An Incarcerated Colon Inguinal Hernia That Perforated into the Scrotum and Exhibited an Air-Fluid Level.

There are few reports of a transverse colon inguinal hernia; furthermore, an inguinal hernia perforating the scrotum is rare. Here we report the case of a 79-year-old man who died after developing an incarcerated colon inguinal hernia that perforated the scrotum and exhibited an air-fluid level. The patient was referred to our hospital in November 2011 with a complaint of inability to move. Physical examination revealed an abnormally enlarged left scrotum and cold extremities. He reported a history of gastric cancer that was surgically treated more than 30 years ago. His white blood cell count and C-reactive protein level were elevated. Abdominal and inguinal computed tomography revealed that his transverse colon was incarcerated in the left inguinal canal. Free air and air-fluid level were observed around the transverse colon, suggestive of a perforation. The patient and his family refused any surgical intervention; therefore, he was treated with sultamicillin tosilate hydrate and cefotiam hydrochloride. However, he succumbed to panperitonitis 19 days after admission. The findings from this case indicate that the transverse colon can perforate into an inguinal hernia sac.

Cronkhite-Canada syndrome showing elevated levels of antinuclear and anticentromere antibody.

A 56-year-old female initially visited an otorhinolaryngologist because of an impaired sense of taste in September, 2010 and was referred to our facility in October, 2010. She was diagnosed with Basedow's disease for which she underwent subtotal thyroidectomy in 1984 and arthritis involving multiple joints, primarily affecting her hands. In addition, the anticentromere antibody (ACA) level was markedly high. On physical examination, alopecia as well as hyperpigmentation of the dorsum of the hands and back was observed. Dystrophic changes of the fingernails and a bilateral thumb abduction deformity were observed. Antinuclear antibodies were elevated. Gastrointestinal endoscopy and colonoscopy revealed the mucosa carpeted with strawberry-like polypoid lesions. Histopathological examination of the biopsied specimen of the stomach revealed a corkscrew-like appearance. Thus, the patient was diagnosed with Cronkhite-Canada syndrome (CCS). She admitted to our hospital in November, 2010. Oral prednisolone was administered with success. In July, 2012, her antimitochondrial M2 antibody level was elevated. To the best of our knowledge, the present case is the first patient with CCS, a history of Basedow's disease, and elevated levels of ACA and antimitochondrial M2 antibody. We consider the present case suggests CCS could be caused by immunological abnormality.

Impact of alpha-fetoprotein on hepatocellular carcinoma development during entecavir treatment of chronic hepatitis B virus infection.

BACKGROUND: Entecavir (ETV) is one of the first-line nucleoside analogs for treating patients with chronic hepatitis B virus (HBV) infection. However, the hepatocellular carcinoma (HCC) risk for ETV-treated patients remains unclear. METHODS: A total of 496 Japanese patients with chronic HBV infection undergoing ETV treatment were enrolled in this study. The baseline characteristics were as follows: age 52.6 ± 12.0 years, males 58%, positive for hepatitis B e antigen 45 %, cirrhosis 19%, and median HBV DNA level 6.9 log copies (LC) per milliliter. The mean treatment duration was 49.9 ± 17.5 months. RESULTS: The proportions of HBV DNA negativity (below 2.6 LC/mL) were 68% at 24 weeks and 86% at 1 year, and the rates of alanine aminotransferase (ALT) level normalization were 62 and 72%, respectively. The mean serum alpha-fetoprotein (AFP) levels decreased significantly at 24 weeks after ETV treatment initiation (from 29.0 ± 137.1 to 5.7 ± 27.9 ng/mL, p < 0.001). The cumulative incidence of HCC at 3, 5, and 7 years was 6.0, 9.6, and 17.2%, respectively, among all enrolled patients. In a multivariate analysis, advanced age [55 years or older, hazard ratio (HR) 2.84; p = 0.018], cirrhosis (HR 5.59, p < 0.001), and a higher AFP level (10 ng/mL or greater) at 24 weeks (HR 2.38, p = 0.034) were independent risk factors for HCC incidence. HCC incidence was not affected by HBV DNA negativity or by ALT level normalization at 24 weeks. CONCLUSIONS: The AFP level at 24 weeks after ETV treatment initiation can be the on-treatment predictive factor for HCC incidence among patients with chronic HBV infection.

