Objective Response and Progression-Free Survival Contribute to Prolong Overall Survival in Atezolizumab plus Bevacizumab Treatment for Unresectable Hepatocellular Carcinoma.

INTRODUCTION: Atezolizumab plus bevacizumab (Atez/Bev) is a standard treatment for unresectable hepatocellular carcinoma (HCC) due to its good antitumor and survival prolongation effects. Post-progression survival (PPS) has been reported to be a great contributor in the treatment with tyrosine kinase inhibitors for unresectable HCC. This study aimed to clarify the significance of progression-free survival (PFS) or PPS of Atez/Bev treatment for HCC. METHODS: We analyzed the correlations of PFS and PPS with overall survival (OS) in studies of HCC patients treated with Atez/Bev and evaluated the contribution to OS in Atez/Bev treatment with patients at our institutions as clinical practice. RESULTS: Analysis of 18 studies involving 3,752 patients treated with Atez/Bev found that PPS had a stronger correlation with OS (R2 = 0.872, p < 0.001) than did PFS (R2 = 0.605, p = 0.001). Analysis of 80 patients with unresectable HCC treated with Atez/Bev found that presence of antitumor responses during Atez/Bev was the most significant contributor to OS, and post-progression treatment after Atez/Bev also significantly contribute to OS. CONCLUSION: The presence of antitumor response with tumor shrinkage during Atez/Bev treatment contributes to good OS through its durable response. Atez/Bev treatment could be considered as first-line treatment for unresectable HCC. However, there is a need for optimal biomarkers for good antitumor response.

Long term changes in thrombocytopenia and leucopenia after HCV eradication with direct-acting antivirals.

BACKGROUND: Thrombocytopenia due to hypersplenism is a major complication of hepatitis C virus (HCV)-associated cirrhosis. HCV eradication improves these complications in some patients, but the long-term effects of HCV eradication on these complications remain unclear, especially in patients treated with direct acting antivirals (DAAs). The aim was to evaluate long term changes in thrombocytopenia and leucopenia after HCV eradication with DAAs. METHODS: The present multicenter study retrospectively evaluated changes over 5 years in thrombocytopenia and leukocytopenia, as well as changes in liver fibrosis markers and spleen size, in 115 patients with HCV-cirrhosis treated with DAAs. RESULTS: Thrombocytopenia and leukocytopenia were improved 4 weeks after DAA administration, with thrombocytopenia show further gradual improvement over the next year. Fib-4 index was markedly reduced 1 year after DAA, followed by subsequent gradual reduction over the next 4 years. Spleen size showed gradual annual reductions, with patients experiencing spleen size reduction characterized at baseline by bilirubinemia. CONCLUSIONS: Rapid DAA-associated HCV eradication might lead to rapid disappearance of liver inflammation and bone marrow suppression due to HCV infection. HCV eradication may gradually improve portal hypertension, reducing spleen size.

Nadir lymphocytopenia as a risk factor of bloodstream infection during molecular targeting pharmacotherapy in multiple myeloma.

OBJECTIVE: Molecular targeting pharmacotherapy (MTP) with proteasome inhibitors and immunomodulatory drugs has led to a remarkable improvement in the effectiveness of multiple myeloma (MM) therapy. However, the effect of MTP on the occurrence of infections in patients with MM remains unclear. We aimed to identify the incidence of and risk factors for bloodstream infection (BSI) in patients with MM undergoing MTP. MATERIALS AND METHODS: We conducted a retrospective cohort study. We reviewed the medical records of 108 inpatients with MM at the National Defense Medical College Hospital between January 2010 and January 2017. Univariate and multivariate analyses were conducted to identify risk factors for BSI. RESULTS: The incidence of BSI in patients with MM receiving MTP (n = 188) was 6.9%, which was significantly lower than the 52.6% in patients receiving cytotoxic chemotherapy (n = 57). We found that the most important risk factor for BSI in patients receiving MTP was lymphocytopenia at nadir (< 200/µL). In contrast, the risk factor for BSI in patients receiving cytotoxic chemotherapy was the number of regimens performed. CONCLUSION: Our study suggests that the incidence of BSI is lower in patients with MM receiving MTP than in those receiving cytotoxic chemotherapy and that lymphocytopenia at nadir may be a risk factor for BSI in patients with MM receiving MTP. Since previous clinical trials with MTP showed that the frequency of myelosuppression and infections was high in the Japanese population, these findings might provide novel insights into MTP for Japanese patients with MM.
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Survival Benefit of Tolvaptan for Refractory Ascites in Patients with Advanced Cirrhosis.

