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Japanese patients with very high-risk cutaneous squamous cell carcinomas (cSCCs), based on the National Comprehensive Cancer Network guidelines, have been reported to display a higher cumulative incidence of relapse and disease-specific death (DSD) than those with high-risk cSCC. Therefore, prognosis prediction is crucial for Japanese patients with very high-risk cSCCs. Herein, we aimed to evaluate the prognostic prediction ability of our novel Japanese Risk Factor Scoring Systems (JARF scoring) in a Japanese cohort of cSSC patients. Data of 424 Japanese patients with resectable very high-risk cSCCs were analysed. We compared the prognostic ability of the following three staging systems: Brigham and Women's Hospital (BWH) tumour staging, number of NCCN very high-risk factors, and JARF scoring, including recurrent tumour, high-risk histological features, deep tumour invasion and lymphatic or vascular involvement as risk factors. The prognostic ability of these staging systems was evaluated according to the cumulative incidence of local recurrence (LR), regional lymph node metastasis (RLNM), DSD, and overall survival (OS). When BWH staging was used, high T stage led to significantly poor outcomes only in the cumulative incidence of RLNM (p = 0.01). The presence of very high-risk NCCN factors led to significantly poor outcomes in terms of RLNM (p = 0.03) and OS (p = 0.02). Meanwhile, a high number of risk factors in the JARF scoring system clearly led to poor outcomes in terms of LR (p = 0.01), RLNM (p < 0.01), DSD (p = 0.03), and OS (p < 0.01). The JARF scoring system may accurately predict the risk of recurrence and death in very high-risk cSCC patients in Japan.
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Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Estudos Transversais , População do Leste Asiático , Japão , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgiaRESUMO
In older patients with facial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), surgery should be aimed to reduce treatment-related sequelae and burden with achieving local tumor care. Therefore, we adopted a two-step surgery (TSS) involving the application of a dermal regeneration template onto the skin defect after tumor resection and subsequent reconstruction by full-thickness skin grafting. We performed a detailed comparison of conventional one-step surgery (OSS) and TSS, including evaluation of local tumor curability, postoperative cosmetic and/or functional impairments, and patient burden. Forty-six patients who underwent TSS and 104 patients treated with OSS were retrospectively investigated. The cohort consisted of 77 men and 73 women (median age, 83â years). The BCC: SCC ratio was 56.7%: 43.3%. The tumor size and excision margin were significantly larger in the TSS group than in the OSS group (p = 0.03). The histopathological margin was positive after the first surgery in six cases, but was negative after additional resection in all cases, regardless of OSS or TSS. Local recurrence was not observed in this study. The frequency of postoperative sequelae (POS) in TSS was slightly lower than in OSS (17.4% vs. 27.9%, p = 0.16). A shorter average operation time per session was significantly associated with the location of the vertical defect [below adipose tissue vs. within adipose tissue, estimate: -0.28 (hour), p < 0.001] and surgical procedure [OSS vs. TSS, estimate: -0.13 (hour), p = 0.03] by multiple regression models. The ratio of general anesthesia was relatively lower in TSS than in OSS (9.8% vs. 17.3%, p = 0.12). Thus, TSS showed a good local curability and POS statistically equivalent to OSS, reducing the surgical burden, particularly shortening each operation time without any adverse events, despite the TSS group having significantly larger tumors than the OSS group. Since TSS is a simple procedure, it can be an outstanding option for facial BCC and SCC.
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BACKGROUND AND OBJECTIVES: 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. PATIENTS/METHODS: 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. RESULTS: 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). CONCLUSIONS: Surgical margin size has limited impact on margin control, relapse, and disease-specific death in high-risk cSCC.
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Carcinoma de Células Escamosas , Neoplasias Cutâneas , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Humanos , Margens de Excisão , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgiaRESUMO
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/mm3). Computed tomography demonstrated a diffuse thickening of the gastric wall. Esophagogastroduodenoscopy and endoscopic ultrasonography showed mucosal thickening due to edema, and histologic examination revealed severe invasion of eosinophils in the lamina propria. Subsequently, she was diagnosed with eosinophilic gastritis due to irAEs induced by nivolumab. Oral administration of prednisolone rapidly normalized her endoscopic and histologic findings, dramatically reducing her symptoms. This is a very rare and important case report of nivolumab-induced severe eosinophilic gastritis. Although gastric lesions as IrAEs is rare, it is necessary to differentiate eosinophilic gastritis if unexplained nausea occurred during the administration of immune checkpoint inhibitors.