The prospective randomized study on telaprevir at 1500 or 2250 mg with pegylated interferon plus ribavirin in Japanese patients with HCV genotype 1.

BACKGROUND: Triple therapy with telaprevir (TVR), pegylated interferon and ribavirin has improved antiviral efficacy in patients with chronic hepatitis C (CH-C). However, the severe adverse effects caused by TVR are important to resolve. In this prospective, randomized, multicenter, open-label study, the antiviral efficacy and safety in the reduced administration of TVR were examined. METHODS: A total of 81 CH-C Japanese patients with HCV genotype 1 were randomized into two regimens of TVR 2250 mg (TVR-2250) or 1500 mg (TVR-1500) and treated with triple therapy for 24 weeks. RESULTS: The mean HCV RNA at start, 2 and 4 weeks of treatment were 6.69 ± 0.70, 1.05 ± 0.74, 0.22 ± 0.48 log10 IU/ml in the TVR-2250 group and 6.70 ± 0.62, 1.02 ± 0.62, 0.13 ± 0.41 log10 IU/ml in the TVR-1500 group. The SVR rates were 85% in both groups (35/41 and 34/40, respectively). There were no patients with viral breakthrough in either group. As for adverse effects, rash more than moderate and severe anemia with <8.5 g/dl of hemoglobin were higher in the TVR-2250 group than in the TVR-1500 group (p = 0.046, p < 0.001, respectively). The increase in serum creatinine levels and decrease in estimated glomerular filtration rates were higher in the TVR-2250 group than in the TVR-1500 group. CONCLUSIONS: The lower dose of TVR (1500 mg/day) can result in similar SVR rates and lower treatment-related adverse effects compared to the higher dose of TVR (2250 mg/day) in triple therapy (UMIN: 000007313, 000007330).

Severe case of peripheral leukocytosis initially diagnosed as myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable, but possibly prefibrotic primary myelofibrosis.

Leukocytosis is occasionally seen in patients with presumptive but undiagnosed myeloproliferative disorders (MPD). A 74-year-old woman was admitted to our hospital for tarry stools, anemia, and marked peripheral leukocytosis of 1.4×10(5)/µL. Gastroenteroscopy revealed an acute gastric and duodenal mucosal lesion that was treated successfully via endoscopic hemoclipping. Bone marrow aspiration revealed marked megakaryocyte proliferation with atypia of naked nuclei and marrow hypercellularity (90% cellularity). A fluorescence in situ hybridization test could not detect the BCR-ABL fusion gene. Bone marrow aspiration later revealed further abnormalities of megakaryocytes. The patient died from cerebral bleeding. The present case fulfilled 2 of the 3 major criteria of primary myelofibrosis according to the World Health Organization 2008 classification:namely, megakaryocytic hyperplasia with hypercellular marrow and granulocytic hyperplasia. However, the megakaryocytic abnormality was not strictly compatible with the criteria. Instead, we considered prefibrotic primary myelofibrosis as a possibility, although myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) was technically the correct diagnosis. The present case shows that MPN diagnosis remains difficult and suggests that other cases of peripheral leukocytosis with diagnosed MDS/MPN-U might include similar findings.

Using early viral kinetics to predict antiviral outcome in response-guided pegylated interferon plus ribavirin therapy among patients with hepatitis C virus genotype 1.

BACKGROUND: HCV kinetics during treatment demonstrated strong association with the antiviral outcome of patients treated with pegylated interferon (Peg-IFN) plus ribavirin. However, the relationship between HCV kinetics and pre-treatment factors remains unclear. METHODS: Of 547 patients with HCV genotype 1 treated with Peg-IFN alfa-2b plus ribavirin, 401 completed the response-guided therapy and were assessed for per protocol analysis. RESULTS: The sustained virologic response (SVR) rate was 53 % for all patients, 60 % for those with genotype TT, and 19 % for those with genotype TG/GG according to IL28B (rs8099917) single nucleotide polymorphisms. The SVR rates increased with HCV decrease at week 4; 4 % (2/56) with <1 log10 decrease, 13 % (7/56) with 1-2 log10 decrease, 51 % (44/87) with 2-3 log10 decrease, 64 % (56/87) with 3-4 log10 decrease, 88 % (72/82) with more than 4 log10 decrease but with detectable HCV RNA and 100 % (33/33) with undetectable HCV RNA (p < 0.001). Similarly, SVR rates increased step-by-step in proportion to HCV decrease in both IL28B TT and TG/GG groups, showing almost the same SVR rates for the same conditions. In multivariate analysis, age (p = 0.005) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with SVR. Advanced liver fibrosis (p = 0.004) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with non-response. CONCLUSIONS: The magnitude of the HCV decrease at week 4 seems to be the most reliable marker for predicting antiviral outcome after starting Peg-IFN plus ribavirin therapy.