AIMS: The study aimed to evaluate the effects of tolvaptan treatment on survival of patients with decompensated liver cirrhosis with refractory ascites. METHODS: This multicenter, retrospective, observational study included patients with cirrhosis who were treated with tolvaptan for hepatic ascites refractory to conventional diuretics. Patients who could and could not decrease accompanying diuretics within 1 month after tolvaptan administration were defined as the "Decreased" and "Not-decreased" groups, respectively. RESULTS: Median body weight change 1 week after tolvaptan treatment was -1.95 kg, with the 50% of patients experiencing a 2 kg/week reduction. Spot urinary sodium was found to be a better predictor of tolvaptan response than liver function and liver fibrosis markers. Median survival was significantly longer (not reached versus 116 days, p = 0.005) and serum creatinine concentrations 12 weeks after tolvaptan administration significantly lower (0.99 vs. 1.55 mg/dL, p < 0.05) in the Decreased than in the Not-decreased group. Multivariate analysis showed that the presence of viable hepatocellular carcinoma (hazards ratio [HR] 2.14, p = 0.02) and a decrease in diuretics were independently prognostic of survival (HR 0.36, p < 0.01). CONCLUSIONS: The maintenance of renal function is essential in enhancing survival of patients with cirrhosis. Doses of diuretics should be adjusted appropriately during tolvaptan treatment.

A comprehensive intervention following the clinical pathway of eating and swallowing disorder in the elderly with dementia: historically controlled study.

BACKGROUND: Eating problems in patients with advanced dementia are strongly associated with their deteriorating survival. Food and drink intake in people with dementia may be supported by specific interventions, but the effectiveness of such interventions is backed by almost no evidence. However, comprehensive geriatric assessment (CGA) might potentially clarify the etiology of decreased oral intake in people with dementia; thus improving their clinical outcomes. METHODS: This study was a single-arm, non-randomized trial that included historically controlled patients for comparison. We defined elderly patients with both severely decreased oral intake depending on artificial hydration and/or nutrition (AHN) and dementia as "Eating and Swallowing Disorder of the Elderly with Dementia (ESDED)". In the intervention group, participants received CGA through the original clinical pathway with multidisciplinary interventions. This was followed by individualized therapeutic interventions according to assessment of the etiology of their eating problems. RESULTS: During the intervention period (between 1st April 2013 and 31st March 2015), 102 cases of ESDED were enrolled in the study and 90 patients had completed receiving CGA. Conversely, 124 ESDED patient controls were selected from the same hospital enrolled during the historical period (between 1st April 2011 and 31st March 2012). Most participants in both groups were bedridden with severe cognitive impairment. For the intervention group, an average of 4.3 interventional strategies was recommended per participant after CGA. Serological tests, diagnostic imaging and other diagnostic examinations were much more frequently performed in the intervention group. Recovery rate from ESDED in the intervention group was significantly higher than that in the historical group (51% v.s. 34%, respectively, P = 0.02). The 1-year AHN-free survival in the intervention group was significantly higher than that in the historical group (28% v.s. 15%, respectively, P = 0.01). No significant difference between the two groups was found for 1-year overall survival (37% v.s. 28%, respectively, P = 0.08). CONCLUSIONS: Use of CGA with multidisciplinary interventions could improve the functional status of eating and allow elderly patients with severe eating problems and dementia to survive independently without the need for AHN. TRIAL REGISTRATION: ISRCTN57646445 , this trial was retrospectively registered on 8th December 2015.

A novel type of selective immunoglobulin m deficiency in a patient with autoimmune liver cirrhosis with recurrent hepatocellular carcinoma: a case report and review of the literature.

A 64-year-old female with advanced liver cirrhosis who had never experienced severe infections presented in 2004 with general malaise. At the time, her serum showed low levels of immunoglobulin (Ig) M (11 mg/dl) with high levels of both IgG (2,942 mg/dl) and IgA (808 mg/dl). Because serum levels of IgG and IgA in previous cases of selective IgM deficiency were normal, this case could have a novel immunological mechanism. By 2006, serum IgM was undetectable (<5 mg/dl). Liver biopsy showed liver cirrhosis from autoimmune hepatitis. She had no other autoimmune diseases or hematological malignancies. She developed hepatocellular carcinoma (HCC) several times and died of liver failure. Immunological analyses performed before the first diagnosis of HCC showed polyclonal γ-globulin elevation, normal chromosome and normal gene rearrangement of immunoglobulin heavy chain Cµ. Peripheral blood showed low count B cells with few surface IgM-positive B lymphocytes, but the percentages of T cell subsets were normal. Expression of activation-induced cytidine deaminase (AID), which plays a critical role in immunoglobin class switching, was found to be overexpressed in the HCC tissue and B cells in bone marrow. This phenomenon could account for the clinical and immunological features of this case. In conclusion, we propose a novel type of selective IgM deficiency in association with the overexpression of AID.