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Antineoplásicos Imunológicos , Eosinofilia , Melanoma , Segunda Neoplasia Primária , Neoplasias Cutâneas , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Enterite , Eosinofilia/induzido quimicamente , Feminino , Gastrite , Humanos , Inibidores de Checkpoint Imunológico , Melanoma/tratamento farmacológico , Melanoma/patologia , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Nivolumabe/efeitos adversos , Prednisolona/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
HINTERGRUND UND ZIELE: 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. PATIENTEN/METHODEN: 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. ERGEBNISSE: 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. SCHLUSSFOLGERUNGEN: Die Größe des Resektionsrands hat einen begrenzten Einfluss auf Randkontrolle, Rezidive und krankheitsspezifischen Tod bei PEK mit hohem Risiko.
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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)-1ß, 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.
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Hidradenite Supurativa , Psoríase , Adalimumab/uso terapêutico , Anticorpos Monoclonais Humanizados , Hidradenite Supurativa/complicações , Hidradenite Supurativa/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/complicações , Psoríase/tratamento farmacológicoRESUMO
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.
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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.
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Antígenos CD34/metabolismo , Hemangiopericitoma/metabolismo , Miofibromatose/congênito , Neoplasias de Tecidos Moles/metabolismo , Actinas/imunologia , Actinas/metabolismo , Índice de Apgar , Biomarcadores Tumorais/metabolismo , Biópsia , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a Calmodulina/metabolismo , Desmina/metabolismo , Hemangiopericitoma/diagnóstico , Hemangiopericitoma/patologia , Humanos , Imuno-Histoquímica , Recém-Nascido de Baixo Peso , Recém-Nascido , Imageamento por Ressonância Magnética/métodos , Masculino , Proteínas dos Microfilamentos/metabolismo , Miofibromatose/diagnóstico , Miofibromatose/metabolismo , Miofibromatose/patologia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologia , Vimentina/metabolismo , CalponinasRESUMO
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Melanoma/mortalidade , Melanoma/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Criança , Feminino , Hospitais Universitários , Humanos , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
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.
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Antígenos CD19/sangue , Linfócitos B/imunologia , Movimento Celular , Hepatite C Crônica/imunologia , Fígado/virologia , Receptores CXCR3/sangue , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Hepatite C Crônica/sangue , Hepatite C Crônica/patologia , Humanos , Ligantes , Fígado/imunologia , Fígado/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
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.
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Fígado Gorduroso/fisiopatologia , Hepatite C , Cirrose Hepática Alcoólica/fisiopatologia , Cirrose Hepática/virologia , Fígado/irrigação sanguínea , Idoso , Velocidade do Fluxo Sanguíneo , Feminino , Artéria Hepática , Humanos , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Veia Porta , Tomografia Computadorizada por Raios X , XenônioRESUMO
AIM: We tailored extended treatments using pegylated interferon (PEG IFN) and ribavirin (RBV) to viral responses after initiation of therapy and investigated the efficacy and safety of its therapy for chronic hepatitis C (CHC) patients. METHODS: Eighty-two genotype 1b CHC patients were enrolled in the present study. All patients received PEG IFN-alpha-2b and weight-based RBV therapy. We defined a viral response in which serum HCV-RNA is undetectable at week 4 as rapid viral response (RVR), detectable at week 4 and undetectable by week 12 as early viral response (EVR), and detectable at week 12 and undetectable by week 24 as late viral response (LVR). We set the treatment duration depending on viral response; 48 weeks for RVR patients and 72 weeks for LVR. Furthermore, EVR patients received a short-term extension of treatment duration to 52-60 weeks. We prospectively investigated sustained viral response (SVR) rates of these groups. RESULTS: Overall SVR rate for the total patient group was 57.3%. SVR rates of the RVR, EVR and LVR patients were 100%, 80.5% and 40.0%, respectively. Nine patients could not complete this treatment protocol. Baseline platelet count and mutation in the interferon sensitivity-determining region of NS5A were significant independent predictors of SVR, and amino acid substitution of the core region was a significant independent predictor of non-viral response by multivariate logistic regression analyses. CONCLUSION: The results indicate that short-treatment extension of PEG IFN plus RBV treatment protocols in EVR patients can improve overall SVR rates.