Post-treatment levels of α-fetoprotein predict incidence of hepatocellular carcinoma after interferon therapy.

BACKGROUND & AIMS: In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pretreatment factors are known to affect HCC incidence, less is known about post-treatment factors-many change during the course of interferon therapy. METHODS: We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsy specimens were collected before treatment; all patients received Peg-IFN plus ribavirin for 48 to 72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings. RESULTS: HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in nonresponders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 level and older age; among those without SVRs, risk factors included higher AFP24 level, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (≥10 ng/mL, 10-5 ng/mL, and then <5 ng/mL) was a better predictor of HCC incidence than pretreatment level of AFP among patients with and without SVRs. CONCLUSIONS: In patients with chronic HCV infection, levels of α-fetoprotein decrease during interferon therapy. High post-treatment levels of α-fetoprotein predict HCC, regardless of whether patients achieve an SVR. University Hospital Medical Information Network Clinical Trials Registry: C000000196, C000000197.

A case of systemic lupus erythematosus presenting with an acute abdomen: successful treatment with steroid.

Abdominal pain continues to pose diagnostic challenges for emergency clinicians. A 56-year-old Japanese woman was referred to our hospital due to severe abdominal pain which presented as occasional epigastric pain five months before and intermittent abdominal pain. She had a past history of ileus twice, for both of which laparotomy was performed without an alimentary tract resection. The wall thickening with marked three-wall structure from terminal ileum to sigmoid colon was seen and bladder wall was irregularly thick and enhanced irregularly. Among the differential diagnosis of the acute abdomen, autoimmune diseases were suspected, especially lupus erythematosus and Henoch-Schönlein purpura. On the second day of admission, abdominal pain worsened. The results of examinations of antinuclear antibody, anti-double-stranded DNA antibody, ANCA, and the complements were not obtained at that time; however, we started 1-g steroid pulse treatment for three days with success. With the results obtained later, the patient was given a diagnosis of probable systemic lupus erythematosus (SLE). The present case shows that SLE can present with acute abdomen and should be included in the wide range of the differential diagnosis of acute abdomen.

Two cases of acute erythroid leukemia presenting with marked macrocytic anemia, reticulocytosis and hemolysis.

Case 1. The laboratory findings of a hematological analysis of a 53-year-old woman with palpitations and dyspnea revealed the following: red blood cell (RBC) count: 9.4×10(5)/µL with 60.0‰ reticulocytes; Hb: 3.7 g/dL; mean corpuscular volume (MCV): 124.5 fL; white blood cell (WBC) count: 2,800/µL with 10.0% myeloblasts. Case 2. Similarly, a 42-year-old man with dizziness had a RBC count of 1.63×10(6)/µL with 24.0% reticulocytes, an Hb level of 6.0 g/dL, an MCV of 120.2 fL and a WBC count of 3,100/µL with 4.0% myeloblasts. Bone marrow aspirates in both patients confirmed a diagnosis of acute erythroid leukemia (AEL), which can present as marked macrocytic anemia with an MCV in excess of 120 fL and hemolysis.

Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection.

