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.

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.

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.

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.

[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.

Impact of chromosomal abnormalities on the efficacy of lenalidomide plus dexamethasone treatment in patients with relapsed/refractory multiple myeloma.

Lenalidomide is an effective therapeutic agent for multiple myeloma (MM). However, its efficacy in the context of chromosomal abnormalities (CA) is poorly understood. We retrospectively analyzed 83 patients with relapsed/refractory (RR) MM, who received lenalidomide plus low-dose dexamethasone (Ld), in the context of CA. The median age and number of prior therapies were 69 and 2, respectively. Three, 11, 45, and 19 patients achieved complete response, very good partial response, partial response, and stable disease, respectively. Median progression-free survival (PFS) and overall survival (OS) were 11.1 and 38.8 months, respectively. Seventy-two patients were evaluated for frequently observed translocations; median PFS was 24.4 months in 20 patients with t(11;14), 13.0 months in 16 patients with t(4;14), and 3.7 months in seven patients with t(14;16). G-banded karyotype analysis detected 11 hypodiploid patients, who had shorter PFS and OS (2.5 and 6.2 months, respectively) compared to others (13.0 and 43.7 months, respectively). Hypodiploid patients showed poor clinical outcome, whereas patients with t(11;14) showed favorable outcome. In summary, the present study presents the clinical impact of chromosomal abnormalities on the outcome of Ld therapy, and contributes to understanding the appropriate choice of lenalidomide-based therapy to achieve effective treatment of RR MM.

Exophiala dermatitidis Fungemia Diagnosed Using Time-of-flight Mass Spectrometry during Chemotherapy for Malignant Lymphoma and Successful Treatment with Voriconazole.

Infectious diseases, including those caused by fungi, remain important issues in patients receiving malignant lymphoma chemotherapy. We herein report a rare case of Exophiala dermatitidis fungemia during chemotherapy in a 67-year-old woman admitted to our hospital. She had a fever that could not be resolved despite antifungal therapy. Yeast-like fungi were detected in blood culture samples, but biochemical identification was difficult. E. dermatitidis, a black mold, was identified using time-of-flight mass spectrometry. The patient finally improved after her treatment was switched to voriconazole. Fungal infection is difficult to diagnose and treat, but this novel approach can improve patients' outcomes.

Pre- and post-transplant ponatinib for a patient with acute megakaryoblastic blast phase chronic myeloid leukemia with T315I mutation who underwent allogeneic hematopoietic stem cell transplantation.

A 42-year-old female complaining of fever and night sweats was diagnosed with acute megakaryoblastic blast phase chronic myeloid leukemia (CML-BP). She had massive splenomegaly, left pleural effusion with leukemia infiltration, and moderate myelofibrosis. She received dasatinib monotherapy (140 mg/day) as for induction, after which her pleural effusion rapidly resolved and hematological remission was achieved. However, CML relapsed 4 months after starting dasatinib due to increased BCR-ABL fusion signals in the peripheral blood. The T315I mutation was also detected at the recurrence of CML. As a salvage treatment, ponatinib monotherapy (45 mg/day) was started immediately. After 5 months, BCR-ABL fusion signals decreased to 5%, and myelofibrosis improved from MF Grade 2 to 1; she then underwent allogeneic bone marrow transplantation from an unrelated donor. However, the graft failed, and cord blood transplantation (CBT) was performed. Ponatinib (15 mg/day) was continued after CBT as a maintenance treatment, with molecular complete response continuing for more than 1 year with no severe adverse events, including cardiovascular events. There is limited evidence regarding the optimal dose and schedule of ponatinib before and after allogeneic hematopoietic stem cell transplantation, especially in patients with CML-BP having T315I mutation; thus, well-designed clinical trials are warranted.

Outcomes of endoscopic endonasal dacryocystorhinostomy for intractable lacrimal dacryostenosis and associated factors.

