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Cancer immunotherapy using immune checkpoint inhibitors can cause immune reactions at various sites as a side effect called immune-related adverse events (irAEs). The gastrointestinal tract is susceptible to irAEs, however, the degree and presentation vary considerably from case to case. A 76-year-old woman was diagnosed with anal mucosal melanoma. She underwent radical surgery and received postoperative adjuvant therapy. However, because new metastases were also found in bilateral inguinal lymph nodes, immunotherapy with nivolumab was performed. Approximately 10 months after the initiation of nivolumab administration, she presented with epigastric discomfort and nausea, and her laboratory data showed severe eosinophilia (1938/mm

In cutaneous squamous cell carcinoma (cSCC), adherence to guideline-recommended fixed surgical margins is often difficult, and narrower margins are preferable. This study aimed to evaluate relapse and disease-specific death with narrower margins for high or very high-risk cSCC.We retrospectively investigated high or very high-risk cSCC patients who underwent tumor excision. Patients were divided into guideline-recommended standard margin group (SMG) and narrower-margin group (NMG). Co-primary outcomes were local relapse, SCC relapse, and SCC death. Cumulative incidence function (CIF) was used to describe SCC death probability and competing risk mortality. Gray's test was used to compare differences in CIF between the groups.In total, 1,000 patients with cSCC (high-risk, 570; very high-risk, 430) were included. In the high-risk cohort, there were no significant differences in incomplete excision rate (IER) between SMG and NMG (2.6 % vs. 3.0 %, P 0.99). However, in the very high-risk cohort, IER in SMG was significantly lower than in NMG (8.9 % vs. 16.2 %, P = 0.03). No significant differences were observed between SMG and NMG for local relapse (high-risk, P = 0.56; very high-risk, P = 0.70), SCC relapse (high-risk, P = 0.30; very high-risk, P = 0.47), and SCC death (high-risk, P = 0.23; very high-risk, P = 0.83).Surgical margin size has limited impact on margin control, relapse, and disease-specific death in high-risk cSCC.

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory skin disease mainly affecting apocrine gland-rich areas of the body with painful nodules, persisted abscess, sinus tracts, and scarring. The etiopathology of HS remains unclearly understood, but the disease is considered as a polygenic autoinflammation condition originating from follicular hyperkeratosis and occlusion. Recent advances concerning the substantial roles of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-17, and IL-23 have accelerated in developing a repertoire of therapeutic biologics in HS. Currently five biologics antagonistic for these different cytokines, adalimumab, anakinra, etanercept, infliximab, and ustekinumab, have been explored in the treatment setting of HS; however, only limited evidence is available for the therapeutic advantage of IL-17 pathway blockade. We present a 47-year-old Japanese man who had a long-standing, debilitating HS complicated with psoriasis, both of which were refractory to a series of the standard treatment. Not only psoriatic skin but also HS lesions responded dramatically to brodalumab, an IL-17 receptor antagonist, accompanied with decrease of validated assessments, namely the Hurley's staging classification and modified Sartorius score. Brodalumab was well tolerated with rapid improvement and no adverse reaction, and finally gave a satisfactory maintenance of disease remission. To our best knowledge, this is the first successful use of anti-IL-17 receptor antibody in a Japanese case with coexistence of HS and psoriasis. We also discuss extending understanding of the potential benefit and current limitation of brodalumab in the treatment of HS.

Bei kutanen Plattenepithelkarzinomen (PEK) ist die Einhaltung der in Leitlinien empfohlenen festen Resektionsränder oft schwierig und knappere Ränder sind wünschenswert. Ziel dieser Studie war die Bewertung des Auftretens von Rezidiven und krankheitsspezifischen Todesfällen bei knapperen Resektionsrändern für PEK mit hohem oder sehr hohem Risiko.PEK-Patienten mit hohem oder sehr hohem Risiko, bei denen eine Tumorexzision durchgeführt wurde, wurden retrospektiv untersucht. Die Patienten wurden in eine Gruppe mit Standardrand gemäß Leitlinienempfehlung (standard margin group, SMG) und eine Gruppe mit knapperen Rändern (narrower-margin group, NMG) eingeteilt. Gemeinsame primäre Endpunkte waren lokales Rezidiv, PEK-Rezidiv und PEK-bedingter Tod. Die Wahrscheinlichkeit eines PEK-bedingten Tods und konkurrierender Mortalitätsrisiken wurde mittels kumulativer Inzidenzfunktion (CIF) beschrieben. Unterschiede bei der CIF zwischen den Gruppen wurden mit dem Test nach Gray verglichen.Insgesamt wurden 1.000 Patienten mit PEK (hohes Risiko, 570; sehr hohes Risiko, 430) eingeschlossen. In der Kohorte mit hohem Risiko gab es keine signifikanten Unterschiede bei der unvollständigen Exzisionsrate (IER) zwischen SMG und NMG (2,6 % vs. 3,0 %, P 0,99). In der Kohorte mit sehr hohem Risiko war die IER in der SMG jedoch signifikant geringer als in der NMG (8.9 % vs. 16.2 %, P = 0,03). Keine signifikanten Unterschiede zwischen SMG und NMG wurden für Lokalrezidiv (hohes Risiko, P = 0.56; sehr hohes Risiko, P = 0,70), PEK-Rezidiv (hohes Risiko, P = 0,30; sehr hohes Risiko, P = 0,47) und PEK-bedingtem Tod (hohes Risiko, P = 0,23; sehr hohes Risiko, P = 0,83) beobachtet.Die Größe des Resektionsrands hat einen begrenzten Einfluss auf Randkontrolle, Rezidive und krankheitsspezifischen Tod bei PEK mit hohem Risiko.