BACKGROUND: Altered functions of dendritic cells (DCs) and/or increases of regulatory T cells (Tregs) are involved in the pathogenesis of chronic hepatitis C virus (HCV) infection. A tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO), is reported to be an inducer of immune tolerance. Our aim was to clarify whether or not IDO is activated in chronic hepatitis C patients and its role in immune responses. METHODS: This study enrolled 176 patients with chronic HCV infection and 37 healthy volunteers. Serum kynurenine concentration was evaluated by high-performance liquid chromatography, and its correlation with clinical parameters was examined. Monocyte-derived DCs were prepared from the subjects and subsequently stimulated with a combination of lipopolysaccharide and interferon-gamma to induce functional IDO (defined as IDO-DCs). The phenotypes, kynurenine or cytokine production, and T-cell responses with IDO-DCs were compared between the patients and healthy volunteers. RESULTS: The serum kynurenine level in the patients was significantly higher than that in the healthy volunteers, and the level of serum kynurenine was positively correlated with the histological activity or fibrosis score. IDO activity in IDO-DCs from the patients was significantly higher than that in IDO-DCs from the volunteers. Furthermore, IDO-DCs from the patients induced more Tregs in vitro compared with those from the volunteers, and the frequency of induced Tregs by IDO-DCs was decreased with an IDO-specific inhibitor. CONCLUSIONS: Systemic IDO activity is enhanced in chronic hepatitis C patients in correlation with the degree of liver inflammation and fibrosis. In response to inflammatory stimuli, DCs from the patients tend to induce Tregs, with some of this action being dependent on IDO.

Incidence of hepatocellular carcinoma in HCV-infected patients with normal alanine aminotransferase levels categorized by Japanese treatment guidelines.

BACKGROUND: This study was conducted to evaluate Japanese treatment guidelines for patients with chronic hepatitis C virus (HCV) infection and normal alanine aminotransferase (N-ALT) levels from the viewpoint of the incidence of hepatocellular carcinoma (HCC). METHODS: Four groups of patients with chronic HCV infection treated with pegylated interferon (Peg-IFN) plus ribavirin, and classified according to the N-ALT guidelines, were examined for HCC incidence: group A (n = 353), ALT ≤30 IU/L and platelet (PLT) ≥15 × 10(4)/mm(3); group B (n = 123), ALT ≤30 IU/L and PLT <15 × 10(4)/mm(3); group C (n = 233), 30 < ALT ≤ 40 IU/L and PLT ≥15 × 10(4)/mm(3); and group D (n = 100), 30 < ALT ≤ 40 IU/L and PLT <15 × 10(4)/mm(3). The mean observation period was 36.2 ± 16.5 months RESULTS: In groups A and C, the HCC incidence was low even in patients with non-response (NR) (cumulative rates at 3 years, 0.0 and 2.9 %, respectively). In groups B and D, 14.5 and 5.3 % of NR patients had developed HCC at 3 years, but none of the patients with sustained virologic response (SVR) or relapse had developed HCC. In group B, no patients with mild fibrosis developed HCC irrespective of the antiviral effect of the treatment. Among patients with PLT <15 × 10(4)/mm(3) (group B plus group D), the HCC incidence was significantly lower in patients with SVR and relapse than in NR patients (p < 0.001, p = 0.021, respectively). CONCLUSION: These results suggest that N-ALT patients with PLT <15 × 10(4)/mm(3) could be candidates for early antiviral therapy.

TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis.

UNLABELLED: Angiogenesis is a critical step in the development and progression of hepatocellular carcinoma (HCC). Myeloid lineage cells, such as macrophages and monocytes, have been reported to regulate angiogenesis in mouse tumor models. TIE2, a receptor of angiopoietins, conveys pro-angiogenic signals and identifies a monocyte/macrophage subset with pro-angiogenic activity. Here, we analyzed the occurrence and kinetics of TIE2-expressing monocytes/macrophages (TEMs) in HCC patients. This study enrolled 168 HCV-infected patients including 89 with HCC. We examined the frequency of TEMs, as defined as CD14+CD16+TIE2+ cells, in the peripheral blood and liver. The localization of TEMs in the liver was determined by immunofluorescence staining. Micro-vessel density in the liver was measured by counting CD34+ vascular structures. We found that the frequency of circulating TEMs was significantly higher in HCC than non-HCC patients, while being higher in the liver than in the blood. In patients who underwent local radio-ablation or resection of HCC, the frequency of TEMs dynamically changed in the blood in parallel with HCC recurrence. Most TEMs were identified in the perivascular areas of tumor tissue. A significant positive correlation was observed between micro-vessel density in HCC and frequency of TEMs in the blood or tumors, suggesting that TEMs are involved in HCC angiogenesis. Receiver operating characteristic analyses revealed the superiority of TEM frequency to AFP, PIVKA-II and ANG-2 serum levels as diagnostic marker for HCC. CONCLUSION: TEMs increase in patients with HCC and their frequency changes with the therapeutic response or recurrence. We thus suggest that TEM frequency can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver.

