Immune Determinants in the Acquisition and Maintenance of Antibody to Hepatitis B Surface Antigen in Adults After First-Time Hepatitis B Vaccination.

Global implementation of a birth-dose hepatitis B (HB) vaccine has significantly reduced the prevalence of hepatitis B virus (HBV) carriers. Durable and sufficient titers of antibodies to hepatitis B surface antigen (anti-HBs) are desirable for vaccinees to gain resistance to HBV exposure. However, the existence of primary nonresponders and vaccinees who lost anti-HBs over time remains a challenge for the strategy of HBV elimination. We thus aim to clarify the mechanisms of acquisition and maintenance of vaccine-induced anti-HBs in healthy adults. We retrospectively analyzed the vaccination records of 3,755 first-time HB-vaccinated students and also traced the acquired antibody transition of 392 first-time vaccinees for 10 consecutive years. To understand the cellular and humoral immune response, we prospectively examined peripheral blood from 47 healthy first-time HB-vaccinated students, 62 booster-vaccinated health care workers, and 20 individuals who maintained their anti-HBs. In responders, a significant increase of follicular helper T (Tfh) cells, activated plasmablasts, and plasma cells was observed in first-time-vaccinated but not booster-vaccinated persons. We also discovered memory B cells and antibody-secreting cells were more abundant in individuals who maintained anti-HBs. According to vaccination records, higher anti-HBs antibody titer acquisition was related to the longer term maintenance of anti-HBs, the level of which was positively correlated with prevaccination levels of serum interferon-γ and related chemokines. The second series of vaccination as a booster provided significantly higher anti-HBs antibody titers compared to the initial series. Conclusion: Coordinated activation of Tfh and B-cell lineages after HB vaccination is involved in the acquisition and maintenance of anti-HBs. Our findings support the rationale of preconditioning the immune status of recipients to ensure durable vaccine responses.

Prognostic Index for Survival in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Third-Generation Agents.

We retrospectively evaluated clinical data from patients with advanced non-small-cell lung cancer (NSCLC) treated with third-generation chemotherapy agents prior to treatment, to determine a reliable method for predicting prognosis in such patients. We analyzed 100 patients who received third-generation agents (paclitaxel, docetaxel, gemcitabine, irinotecan, and vinorelbine) for the treatment of advanced NSCLC. Factors significantly related to prognosis were evaluated using the Cox regression model, and the prognostic index (PI) was determined by combining these factors. The mean follow-up duration was 12.6 months (0.2-67.0 months). Multivariate analysis identified pleural effusion, absolute neutrophil count (ANC), and C-reactive protein (CRP) level as significant factors that independently contribute to prognosis in patients with advanced NSCLC treated with third-generation agents (p < 0.05). The PI was calculated using these 3 factors, according to the following formula: PI = 0.581 × pleural effusion + 0.125 × ANC + 0.105 × CRP. The death rate in the group with the highest PI scores was significantly higher than in the group with the lowest scores (p < 0.001). Pleural effusion, ANC, and CRP level were the most important factors that contributed to prognosis following chemotherapy with third-generation agents in patients with advanced NSCLC. The PI is suggested to be an appropriate index to predict the prognosis of patients with NSCLC.

Chemotherapy-induced neutropenia as a prognostic factor in patients with unresectable pancreatic cancer.

PURPOSE: We conducted a retrospective cohort study to examine whether neutropenia could be an indicator of good prognosis in patients treated with gemcitabine (GEM) for unresectable pancreatic cancer. METHODS: A total of 178 patients with unresectable pancreatic cancer, who were treated with first-line (n = 121) or second-line (n = 57) GEM, were included in our analyses. A Cox proportional hazard model was used to examine the effect of the grade of GEM-induced neutropenia on prognosis. Furthermore, the difference in survival time for each grade was assessed using a log-rank test. RESULTS: In the first-line population, the hazard ratios of patients with grade 2 or grade 3 neutropenia compared with the ratios of those without neutropenia (grade 0) were 0.43 (95% CI 0.27-0.70) and 0.37 (0.21-0.65), respectively (p < 0.05). The median survival time (MST) was 3.8 months for grade 0, 9.4 months for grade 2, and 10.1 for grade 3. Landmark analysis of the second-line population revealed a hazard ratio of 0.52 (0.30-0.82) for grade 1 and 0.49 for grade 2 (0.28-0.72) (p < 0.05). MST was 1.3 months for grade 0, 4.7 months for grade 1, and 4.6 months for grade 2. CONCLUSIONS: We found that neutropenia grade was an indicator of good prognosis in patients treated with first-line and second-line GEM for unresectable pancreatic cancer. A prospective study should be performed to examine whether dosage adjustment using neutropenia grade as an indicator would improve prognosis.