Immune checkpoint inhibitors, such as ipilimumab and nivolumab, reverse the imbalance of antitumor self-tolerance and enhance T-cell responses. Currently, ipilimumab and nivolumab have a reported therapeutic impact on unresectable or metastatic melanomas; however, they also induce immune-related adverse events (irAEs). Ipilimumab-induced cutaneous irAEs are mostly low grade and manageable, although all-grade rash may occur in approximately 45% of all patients. We here report the case of a young woman with erythema multiforme major, which developed after sequential use of these 2 immune checkpoint inhibitors for advanced melanoma of the scalp. Initially, she received 12 cycles of nivolumab monotherapy followed by ipilimumab. A week later, multiple erythematous papulo-erythemas appeared on almost her entire body, with high-grade fever, mucosal involvements, and dyspnea. Immunohistochemistry using the lesioned skin revealed lymphocytic infiltration predominantly positive for CD8, contrasting with those for CD4 and Foxp3. Ipilimumab was stopped but she continued to receive empirical antibiotics; additionally, she was treated with intravenous steroid pulse therapy and immunoglobulin, followed by oral prednisolone. Her symptoms subsided rapidly, allowing a restart of nivolumab monotherapy alone. In our case, the long-standing preceding nivolumab monotherapy may synergistically and/or complementary have contributed to – in combination with the later administration of ipilimumab – recover antigen-responsive T-cell immunity, which is similar to the concept of immune reconstitution inflammatory syndrome, resulting in the establishment of an underlying immunopathology of erythema multiforme and life-threatening airway obstruction.

Background:Nail unit melanoma (NUM) poses a considerable treatment challenge, particularly in cases with in situ or early invasive lesions, and wide excision with phalanx amputation. For post-excisional skin defects, stump plasty and/or split-thickness skin grafting may cause persisted irritation and ulceration as a post-operative complication, because of the insufficient underlying tissue volume, vascularity, and stability.Objective:To seek out other superior management avoiding disadvantages associated with the conventional NUM surgery.Method:Three consecutive cases with NUM were treated by a novel two-phase surgical procedure using a commercially available dermal regeneration template; as the first phase, the lesional nail unit was excised and subsequently covered by a dermal regeneration template onto the phalangeal bone surface, allowing development of robust granulation with extracellular matrix and vascular network. Thereafter, the second phase employed a full-thickness skin grafting.Results:All three cases accomplished complete removal of the NUM lesion, and achieved a good cosmetic and functional outcome, maintaining physiological firmness, contour, and less contraction and atrophy of the overlying skin. They did not complain of major post-operative complications.Conclusion:Our two-phase approach using a dermal regeneration material is a satisfactory and straightforward technique, achieving a substantial benefit functionally and cosmetically in the post-operative period. We propose that the additional use of a tissue regeneration material can provide superior results for the reconstruction step of excised NUM.

Dermatomyositis is an autoimmune inflammatory myopathy with characteristic cutaneous features. Dysphagia secondary to oropharyngeal and oesophageal involvement develops in a part of patients with dermatomyositis and may affect prognosis. Systemic immunosuppressive therapy is usually effective for dysphagia as well as cutaneous lesion and myositis. Here, we report a 78-year-old man with anti-TIF-1γ antibody-positive dermatomyositis that presented with an early gastric carcinoma and dysphagia resistant to oral prednisolone and tacrolimus therapy. Endoscopic examination demonstrated saliva retention in the piriform recess and saliva entering the larynx. A videofluoroscopy swallow study revealed a stricture of the oesophagus and accumulation of contrast media in the pharynx. A repetitive combination therapy of intravenous immunoglobulins and balloon dilatation was effective for dysphagia. In dermatomyositis patients with dysphagia, swallowing function should be evaluated at an early stage. Moreover, c...

We describe a case of CD34-positive infantile myofibromatosis with hemangiopericytoma-like pattern. A 2-day-old Japanese boy presented with multiple hemispherical nodules on the extremities and back. There was a biphasic histological growth in the dermis, accompanied by a hemangiopericytoma-like pattern with antler-like branching vessels. Tumor cells were oval to spindle-shaped myoid cells with bland appearance. Immunohistochemically, vimentin, calponin and CD34 were positive, while α-smooth muscle actin, h-caldesmon, HHF35 and desmin were negative. Although CD34 was positive, the present case could be diagnosed as infantile myofibromatosis. Myopericytoma, myofibroma/myofibromatosis, glomus tumor, glomangiopericytoma and angioleiomyoma share a continuous spectrum of benign hemangiopericytoma-like pattern tumors. Myofibroma/myofibromatosis is nearly included in myopericytoma among pericytic (perivascular) tumors, and could be positive for CD34. Several immunohistochemical panels of smooth muscle markers are needed for the diagnosis of pericytic (perivascular) tumors.

