Real-world use of first-line pembrolizumab + platinum + taxane combination regimens in recurrent / metastatic head and neck squamous cell carcinoma.

Introduction: The programmed death-1 (PD-1) immune checkpoint inhibitor pembrolizumab is currently approved in the US for the first-line (1L) treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), either alone or in combination with platinum and 5-fluorouracil (5-FU). However, the toxicity of 5-FU has motivated the study of alternate combinations that replace 5-FU with a taxane. The objective of the current study was to describe the baseline characteristics, treatment patterns and sequences, and real-world outcomes of individuals receiving pembrolizumab + platinum + taxane as 1L treatment for R/M HNSCC in the US. Methods: This was a retrospective study of US adults ≥18 years of age receiving pembrolizumab + platinum + taxane as 1L treatment for R/M HNSCC, using electronic health record data from a nationwide de-identified database. Real-world overall survival (rwOS), time on treatment (rwToT), and time to next treatment (rwTTNT) outcomes were assessed using Kaplan-Meier analysis. Results: The study population comprised 83 individuals (80.7% male) with a median age of 64 years. The most common tumor site was the oropharynx (48.2%); 70.0% of these tumors were HPV-positive. A total of 71.1% of the study population had an Eastern Cooperative Oncology Group performance status of 0-1 at index date, 71.8% had a combined positive score for programmed death ligand-1 (PD-L1) expression of ≥1, and 30.8% had a score of ≥20. The median (95% CI) rwOS was 14.9 (8.8-23.3) months, rwToT was 5.3 (4.0-8.2) months, and rwTTNT was 8.7 (6.8-12.3) months. Among the 24 individuals who received a subsequent therapy, the most common second-line therapies were cetuximab-based (n = 9) or pembrolizumab-containing (n = 8) regimens. Conclusions: The rwOS and other real-world outcomes observed for this study population further support pembrolizumab + platinum + taxane combination therapy as a potential 1L treatment option for R/M HNSCC.

Corrigendum: Real-world treatment patterns and outcomes among individuals receiving first-line pembrolizumab therapy for recurrent/metastatic head and neck squamous cell carcinoma.

[This corrects the article DOI: 10.3389/fonc.2023.1160144.].

Real-world treatment patterns and outcomes among individuals receiving first-line pembrolizumab therapy for recurrent/metastatic head and neck squamous cell carcinoma.

Background: Pembrolizumab, a PD-1 immune checkpoint inhibitor, is approved as first-line (1L) treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) as monotherapy or in combination with platinum and 5-fluorouracil chemotherapy. Limited data exist on the use of these regimens in real-world settings. Objective: Our primary objectives were to describe baseline characteristics and real-world overall survival (rwOS), time on treatment (rwToT), and time to next treatment (rwTTNT) among individuals with R/M HNSCC receiving approved 1L pembrolizumab therapies. We also aimed to identify baseline factors associated with choice of 1L pembrolizumab therapy and with rwOS. Methods: This was a retrospective cohort study of adults with R/M HNSCC receiving 1L pembrolizumab monotherapy or pembrolizumab plus chemotherapy. We used Kaplan-Meier analyses to assess real-world outcomes, logistic regression modeling to identify factors associated with choice of 1L pembrolizumab therapy, and Cox proportional hazards models to identify factors associated with rwOS. Results: The study population included 431 individuals receiving 1L pembrolizumab monotherapy and 215 receiving 1L pembrolizumab plus chemotherapy. The use of 1L pembrolizumab monotherapy was associated with higher baseline combined positive score for PD-L1 expression, older age, higher Eastern Cooperative Oncology Group performance status (ECOG PS), laryngeal tumor site, and human papillomavirus (HPV)-positive tumor status. The pembrolizumab monotherapy group had a median (95% CI) rwOS of 12.1 (9.2-15.1) months, rwToT of 4.2 (3.5-4.6) months, and rwTTNT of 6.5 (5.4-7.4) months. Among this group, HPV-positive tumor status and lower ECOG PS were associated with longer rwOS, and oral cavity tumor site with shorter rwOS. The pembrolizumab plus chemotherapy cohort had a median (95% CI) rwOS of 11.9 (9.0-16.0) months, rwToT of 4.9 (3.8-5.6) months, and rwTTNT of 6.6 (5.8-8.3) months. In this group, HPV-positive tumor status was associated with longer rwOS. Conclusions: This study adds to clinical trial data by summarizing real-world treatment outcomes with 1L pembrolizumab-containing therapies in a more heterogeneous population. Overall survival outcomes in both treatment groups were similar to those observed in the registration clinical trial. These findings support the use of pembrolizumab as standard of care for R/M HNSCC.