Identification and Prognostication of End-of-Life State Using a Japanese Guideline-Based Diagnostic Method: A Diagnostic Accuracy Study.

Purpose: Prognostic uncertainty can be a barrier to providing palliative care. Accurate prognostic estimation for patients at the end of life is challenging. This study aimed to evaluate the accuracy of end-of-life diagnosis using our unique diagnostic method. Patients and Methods: A retrospective longitudinal observational study was conducted through collaboration among three medical facilities in a rural super-aged community in Japan. In 2007, we established a unique end-of-life diagnostic process comprising (1) physicians' judgement, (2) disclosure to patients, and (3) discussion at an end-of-life case conference (EOL-CC), based on Japanese end-of-life-related guidelines. Research subjects were consecutive patients discussed in EOL-CC between January 1, 2010, and September 30, 2017. The primary outcome was mortality within 6 months after the initial EOL-CC decision. Sensitivity, specificity, and diagnostic odds ratio were calculated using EOL-CC diagnosis (end-of-life or non-end-of-life) as an index test and overall survival (<6 months or ≥6 months) as a reference standard. Results: In total, 315 patients were eligible for survival analysis (median age 89, range 54-107). The study population was limited to patients with severe conditions such as advanced cancer, organ failures, advanced dementia with severe deterioration in functioning. EOL-diagnosis by our methods was associated with much lower survival rate at 6 months after EOL-CC than non-EOL-diagnosis (6.9% vs 43.5%; P < 0.001). Of the patients, 297 were eligible for diagnostic accuracy analysis (median age 89, range 54-107). The EOL-diagnosis showed high sensitivity (0.95; 95% confidence interval [CI] 0.92-0.97) but low specificity (0.35; 95% CI 0.20-0.53) against the outcomes. It also showed a high diagnostic odds ratio (10.32; 95% CI 4.08-26.13). Conclusion: The diagnostic process using the Japanese end-of-life guidelines had tolerable accuracy in identification and prognostication of end of life.

Direct-acting antivirals for hepatitis C virus-infected patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients has a high risk of recurrence. Although eradication of HCV is expected to reduce this risk, the risk in patients with a history of HCC may be high after treatment with direct-acting antivirals (DAAs). AIM: To determine the risk factors for HCC recurrence in patients with HCV and a history of HCC. METHODS: The risk of HCC recurrence in patients with a history of HCC and/or of HCC occurrence in patients without a history of HCC after DAA therapy was retrospectively analyzed in 311 HCV patients treated at our institution and several neighboring hospitals. The frequency and predictors of HCC recurrence/ occurrence after DAA treatment were included in these analyses. The clinical course of HCC before and after DAA treatment was also evaluated. RESULTS: HCV patients with a history of HCC were older and had greater progression of liver fibrosis and diabetes than patients without a history of HCC. Median recurrence-free survival (RFS) was 1092 d in patients with a history of HCC, and post-DAA HCC recurrence/occurrence was observed in 29 patients (53.7%) with and 5 (1.9%) without a history of HCC over 6 years (P < 0.001). RFS in patients with a history of HCC did not differ significantly before and after DAA treatment. The frequency of HCC recurrence/occurrence in patients with a history of HCC was lower after than before DAA treatment. Multivariate analysis showed that the incidence rate of HCC recurrence/occurrence before DAA treatment was the only independent predictor of HCC recurrence/occurrence after DAA treatment. Liver function was well preserved and clinical course was good in patients with HCC recurrence/occurrence after DAA therapy. CONCLUSION: DAA therapy in patients infected with HCV is also effective in patients with a history of HCC. Curative treatment for HCC is desirable before DAA therapy. The frequency of HCC recurrence/occurrence before DAA therapy was associated with a significantly increased risk of HCC recurrence after DAA therapy. Careful observation after DAA therapy is required in patients with a history of HCC.