10063 Background: Controversy exists regarding the optimal surgical margin for cutaneous squamous cell carcinoma (cSCC). Current NCCN Guidelines recommend excision with a 4–6-mm clinical margin for low-risk cSCC and wider ( > 6-mm) clinical margin for high-risk cSCC tumors. However, adherence to this guideline is often difficult, as high-risk cSCCs frequently occur on the faces of elderly patients. Thus, we aim to investigate the correlation between different surgical margins and prognosis in patients with cSCC. Methods: Patients with cSCC who had undergone surgical excision of the primary site between 2011 and 2019 at 11 Japanese institutions were included in this study. Patients were divided into two groups: the standard margin group (SMG) with excisions adhering to the guideline-recommended margins, and narrower margin group (NMG) with excisions with narrower margins than are guideline-recommended. Local recurrence-free survival (LRFS), relapse-free survival (RFS), and overall survival (OS) were estimated using Kaplan–Meier analysis and compared between the two groups. Results: A total of 1204 patients with cSCC (SMG, 637; NMG, 567) were included in this study. RFS was significantly lower in SMG than in NMG (5-year RFS 72% vs 79%; P = 0.03); however, no statistically significant differences were observed between the two groups in LRFS (5-year LRFS 80% vs 82%; P = 0.41) or OS (5-year OS 84% vs 83%; P = 0.90). Due to striking statistical significance in several characteristics of patients between the two groups, subgroup analyses, focusing on the cohort of head and neck cSCCs, were also performed. The patient characteristics were similar between SMG and NMG in both the T1-sized tumor ( < 2 cm, SMG, 182; NMG, 250) and T2-sized tumor (2 cm ≤ tumor < 4 cm, SMG, 130; NMG, 136) cohorts, based on AJCC-TNM staging (8th edition). There were also no significant differences between the SMG and NMG in LRFS (5-year LRFS, T1: 80% vs 86%; P = 0.59; T2: 85% vs 84%; P = 0.84), RFS (5-year RFS, T1: 80% vs 81%; P = 0.84; T2: 77% vs 76%; P = 0.99), or OS (5-year OS, T1: 82% vs 87%; P = 0.42; T2: 88% vs 85%; P = 0.68). Furthermore, when the NMG was divided into the two margin groups (margins reduced by < 3 mm or ≥3 mm from the standard margin), no significant difference was observed in LRFS, RFS, and OS. Conclusions: This study did not reveal a significant impact of the size of clinical excision margins on survival in patients with cSCCs. Strikingly, the narrower margins may be more appropriate for < 4 cm-sized head and neck cSCCs.

The survival rate of patients with malignant melanoma is still low, and there is no established chemotherapeutic method. With the appearance of molecular targeted drugs, improvement in the survival rate can be expected. However, at present, malignant melanoma remains a disease associated with one of the poorest prognoses.We analyzed a total of 51 cases of malignant melanoma who were treated at the Department of Dermatology, University of Fukui from September 2001 to May 2013.The survival rate was significantly lower in patients aged ≥65 years. The 5-year survival rate was 100 % for Stage 0/I, 79.59 % for Stage II, and 52 % for Stage III. The incidence of lymph node metastasis was highest in nodular melanoma, and zero in lentigo maligna melanoma. There was a significantly high risk of lymph node metastasis in the presence of ulceration. There was no association between incisional biopsy and lymph node metastasis.Although the data were obtained in only one institution and the number of cases was limited in this study, the results are close to previous international data.

Case 74 y.o. male Chief Complaint Lower lip nodule Present History On July in XXXX, left hilar tumor was detected by chest computed tomography, and the patient was admitted to our hospital for scrutiny and treatment. It was diagnosed as stage IVa non-small cell lung cancer with undecidable histopathological subtype.Tumor proportion score of PD-L1 had shown 75%. Since Aug. in XXXX, Pembrolizumab was started. The tumor soon became smaller, so the therapy was thought to be effective. However, after 4 courses of those therapies, lower lip nodules appeared on October. Clinical Course Lower lip nodule had grown and formed a tumor in 1cm diameter, with scar in the central area and angiogenesis in the peripheral area. Lip tumor biopsy was performed at the end of October. In dermic layer, large cells with strain nucleus had increased. Abnormal cells showing CD3+, CD4+, CD8+, TIA-1+, CD30+, EBER(-), ISH(-), have indicated the possibility of T cell lymphoma. Since the association between immunotherapy and the lip nodule could not be denied, immunotherapy was ceased. In order to establish an accurate diagnosis of the lip tumor, resection of the nodule was carried out. At that time, the tumor had shrunk spontaneously, and the large abnormal cells had disappeared, which were detected in incisional biopsy. Considered with pathological findings and clinical course, primary skin lymphoproliferative diseases (LPD) had been diagnosed. As lung lesion was also enlarged simultaneously, Re-bronchoscopic exam revealed not LPDs but progression of cancer in the lung. Discussion LPD was confined in dermal layer of skin, occurred and disappeared in natural course. As the size of lip tumor decreased after cessation of immunotherapy, it was supposed that immunodeficiency due to the effect of Pembrolizumab might induce LPD.

