sensitive marker, followed by CD79a (63%), PAX5 (52%), CD138 (42%), and CD19 (36%). EBER 1 and HHV8 were positive in 32% and 0% of the cases. For peripheral T/NK-cell lymphomas other than ALCL, CD45RO and CD43 were positive in nine cases; however, cytotoxic molecules (TIA1, 86%; granzyme B, 71%) were the most sensitive markers. In conclusion, most cases of the 118 (2.4%) CD3- CD20- extramedullary leukemia/lymphoma were represented by anaplastic large cell lymphomas (41%). The second most frequent group of neoplasia, large B-cell lymphoma/plasmablastic lymphoma (30%), characterized a special diagnostic challenge when B-cell markers were not expressed, requiring immunohistochemistry for multiple B-cell markers and molecular analysis in some cases.

Linear imaging theory for differential phase contrast and other phase imaging modes in scanning transmission electron microscopy.

We propose a linear imaging theory for differential phase contrast under the weak-phase-weak-amplitude object approximation. Contrast transfer functions are defined for thin and thick weak objects, and they successfully describe several imaging characteristics of differential phase contrast. We discuss the defocus dependence of the contrast for several examples: atomic resolution, a p-n junction, a heterointerface, and grain boundaries. Understanding the imaging characteristics helps in adjusting aberrations in DPC STEM.

The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis.

The potent and selective dipeptidyl peptidase-4 inhibitor vildagliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and ß-cell responsiveness to glucose. We conducted a prospective, open-label, parallel group, controlled study of 51 patients with type 2 diabetic patients undergoing hemodialysis (HD) during the 24-week study period. Patients were assigned to two groups: the vildagliptin group (n = 30) and the control group (n = 21). Vildagliptin was administered at 50 mg/day for the first 8 weeks. Then doses were titrated by dose-doubling to a maximum of 100 mg/day if hemoglobin A1c (HbA1c) or glycated albumin (GA) target levels had not been reached. No vildagliptin was administered to the controls. The average final dose of vildagliptin was 80 ± 5 mg daily. After 24 weeks, vildagliptin had decreased average HbA1c levels from 6.7 % baseline to 6.1 %, average GA levels from 24.5 % baseline to 20.5 % and average postprandial plasma glucose levels from 186 mg/dL baseline to 140 mg/dL (all p < 0.0001). In the control group, we observed no such changes. Vildagliptin efficacy did not differ according to age or body mass index, but the GA reduction was significantly greater in the anti-diabetic agents-naïve group. Furthermore, in patients with higher baseline GA levels, a higher vildagliptin dosage was required to produce a noticeable effect. No serious adverse effects such as hypoglycemia or liver impairment were observed in any patient. Vildagliptin was effective as a treatment for diabetic patients undergoing HD.

[Assessment of quality of life by questionnaires between S-1/CPT-11 and mFOLFOX6 in patients with advanced colorectal cancer].

UNLABELLED: Injectable combination chemotherapy with 5-fluorouracil (5-FU)/Leucovorin (LV), oxaliplatin (OHP), and irinotecan (CPT-11) has been a standard treatment for advanced colorectal cancer (CRC). An oral fluoropyrimidine, S-1 (tegafur, gimeracil, and oteracil), has been developed recently, and a combination of S-1/CPT-11 demonstrated effects comparable to FOLFIRI for the treatment of advanced CRC. Being without continuous infusion lasting for days, combination chemotherapy with oral fluoropyrimidine may limit inconvenience and improve the quality of life (QOL) of patients. There have been few studies evaluating chemotherapy with oral fluoropyrimidine in terms of patient QOL and convenience. PATIENTS AND METHODS: We assessed the patients' QOL by questionnaire, comparing experiences of those treated with S-1/CPT-11 to those treated with mFOLFOX6 in patients with advanced CRC. The questionnaire, selected from EORTC QLQ, FACT-G, and FACT/GOG-Ntx, consisted of six categories: moving activity, willingness, pain and numbness, gastrointestinal symptoms, daily life, and convenience. The questionnaire had 5 questions in each category and a total of 30 questions. RESULTS: Patients' background and characteristics were similar. No significant difference was observed in response rates and time to progression between the groups. As for adverse effects, there was a case of fatigue (grade 2), five cases of neurotoxicites (grade 1 and 2) in mFOL-FOX6, and a case of diarrhea (grade 3) in S-1/CPT-11. No difference between the two groups was observed in responses to the questionnaire asking about moving activity, willingness, gastrointestinal symptoms, and daily life. As for neurotoxicity and convenience, however, S-1/CPT-11 showed significantly better results than mFOLFOX6. CONCLUSION: The present results suggest that questionnaires are useful for assessing patients' QOL with advanced CRC treated chemotherapy. Combination chemotherapy with oral fluoropyrimidine S-1 could provide similar response rates, limit inconvenience, and improve QOL.