Practical prognostic index for survival in patients with unresectable pancreatic cancer treated with gemcitabine or S-1.

BACKGROUND/AIMS: We performed this retrospective cohort study to identify prognostic factors for unresectable pancreatic cancer treated with current standard therapy using gemcitabine (GEM) or S-1 and to stratify patients prior to treatment using a prognostic index (PI). METHODOLOGY: We analyzed 182 patients with unresectable pancreatic cancer, who had received GEM or S-1 as first-line chemotherapy. Factors that contributed to the prognosis were identified by univariate and multivariate analysis using a Cox proportional hazards model. The PI was constructed using the factors identified in the multivariate analysis. RESULTS: By multivariate analysis, performance status (PS), stage, and absolute neutrophil count (ANC) were identified as factors that independently contributed to the prognosis of unresectable pancreatic cancer (P < 0.05). The hazard ratios were 1.69, 3.33, and 1.18, respectively. In addition, PI was calculated using these three factors. Patients were classified into three groups according to the PI values. A significant difference was observed among the survival curves of these three groups (P < 0.05). CONCLUSIONS: We identified three prognostic factors in the population after the introduction of S-1, and have created a simple and useful PI. This index demonstrates the ability to accurately classify advanced pancreatic cancer patients before the start of treatment.

[Analysis of the risk factors for severe neutropenia in advanced non-small cell lung cancer after the first course of chemotherapy with third-generation agents].

  We retrospectively evaluated clinical data before therapy to determine the risk factors for severe neutropenia in advanced non-small-cell lung cancer (NSCLC) patients treated with third-generation agents. We analyzed 100 patients who received such agents (paclitaxel, docetaxel, gemcitabine, irinotecan, or vinorelbine) for advanced NSCLC. The endpoint of the survey was the occurrence of severe neutropenia (grade 4). Risk factors significantly related to severe neutropenia were identified using logistic regression analysis. Of the 100 patients studied, the median age was 62.0 (32-81 years), and 77 (77.0%) were male. CEA 6.6 (0-2220) ng/dL and cytokeratin 19 fragment 21-1 (CYFRA) 4.8 (0.2-173.8) ng/dL before chemotherapy were higher than normal range. Severe neutropenia occurred in 36.0%, the incidence being highest in the first cycle (61.1%). In the univariate analysis, variables associated with severe neutropenia were sex, chest pain, absolute neutrophil count (ANC), Cr, CRP, and CYFRA. In the multivariate analysis, low CYFRA level was identified as a significant risk factor that contributed independently to chemotherapy-induced severe neutropenia (p<0.05). Our analysis suggests that low CYFRA level is the most important risk factor for severe neutropenia in advanced NSCLC patients after the first course of chemotherapy with third-generation agents.

Factors involved in resistance to early treatment of acute cholangitis patients.

BACKGROUND/AIMS: Severity-based treatment is not homogenously effective for acute cholangitis patients and some are resistant to early treatment. We performed a retrospective cohort study involving acute cholangitis patients and analyzed factors strongly associated with resistance to early treatment. METHODOLOGY: The subjects were 94 patients admitted to the Department of Gastroenterology, Showa University Hospital and diagnosed with acute cholangitis. The endpoint was set as the presence or absence of resistance to early treatment. Background and blood test results of the patients immediately after admission were surveyed and significant factors independently contributing to resistance to early treatment were extracted from the surveyed factors employing a logistic regression model. RESULTS: The mean age of the patients was 73.2 ± 11.6 years and 58 were male (61.7%). Jaundice, fever and abdominal pain were observed in 46 (48.9%), 66 (70.2%) and 85 patients (90.4%), respectively. Twenty-eight patients (29.8%) were resistant to early treatment. On multivariate analysis, 3 factors (fever, serum amylase level and systolic blood pressure (below 100 mm Hg)) were extracted as significant factors independently contributing to resistance to early treatment (p<0.05). CONCLUSIONS: If such resistance can be predicted before treatment, appropriate treatment may be selected to shorten the persistence of symptoms, improving the patient's QOL.

