Efficacy and safety of a nanoparticle therapeutic vaccine in patients with chronic hepatitis B: A randomized clinical trial.

BACKGROUND AND AIM: HBV DNA can be reduced using antiviral drugs in patients with chronic hepatitis B (CHB); however, the rate of HBeAg seroconversion remains low. A clinical trial was conducted to assess the efficacy and safety of a de novo designed liposome-based nanoparticle lipopeptide vaccine, εPA-44, for CHB. APPROACH AND RESULTS: A two-stage phase 2 trial, which included a 76-week, randomized, double-blind, placebo-controlled trial (stage 1) and a 68-week open-label extension (stage 2), was conducted in 15 centers across China (Clinicaltrials.gov No. NCT00869778). In stage 1, 360 human leukocyte antigen A2 (HLA-A2)-positive and HBeAg-positive patients were randomly and equally distributed to receive six subcutaneous injections of 600 µg or 900 µg εPA-44 or placebo at week 0, 4, 8, 12, 20, and 28. In stage 2, 183 patients received extended 900 µg εPA-44, and 26 patients were observed for relapse without further treatment. The primary endpoint was the percentage of patients with HBeAg seroconversion at week 76. At week 76, patients receiving 900 µg εPA-44 achieved significantly higher HBeAg seroconversion rate (38.8%) versus placebo (20.2%) (95% CI, 6.9-29.6%; p = 0.002). With a combined endpoint of HBeAg seroconversion, alanine aminotransferase normalization and HBV DNA < 2,000 IU/mL, both 900 µg (18.1%) and 600 µg (14.3%), resulted in significantly higher rate versus placebo (5.0%) (p = 0.002 and p = 0.02, respectively) at week 76. In stage 2, none (0 of 20) of 900 µg εPA-44-treated patients experienced serologic relapse. The safety profile of εPA-44 was comparable to that of placebo. CONCLUSIONS: Among HLA-A2-positive patients with progressive CHB, a finite duration of 900 µg εPA-44 monotherapy resulted in significantly higher HBeAg seroconversion rate than placebo and sustained off-treatment effect. A phase 3 trial is ongoing (ChiCTR2100043708).

A quantitative study of airway ultrasound in predicting difficult laryngoscopy: A prospective study.

PURPOSE: As common clinical screening tests cannot effectively predict a difficult airway, and unanticipated difficult laryngoscopy remains a challenge for physicians. We herein used ultrasound to develop some point-of-care predictors for difficult laryngoscopy. METHODS: This prospective observational study included 502 patients who underwent laryngoscopy and a detailed sonographic assessment. Patients under 18 years old, or with maxillofacial deformities or fractures, limited mouth opening, limited neck movement or history of neck surgery were excluded from the study. Laryngoscopic views of all patients were scored and grouping using the modified Cormack-Lehane (CL) scoring system. The measurements acquired comprised tongue width, the longitudinal cross-sectional area of the tongue, tongue volume, the mandible-hyoid bone distance, the hyoid bone-glottis distance, the mandible-hyoid bone-glottis angle, the skin-thyrohyoid membrane distance, the glottis-superior edge of the thyroid cartilage distance (DGTC), the skin-hyoid bone distance, and the epiglottis midway-skin distance. ANOVA and Chi-square were used to compare differences between groups. Logistic regression was used to identify risk factors for difficult laryngoscopy and it was visualized by receiver operating characteristic curves and nomogram. R version 3.6.3 and SPSS version 26.0 were used for statistical analyses. RESULTS: Difficult laryngoscopy was indicated in 49 patients (CL grade Ⅲ - Ⅳ) and easy laryngoscopy in 453 patients (CL grade Ⅰ - Ⅱ). The ultrasound-measured mandible-hyoid bone-glottis angle and DGTC significantly differed between the 2 groups (p < 0.001). Difficult laryngoscopy was predicted by an area under the curve (AUC) of 0.930 with a threshold mandible-hyoid bone-glottis angle of 125.5° and by an AUC of 0.722 with a threshold DGTC of 1.22 cm. The longitudinal cross-sectional area of the tongue, tongue width, tongue volume, the mandible-hyoid distance, and the hyoid-glottis distance did not significantly differ between the groups. CONCLUSION: Difficult laryngoscopy may be anticipated in patients in whom the mandible-hyoid bone-glottis angle is smaller than 125.5° or DGTC is larger than 1.22 cm.

Efficacy and Safety of Peginterferon Alfa-2a (40KD) in Children With Chronic Hepatitis B: The PEG-B-ACTIVE Study.