Endoscopic placement of covered versus uncovered self-expandable metal stents for palliation of malignant gastric outlet obstruction.

OBJECTIVE: Stenting is an established endoscopic therapy for malignant gastric outlet obstruction (mGOO). The choice of stent (covered vs uncovered) has been examined in prior randomised studies without clear results. DESIGN: In a multicentre randomised prospective study, we compared covered (CSEMS) with uncovered self-expandable metal stents (UCSEMS) in patients with mGOO; main outcomes were stent dysfunction and patient survival, with subgroup analyses of patients with extrinsic and intrinsic tumours. RESULTS: Overall survival was poor with no difference between groups (probability at 3 months 49.7% for covered vs 48.4% for uncovered stents; log-rank for overall survival p=0.26). Within that setting of short survival, the proportion of stent dysfunction was significantly higher for uncovered stents (35.2% vs 23.4%, p=0.01) with significantly shorter time to stent dysfunction. This was mainly relevant for patients with extrinsic tumours (stent dysfunction rates for uncovered stents 35.6% vs 17.5%, p<0.01). Subgrouping was also relevant with respect to tumour ingrowth (lower with covered stents for intrinsic tumours; 1.6% vs 27.7%, p<0.01) and stent migration (higher with covered stents for extrinsic tumours: 15.3% vs 2.5%, p<0.01). CONCLUSIONS: Due to poor patient survival, minor differences between covered and uncovered stents may be less relevant even if statistically significant; however, subgroup analysis would suggest to use covered stents for intrinsic and uncovered stents for extrinsic malignancies.

Reassessment of early 131I inhalation doses by the Fukushima nuclear accident based on atmospheric 137Cs and 131I/137Cs observation data and multi-ensemble of atmospheric transport and deposition models.

The Fukushima Dai-ichi Nuclear Power Plant accidents following the March 11, 2011 Tohoku earthquake, and subsequent tsunami released radioactive materials into the atmosphere and caused significant public health concerns, particularly thyroid cancers in children. However, the lack of measurement data for atmospheric concentrations of 131I has caused persistent and widespread uncertainty. This study estimated the maximum potential thyroid doses of inhaled 131I in the early post-accident phase between March 12 and 23, 2011 by using the hourly measured data of the 137Cs concentrations at 101 suspended particulate matter (SPM) monitoring sites, a new multi-model ensemble (MME) method of simulating 137Cs concentrations using two Atmospheric Transport and Deposition Models (ATDMs), the 131I/137Cs ratio obtained from measurement data analysis, and the internal exposure model. Based on the measurements, the maximum potential thyroid doses were estimated at 3.1-160 mSv at 5 sites in the Fukushima-Hamadori area for 1-year-old children assumed to remain outdoors, whereas they were less than 4.3 mSv at the other sites in the base case of the 131I/137Cs ratio. The spatial distribution of the maximum potential of early inhalation doses was estimated by using the MME and measurements. The inhalation thyroid doses in the evacuation scenarios were compared to the estimates reported by previous studies. The results of the present study were almost congruent with the outcomes of previous investigations except for thyroid doses contributed by highly contaminated plumes on March 12 and 15. The sensitivity analysis for the 131I/137Cs ratio indicated that these plumes carried the potential to significantly increase the thyroid doses of residents.

Utilization of novel systemic therapies for multiple myeloma: A retrospective study of front-line regimens using the SEER-Medicare data.