It has been suggested that hepatitis C virus (HCV) infects not only hepatocytes but also immune cells, including B cells. HCV infection of B cells is the likely cause of B-cell dysregulation disorders such as mixed cryoglobulinemia, rheumatoid factor production, and B-cell lymphoproliferative disorders that may evolve into non-Hodgkin's lymphoma. To clarify the effects of chronic HCV infection on B-cell dynamics, peripheral B cells from chronic hepatitis C patients (CHC) were characterized. We found that the frequency of CD27(+) B cells, that is memory phenotype, was significantly reduced in the peripheral blood of CHC. At the same time, the amount of IFN-gamma-inducible protein-10 (IP-10), a CXCR3 ligand, was markedly elevated in the plasma of CHC. Furthermore, the CD27(+) B-cell population was found to highly express CXCR3 in CHC, thus suggesting that the CD27(+) B-cell population was recruited from peripheral blood to the inflammatory site of the liver of CHC, where IP-10 is produced. Immunohistochemical analyses of intrahepatic lymphocytes indicated that CXCR3(+) B cells were infiltrated in the liver of CHC. Our results thus offer new insight into the role of memory B cells in the HCV pathogenesis.

Background/Aims: Xenon computed tomography (Xe-CT) is a noninvasive method of quantifying and visualizing tissue blood flow (TBF). For the liver, Xe-CT allows separate measurement of hepatic arterial and portal venous TBF. The present study evaluated the usefulness of Xe-CT as a noninvasive diagnostic procedure for measuring hepatic TBF in alcoholic liver cirrhosis (AL-LC), compared with liver cirrhosis related to nonalcoholic steatohepatitis (NASH), (NASH-LC), and hepatitis C virus (HCV), (C-LC). Methods: Xe-CT was performed on 22 patients with AL-LC, 7 patients with NASH-LC, and 24 patients with C-LC. Severity of LC was classified according to Child-Pugh classification. Correlations between hepatic TBF, Child-Pugh classification, and indocyanin green retention (ICG) rate after 15 minutes (ICG15R) were examined. Correlations of hepatic TBF in Child-Pugh class A to AL-LC, NASH-LC, and C-LC were also examined. Results: Portal venous TBF (PVTBF) displayed a significant negative correlation with Child-Pugh score and ICG15R (r = ―0.432, p < 0.01, r = ―0.442, p < 0.01, respectively). Moreover, ICG15R displayed a significant positive correlation with Child-Pugh score (r = 0.661, p < 0.001). Meanwhile, mean PVTBF and total hepatic TBF (THTBF) was significantly lower in AL-LC than in C-LC (p < 0.05). Mean PVTBF was significantly lower in Child-Pugh class A to AL-LC and NASH-LC than in that to C-LC (p < 0.05). Similarly, mean THTBF was significantly lower in Child-Pugh class A to NASH-LC than in that to C-LC (p < 0.05). Conclusions: Measurement of hepatic TBF using Xe-CT is useful as a noninvasive, objective method of assessing the state of the liver in chronic liver disease.

Aim: The diagnosis of non-alcoholic steatohepatitis (NASH) can be difficult using blood tests and imaging studies. Histological diagnosis by liver biopsy remains the gold standard of NASH diagnosis. There is an urgent need to develop and validate simple, reproducible, noninvasive tests to accurately assess NASH stage and grade. We assess the usefulness of xenon computed tomography (Xe-CT), as a non-invasive method of quantitatively and visually determining hepatic tissue blood flows (TBFs), and xenon solubility (λ value) simultaneously with TBF, in the evaluation of NASH pathophysiology. Methods: Histological severity of fatty changes and severity of fibrosis based on Brunt's classification were determined in 38 NASH patients. We evaluated correlations between the grade of fatty changes and λ value, and correlations between the stage of fibrosis and TBFs. Results: The λ value showed significant positive correlations with both grade of steatosis (r = 0.813, P

Background: Combined pegylated interferon and ribavirin has improved chronic hepatitis C (CH-C) therapy, however sustained virologic response is achieved in about half of patients with a 1b genotype infection. We assessed oral ursodeoxycholic acid (UDCA) on serum biomarkers as a possible treatment for interferon nonresponders. Methods: CH-C patients with elevated alanine aminotransferase (ALT) were assigned randomly to 150 (n = 199), 600 (n = 200), or 900 mg/day (n = 197) UDCA intake for 24 weeks. Changes in ALT, aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) were assessed. This study is registered at ClinicalTrial.gov, NCT00200343. Results: ALT, AST, and GGT decreased at week 4 then remained constant during drug administration. The median changes (respectively 150, 600, and 900 mg/day) were: ALT, -15.3, -29.2, and -36.2%; AST, -13.6, -25.0, and -29.8%; GGT, -22.4, -41.0, and -50.0%. These biomarkers decreased significantly less in the 150 mg/day than in the other two groups. Although changes in ALT and AST did not differ between the 600 and 900 mg/day groups, GGT was significantly lower in the 900 mg/day group. In subgroup analysis, ALT decreased significantly in the 900 mg/day group when the baseline GGT exceeded 80 IU/L. Serum HCV-RNA did not change in any group. Adverse effects were reported by 19.1% of the patients, with no differences between groups. Conclusions: A 600 mg/day UDCA dose was optimal to decrease ALT and AST levels in CH-C patients. The 900 mg/day dose decreased GGT levels further, and may be preferable in patients with prevailing biliary injuries.