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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 (lambda 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 lambda value, and correlations between the stage of fibrosis and TBFs. RESULTS: The lambda value showed significant positive correlations with both grade of steatosis (r = 0.813, P < 0.001) and each 10% range of histological fatty infiltration (r = 0.926, P < 0.001). A significant negative correlation was seen between lambda value and the liver : spleen ratio (r = -0.835, P < 0.001). Portal venous tissue blood flow and total hepatic tissue blood flow showed significant negative correlations with the progression of fibrosis (r = -0.465, P < 0.01; r = -0.433, P < 0.01, respectively). Total hepatic tissue blood flow tended to decrease with progressing grade of steatosis. CONCLUSION: Xe-CT offers a convenient and objective method for evaluating fatty infiltration and changes in blood flow in the entire liver, and appears useful for detailed evaluation of patients with NASH.
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BACKGROUND AND OBJECTIVE: In Japan the prevalence of the hepatitis C virus (HCV) antibody is highest in the elderly population. Therefore, it is important for elderly patients to undergo interferon (IFN) therapy. In patients with HCV genotype 1b and a high viral load, the sustained virological response (SVR) rate is lower in older compared with younger patients receiving combination antiviral therapy. In addition, inadequate adherence to combination therapy is often seen in elderly patients, and is associated with reduced response rates. The aim of this retrospective analysis was to evaluate the effects of host-related factors (i.e. sex, age, baseline HCV RNA level, bodyweight and fibrosis stage) and peginterferon (PEG IFN)-alpha-2a plus ribavirin dose reductions on SVR rates. METHODS: A total of 192 treatment-naive patients with a HCV genotype 1b infection and a high viral load were included in the analysis. Patients had been enrolled into a phase III trial of 48 weeks of treatment with PEG IFN-alpha-2a plus ribavirin or PEG IFN-alpha-2a plus placebo. All patients were evaluated for effect of drug exposure on SVR. In addition, the impact of host-related factors or dose reductions on SVR was assessed. RESULTS: Approximately 30% of patients were considered elderly (> or =60 years of age). The overall SVR rate was significantly higher in patients treated with combination therapy versus monotherapy (59.4% vs 24.0%, p < 0.001). Attainment of an SVR following combination therapy was not influenced by any factor evaluated in the analysis, although elderly males were associated with decreased SVR rates. Younger age (odds ratio [OR] 1.081; 95% CI 1.125, 1.034; p = 0.0009), lower baseline HCV RNA levels (OR 1.003; 95% CI 1.006, 1.001; p = 0.006) and a severe fibrosis stage (F3/4) [OR 6.194; 95% CI 1.037, 37.000; p = 0.0455] significantly increased the likelihood of achieving an SVR with monotherapy. In the combination therapy group, patients maintaining a full dosage schedule of PEG IFN-alpha-2a and ribavirin and those requiring dose reductions of either study drug had similar SVR rates (64.5% vs 61.9%). However, the SVR rate was reduced to 33.3% among patients who discontinued combination therapy. Three out of the 31 patients who received the full dosage schedule were elderly patients. In addition, of the 15 patients who discontinued combination therapy, three were <50 years of age and six were > or =60 years of age. The SVR rate was reduced in patients with cumulative PEG IFN-alpha-2a and ribavirin doses of <60%; the majority of these patients were elderly. CONCLUSION: The attainment of an SVR following PEG IFN-alpha-2a plus ribavirin combination therapy was not influenced by any of the host-related factors evaluated in this analysis, although elderly males were associated with a decreased SVR rate. Younger age, male sex and lower baseline HCV RNA levels significantly increased the likelihood of achieving an SVR with monotherapy. In addition, dose reductions appeared to have a negative impact on SVR in elderly patients. Therefore, it is important to minimize PEG IFN-alpha-2a and ribavirin dose reductions by effectively managing treatment-related adverse events in elderly patients.