The landscape of treatment for multiple myeloma (MM) has significantly changed over the last decade due to novel agents that have shown superiority in efficacy such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) over traditional therapies. However, the real-world utilization of these new agents has not been studied well. This study evaluated year-to-year changes in treatment choices in a cohort of patients aged 66 or older in the Surveillance, Epidemiology, and End Results (SEER) registry linked with Medicare claims (SEER-Medicare) data who were diagnosed with MM between 2007 and 2011. We identified 2477 symptomatic newly diagnosed patients who were followed for 6 months or more postdiagnosis and treated with systemic therapies but not with stem cell transplantation. Symptomatic patients were identified by evidence of hypercalcemia, renal failure, anemia, or bone lesions (CRAB criteria). The minimum follow-up was imposed to ensure sufficient data to characterize treatment. Our analysis found that the proportion of treated patients increased from 75% in the 2007 cohort to 79% in the 2011 cohort. The share of PI-based regimens including PI plus alkylating agents, PI plus IMiD, and PI-only increased from 9% to 21%, 3% to 11%, and 16% to 22%, respectively, between 2007 and 2011. These findings translate to the share of PI-based regimens having increased from 28% to 55% and that of IMiDs-based regimens (excluding PI plus IMiD) having decreased from 43% to 27%. In conclusion, while the usage of PIs among elderly MM patients increased significantly replacing IMiD-based regimens (with or without alkylating agents but not with PI) between 2007 and 2011, this significant shift did not increase the proportion of treated patients.

Long-term outcomes of EUS-guided transluminal stent deployment for benign biliary disease: Multicenter clinical experience (with videos).

BACKGROUND AND OBJECTIVES: Biliary drainage (BD) under EUS guidance is usually indicated for malignant biliary obstruction. Recently, EUS-guided transluminal treatment has been applied to benign biliary disease (BBD). This multicenter retrospective study evaluated the clinical impact of EUS-guided transluminal stent deployment for BBD with long-term follow-up. PATIENTS AND METHODS: This retrospective study investigated patients treated between September 2015 and October 2016 at participating hospitals in the therapeutic endoscopic group. The inclusion criteria comprised complications with BBD obstructive jaundice or cholangitis and failed endoscopic retrograde cholangiopancreatography or inaccessible ampulla of Vater. RESULTS: Twenty-six patients underwent EUS-guided transluminal stent deployment. Indications for EUS-guided transluminal stent deployment comprised anastomotic biliary stricture (n = 17), bile duct stones (n = 5), inflammatory biliary stricture (n = 3), and acute pancreatitis prevention (n = 1). Thirteen of these 26 patients underwent scheduled reintervention, with technical success achieved in all 13 patients. None of the deployed stents became dysfunctional. Among the 13 patients who underwent reintervention on demand, stents had become dysfunctional in six patients (stent patency: 48, 90, 172, 288, 289, and 608 days). Reintervention was successfully performed in all patients. During follow-up (median, 749 days), severe adverse events were not seen in any patients. CONCLUSION: We concluded that EUS-guided transluminal stent deployment for BBD is feasible and safe. Because metal stent dysfunction was more frequent when deployed on demand, such stents should be exchanged for plastic stents in a scheduled manner if a metal stent is used.

Allergy inhibitory receptor-1 inhibits autoantibody production via upregulation of apoptotic debris clearance by macrophages.

AIM: Allergy inhibitory receptor-1 (Allergin-1) is a newly identified immune regulatory molecule thought to influence autoantibody production. Autoantibody production, like that observed in Allergin-1-deficient mice, is crucial in the pathogenesis of several autoimmune diseases such as systemic lupus erythematosus. The purpose of this study is to clarify the regulatory role of Allergin-1-mediated autoantibody production using a murine model of thymocytic anaphylaxis. METHODS: C57BL/6 (WT) and Allergin-1-deficient mice were treated with apoptotic cells from naive thymocytes stimulated by dexamethasone. Antibody titers of total or immunoglobulin G (IgG) subclass of anti-double-stranded DNA (anti-dsDNA) and anti-histone antibody from serum were measured using an enzyme-linked immunosorbent assay. Macrophages from wild-type (WT) or Allergin-1-deficient mice were co-cultured with fluorescence-labeled apoptotic thymocytes or fluorogenic reagent and resultant phagocytic activity was quantified by with flow cytometry. RESULTS: After apoptotic cells injection, antibody titers of total and IgG3 anti-dsDNA and total anti-histone from serum were significantly increased in Allergin-1-deficient versus WT mice. Phagocytic activity was significantly lower in macrophages from Allergin-1-deficient mice versus WT mice. CONCLUSION: Allergin-1 might play an inhibitory role in autoantibody production via upregulation of macrophage phagocytosis.

Endoscopic Ultrasound-Guided Rendezvous Technique for Failed Biliary Cannulation in Benign and Resectable Malignant Biliary Disorders.