Impact of Post-progression Survival on Outcomes of Lenvatinib Treatment for Unresectable Hepatocellular Carcinoma: A Systematic Review and Retrospective Cohort Study.

BACKGROUND/AIM: Lenvatinib is a tyrosine kinase inhibitor (TKI) more effective against hepatocellular carcinoma (HCC) than sorafenib, making lenvatinib a first-line treatment option for patients with unresectable HCC. In patients treated with sorafenib, post-progression survival (PPS) rather than progression-free survival (PFS) is essential for overall survival (OS). However, the importance of PPS for OS in patients treated with lenvatinib is uncertain, and optimal treatment after lenvatinib failure has not yet been established. PATIENTS AND METHODS: The present study investigated the correlations of PFS and PPS with OS in studies of HCC patients treated with lenvatinib by weighted linear regression analysis. Furthermore, the contribution of treatment regimens after lenvatinib failure to OS were evaluated in daily clinical practice. RESULTS: An analysis of 20 studies with 4,054 patients found that PPS had a stronger correlation with OS (r=0.869, p<0.001) than did PFS (r=0.505, p=0.007). Analysis of 79 patients with unresectable HCC treated with first-line lenvatinib showed that subsequent treatment was the most significant contributor to OS. Second-line sorafenib was administered to 25 patients, with late transition to third-line treatment being highest among patients who received second-line treatment. CONCLUSION: PPS contributes significantly to OS in HCC treatment with TKIs, with multi-sequential treatment being a key determinant of longer OS.

Pulmonary Pleomorphic Carcinoma Mimicking Primary Sarcoma of the Neck: A Case Report and Literature Review.

We describe our challenge in diagnosing an unusual and rapidly progressing case of pulmonary pleomorphic carcinoma (PPC)-a rare, poorly differentiated, or undifferentiated non-small-cell carcinoma that can metastasize locally or distantly and has a poor prognosis. Our patient was an elderly man with a one-month history of abdominal pain, anorexia, and weight loss, diagnosed with atrophic gastritis via endoscopy, and treated medically without improvement. A week later, this patient developed pain in the head, neck, and shoulder area, and further examination revealed a thickening of his left neck and shoulder, with no palpable lymph nodes. Computed tomography (CT) of the neck, chest, and abdomen led us to believe that we might be dealing with primary sarcoma of the neck since no lung mass was evident. Further investigation could not be performed because the patient's status deteriorated rapidly. An autopsy revealed that soft tissue in the left neck and the mesentery was invaded by poorly differentiated polymorphic malignant cells, which were also seen in the lung lesion. Immunohistochemically, these malignant cells were all positive for AE1/AE3, CAM5.2, TTF-1, Napsin-A, and Vimentin. The cells were also positive for programmed death-ligand 1 staining with a low level of tumor proportion score (over 1%). The final diagnosis was PPC with metastases to soft tissues in the left neck and the mesentery. A review of previous case reports of PPC revealed that soft tissue is an uncommon site for metastasis, and that our CT findings were rather unusual. We hereby present our case and review of published case reports, with the hope that an awareness of the heterogeneous features of PPC could prompt timely biopsy and histological diagnosis.

Understanding the immunopathogenesis of COVID-19: Its implication for therapeutic strategy.

Although 80% of individuals infected with the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) recover without antiviral treatments, the other 20% progress to severe forms of pulmonary disease, suggesting that the host's immune response to the virus could influence the outcome of coronavirus disease 2019 (COVID-19). SARS-CoV-2 infects alveolar epithelial type 2 cells expressing angiotensin-converting enzyme 2, and these infected epithelial cells recruit dendritic cells, neutrophils and monocytes /macrophages, leading to the activation of CD4+ and CD8+ T cells. These cells launch an antiviral immune response, but are able to completely suppress viral replication or completely eradicate virus in a limited proportion of infected patients. In other patients, viral suppression is incomplete and the numbers of circulating B and T cells are subsequently reduced by as yet unknown mechanisms. Some patients with sustained viral replication progress to a severe condition called cytokine storm. Although antiviral drug(s) should be considered early in infection to prevent progression, there have been no antiviral therapies proven to be effective for significantly inhibiting the viral replication in vivo and suppressing the progression to cytokine storm. Blocking the action of cytokines with dexamethasone or anti-interleukin-6 could have a pivotal role in treatment of those patients. Therapeutic strategy should therefore be based on viral kinetics and the immunopathology of COVID-19.