[Investigation of chemotherapy based on enzyme expression and drug sensitivity test in colorectal cancer].

UNLABELLED: In colorectal cancer (CRC), 5-fluorouracil (5-FU) has been a basic chemotherapeutic agent. Orotate phosphoribosyltransferase (OPRT) and thymidine phosphorylase (TP) are essential enzymes for activation of 5-FU. Dihydropyrimidine dehydrogenase (DPD) is an enzyme for degradation. The feasibility of individualized chemotherapy was studied using the enzyme expression and drug sensitivity test. METHODS: The study included 160 surgical patients (stage II to IV). OPRT, TP, and DPD expressions, assessed with immunohistochemistry, were evaluated in relation to clinicopathological features and patient survival. We assessed 5-FU sensitivity using the collagen gel droplet. Embedded culture-drug sensitivity test(CDDST). The area under the concentration curve (AUC) and growth inhibition curve (IR) were combined in the AUC-IR curve, according to which the individual AUC(IR50) was calculated. Durations to achieve AUC(IR50) were calculated using AUC(24hr) values in UFT and S-1. RESULTS: TP and DPD expression were positively associated with CRC progression and related with poor prognosis, although OPRT expression was negatively associated with CRC progression and related with better prognosis. Patient survival was best in patients with OPRT (+) DPD (-), and worst in those with OPRT (-) DPD (+). Individual AUC(IR50) ranged from less than 100 mg·hr/mL to more than 10,000 mg·hr/mL. In the chemotherapy with UFT, 55% of patients achieved AUC(IR50) within 6 months, 13% of patients achieved it 6 to 12 months, another 13% of patients in 12 to 24 months, and the other 19% after 24 months of chemotherapy. In the chemotherapy with S-1, 31% of patients achieved AUC(IR50) within 1 course, 15% in 1 to 2 courses, another 23% in 2 to 6 courses and the other 31% of patients achieved AUC(IR50) after 6 courses. CONCLUSIONS: The present results suggest that patients' prognosis may be improved with selection of an anti-cancer drug based on the 5-FU metabolizing enzyme expressions and prognostic factors. CD-DST may predict the duration of chemotherapy.

Arterial and Venous Thrombosis Complicated in COVID-19: A Retrospective Single Center Analysis in Japan.

Background: Thrombosis is a characteristic complication in coronavirus disease 2019 (COVID-19). Since coagulopathy has been observed over the entire clinical course, thrombosis might be a clue to understanding the specific pathology in COVID-19. Currently, there is limited epidemiological data of COVID-19-associated thrombosis in the Japanese population and none regarding variant strains of SARS-CoV-2. Here, we elucidate the risk factors and the pattern of thrombosis in COVID-19 patients. Methods: The patients consecutively admitted to Tokyo Medical and Dental University Hospital with COVID-19 were retrospectively analyzed. SARS-CoV-2 variants of concern/interest (VOC/VOI) carrying the spike protein mutants E484K, N501Y, or L452R were identified by PCR-based analysis. All thrombotic events were diagnosed by clinical symptoms, ultrasonography, and/or radiological tests. Results: Among the 516 patients, 32 patients experienced 42 thromboembolic events. Advanced age, severe respiratory conditions, and several abnormal laboratory markers were associated with the development of thrombosis. While thrombotic events occurred in 13% of the patients with a severe respiratory condition, those events still occurred in 2.5% of the patients who did not require oxygen therapy. Elevated D-dimer and ferritin levels on admission were independent risk factors of thrombosis (adjusted odds ratio 9.39 and 3.11, 95% confidence interval 2.08-42.3, and 1.06-9.17, respectively). Of the thrombotic events, 22 were venous, whereas 20 were arterial. While patients with thrombosis received anticoagulation and antiinflammatory therapies with a higher proportion, the mortality rate, organ dysfunctions, and bleeding complications in these patients were higher than those without thrombosis. The incidence of thrombosis in COVID-19 became less frequent over time, such as during the replacement of the earlier strains of SARS-CoV-2 by VOC/VOI and during increased use of anticoagulatory therapeutics. Conclusion: This study elucidated that elevated D-dimer and ferritin levels are useful biomarkers of thrombosis in COVID-19 patients. The comparable incidence of arterial thrombosis with venous thrombosis and the development of thrombosis in less severe patients required further considerations for the management of Japanese patients with COVID-19. Further studies would be required to identify high-risk populations and establish appropriate interventions for thrombotic complications in COVID-19.