BACKGROUND: Endoscopic ultrasound-guided rendezvous technique (EUS-RV) has emerged as an effective salvage method for unsuccessful biliary cannulation. However, its application for benign and resectable malignant biliary disorders has not been fully evaluated. AIMS: To assess the efficacy and safety of EUS-RV for benign and resectable malignant biliary disorders. METHODS: This was a multicenter prospective study from 12 Japanese referral centers. Patients who underwent EUS-RV after failed biliary cannulation for biliary disorder were candidates for this study. Inclusion criteria were unsuccessful biliary cannulation for therapeutic endoscopic retrograde cholangiopancreatography with benign and potentially resectable malignant biliary obstruction. Exclusion criteria included unresectable malignant biliary obstruction, inaccessible papillae due to surgically altered upper gastrointestinal anatomy or duodenal stricture, and previous sphincterotomy and/or biliary stent placement. The primary outcome was the technical success rate of biliary cannulation; procedure time, adverse events, and clinical outcomes were secondary outcomes. RESULTS: Twenty patients were prospectively enrolled. The overall technical success rate and median procedure time were 85% and 33 min, respectively. Guidewire manipulation using a 4-Fr tapered tip catheter contributed to the success in advancing the guidewire into the duodenum. Adverse events were identified in 15% patients, including 2 with biliary peritonitis and 1 mild pancreatitis. EUS-RV did not affect surgical maneuvers or complications associated with surgery, or postoperative course. CONCLUSIONS: EUS-RV may be a safe and feasible salvage method for unsuccessful biliary cannulation for benign or resectable malignant biliary disorders. Use of a 4-Fr tapered tip catheter may improve the overall EUS-RV success rate.

The intra-conduit release method is useful for avoiding migration of metallic stents during EUS-guided hepaticogastrostomy (with video).

PURPOSE: Although EUS-guided hepaticogastrostomy (EUS-HGS) with a covered self-expandable metal stent (SEMS) is a useful procedure, it is associated with severe adverse events, including stent migration. We, therefore, developed an intra-conduit release method, and investigated whether the technique yields a safer and more stable procedure. METHODS: The intra-conduit release method is a procedure to release the SEMS in the working channel conduit of the scope for anchoring between the liver and stomach to avoid stent migration. Forty-three patients who underwent EUS-HGS at two high-volume centers in Japan were enrolled in this retrospective study, and the safety and usefulness of this method were evaluated retrospectively. RESULTS: The intra-conduit release method was applied in 36 cases. The technical success rate of EUS-HGS with the intra-conduit release method was significantly higher in comparison with the conventional method. Additionally, the rate of early adverse events was significantly lower than that for the conventional method. CONCLUSION: The intra-conduit release method during EUS-HGS is useful for a stable procedure that avoids early adverse events.

Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases. METHODS: We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. RESULTS: We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10-10 and 6.6×10-10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell. CONCLUSIONS: GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

Linkage of Lower Urinary Tract Symptoms to Sleep Quality in Elderly Men with Nocturia: A Community Based Study Using Home Measured Electroencephalogram Data.

PURPOSE: We objectively investigated the relationship between sleep quality/efficiency and factors associated with micturition using at-home electroencephalogram assessment. MATERIALS AND METHODS: Participants were recruited from among those enrolled in the Fujiwara-kyo Study, a community based longitudinal evaluation that began in Nara Prefecture, Japan, in 2007. Included participants were men at least 65 years old who woke up in the middle of the night/early morning at least 3 times per week with the urge to void. We evaluated lower urinary tract symptoms using the I-PSS and subjective sleep quality using the Pittsburgh Sleep Quality Index. Uroflowmetry and 3-day frequency volume charting measurements were also obtained. Electroencephalogram recordings were obtained during sleep to evaluate objective sleep quality. RESULTS: Final analysis included data from 47 participants. I-PSS-quality of life score and slow wave sleep time were independent predictors of good subjective sleep quality as determined by Pittsburgh Sleep Quality Index scores. Nocturnal urinary volume was an independent predictor of greater sleep efficiency. Maximum flow rate was an independent predictor of longer slow wave sleep time. CONCLUSIONS: In elderly men with nocturia, sleep quality is associated with lower urinary tract function. Higher subjective sleep quality is associated with longer slow wave sleep time and less severe lower urinary tract symptoms. Higher objective sleep quality is further associated with a higher urinary flow rate and lower nocturnal urinary volume.