Factors predicting the appearance of neutropenia in patients with advanced pancreatic cancer undergoing gemcitabine therapy.

BACKGROUND/AIM: Factors predicting the appearance of neutropenia were evaluated in patients with advanced pancreatic cancer undergoing gemcitabine hydrochloride (GEM) therapy. METHODOLOGY: The subjects were 92 patients who were diagnosed with unresectable advanced pancreatic cancer and underwent GEM therapy. Mono- and multivariate analyses were performed concerning each evaluated factor. The toxicity index (TI) was also prepared by combining the extracted predictive factors. RESULTS: Severe neutropenia occurred in 26 patients (28.2%). As a result of multivariate analysis, the white blood cell count (WBC), CA19-9 and liver metastasis were extracted as factors independently and significantly contributing to the appearance of severe neutropenia (p<0.05). The TI was prepared by combining these 3 factors and their regression coefficients: TI = 4.777-0.605xWBC (x103/microL)-0.511xlog (CA19-9)-1.285xliver metastasis. CONCLUSIONS: The WBC, CA19-9 and liver metastasis before treatment were shown to be related to the appearance of severe neutropenia after GEM therapy.

Analysis of the risk factors for myelosuppression after chemoradiotherapy involving 5-fluorouracil and platinum for patients with esophageal cancer.

BACKGROUND/AIMS: Myelosuppression is a serious adverse effect of chemotherapy, but its risk factors remain largely unknown. The present study retrospectively evaluated clinical data obtained before therapy to clarify the risk factors for myelosuppression after chemoradiotherapy in patients with esophageal cancer. METHODOLOGY: One-hundred-and-eight patients who received 5-fluorouracil combined with platinum and 60Gy radiation for esophageal cancer were analyzed. The endpoint of this survey was the occurrence of grade 3 or higher myelosuppression (neutropenia, anemia or thrombocytopenia). Risk factors significantly related to myelosuppression were extracted using logistic regression analysis. RESULTS: Grade 3 or higher neutropenia, anemia or thrombocytopenia occurred in 32.4%, 13.0% and 10.2% of the patients, respectively. According to the multivariate analysis, the risk factors included hoarseness, platelet count and the type of platinum for neutropenia; performance status and hemoglobin for anemia; and performance status, platelet count and serum creatinine concentration for thrombocytopenia (p<0.05). CONCLUSIONS: It was found that performance status, bone marrow function and hoarseness are the most important factors for chemoradiotherapy-induced myelosuppression in esophageal cancer. The prediction of myelosuppression is expected to be useful for the determination of the appropriate therapeutic approach for each patient by a physician.

[Cost-effectiveness analysis of chemotherapy with GEM or S-1 for patients with non-resectable pancreatic cancer].

OBJECTIVE: To assess the cost-effectiveness of chemotherapy for patients with non-resectable pancreatic cancer, we compared two regimens containing either gemcitabine (GEM) or S-1. METHODS: We developed a decision tree that showed the clinical processes of non-resectable pancreatic cancer patients. We calculated the probabilities of endpoint and life months gained (LMG) based on previously reported articles. To estimate the costs, we analyzed medical records of 44 inpatients with non-resectable pancreatic cancer treated with GEM(n=34)or S-1(n=10). Sensitivity analysis was used to check the robustness of the results. RESULTS: In the GEM group and S-1 group, costs were 1,636,393 and 985,042 yen, and LMG was 6. 0 and 9. 0 months, respectively. Thus, the cost-effectiveness ratio(CER)was calculated to be 272,732 and 109,449 yen/LMG, respectively, and the incremental cost effectiveness ratio (ICER) was -217,117 yen/LMG. The sensitivity analysis showed that the result was definitely robust. CONCLUSION: Our findings suggest that the markedly cost-effective S-1 regimen could prolong LMG with less cost than the GEM regimen.