Aim: The clinical significance of hepatitis B virus (HBV) core-related antigen (HBcrAg) in predicting the reactivation of hepatitis after halting lamivudine administration was analyzed. Methods: A total of 34 patients with chronic hepatitis B were enrolled. Lamivudine was administered for at least 6 months before cessation, and reactivation of hepatitis was defined as elevation of alanine aminotransferase levels to more than 80 IU/L within 12 months of cessation. Results: In total, 20 (59%) patients experienced hepatitis reactivation. Although concentrations of HBV DNA and HBcrAg in serum did not differ between the two groups of patients at the onset of lamivudine administration, HBcrAg serum levels were significantly higher (P = 0.009) in the reactivation patients (median 4.9, 25–75% range 4.7– 5.9 log unit/mL) than the non-reactivation patients (median 3.2, 25–75% range

Aim: Xenon computed tomography (Xe-CT) is a non-invasive method of quantifying and visualizing tissue blood flow (TBF). Xe-CT allows separate measurement of hepatic arterial and portal venous flow. The aim of this study was to investigate correlations between the progression of fibrosis and hemodynamic changes in chronic hepatitis C (CHC) patients using Xe-CT. Methods: Separate measurements of portal venous TBF (PVTBF) and hepatic arterial TBF (HATBF) were performed using Xe-CT, and total hepatic TBF (THTBF) was calculated as the sum of PVTBF and HATBF. A total of 50 patients with CHC underwent Xe-CT. Liver biopsy was performed on 42 of the 50 patients, and hepatic fibrosis was classified as mild (F1), moderate (F2), severe (F3) or Child–Pugh class A cirrhosis (F4a). In addition, eight patients with Child–Pugh class B cirrhosis (F4b) were evaluated. Results: Significant negative correlations were identified between PVTBF and progression of stage (rs = –0.622, P < 0.0001) and between THTBF and progression of stage (rs = –0.458, P = 0.0041). Conclusion: Separate measurement of PVTBF and HATBF using non-invasive Xe-CT provided quantitative and visual information regarding hemodynamics of the entire liver in CHC patients. PVTBF decreases with the progression of fibrosis, even in CHC patients.

Genotypes of hepatitis B virus (HBV) were determined in 485 patients with acute hepatitis B from all over Japan. They were A in 92 (19%), Ba in 26 (5%), Bj in 32 (7%), C in 330 (68%) and D in 5 (1%). Sexual contacts were the main route of transmission in them. Overall, HBV persisted in only 5 of the 464 (1%) followed patients. Genotypes C accounted for more than 68% in northern as well as southern areas, contrasting with genotype A accounting for 34% in and around the Metropolitan areas. During 24 years from 1982 to 2005, genotype A increased from 5% to 33%, while genotype B gradually decreased from 26% to 8%. Fulminant hepatitis was significantly more frequent in infection with genotype Bj (41%) than those with the other genotypes (p

Objective: The clinical usefulness of hepatitis B virus core-related antigen (HBVcrAg) assay was compared with that of HBV DNA assay in predicting the occurrence of lamivudine resistance in patients with chronic hepatitis B. Patients: Of a total of 81 patients who were treated with lamivudine, 25 (31%) developed lamivudine resistance during a median follow-up period of 19.3 months. Results: The pretreatment positive rate of HBe antigen, or pretreatment levels of HBVcrAg or HBV DNA did not differ between patients with and without lamivudine resistance. Levels of both HBVcrAg and HBV DNA decreased after the initiation of lamivudine administration; however, the level of HBVcrAg decreased significantly more slowly than that of HBV DNA. The occurrence of lamivudine resistance was significantly less frequent in the 56 patients whose HBV DNA level was less than 2.6 log copy/ml at 6 months of treatment than in the remaining 25 patients. The cumulative rate of lamivudine resistance was as high as 70% within 2 years in the latter group, while it was only 28% in the former group. Lamivudine resistance did not occur during the follow-up period in the 19 patients whose HBVcrAg level was less than 4.6 log U/ml at 6 months of treatment, while it did occur in 50% of the remaining patients within 2 years. Conclusion: These results suggest that measurement of HBV DNA is valuable for identifying patients who are at high risk of developing lamivudine resistance, and that, conversely, measurement of HBVcrAg is valuable for identifying those who are at low risk of lamivudine resistance.