Comparative analyses of regulatory T cell subsets in patients with hepatocellular carcinoma: a crucial role of CD25(-) FOXP3(-) T cells.

Regulatory T cells (Tregs) play pivotal role in cancer-induced immunoediting. Increment of CD25(high+) FOXP3+ natural Tregs has been reported in patients with hepatocellular carcinoma (HCC); however, the involvement of other type of Tregs remain elusive. We aimed to clarify whether FOXP3- Tregs are increased and functionally suppressive or not in patients with HCC. We enrolled 184 hepatitis C-infected patients with chronic liver diseases or HCC, 57 healthy subjects and 27 HCC patients with other etiology. Distinct Treg subsets were phenotypically identified by the expression of CD4, CD25, CD127 and forkhead/winged helix transcription factor (FOXP3). Their gene profiles, frequency and suppressor functions against T cell proliferation were compared among the subjects. To examine the molecules involving in Treg differentiation, we cultured naive CD4+ T cells in the presence of HCC cells and dendritic cells. We determined two types of CD4+ CD127- T cells with comparable regulatory ability; one is CD25(high+) cells expressing FOXP3 (CD25(high+) FOXP3+ Tregs) and the other is CD25- cells without FOXP3- expression (CD25- FOXP3- cells). The peripheral or intrahepatic frequency of CD25- FOXP3- Tregs in HCC patients is higher than those in other groups, of which significance is more than CD25(high+) FOXP3+ cells. Of importance, CD25- FOXP3- Tregs, but not CD25(high+) FOXP3+ cells, dynamically change in patients accompanied by the ablation or the recurrence of HCC. CD25- FOXP3- T cells with CD127- IL-10+ phenoype are inducible in vitro from naive CD4(+) T cells, in which programmed cell death 1 ligand 1, immunoglobulin-like transcript 4 and human leukocyte antigen G are involved.. In conclusion, CD25- FOXP3- Tregs with suppressive capacity are increased in patients with HCC, suggesting their distinct roles from CD25+ FOXP3+ Tregs.

Long-term effect of lamivudine treatment on the incidence of hepatocellular carcinoma in patients with hepatitis B virus infection.

BACKGROUND: Nucleotide analogues have recently been approved for the treatment of patients with hepatitis B virus (HBV) infection. However, it is still controversial whether the decrease of HBV-DNA amount induced by treatment with nucleotide analogues can reduce the risk of hepatocellular carcinoma (HCC) development in HBV patients. METHODS: A total of 293 HBV patients without HCC who were treated with lamivudine (LAM) were enrolled in a multicenter trial. The incidence of HCC was examined after the start of LAM therapy, and the risk factors for liver carcinogenesis were analyzed. The mean follow-up period was 67.6 ± 27.4 months. RESULTS: On multivariate analysis for HCC development in all patients, age ≥50 years, platelet count <14.0 × 10(4)/mm(3), cirrhosis, and median HBV-DNA levels of ≥4.0 log copies/ml during LAM treatment were significant risk factors. The cumulative carcinogenesis rate at 5 years was 3% in patients with chronic hepatitis and 30% in those with cirrhosis. For the chronic hepatitis patients, the log-rank test showed the significant risk factors related to HCC development to be age ≥50 years, platelet count <14.0 × 10(4)/mm(3), and hepatitis B e antigen negativity, but median HBV-DNA levels of <4.0 log copies/ml (maintained viral response, MVR) did not significantly suppress the development of HCC. In cirrhosis patients, however, the attainment of MVR during LAM treatment was revealed to reduce the risk of HCC development. CONCLUSIONS: These results suggest that the incidence of HCC in HBV patients with cirrhosis can be reduced in those with an MVR induced by consecutive LAM treatment.

Dynamics of regulatory T cells and plasmacytoid dendritic cells as immune markers for virological response in pegylated interferon-α and ribavirin therapy for chronic hepatitis C patients.

