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.

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.

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.

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.

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.

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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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.

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.

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.

Persistent molecular remission of refractory acute myeloid leukemia with inv(16)(p13.1q22) in an elderly patient induced by cytarabine ocfosfate hydrate.

The prognosis of relapsed acute myeloid leukemia (AML) in elderly patients is dismal, even if the AML exhibits a good prognostic karyotype, such as inv(16)(p13.1q22). We present a 72-year-old female with AML with inv(16)(p13.1q22) who suffered five episodes of relapse with temporary complete remission. Maintenance chemotherapy with oral cytarabine ocfosfate hydrate eventually produced persistent molecular complete remission of her AML that had not been induced by conventional regimens including intensive chemotherapy and low dose cytarabine therapy. The high level of tolerability to oral cytarabine ocfosfate hydrate may offer elderly patients with this type of AML a good chance for a cure.

Branched-chain amino acids in liver diseases.

Branched chain amino acids (BCAAs) have been shown to affect gene expression, protein metabolism, apoptosis and regeneration of hepatocytes, and insulin resistance. They have also been shown to inhibit the proliferation of liver cancer cells in vitro, and are essential for lymphocyte proliferation and dendritic cell maturation. In patients with advanced chronic liver disease, BCAA concentrations are low, whereas the concentrations of aromatic amino acids such as phenylalanine and tyrosine are high, conditions that may be closely associated with hepatic encephalopathy and the prognosis of these patients. Based on these basic observations, patients with advanced chronic liver disease have been treated clinically with BCAA-rich medicines, with positive effects.

Hepatic manifestations in hematological disorders.

Liver involvement is often observed in several hematological disorders, resulting in abnormal liver function tests, abnormalities in liver imaging studies, or clinical symptoms presenting with hepatic manifestations. In hemolytic anemia, jaundice and hepatosplenomegaly are often seen mimicking liver diseases. In hematologic malignancies, malignant cells often infiltrate the liver and may demonstrate abnormal liver function test results accompanied by hepatosplenomegaly or formation of multiple nodules in the liver and/or spleen. These cases may further evolve into fulminant hepatic failure.

Liver physiology and liver diseases in the elderly.

The liver experiences various changes with aging that could affect clinical characteristics and outcomes in patients with liver diseases. Both liver volume and blood flow decrease significantly with age. These changes and decreased cytochrome P450 activity can affect drug metabolism, increasing susceptibility to drug-induced liver injury. Immune responses against pathogens or neoplastic cells are lower in the elderly, although these individuals may be predisposed to autoimmunity through impairment of dendritic cell maturation and reduction of regulatory T cells. These changes in immune functions could alter the pathogenesis of viral hepatitis and autoimmune liver diseases, as well as the development of hepatocellular carcinoma. Moreover, elderly patients have significantly decreased reserve functions of various organs, reducing their tolerability to treatments for liver diseases. Collectively, aged patients show various changes of the liver and other organs that could affect the clinical characteristics and management of liver diseases in these patients.

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.

An elderly man with syncytial giant cell hepatitis successfully treated by immunosuppressants.

Here, we report an elderly man with acute-on-chronic hepatitis accompanied by massive ascites. He showed elevated serum transaminase and anti-nuclear antibody (ANA) levels. Liver biopsy showed diffuse multinucleated giant hepatocytes with interface hepatitis, and he recovered with administration of azathioprine in addition to corticosteroids. Follow-up liver biopsy after recovery showed improvement of hepatic inflammation and reduction of giant hepatocyte formation. The patient is receiving low-dose corticosteroid maintenance therapy and he has remained healthy for 8 years to date. Active immunosuppressive treatment may be beneficial in patients with adult syncitial giant cell hepatitis (AGCH).

Role of liver-infiltrating CD3+CD56+ natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease.

BACKGROUND/AIMS: Natural killer T (NKT) cells have been recently reported to concern with various lipid disorders. The role of NKT cells in the hepatic lipid disorder, nonalcoholic fatty liver disease (NAFLD), has, however, not yet been clarified. To assess the role of NKT cells in the pathogenesis of NAFLD, we analyzed the composition and function of liver-infiltrating cells isolated from liver biopsy specimens of patients with NAFLD. METHODS: Specimens from 62 patients with NAFLD were studied, and 54 specimens among them reacted immunohistochemically with monoclonal antibodies against various surface markers. Moreover, using flow cytometry, we analyzed surface markers and intracytoplasmic cytokines of intrahepatic CD3+CD56+ cells in 12 patients among them. RESULTS: Among the various populations of liver-infiltrating cells, only the numbers of CD56+ cells were significantly increased as NAFLD disease activity (NAFLD activity score, NAS) increased. Furthermore, expression of CD1d, a ligand for NKT cells, was also increased in NAFLD as NAS increased. Flow cytometric analysis showed that most CD56+ cells were Valpha24+ NKT cells, which produced more IFN-gamma and IL-4 as NAS increased. CONCLUSION: Intrahepatic CD3+CD56+ NKT cells are increased in NAFLD as NAS increased. These cells may enhance disease activity through cytokine production after the recognition of lipid antigens presented with CD1d in livers of NAFLD.