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Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Carga Viral , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Bases de Dados Factuais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C/sangue , Hepatite C/virologia , Interações Hospedeiro-Patógeno , Humanos , Injeções Subcutâneas , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/uso terapêutico , Japão , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , RNA Viral/sangue , RNA Viral/isolamento & purificação , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
AIM: Nearly 20% of chronic hepatitis C (CHC) patients with genotype 2 hepatitis C virus (HCV) infection are not curable, even by interferon (IFN)-ribavirin combination therapy. The aim of this study is to investigate the factors that determine the efficacy of combination therapy in patients with genotype 2 HCV infection. METHODS: Fifty patients with CHC who underwent a treatment of 6 MU IFN alpha-2b with ribavirin for 24 weeks were retrospectively analyzed. RESULTS: All the patients showed no serum HCV-RNA within 12 weeks after starting the therapy. Forty-one of the 50 patients (82%) achieved a sustained virological response (SVR). The age, sex, genotype (2a vs. 2b) and grade/stage of the liver by histopathology and pretreatment viral load werenot different between the sustained responders and relapsers. Univariate analysis showed that an earlier viral clearance from blood and a larger number of amino acid substitutions in the interferon sensitivity determining region (ISDR) were predictors of SVR. Multivariate analysis showed that a large number of amino acid substitutions in the ISDR was a predictor of SVR. CONCLUSION: The characterization of the amino acid sequences of ISDR may be helpful for predicting a relapse after combination therapy in patients with genotype 2 HCV infection.
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BACKGROUND: Combined pegylated interferon and ribavirin has improved chronic hepatitis C (CH-C) therapy; however, sustained virological response is achieved in only about half of the patients with a 1b genotype infection. We assessed oral ursodeoxycholic acid (UDCA) on serum biomarkers as a possible treatment for interferon non-responders. 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, identifier NCT00200343. RESULTS: ALT, AST and GGT decreased at week 4 and then remained constant during drug administration. The median changes (150, 600 and 900 mg/day, respectively) 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.
Assuntos
Colagogos e Coleréticos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Idoso , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Ácidos e Sais Biliares/sangue , Biomarcadores/sangue , Colagogos e Coleréticos/administração & dosagem , Colagogos e Coleréticos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Hepacivirus/isolamento & purificação , Hepatite C Crônica/enzimologia , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/efeitos adversos , Carga Viral , gama-Glutamiltransferase/sangueRESUMO
BACKGROUND: An increase in the number of acute hepatitis patients with hepatitis B virus (HBV) of non-indigenous genotypes may reduce the efficacy of vaccination against HBV. METHODS: We have determined the amino acid (aa) sequences in the major hydrophilic region (MHR) in the S region of HBV in patients with acute hepatitis B and compared those with the ones from HBV strains used for the production of HBV vaccines commercially available in Japan. RESULTS: Of 48 patients studied, 11 were infected with genotype A, 11 with genotype B and 26 with genotype C HBV. The aa sequences of the nine genotype A isolates were the same as the aa sequence of J02205 which is used for the production of one of the commercially available recombinant vaccines. The aa sequences of the 11 genotype B isolates differed from the aa sequence of J02205 in two or three amino acids. Of the26 genotype C isolates, 22 had the same aa sequence as X01587 which is used for the production of another recombinant vaccine. The remaining genotype C isolates had aa substitutions at aa131, which have a potential to alter the hydropathy and the three-dimensional structure of the MHR. The differences among the three current HBV vaccines in aa sequences in the MHR theoretically alter the hydropathy and three-dimensional structure. CONCLUSION: Our results suggest that the transmission of HBV isolates with different genotypes or with aa substitutions in the MHR might reduce the efficacy of currently available HBV vaccines in the protection of HBV infections.