Liver in systemic disease.

Potential causes of abnormal liver function tests include viral hepatitis, alcohol intake, nonalcoholic fatty liver disease, autoimmune liver diseases, hereditary diseases, hepatobiliary malignancies or infection, gallstones and drug-induced liver injury. Moreover, the liver may be involved in systemic diseases that mainly affect other organs. Therefore, in patients without etiology of liver injury by screening serology and diagnostic imaging, but who have systemic diseases, the abnormal liver function test results might be caused by the systemic disease. In most of these patients, the systemic disease should be treated primarily. However, some patients with systemic disease and severe liver injury or fulminant hepatic failure require intensive treatments of the liver.

Practical guidelines for diagnosis and early management of drug-induced liver injury.

The spectrum of drug-induced liver injury (DILI) is both diverse and complex. The first step in diagnosis is a suspicion of DILI based on careful consideration of recent comprehensive reports on the disease. There are some situations in which the suspicion of DILI is particularly strong. Exclusion of other possible etiologies according to the pattern of liver injury is essential for the diagnosis. In patients with suspected DILI, diagnostic scales, such as the Councils for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) scale, may be helpful for the final diagnosis. Early management of DILI involves prompt withdrawal of the drug suspected of being responsible, according to serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin (T-Bil). However, as DILI patients may show resolution of liver injury without discontinuation of the drug, it should be carefully evaluated whether the suspected drug should be discontinued immediately with adequate consideration of the importance of the medication.

Gut microbiota in common elderly diseases affecting activities of daily living.

Gut microbiota are involved in the development or prevention of various diseases such as type 2 diabetes, fatty liver, and malignancy such as colorectal cancer, breast cancer and hepatocellular carcinoma. Alzheimer's disease, osteoporosis, sarcopenia, atherosclerotic stroke and cardiovascular disease are major diseases associated with decreased activities of daily living (ADL), especially in elderly people. Recent analyses have revealed the importance of gut microbiota in the control of these diseases. The composition or diversity of these microbiota is different between patients with these conditions and healthy controls, and administration of probiotics or prebiotics has been shown effective in the treatment of these diseases. Gut microbiota may affect distant organs through mechanisms that include regulating the absorption of nutrients and/or the production of microbial metabolites, regulating and interacting with the systemic immune system, and translocating bacteria/bacterial products through disrupted mucosal barriers. Thus, the gut microbiota may be important regulators in the development of diseases that affect ADL. Although adequate exercise and proper diet are important for preventing these diseases, their combination with interventions that manipulate the composition and/or diversity of gut microbiota could be a promising strategy for maintaining health condition and preserving ADL. This review thus summarizes current understanding of the role of gut microbiota in the development or prevention of diseases closely associated with the maintenance of ADL.

Branched-chain amino acids in liver diseases.

Branched chain amino acids (BCAAs) are involved in various bioprocess such as protein metabolism, gene expression, insulin resistance and proliferation of hepatocytes. BCAAs have also been reported to suppress the growth of hepatocellular carcinoma (HCC) cells in vitro and to be required for immune cells to perform the function. In advanced cirrhotic patients, it has been clarified that serum concentrations of BCAA are decreased, whereas those of aromatic amino acids (AAAs) are increased. These alterations are thought to be the causes of hepatic encephalopathy (HE), sarcopenia and hepatocarcinogenesis and may be associated with the poor prognosis of patients with these conditions. Administration of BCAA-rich medicines has shown positive results in patients with cirrhosis.

Band calculations for 4f systems based on the dynamical mean field theory.

Recent band calculations for Ce compounds based on the dynamical mean field theory (DMFT) are reported. The auxiliary impurity problem has been solved by a method named NCAf(2)vc, which includes the correct exchange process of the [Formula: see text] virtual excitation, the crystalline field splitting (CFS), and the spin-orbit interaction (SOI) of the self-energy. These are necessary features in the quantitative band theory for Ce compounds. The results of applications on Ce metal and Ce-monopnictides are presented.

Recent advances in the management of pruritus in chronic liver diseases.

Pruritus is a symptom found in patients with chronic liver diseases, especially cholestatic liver diseases such as primary biliary cholangitis. This symptom impairs patient quality of life by disturbing sleep and may lead to consideration of liver transplantation. Mechanisms implicated in pruritus have been associated with the peripheral and central nervous systems, leading to the development of various therapeutic options. Little evidence for the efficacy of most of these treatments is currently available, indicating a need for further investigations.