BACKGROUND: For the treatment of chronic hepatitis C, a combination of pegylated interferon-α (PEG-IFNα) and ribavirin has been widely used as a standard of care. Enhancement of immune response against hepatitis C virus (HCV) is known to be involved in the efficacy of the combination therapy. Our aim was to elucidate whether or not the frequency or function of blood cells is related to the outcome of the therapy. METHODS: Sixty-seven chronic hepatitis C patients with high viral load of HCV genotype 1 infection who underwent 48 weeks of PEG-IFNα2b and ribavirin therapy were examined. During the treatment, frequencies of myeloid or plasmacytoid dendritic cells, Th1, Th2 cells, NK cells, and regulatory T cells were phenotypically determined. RESULTS: Among the patients enrolled, 29 showed a sustained virological response (SVR), 18 a transient response (TR) and 17 no response (NR). The clinical and immunological markers were compared between the SVR and non-SVR patients, including TR and NR. Based on clinical, histological, immunological parameters, and cumulative dosage of PEG-IFNα2b and ribavirin, multivariate analyses revealed that higher platelet counts and higher regulatory T cell frequency at week 12 are indicative of SVR. Even in patients who attained complete early virological response at week 12, multivariate analyses disclosed that higher platelet counts and higher plasmacytoid dendritic cell frequency are indicative of SVR. CONCLUSIONS: In PEG-IFNα and ribavirin combination therapy for chronic hepatitis C patients, the increments of regulatory T cells and plasmacytoid dendritic cell frequency are independently related to favorable virological response to the therapy.

Reducing Peg-IFN doses causes later virologic response or no response in HCV genotype 1 patients treated with Peg-IFN alfa-2b plus ribavirin.

BACKGROUND: The timing to the first undetectable hepatitis C virus (HCV) RNA level is strongly associated with sustained virologic response in pegylated interferon (Peg-IFN) plus ribavirin combination therapy for patients with chronic hepatitis C (CH-C) with genotype 1. This study was conducted to clarify the impact of drug exposure to Peg-IFN on the timing of HCV RNA negativity in Peg-IFN plus ribavirin combination therapy for CH-C patients with genotype 1. METHODS: A total of 1409 patients treated with Peg-IFN alfa-2b plus ribavirin were enrolled and classified into four categories according to the Peg-IFN dosage. Furthermore, 100 patients were extracted from each Peg-IFN dosage category to adjust for characteristic factors, using the propensity score method. RESULTS: Peg-IFN exposure was dose-dependently associated with the timing of HCV RNA negativity (p ≤ 0.001). The HCV RNA negative rate at week 4 decreased from 12% with a Peg-IFN dose of >1.5 µg/kg/week to 1-3% with a dose of <1.5 µg/kg/week (p ≤ 0.001), and at week 12 the rate had decreased from 44% with a dose of ≥1.2 µg/kg/week to 18% with a dose of <1.2 µg/kg/week (p = 0.001). Treatment failure (patients without a 1-log decrease of HCV RNA at week 4 or a 2-log decrease of HCV RNA at week 12, or positive at week 24) was found in 54-66% of patients given <1.2 µg/kg/week (p ≤ 0.001), and these patients accounted for 64% of the non-responders. CONCLUSIONS: The timing of HCV RNA negativity depends significantly on the Peg-IFN dose. Reducing the Peg-IFN dose can induce a later virologic response or non-response in HCV genotype 1 patients treated with Peg-IFN plus ribavirin.

Efficacy of pegylated interferon plus ribavirin combination therapy for hepatitis C patients with normal ALT levels: a matched case-control study.