Outcome of self-expandable metallic stent deployment in patients with malignant gastroduodenal outlet obstruction and Niti-S and WallFlex comparison: a multicenter retrospective clinical study.

OBJECTIVES: Several studies report on the outcomes of self-expandable metallic stents (SEMSs) deployment for malignant gastric outlet obstruction (GOO). However, data was mostly based on the analysis of single-center studies including only a small number of patients. This study aimed to evaluate clinical outcomes after the deployment of SEMS in patients with malignant GOO and to compare the clinical outcomes of two metallic stents with different designs. METHODS: Altogether 125 consecutive patients from five institutions were included. Clinical outcomes were evaluated according to technical success, clinical success, stent patency period, survival period and complications. A comparison of clinical outcomes between Niti-S pyloric/duodenal and WallFlex duodenal stents was also undertaken. RESULTS: Rates for clinical and technical success were 100% and 92.0%, respectively. The median stent patency and survival periods were 72.0 days (range 3-775 days) and 75.0 days (range 3-775 days), respectively. The rate of overall adverse events was 28.8%. The rate of stent dysfunction was 16.8%, and that of adverse events, except stent dysfunction was 12.0%. Massive bleeding occurred in two patients as a late complication. The clinical success rate for Niti-S stent was significantly higher than that for WallFlex stent (96.2% vs 84.8%, P = 0.023). CONCLUSIONS: We successfully deployed a SEMS in malignant GOO. The selection of a SEMS with a lower axial force may be important for patients to resume the oral food intake. Additionally, consideration must be given to the appropriate management of fatal bleeding as a late complication.

[A case of ruptured duodenal varices successfully treated by combination therapy with endoscopic clipping and balloon-occluded retrograde transvenous obliteration].

An 80-year-old woman with a history of chronic hepatitis B was referred to our hospital because of upper gastrointestinal bleeding of unknown origin. Dynamic computed tomography revealed liver cirrhosis and hepatofugal collateral vessels around the duodenum. Emergency esophagogastroduodenoscopy showed duodenal varices with an erosive spot, highly suggestive of a variceal rupture site. We immediately performed endoscopic clipping of the ruptured site to achieve temporary hemostasis. Ten days later, elective balloon-occluded retrograde transvenous obliteration (B-RTO) was performed to prevent recurrence. We describe a successfully treated case of duodenal variceal rupture managed by combination therapy with endoscopic clipping and B-RTO.

Correlation between serum cytokeratin-18 and the progression or regression of non-alcoholic fatty liver disease.

BACKGROUND: Diagnosis of non-alcoholic fatty liver disease (NAFLD) is limited by the need for liver biopsies. Serum cytokeratin 18 (CK-18) levels have been investigated as potential biomarkers for the presence of NAFLD and non-alcoholic steatohepatitis (NASH). Herein, we assessed the correlation between CK-18 levels and NAFLD progression. MATERIAL AND METHODS: Serum CK-18 levels were estimated using the M30 antibody enzyme-linked immunosorbent assay in 147 patients diagnosed with NAFLD. In 72 patients, disease progression was evaluated by repeated liver biopsy, which was conducted after 4.3 ± 2.6 years. The relationship between the CK-18 levels and liver histological findings was assessed. RESULTS: The CK-18 levels were useful for identifying NAFLD patients with NAFLD activity scores (NAS) ≥ 5 (NAS ≥ 5 vs. ≤ 4: 675.1 U/L vs. 348.7 U/L; p < 0.0001). A cut-off value of 375 U/L was calculated using the receiver operating characteristic curve approach, with a specificity and sensitivity of 81.5 and 65%, respectively, for the diagnosis of NASH. Among the 72 patients who underwent repeated liver biopsy, 11 patients with a progressed NAS also had significantly increased serum CK-18 levels (p < 0.01); in 30 patients with an improved NAS, there was a significant improvement in the mean CK-18 levels (p < 0.0001). The 31 patients with static NAS had static CK-18 levels. CONCLUSIONS: In conclusion, serum CK-18 levels can predict NAS ≥ 5 in NAFLD patients. In NAFLD patients, serum CK-18 levels reflect NAS values and correlate with histological changes, and they appear to be useful indicators of progression and improvement.

Functional structure and physiological functions of mammalian wild-type HSP60.