Thymalfasin (thymosin alpha-1; Talpha1) is a 28-amino acid polypeptide that has shown efficacy in the treatment of chronic hepatitis B virus (HBV) infection. The objective of this study was to evaluate the long-term, dose-related efficacy and safety of Talpha1 treatment in chronic hepatitis B patients with positive HBV-DNA and abnormally high alanine aminotransferase (ALT) levels. A total of 316 patients were randomized to receive either 0.8 or 1.6 mg of Talpha1 monotherapy for 24 weeks. At the end of the 72-week observation period (12 months after cessation of therapy), 36.4% of patients in the 1.6-mg treatment group achieved normalization of ALT, 30% achieved clearance of HBV-DNA by branched DNA vs 15% by transcription-mediated amplification, and 22.8% achieved clearance of HBe-antigen. Patients in the 0.8-mg treatment group achieved similar efficacy rates, although patients with advanced fibrosis demonstrated a significantly better response rate when treated with 1.6 mg of Talpha1 monotherapy vs 0.8 mg (as determined by intragroup analysis; patients were not stratified by liver biopsy). All adverse drug reactions were mild and most involved the fluctuation of liver enzymes, which was most likely related to the positive immune effects caused by the response to Talpha1 treatment. Adverse event incidence was similar in the 1.6- and 0.8-mg treatment groups. In conclusion, Talpha1 at doses of 0.8 and 1.6 mg exhibits long-term efficacy against hepatitis B with a good safety profile.

The possibility of delaying progression to hepatocellular carcinoma in chronic hepatitis C patients with genotype 1 and high viral titers with baseline ALT levels of ≥50 IU/L was examined by administration of IFN plus ribavirin combination therapy using ALT normalization as index and IFN monotherapy as control. The rate of sustained ALT normalization (ALT normal at 24 weeks after the end of treatment) was 28.1% with combination therapy and 10.5% with IFN monotherapy ( P = 0.001). Furthermore, the number of patients with sustained viral response (SVR) and with sustained ALT normalization in non-SVR patients was also significantly higher in the combination therapy versus monotherapy group. Mean ALT values during treatment and for 6 months after the end of treatment were significantly lower with combination therapy versus monotherapy even in virological nonresponders, as well as significantly lower during the post-treatment observation period in patients who relapsed after the end of treatment. Since increase in the rate of sustained ALT normalization and SVR were successfully achieved, inhibition of progression to hepatocellular carcinoma should be studied with long-term IFN and ribavirin combination therapy.

自己免疫性肝炎 (AIH) と特発性血小板減少性紫斑病 (ITP) を同時に発症した高齢男性例を経験した. 病勢と抗スルファチド抗体価とが相関し, 興味深い症例と考え報告する. 症例は67歳, 男性. 以前より軽度のγ-GTP上昇を指摘されていたが肝障害および血小板減少が出現し入院. 血小板の著減と肝障害を呈し, PAIgGは高値を示した. 骨髄は過形成性骨髄であり, ITPと診断. プレドニゾロンの投与を開始した. 肝生検標本組織所見は, 自己免疫性肝炎に合致していた. AIHとITPの発症時期, 疾病活動性の変動は一致しており, 抗スルファチド抗体の変動と相関が認められた. 両疾患の発症および病勢の変動に, スルファチドに対する免疫応答が関与していることが示唆された.

Increasing evidence indicates that iron cytotoxicity plays an important role in the pathogenesis of chronic hepatitis C (CHC). However, the biochemical effects of iron reduction therapy on CHC remain to be confirmed in a controlled study. This study aimed to test whether iron removal by repeated phlebotomy improves serum alanine aminotransferase (ALT) levels in patients with CHC.Patients were randomly assigned to an iron reduction therapy or control group. The patients in the treatment group received 3-month iron reduction therapy by biweekly phlebotomy, while the patients in the control group were followed up for 3 months with regular blood tests alone.Thirty-three patients completed the 3-month treatment, while 29 patients received the complete follow-up. The serum ALT levels were reduced from 118 +/- 79 to 73 +/- 39 IU/L in the treatment group, but did not change in the control group (106 +/- 45 versus 107 +/- 48 IU/L). Posttreatment enzyme activity was decreased significantly from the baseline. Furthermore, it was significantly lower than the 3-month control level. Although 5 patients withdrew from the study, none was affected by any side effects of repeated phlebotomy that required them to discontinue the treatment.This short-term controlled trial demonstrated the biochemical efficacy and safety of iron reduction therapy for patients with CHC.

Objective: To understand the autoimmunity associated with chronic hepatitis C (CHC), we investigated autoantibodies (autoAbs) to CD69. Methods: With this aim, we tested the reactivity of serum samples from patients with CHC and asymptomatic carriers of hepatitis C virus (HCV), as well as from patients with chronic hepatitis B (CHB) and autoimmune hepatitis (AIH), to recombinant CD69 molecules. Results: Frequencies of anti-CD69 autoAbs were 38.7% in CHC, 15.8% in AIH and 12.3% in CHB. None of the tested asymptomatic HCV carriers had autoAbs to CD69. It is important clinically that the presence of anti-CD69 autoAbs was found to be associated with a poor response to interferon-α (IFN-α) therapy. In the epitope analysis, multiple epitopes were mapped on CD69, indicating antigen-driven production of the autoAbs. Conclusion: We evidenced existence of anti-CD69 autoAbs in patients with CHC, and found that the anti-CD69 autoAb may have potential for predicting responses to IFN-α therapy.