BACKGROUND: The antiviral effect of pegylated interferon (Peg-IFN) plus ribavirin combination therapy in chronic hepatitis C (CHC) patients with normal alanine aminotransferase (ALT) levels (N-ALT) has been reported to be equivalent to that for patients with elevated ALT levels (E-ALT). However, the actual antiviral effect in N-ALT patients remains obscure because efficacy can be overestimated in patients with an advantageous background. METHODS: In this study, 386 patients were extracted, for a matched case-control study, from 1320 CHC patients treated with Peg-IFN alpha-2b plus ribavirin combination therapy; 193 N-ALT patients [116 with hepatitis C virus genotype 1 (HCV-1), 77 with HCV genotype 2 (HCV-2)] were matched with 193 E-ALT patients by a propensity score method using the variables of age, sex, IFN treatment history, body mass index, and platelet counts. RESULTS: On multivariate analysis for sustained virological response (SVR) in N-ALT patients, younger age, low HCV RNA level at baseline, and HCV-2 were significant factors. The matched case-control study showed that the SVR rates of N-ALT patients were equivalent to those of E-ALT patients; at 49 and 40% in the HCV-1 group (P = 0.146), and 78 and 81% in the HCV-2 group (P = 0.691). However, in N-ALT patients with non-SVR, approximately 40% showed ALT elevation at 24 weeks post-treatment. CONCLUSION: Our findings indicate that the antiviral effect of Peg-IFN plus ribavirin therapy in N-ALT patients is comparable to that for E-ALT patients irrespective of their advantageous background; however, the application of this therapy for N-ALT patients, especially for those with HCV-1, should be considered carefully.

Comprehensive immunological analyses of colorectal cancer patients in the phase I/II study of quickly matured dendritic cell vaccine pulsed with carcinoembryonic antigen peptide.

Dendritic cell (DC) vaccine has been used to treat patients with advanced colorectal cancer (CRC). The results of vaccine-induced clinical responses have not always been satisfactory partially because of DC incompetence. In order to evaluate the feasibility of novel mature DCs for therapeutic adjuvants against CRC, we conducted clinical trials with carcinoembryonic antigen (CEA) peptide-loaded DC quickly generated with a combination of OK432 (Streptococcuspyogenes preparation), prostanoid, and interferon-α (OPA-DC). In the ten patients enrolled in this study, the OPA-DC vaccine was well tolerated and administered four times every 2 weeks except for two patients, who were switched to other treatments due to disease progression. Among the eight evaluable patients, one displayed stable disease (SD), while the remaining seven showed progressive disease (PD). In the SD patient, natural killer (NK) cell frequency and cytolytic activity were increased. In the same patient, the frequency of CEA-specific cytotoxic T cells (CTLs) increased stepwise with repetitive vaccinations; however, most of the CTLs exhibited central memory phenotype. In those with PD, NK cells proliferated well regardless of failure of response, whereas CTLs failed to do so. We concluded that the OPA-DC vaccine is well tolerated and has immune-stimulatory capacity in patients with CRC. Additional modulation is needed to attain significant clinical impact.

Efficacy of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan.

BACKGROUND: It is still not known which patients with chronic hepatitis C who failed to respond to previous pegylated interferon (Peg-IFN) plus ribavirin therapy can benefit from re-treatment. METHODS: Seventy-four patients (HCV genotype 1, n = 56, genotype 2, n = 18) were re-treated with Peg-IFN plus ribavirin. RESULTS: On re-treatment, the sustained virologic response (SVR) rate was 41% for genotype 1 and 56% for genotype 2. With genotype 1, the factors associated with an SVR were previous treatment response and the serum hepatitis C virus (HCV) RNA level at the start of re-treatment. Patients with a ≥ 2-log decrease in HCV RNA at week 12 (partial early virologic response, p-EVR) in previous treatment had significantly higher SVR rates than those without these decreases (p < 0.001); no patient without a p-EVR in the previous treatment attained an SVR with re-treatment (0/16). All patients with <5 log(10) IU/ml of HCV RNA at the start of re-treatment attained an SVR (6/6), while only 33% (15/45) of those patients with ≥ 5 log(10) IU/ml of HCV RNA attained an SVR (p < 0.01). Among the patients with relapse in the previous treatment, those who attained an SVR on re-treatment required a longer duration of re-treatment than the duration of the previous treatment (re-treatment, 63.8 ± 13.0 weeks vs. previous treatment, 53.9 ± 13.5 weeks, p = 0.01). CONCLUSIONS: Re-treatment of genotype 1 patients should be limited to patients with a p-EVR in the previous treatment and a low HCV RNA level at the start of re-treatment. In re-treatment with Peg-IFN plus ribavirin, longer treatment duration can contribute to increasing the anti-viral effect.