The Chaperonins comprise a family of molecular chaperones having a double-ring structure and similar sequence homology. These proteins play an essential role in biological reactions that mediate the folding of newly synthesized polypeptides and partially denatured proteins. In the prokaryotic group I chaperonins, structural and reaction cycle analyses of GroEL and its co-chaperone GroES have been performed in detail. While in eukaryotes, there have been limited reports analyzing the group I chaperonin HSP60 and its co-chaperone HSP10. In the present study, we purified the wild type HSP60 from porcine liver and investigated the interaction between HSP60 and HSP10, including conformation and physiological relationships. Based on the results of transmission electron microscopy, native PAGE, and gel filtration column chromatography, the wild type HSP60 displayed a heptameric single-ring structure in the absence of ATP. In contrast, HSP60 formed mainly a "football-type" complex with HSP10 in the presence of ATP and mediated the refolding of denatured substrate protein. The functional conformation cycle of the purified mammalian HSP60 is distinct from the cycle of the prokaryotic GroEL/GroES chaperonin.

Obstructive jaundice caused by intraductal metastasis of lung adenocarcinoma.

Obstructive jaundice caused by metastases to the porta hepatis is often observed in patients with various advanced cancers; however, metastasis of lung cancer to the common bile duct with subsequent development of jaundice is rare. A 75-year-old female with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutation (15-bp in-frame deletion in exon 19 and T790M in exon 20) developed obstructive jaundice during therapy. Obstruction of the common bile duct caused by an intraductal tumor was identified by computed tomography, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography. Although primary cholangiocarcinoma was highly suspected according to the imaging findings, immunohistochemical evaluation of the intraductal tumor demonstrated thyroid transcription factor-1 positive adenocarcinoma. Furthermore, peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp analysis showed that the tumor contained the same EGFR mutation as that in the primary lung cancer. Thus, we confirmed intraductal metastasis from a lung adenocarcinoma. To our knowledge, this is the second report of obstructive jaundice caused by intraductal metastasis of lung cancer.

Modeling of black carbon in Asia using a global-to-regional seamless aerosol-transport model.

In Asia, the evaluation of black carbon (BC) using global aerosol-transport models has been incomplete due to a lack of available measurements. Recently, new measurements and datasets at various Asian sites have become available for use in model validation. In this study, we compared the BC mass concentrations obtained by an aerosol-coupled global nonhydrostatic model adopting a uniform-grid system with in-situ measurements and other models over Asia. The results revealed that our model, as well as other global models, was unable to reproduce the observed BC values at most sites in China and India, most likely due to strong local hotspots. To overcome the inconsistency between the models and measurements, we developed a new aerosol-transport model using a stretched-grid system for high-resolution simulations with up to approximately 10 km grids. Our model can be used as a global-to-regional seamless aerosol-transport model for low to high horizontal resolution simulations.

Quantitative Levels of Hepatitis B Virus DNA and Surface Antigen and the Risk of Hepatocellular Carcinoma in Patients with Hepatitis B Receiving Long-Term Nucleos(t)ide Analogue Therapy.

BACKGROUND: Serum levels of hepatitis B virus (HBV) DNA are an important predictor of the risk of hepatocellular carcinoma (HCC) in patients with chronic HBV infection. However, little is known about whether high levels of hepatitis B surface antigen (HBsAg) increase the risk for HCC. METHODS: We investigated 167 patients who were treated with nucleos(t)ide analogues (NA) for at least 2 years (median: 5.8 years, range: 2-13.1 years). Relationships between reduced levels of HBsAg and various factors were evaluated. In addition, we evaluated the usefulness of quantitative serum levels of HBV DNA and HBsAg as predictors of HCC development in patients receiving long-term NA therapy. RESULTS: HCC developed in 9 of the 167 NA-treated patients. In the 9 patients with HCC, HBV DNA was undetectable (<2.1 log copies/mL), but HBsAg levels were ≥2000 C.O.I. in 7 patients. No maternal transmission, long NA treatment period, HBV DNA levels <3.0 log copies/mL, and reduced hepatitis B e antigen levels during the first 24 weeks of treatment were a significant factor of HBsAg levels <2000 C.O.I.. CONCLUSIONS: Hepatocarcinogenesis was observed in patients with high HBsAg levels, despite the negative conversion of HBV DNA as a result of long-term NA therapy. Therefore, to suppress hepatocarcinogenesis, it is important to control not only HBV DNA levels but also HBsAg levels.