Psoas muscle volume as a predictor of peripheral neurotoxicity induced by primary chemotherapy in ovarian cancers.

PURPOSE: Low skeletal muscle mass (sarcopenia) has been reported to have an influence on survival and toxicities of chemotherapy in several solid tumors. The impact of sarcopenia on the treatment of ovarian cancers has not been determined. The present study aimed to evaluate correlation between sarcopenia and toxicities of chemotherapy in ovarian cancers. METHODS: Medical charts of the ovarian cancer patients that received chemotherapy with paclitaxel and carboplatin at our hospital between 2010 and 2015 were retrospectively reviewed. Muscle areas of bilateral psoas major muscles at the fifth lumbar vertebra were measured using images obtained by computed tomography. The volume of muscle and clinicopathological factors were evaluated for toxicities of chemotherapy. The protocol of the present study was approved by the institutional review board of our institution. RESULTS: A total of 76 patients with ovarian cancers were identified, and enrolled in the present study. Median psoas index (PI, the psoas muscle major cross-sectional area divided by the height squared) was 583 mm2/m2 (range 326-999). The patients with low PI developed peripheral neuropathy more frequently compared with those with high PI (32 vs. 11%; P = 0.047). PI value was not associated with other toxicities such as neutropenia and thrombocytopenia. PI value was associated with grade 2 or higher peripheral neuropathy in univariate analysis (OR = 3.92; 95% CI 1.21-15.32; P = 0.02) and multivariate analysis (OR = 3.93; 95% CI 1.17-15.87; P = 0.03). CONCLUSIONS: PI value was significantly associated with peripheral neuropathy induced by combination therapy with paclitaxel and carboplatin in ovarian cancer patients. Although further studies are needed to confirm the results, the volume of skeletal muscle mass could be a potential biomarker to predict toxicities in ovarian cancer patients.

Is there any predictor for hypersensitivity reactions in gynecologic cancer patients treated with paclitaxel-based therapy?

PURPOSE: Recently, generic drugs of paclitaxel have been commonly used mainly by economic reasons; however, predictive factors for toxicities are not fully determined. Hypersensitivity reaction (HSR) is one of the most important adverse events in the paclitaxel-based therapy, and sometimes leads to lethal condition. The aim of the study was to identify predictors for HSR in patients treated with paclitaxel-based regimens. METHODS: All the patients treated with chemotherapy including paclitaxel at our hospital between 1998 and 2013 were retrospectively evaluated. Clinicopathological factors of the patients that developed HSR and those without HSR were compared, and predictive factors for HSR were identified. RESULTS: Among 414 patients enrolled in the study, 26 patients (6.3%) developed HSR. Multivariate analyses showed that younger age (odds ratio 6.31), a history of allergy (odds ratio 3.79), and short-course premedication (odds ratio 14.1) were identified as predictive factors for HSR. There was no significant difference in the incidence of HSR between original paclitaxel and generic drug. The incidence of HSR was higher as the number of these predictors was accumulated. CONCLUSIONS: Three factors were identified as predictive factors for HSR: younger age, a history of allergy, and short-course premedication. Accumulation of these factors increased the incidence of HSR; however, the use of generic drug was not associated HSR in gynecologic cancer patients.

New horizon for radical cure of chronic hepatitis B virus infection.

About 250 to 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and about 700000 patients per year die of HBV-related cirrhosis or hepatocellular carcinoma (HCC). Several anti-viral agents, such as interferon and nucleos(t)ide analogues (NAs), have been used to treat this disease. NAs especially have been shown to strongly suppress HBV replication, slowing the progression to cirrhosis and the development of HCC. However, reactivation of HBV replication often occurs after cessation of treatment, because NAs alone cannot completely remove covalently-closed circular DNA (cccDNA), the template of HBV replication, from the nuclei of hepatocytes. Anti-HBV immune responses, in conjunction with interferon-γ and tumor necrosis factor-α, were found to eliminate cccDNA, but complete eradication of cccDNA by immune response alone is difficult, as shown in patients who recover from acute HBV infection but often show long-term persistence of small amounts of HBV-DNA in the blood. Several new drugs interfering with the life cycle of HBV in hepatocytes have been developed, with drugs targeting cccDNA theoretically the most effective for radical cure of chronic HBV infection. However, the safety of these drugs should be extensively examined before application to patients, and combinations of several approaches may be necessary for radical cure of chronic HBV infection.