Evaluation of sclerotherapy with a new sclerosing agent and stapled hemorrhoidopexy for prolapsing internal hemorrhoids: retrospective comparison with hemorrhoidectomy.

BACKGROUND: We retrospectively compared the results of sclerotherapy with a new sclerosing agent (aluminum potassium sulphate/tannic acid) and hemorrhoidopexy using an improved type of circular stapler with hemorrhoidectomy. METHODS: Between January 2006 and September 2008, we performed hemorrhoidectomy in 416 patients, sclerotherapy in 784 patients and hemorrhoidopexy in 118 patients with prolapsing internal hemorrhoids. RESULTS: The median volume of the agent injected into a hemorrhoid was 7 ml (interquartile range = 4). The operation duration was significantly shorter (p < 0.01) in sclerotherapy, 13 min (interquartile range = 7), than in hemorrhoidectomy, 43 min (interquartile range = 15), and hemorrhoidopexy, 31 min (interquartile range = 16). Postoperative pain, needing pain killer injection, occurred in 59 patients (14%) in hemorrhoidectomy, 14 patients (1.8%) in sclerotherapy and 1 patient (0.8%) in hemorrhoidopexy (p < 0.01). The disappearance rates of prolapse were 100% (416/416 patients) in hemorrhoidectomy, 96% (753/784 patients) in sclerotherapy and 98.3% (116/118 patients) in hemorrhoidopexy. CONCLUSIONS: Hemorrhoidectomy, widely applied for hemorrhoids, needs hospitalization, being accompanied by pain. Sclerotherapy could be performed on outpatient bases without any severe pain or complication. Hemorrhoidopexy is a useful alternative treatment with less pain. Less invasive treatments would be useful when performed paying attention to avoid complications.

Study to predict optimal duration of chemotherapy with fluoropyrimidine by multi-point collagen gel droplet embedded drug sensitivity test.

BACKGROUND/AIMS: In colorectal cancer (CRC), 5-fluorouracil (5-FU) has been a basic chemotherapeutic agent. Antitumor effects of 5-FU and its derivatives are likely due to inter-individual difference in the drug sensitivity. METHODOLOGY: We evaluated the 5-FU sensitivity of cancer cells from CRC patients using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) under multiple drug concentration and contact durations. The area under the concentration curve (AUC) and growth inhibition curve (IR) were combined in the AUC-IR curve. Using the AUC-IR curve, the individual AUC(IR50) was calculated. Furthermore, using the AUC values of 5-FU during 24 hours with chemotherapy with UFT and S-1, the durations to achieve the AUC(IR50) were calculated in chemotherapy with UFT or S-1 for individual patient. RESULTS: The value of individual AUC(IR50) ranged widely from less than 100 microg hr/ml to more than 1000 microg hr/ml. Approximately 13% of patients demonstrated a relatively low 5-FU sensitivity. Durations of chemotherapy to achieve the AUC(IR50) differed widely depending on the AUC(IR50) of individual patient. Relapse free survival was significantly better in the patients who have achieved individual AUC(IR50) than those who have not achieved the AUC(IR50). CONCLUSIONS: The present results suggest that the antitumor effects of 5-FU and its derivatives differ widely depending on inter-individual difference of sensitivity, and that individual AUC(IR50) may be useful to predict the optimal duration of chemotherapy.

[Successful management with S-1 of recurrent gastric cancer after adjuvant chemotherapy with paclitaxel/UFT].

We report here two cases of recurrent gastric cancer after post operative adjuvant chemotherapy, in which S-1 has been effective to control the recurrence and provided long-term survival. Case 1: A 75-year-old male presented with malaise. Endoscopy showed an advanced gastric cancer. He underwent total gastrectomy with lymph adenectomy and received adjuvant chemotherapy with 3 courses of weekly paclitaxel and 6 months of UFT. An abdominal tumor developed with elevation of tumor markers 1 year and 2 months after surgery. After 5 courses of S-1(100mg/day), the tumor resolved and a complete response(CR)was obtained with decline of the markers for 2 years. Case 2: A 62-year-old male presented with abdominal pain. Endoscopy showed an advanced gastric cancer. He underwent distal gastrectomy with lymph adenectomy. Peritonitis carcinomatosa developed with ascites though adjuvant chemotherapy with UFT had been continued for 6 months after paclitaxel. After 10 courses of S-1(100 mg/day), ascites disappeared with decline of the markers. He has been well without any sign of recurrence or elevation of tumor markers for 2 years. Differences in the 5-fluorouracil concentration of UFT and that of S-1 may explain the effectiveness of S-1 for recurrence of gastric cancer after adjuvant chemotherapy with UFT.