AIM: To examine the effects of patient age, canalicular obstruction, mode of anesthesia, and duration of nasolacrimal intubation on the outcomes of endoscopic endonasal dacryocystorhinostomy (DCR). METHODS: Totally 56 eyes of 46 patients with prolonged epiphora underwent minimally invasive endoscopic endonasal DCR. A successful surgical outcome was defined as a significant improvement in symptoms, adequate water passage from the puncta to the nasal cavity, and patency of the DCR ostium. All outcomes were assessed at least 6mo after extubation. Fisher's exact test was used to discuss the factors, and then the logistic regression analysis was made by SAS 9.4 software. RESULTS: The overall success rate was 75.0%, and complete resolution was observed in 27 eyes. The success rate was higher for patients with ≥6mo intubation than for those with <6mo intubation. However, there were no significant differences in outcomes between groups stratified by age (<65 or ≥65y), presence or absence of canalicular obstruction, mode of anesthesia (local or general), and use or nonuse of a radiowave unit. One patient developed subcutaneous emphysema around the eye and nose and one developed subcutaneous hemorrhage after surgery. CONCLUSION: Endoscopic endonasal DCR can be considered safe and minimally invasive with reasonable success rates, particularly when the duration of nasolacrimal intubation is ≥6mo.

Clinical Role of Modified Seton Procedure and Coring Out for Treatment of Complex Anal Fistulas Associated With Hidradenitis Suppurativa.

A variety of techniques have been described to treat complex anal fistulas. When complex anal fistulas are associated with hidradenitis suppurativa, the treatment has to be appropriately tailored for the severity and distribution of the disease so as to remove the external fistula tract to prevent recurrence while ensuring fecal continence. Between 2007 and 2011, a total of 10 males (ranging in age from 32 to 54 years) complained of recurrent purulent discharge in the buttocks and thigh regions. The discharge had started about 12 to 18 months prior, and had increased progressively resulting in complex anal fistulas and hidradenitis suppurativa in the buttocks. They underwent surgical operation according to a modified seton procedure for complex anal fistulas and coring out for hidradenitis suppurativa. They were discharged from the hospital in 4 to 5 days, while the seton dropped spontaneously about 6 to 8 months after surgery. They have been well without any morbidities or recurrence. The present paper demonstrates that cases of complex anal fistulas associated with hidradenitis suppurativa can be successfully treated with a modified seton procedure and coring out of hidradenitis suppurativa.

Impact of less invasive treatments including sclerotherapy with a new agent and hemorrhoidopexy for prolapsing internal hemorrhoids.

Conventional hemorrhoidectomy is applied for the treatment of prolapsing internal hemorrhoids. Recently, less-invasive treatments such as sclerotherapy using aluminum potassium sulphate/tannic acid (ALTA) and a procedure for prolapse and hemorrhoids (PPH) have been introduced. We compared the results of sclerotherapy with ALTA and an improved type of PPH03 with those of hemorrhoidectomy. Between January 2006 and March 2009, we performed hemorrhoidectomy in 464 patients, ALTA in 940 patients, and PPH in 148 patients with second- and third-degree internal hemorrhoids according to the Goligher's classification. The volume of ALTA injected into a hemorrhoid was 7.3 ± 2.2 (mean ± SD) mL. The duration of the operation was significantly shorter in ALTA (13 ± 2 minutes) than in hemorrhoidectomy (43 ± 5 minutes) or PPH (32 ± 12 minutes). Postoperative pain, requiring intravenous pain medications, occurred in 65 cases (14%) in hemorrhoidectomy, in 16 cases (1.7%) in ALTA, and in 1 case (0.7%) in PPH. The disappearance rates of prolapse were 100% in hemorrhoidectomy, 96% in ALTA, and 98.6% in PPH. ALTA can be performed on an outpatient basis without any severe pain or complication, and PPH is a useful alternative treatment with less pain. Less-invasive treatments are beneficial when performed with care to avoid complications.

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.

Feasibility of 5-days-on/2-days-off UFT/leucovorin in post-operative long-term adjuvant chemotherapy for colorectal cancer.