Clinical predictive factors for preterm birth in women with threatened preterm labour or preterm premature ruptured membranes?

BACKGROUND: Independent predictive factors of preterm delivery were evaluated using clinical data at hospitalisation by multivariate analysis. AIM: The aim of this study was to clarify independent predictive factors related to preterm delivery by multivariate analysis of clinical data at hospitalisation of patients with threatened preterm delivery or premature rupture of membranes (PROM), and to realise the early and highly reliable prediction of preterm delivery in pregnant women at risk. METHODS: The subjects were 200 patients, which diagnosed with threatened preterm delivery or PROM and admitted at gestational ages of 22-35 weeks. Univariate and multivariate analyses were performed; 20 factors were evaluated concerning clinical data, and we extracted prognostic factors using logistic regression analysis. RESULTS: The mean age of the patients was 30.5 years, and the mean gestational age at admission was 30.0 weeks. Preterm delivery was observed in 55 (27.5%), and term delivery in 145 (72.5%). On multivariate analysis, haemorrhage, prepregnancy body mass index, fetal fibronectin and cervical length were extracted as independent predictive factors related to preterm delivery. CONCLUSIONS: If the reliable and reproducible prediction of preterm delivery becomes possible using the four factors extracted in this study, further evaluation of these factors may lead to clarification of the mechanism of preterm delivery.

Association studies of the IL-23R gene in autoimmune thyroid disease in the Japanese population.

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are caused by interplays of genetic factors and environmental triggers. Interleukin-23 and its receptor (IL-23R) guide T cells towards the Th17 phenotype. IL-23R single nucleotide polymorphisms (SNPs) have been shown to be associated with several autoimmune diseases, including Crohn's disease and rheumatoid arthritis, and Graves' ophthalmopathy (GO) in Caucasians. To determine whether variants in the IL-23R gene are associated with AITDs in Japanese, 464 Japanese AITD patients (290 with GD, 174 with HT) and 179 matched Japanese control subjects were genotyped for four SNPs spanning the IL-23R gene. SNPs rs11209026 and rs7530511 were genotyped using TaqMan allelic discrimination assays and SNPs rs2201841 and rs10889677 were genotyped using a fluorescent-based restriction fragment length polymorphism method. Case-control association studies were performed using the chi(2) and Fisher's exact tests with Yates correction. Of the four SNPs rs11209026 was non-polymorphic in our dataset. The other three SNPs were not associated with GD or GO or HT in our Japanese population. These results suggest that the IL-23R gene is associated with AITDs only in a specific ethnic group.

Scoring system for predicting response to chemoradiotherapy, including 5-Fluorouracil and platinum, for patients with esophageal cancer.

We have retrospectively evaluated clinical data before therapy to enable reliable prediction of the response of esophageal cancer to chemoradiotherapy (CRT). We analyzed 108 patients who received 5-fluorouracil and platinum combined with 60 Gy radiation for esophageal cancer. Factors significantly related to response were extracted by use of logistic regression analysis, and a response score (RS) was prepared by combining these factors. By multivariate analysis, nutritional status, T stage, M stage, and alkaline phosphatase were selected as significant factors that contributed independently to the response of esophageal cancer to CRT (P < 0.05). The odds ratios of the four selected factors was approximated and scored. The group with a high RS was found to include patients with complete response with a significantly higher frequency than the group with a low score (72.7% vs. 14.8%, P < 0.001). The RS is suggested to be an appropriate scoring system with which to predict response for these patients.

[Cost effectiveness of chemoradiotherapy with cisplatin/fluorouracil and nedaplatin/fluorouracil for patients with esophageal cancer].