Short-term lamivudine and its withdrawal were evaluated as regards an immunomodulatory therapy of chronic hepatitis B. Lamivudine was given for 3 or 6 months to 23 patients with chronic hepatitis B who were infected with hepatitis B virus (HBV) genotype C, including 15 with hepatitis B e antigen (HBeAg) and 8 without it. It decreased serum levels of alanine aminotransferase (ALT) and HBV DNA in HBeAg-positive patients. Flare-ups of ALT and HBV DNA after treatment were observed in most patients, and 4 of the 12 (33%) patients with 6-month lamivudine treatment remained in remission 6 months after withdrawal of the therapy. In HBeAg-negative patients, however, flare-ups of ALT and HBV DNA were mild. Normalization of ALT and a decrease in serum HBV DNA were accomplished in 6 of the 9 (75%) patients. Breakthroughs or serious side effects were not observed in any patients. Short-term lamivudine is safe and may offer a therapeutic option to patients with chronic hepatitis B.

Patients with chronic hepatitis C who are infected with hepatitis C virus of genotype 1b and have a high viral load in serum (>1 Mega equivalents/ml) poorly respond to interferon with the standard regimen. Natural interferon-alpha (nIFN-alpha: OPC-18) was given to 106 such patients randomized into two different therapeutic schedules. One group consisting of 53 patients received daily intramuscular injection with 10 mega units (Meq) for 2-4 weeks and then 5 Meq three times per week until 24 weeks and the other group of 53 patients were placed on the same regimen until 48 weeks. At 24 weeks after the completion of therapy, HCV RNA turned negative in 11 (25%) patients with the 48-week therapy, significantly more frequently than in two (5%) patients with the 24-week therapy (P=0.014). There were no differences in the incidence and severity of adverse effects between the patients who received 24- and 48-week nIFN-alpha. Based on these results, nIFN-alpha with a high-dose induction and extended to 48 weeks would be a reasonable therapeutic option for the patients infected with HCV/1b in high viral loads who do not respond to the standard regimen with a 24-week schedule.

Background/Aims : To elucidate the viral factors responsible for progressive liver injury in chronic hepatitis B. Methods : We analyzed 179 persistently infected patients (21 asymptomatic carriers, 126 with chronic hepatitis and 32 with cirrhosis) with genotype C hepatitis B virus (HBV). HBeAg/anti-HBe, levels of HBV DNA, mutations in the basic core promoter (BCP) region at nucleotides 1762/1764 and mutation in the precore (preC) region at nucleotide 1896 were determined. Serial samples from 18 patients also were analyzed. Results : HBeAg/anti-HBe and HBV DNA levels per se were not related to liver fibrosis. The frequency of BCP mutations increased with progression of liver fibrosis. Although the preC mutation was detected more often among the LC group, the role of this mutation in progression of fibrosis seems less than that of the BCP mutations. Sequential analysis showed that (1) rapidly progressing cases were positive continuously for double mutations in the BCP with a wild-type precore sequence, and (2) asymptomatic cases with anti-HBe acquired the preC mutation during their clinical course. Conclusions : Double mutations in the BCP region at nucleotide 1762/1764 are closely related to progression of chronic liver disease. Acquisition of mutation in the preC region at nucleotide 1896 may contribute to inactivation of chronic liver disease.

We conducted a prospective, controlled, multicenter trial to assess if earlier changes of serum HCV RNA levels were predictable for long-term effect, and if a short-term therapy was effective in such patients. All 377 chronic hepatitis C (CH-C) patients were treated with interferon (IFN) daily 9 MU for 4 weeks. Patients positive for HCV RNA at week 1 were treated with IFN three times weekly for additional 22 weeks (group A), while those negative for HCV RNA were randomized into either regimens; three times weekly for another 22 (group B) or 12 weeks (group C). When complete responders (CR) were defined as the subjects showing sustained loss of viremia with therapy, CR rates were 17.7% (25/141) for group A, 80.0% (36/45) for group B and 61.0% (36/59) for group C, respectively. Group B showed a significantly higher CR rate than group C, indicating that a 16-week treatment period was inadequate. Patients with CR showed a rapid decrease in virus levels by day 2 after starting therapy. The CR ratio in patients with HCV RNA levels of

Thirty-five years have already elapsed since the discovery of hepatitis B virus (HBV), and 10 years since that of hepatitis C virus (HCV). Nonetheless, the natural history of HBV and HCV infections has not been fully defined, partly because they do not have subjective symptoms in most cases. Even when liver disease is induced by these hepatitis viruses, the clinical course is slow and mostly insidious. HBV and HCV are much alike in that they both cause a spectrum of clinical conditions ranging from the symptom-free carrier state through chronic hepatitis and liver cirrhosis to eventual hepatocellular carcinoma. Despite a close similarity, infections with HBV and HCV are very different in many aspects, from the early to end stage. Large-scale unbiased studies to sort out the natural history of HBV and HCV infections are lacking, however. Understandably, in view of the fact that only a few decades have passed since these hepatitis viruses were discovered. My personal account on the natural history of HBV and HCV infections is given here, which is based on my experience of over 40 years as a clinical and research hepatologist in Japan, although I am aware that it invites more questions than it answers.