Previous clinical studies have shown that the oral uracil/tegafur (UFT)/leucovorin (LV) regimen, in which the drugs are taken for 28 consecutive days every 35 days, is equivalent to an infusional 5-fluorouracil (5-FU)/LV regimen for the treatment of colorectal cancer. A 5-days-on/2-days-off schedule for UFT/LV has been proposed as the same schedule for UFT has been reported to be safe and have good compliance. However, few studies have been performed with regards to the feasibility of the UFT/LV regimen. The results of the 5-days-on/2-days-off schedule were compared with those of the consecutive schedule in adjuvant chemotherapy. Twenty-eight patients were treated with the 5-days-on/ 2-days-off schedule of UFT (300 mg/m(2)/day)/LV (75 mg/body/day), and another 12 patients were treated with the consecutive schedule. In the 5-days-on/2-days-off schedule, 24 of 28 patients (86%) received all the scheduled doses. In the consecutive schedule, 10 of 12 patients (83%) received all the scheduled doses. The mean relative dose intensities for the 5-days-on/2-days-off and consecutive schedules were 0.92 and 0.87, respectively. The toxicities were milder in the 5-days-on/2-days-off schedule compared with the consecutive schedule. The disease-free survival in patients with the 5-days-on/2-days-off schedule tended (P=0.13) to be longer compared with the consecutive schedule. The results of the present study indicate that the 5-days-on/2-days-off schedule of UFT/LV may be feasible and cause no severe toxicities in long-term adjuvant chemotherapy.

[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.

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.

[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.

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.

Hepatic metastasis from bile duct cancer of the ampulla is effectively controlled by multidisciplinary treatment including S-1, gemcitabine and bevacizumab: A case report.

The liver is the most common site for recurrent metastases from bile duct cancer (BDC) in the ampullary area. However, the optimal chemotherapy regimen for recurrent hepatic metastases has not yet been established. An oral combined fluoropyrimidine drug, S-1 (tegafur, gimeracil and oteracil), has recently been introduced alone or in combination with gemcitabine for BDC. A 67-year-old man underwent a pancreaticoduodenectomy (PD) for early stage distal BDC in the ampullary area. A small hepatic metastasis developed 8 months after the PD. Combined chemotherapy of S-1 (80 mg/m(2)) and gemcitabine (1000 mg/m(2)) was started after radiofrequency ablation (RFA) of the hepatic tumor. Although complete response was achieved and maintained for 4 months with chemotherapy, there was regrowth of the tumor. We performed hepatic segmentectomy for radical treatment. Fourteen months after the hepatectomy, metastasis developed again in the remnant liver. Bevacizumab was added to the combination chemotherapy with S-1 and gemcitabine, since the cancer seemed resistant to the chemotherapy alone. The patient has been well managed for 3 years by a multidisciplinary treatment with surgery, RFA and the combination chemo-therapy on an outpatient basis. This case indicates that distal BDC even in an early stage has a more malignant potential than anticipated. The multidisciplinary treatment including surgery, RFA and combination chemotherapy of S-1, gemcitabine and bevacizumab was effective for BDC with hepatic metastasis. This chemotherapy is feasible on an outpatient basis and may be one of the treatment options for metastatic BDC.

[A case of disease-free survival with low-dose chemotherapy after resection of hepatic and pulmonary metastases from rectal cancer].

We report a case of disease-free survival with low-dose of uracil-tegafur (UFT) after reaction of hepatic and pulmonary metastases from rectal cancer. A 58-year-old male had a medical history of low anterior resection of the rectal cancer. Hepatic and pulmonary metastases developed 3 years and 3 months after the primary operation. Image studies including computed tomography, ultrasonography, and angiography showed multiple metastases in the liver and lung. Two surgeries were performed to resect all of them, followed by adjuvant chemotherapy with low-dose UFT due to relatively low platelet counts. After surgery, the patient has been well without any sign of recurrence or elevation of tumor markers for 2 years and 10 months. This case indicated the usefulness of surgical resection of hepatic and pulmonary metastases, followed by low-dose adjuvant chemotherapy.