OBJECTIVE: To assess the cost-effectiveness of chemoradiotherapy (CRT) regimens for patients with esophageal cancer, we compared two regimens consisting of 5-fluorouracil (5-FU) and cisplatin (CDDP) or 5-FU and nedaplatin (CDGP) with radiotherapy. METHODS: Medical records of 108 patients with esophageal cancer who received CRT of 5-FU+CDDP (CDDP group) or 5-FU+CDGP (CDGP group) were analyzed. In both groups, most of the patients were men with a pathological diagnosis of squamous cell carcinoma. A Markov model was used to show the clinical courses of esophageal cancer after the CRT therapy. An outcome used for economic evaluation was life year gained (LYG). We calculated the cost per-effectiveness ratio (CER) and incremental cost effectiveness ratio (ICER). Clinical effectiveness and costs in this model were investigated retrospectively, and the costs were estimated from the perspective of the medical institution. Sensitivity analysis was used to check the robustness of this model. RESULTS: In CDDP and CDGP group, LYG was 18.23 and 16.31 years and CER was 270,373 and 406,264 yen/LYG, respectively. As a result, ICER was .883,999 yen/LYG. The sensitivity analysis showed that this model was definitely robust. CONCLUSION: Our results suggested that CDDP could prolong LYG with less cost than CDGP and that CRT of 5-FU and CDDP was markedly cost effective treatment.

Prognostic index for survival in patients after treatment for primary hepatocellular carcinoma.

We retrospectively evaluated clinical factors affecting long-term survival after treatment for hepatocellular carcinoma (HCC) to predict the reliability of the prognosis of patients with HCC. We analyzed 157 patients who received treatment for HCC. The prognostic index (PI) was evaluated using the Cox regression model. The overall cumulative survival rates were 79.7% at 1 year, 51.1% at 3 years, and 24.9% at 5 years. The PI was calculated by the following formula, consisting of five factors: PI = 0.637 x number of tumor lesions + 0.103 x tumor diameter + 1.003 x ascites + 0.915 x portal vein tumor thrombosis - 0.006 x cholinesterase + 2.0. It was found that liver function and progression of the tumor are the most important factors for prognosis after treatment for HCC. The PI, based on five factors, will in future be an appropriate index to predict the prognosis of patients with HCC.

Bleeding index after the first course of endoscopic treatment for esophageal varices in liver cirrhotic patients with and without hepatocellular carcinoma.

BACKGROUND/AIMS: We retrospectively evaluated variable clinical data on admission to reliably predict bleeding from esophageal varices after the first course of endoscopic treatment in liver cirrhosis patients with and without hepatocellular carcinoma. METHODOLOGY: We analyzed 27 clinical factors from the medical records of 118 patients who received their first course of endoscopic treatment for esophageal varices. Factors significantly related to bleeding were extracted using Cox's regression model, and the bleeding index was prepared by combining these factors. RESULTS: The cumulative nonbleeding rates after treatment for esophageal varices were 82.1% at 1 year, 64.6% at 3 years and 53.7% at 5 years. By the multivariate analysis, age, the presence of hepatocellular carcinoma, hemoglobin, lactate dehydrogenase and alpha-fetoprotein were selected as significant factors that contributed independently to the post-therapeutic bleeding from esophageal varices (P<0.05). The bleeding index was calculated using the following formula: bleeding index = - 0.045 x Age + 0.934 x hepatocellular carcinoma - 0.151 x hemoglobin + 0.108 x lactate dehydrogenase + 0.842 x alpha-fetoprotein. CONCLUSIONS: The bleeding index, based on 5 factors, will in future be an appropriate index to predict the post-therapeutic bleeding from esophageal varices.

Efficacy and safety of prednisolone in patients with autoimmune hepatitis.