To determine the hepatitis B virus (HBV) genotype distribution among asymptomatic carriers and patients with liver diseases in Nanning, China, where the prevalence of HBV infection is high, the serum samples from 39 asymptomatic HBV carriers and 103 liver diseases patients were examined for the presence of HBV DNA by polymerase chain reaction and for genotypes by restriction fragment length polymorphism analysis. All patients were positive for HBV DNA and 135 (95.1%) patients were classified by RFLP, the remaining seven were classified by sequencing. Finally, six (4.2%), 20 (14.1%), 113 (78.9%) and two (1.4%) patients were identified with genotype A, B, C and D, respectively. One (0.7%) case was confirmed to be co-infected with both genotypes B and C. Genotype C was more frequently observed in cases with advanced liver diseases and relatively less frequently in case with mild liver diseases. In contrast, genotype B showed an opposite distribution pattern, although there was no statistically significant difference (P=0.05). The rate of positivity for anti-HBe was higher, but that for HBeAg was lower in chronic infection patients with genotype B than in those with genotype C, (P

BACKGROUND: Recent studies have revealed that HBV may not be cleared even after the disappearance of serum HBsAg. The purpose of this study was to investigate whether the replication of HBV persists in HBsAg-negative blood donors who lack apparent liver disease. STUDY DESIGN AND METHODS: Serum HBV was examined by using PCR coupled with Southern blotting in 50 blood donors who were identified to be HBsAg negative but anti-HBc positive. RESULTS: HBV DNA was detected in the sera from 19 (38%) of 50 donors. In 11 of the 19, HBV existed exclusively as immune complexes, while HBV presumably did not exist as immune complexes in the remaining eight. The levels of HBV DNA were similar to those in patients who had recovered from acute HBV. Some nucleotide substitutions, which did not confer amino acid changes in the major epitope of HBsAg, were found in the preS-S regions. CONCLUSION: The replication of HBV is ongoing in a substantial proportion of healthy blood donors who have anti-HBc. Blood from such donors may contain very low levels of HBV free of immune complex formation and should be excluded for transfusion. The fact that such blood donors apparently lacked liver disease suggests no pathogenicity of such “occult” HBV.

The geographic distribution of hepatitis B virus (HBV) genotypes in Japan and its clinical relevance are poorly understood. We studied 731 Japanese patients with chronic HBV infection. HBV genotype was determined by the restriction fragment length polymorphism (RFLP) method after polymerase chain reaction (PCR). Of the 720 patients with positive PCR, 12 (1.7%) were HBV genotype A, 88 (12.2%) were genotype B, 610 (84.7%) were genotype C, 3 (0.4%) were genotype D, and 7 (1.0%) were of mixed genotype. Over 94% of patients on the Japanese mainland had genotype C, while 60% of the patients on Okinawa, the most southern islands, and 22.9% in the Tohoku area, the northern part of the mainland, harbored genotype B. Compared with genotype C patients, genotype B patients were older (53.6 to 42.2 years; P

Clinical and molecular virological differences were evaluated in 50 Japanese patients chronically infected with HBV of genotype B and C who were matched for age and sex as well as the severity of liver disease in a case-control study. Hepatitis B e antigen (HBeAg) was significantly less frequent (16% vs. 42%, P or = 35 years (OR, 5.5; CI, 1.5-20.5), and more advanced liver disease (OR, 4.1; CI, 1.6-10.2), but it was not associated with sex, HBeAg, HBV DNA, or the precore mutation (A1896). These results suggest a role of the double mutation in the basic core promoter in association with genotype C and a longer duration of infection in the aggravation of chronic hepatitis B.

It has been previously reported that the non-structural region 5A (NS5A) of the hepatitis C virus (HCV) includes an interferon sensitivity determining region (ISDR) and that amino acid substitutions in this region are closely associated with the response to interferon (IFN) treatment. We assessed the clinical significance of serial changes of amino acid sequences in the ISDR during repeated IFN treatment in patients with chronic hepatitis C (genotype 1b), related to serum HCV RNA load. During treatment, additional amino acid substitutions in the ISDR were observed in four of eight patients (50% 2/5 of complete responders (CR); 2/3 of non-responders (NR). However, comparing these amino acid substitutions to wild-type ISDR, the number of amino acid mutations was limited to only one amino acid identified in two CRs. The virus load changed regardless of the amino acid substitutions in the ISDR during treatment, and the wild-type and intermediate type (with less than three amino acid substitutions) showed wide variations in virus load. These data indicate that amino acid mutations in the ISDR, which indicate the switch to mutant-type do not occur easily even during repeated IFN treatment, and the additional amino acid substitutions in the ISDR are not a sensitive marker during repeated IFN treatment. In cases where virus load is used as a marker of response to repeated UN treatment, serial examinations are necessary to determine the precise virus load levels.