A retrospective cohort study involving 29 Japanese patients with autoimmune hepatitis (AIH) was performed to clarify factors that predict the efficacy of prednisolone and the occurrence of various serious adverse effects. Independent predictors were identified by logistic analysis and with use of the Cox proportional hazard model. Responses to prednisolone were noted in 28 patients, who were classified into the complete remission group (52%) or the relapse group (48%). Multivariate analysis identified alanine aminotransferase, alkaline phosphatase, and immoglobulin G levels as independent predictors of relapse. The adverse effects most frequently observed were diabetes mellitus (37.9%), psychiatric/ neurologic symptoms (34.5%), and circulatory symptoms (34.5%). Predictive factors included lactate dehydrogenase, albumin, and fasting blood glucose levels for diabetes mellitus, alkaline phosphatase and C-reactive protein for psychiatric/ neurologic symptoms, and autoimmune hepatitis score and lactate dehydrogenase for circulatory symptoms. Selection of an optimal treatment method for individual patients may be possible after the risks of relapse and adverse effects have been estimated.

[A case of repeated seroconversion to HBe antibody due to co-infection with Mutant- and wild-type hepatitis B virus clones].

It is reported that co-infection with different hepatitis B virus (HBV) clones in a patient with chronic hepatitis B induces rare serotypes (adywr) or abnormal laboratory data such as negative HBs antigen, in the presence of positive HBV DNA. In this study, we experienced a case of repeated seroconversion to HBe antibody in a patient with chronic hepatitis B. Since seroconversion is considered to be related to genetic mutations, we investigated the HBV genes in this male patient in his 30's. We amplified and cloned parts of the HBV genes by the polymerase chain reaction (PCR), and sequenced the PCR products. As a result, mutated HBV genes were found in the serum of each specified period. By DNA sequencing we confirmed the coexistence of different HBV clones (wild-type clone and pre-S deletion mutant) and that both clones had the same genotype C. These clones took turns to be dominant; when the wild-type clone was dominant, HBe antigen was positive, and when the mutant clone was dominant, HBe antibody was positive. These findings demonstrated that repeated seroconversion of HBe antigen to HBe antibody was induced by co infection with mutant- and wild-type HBV clones. It is interesting that increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was noted at the time of the change from positive wild-type HBV clone to positive mutant clone.

Prognostic index of cirrhotic patients with hepatic encephalopathy with and without hepatocellular carcinoma.

This study was carried out in Japanese patients to clarify the state of liver cirrhosis complicated by hepatic encephalopathy with and without hepatocellular carcinoma and its prognosis. The subjects were 100 patients with liver cirrhosis complicated by hepatic encephalopathy. Clinical data were investigated, and prognostic factors were extracted using Cox's proportional hazard model. The cumulative survival rate after the first episode of hepatic encephalopathy was 59.1% after 1 year, 48.3% after 2 years, and 22.2% after 5 years. The prognostic index (PI) was calculated using the following formula consisting of these six factors. PI = 0.806 x Child-Pugh classification + 1.149 x presence or absence of HCC + 0.024 x BUN + 0.036 x LDH + 0.093 x WBC + 0.381 x PIVKA-II. The PI value was suggested to be useful for the prognosis of liver cirrhosis after the first episode of hepatic encephalopathy.

Analysis of background factors influencing long-term prognosis of patients with chronic hepatitis C treated with interferon.

OBJECTIVE: Interferon (IFN) therapy has been used as antiviral therapy for chronic hepatitis C (CH-C); however, complete response to the therapy is observed in only about 30% of patients in Japan. Background factors involved in the responsiveness to IFN therapy, and progression to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) after IFN therapy have not yet been sufficiently investigated. METHODS: One hundred twenty-one patients with CH-C who received IFN therapy at Showa University Hospital between 1984 and 1999 were analyzed. RESULTS: At 6 months after the termination of IFN therapy, 53 patients achieved a complete response, 11 patients incomplete response, and 57 patients no response. During a mean follow-up of 52.7 months, 12 patients progressed to LC, and 10 patients developed HCC. Multivariate analysis showed that significant independent factors involved in progression to LC were platelet count and the efficacy of IFN therapy. The significant independent factor involved in the development of HCC was platelet count. The factor involved in the therapeutic effect at 6 months after the termination of IFN administration was the serum hepatitis C virus (HCV) RNA levels before IFN therapy. CONCLUSION: Patients with high HCV RNA levels and low platelet counts should be considered to be at high risk of progressing to LC and developing of HCC and should be carefully followed after IFN therapy using ultrasonography, CT scan and MRI.