Children with chronic hepatitis B (CHB) represent an area of unmet medical need, attributed to increased lifetime risk of CHB sequelae and limited therapeutic options compared with adult CHB patients. The PEG-B-ACTIVE (NCT01519960) phase III study evaluated peginterferon (PegIFN) alfa-2a treatment in children aged 3 to <18 years with CHB. A total of 161 hepatitis B e antigen (HBeAg)-positive immune-active patients without advanced fibrosis (AF)/cirrhosis were randomized (2:1) to PegIFN alfa-2a (Group A, n = 101) or no treatment (Group B, n = 50); patients with AF were assigned to PegIFN alfa-2a (Group C, n = 10). PegIFN alfa-2a was administered for 48 weeks by body surface area (BSA) category, based on 180 µg/1.73 m2 . HBeAg seroconversion rates at 24 weeks posttreatment were significantly higher in Group A (25.7% vs. 6%; P = 0.0043), as were the rates of hepatitis B surface antigen (HBsAg) clearance (8.9% vs. 0%; P = 0.03), hepatitis B virus (HBV) DNA <2,000 IU/mL (28.7% vs. 2.0%; P < 0.001) or undetectable (16.8% vs. 2.0%; P = 0.0069), and alanine aminotransferase (ALT) normalization (51.5% vs. 12%; P < 0.001). Safety, including incidence of ALT flares and neutropenia, was comparable to the established PegIFN alfa-2a profile in HBV-infected adults or hepatitis C virus-infected children. Changes in growth parameters were minimal during treatment and comparable to those in untreated patients. Safety and efficacy outcomes in Group C were in line with Group A. Conclusion: PegIFN alfa-2a treatment of children in the immune-active phase of CHB was efficacious and well tolerated, and associated with higher incidence of HBsAg clearance than in adults. This represents an important advance to the treatment options for children with CHB.

Pretreatment microRNA levels can predict HBsAg clearance in CHB patients treated with pegylated interferon α-2a.

BACKGROUND: To investigate the predictive capability of microRNAs (miRNAs) prior treatment for HBsAg clearance in chronic hepatitis B (CHB) treated with pegylated interferon α-2a (PEG-IFNα-2a). METHODS: The treatment effect was determined by HBsAg clearance and subjects were classified into HBsAg clearance group and non HBsAg clearance group. Differential miRNAs expression in peripheral blood mononuclear cells (PBMC) was screened using microarrays in an identification cohort (n = 20) and validated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in a confirmation cohort (n = 47). Receiver operating characteristic curve (ROC), logistic regression and gene ontology (GO)/Pathway analyses were used to evaluate the predictive capability of selected miRNAs for HBsAg clearance and determine their mechanistic roles. RESULTS: Twenty-seven subjects (40.3%) acquired HBsAg clearance, ten in the identification cohort and seventeen in the confirmation cohort. Four miRNAs out of twelve (miR-3960, miR-126-3p, miR-335-5p, miR-23a-3p) were verified to be differential expressed by qRT-PCR in the confirmation cohort. Their expression patterns were consistent with the microarray results. Their levels were lower in the response group compared with the nonresponse group (p < 0.05). The areas under curve (AUC) were 0.8333 (p = 0.001), 0.751 (p = 0.01), 0.7294 (p = 0.013), 0.6275 (p = 0.094) and positive predict values (PPV) were 84.62, 60.00, 70.00, 28.57% for miR-3960, miR-126-3p, miR-335-5p, and miR-23a-3p respectively. The AUC and PPV of the combination of miR-3960 and miR-126-3p were 0.8529 and 92.31%, which were better than using miR-3960 alone, but the differences were not statistically significance (p > 0.05). CONCLUSIONS: We identified differential expressed miRNAs between response and nonresponse groups of PEG-IFNα-2a treatment and demonstrated that miR-3960 was the optimal predictor for HBsAg clearance compared with other miRNAs, but it requires to be further comfired in larger cohort studies. TRIAL REGISTRATION: ChiCTR ChiCTR-ROC-16008735, registered retrospectively on 28 June, 2016.

Modified nanoparticle mediated IL-12 immunogene therapy for colon cancer.

For the past few years, immunotherapy has recently shown considerable clinical benefit in CRC therapy, and the application of immunologic therapies in cancer treatments continues to increase perennially. Interleukin-12, an ideal candidate for tumor immunotherapy, could activate both innate and adaptive immunities. In this study, we developed a novel gene delivery system with a self-assembly method by MPEG-PLA and DOTAP(DMP) with zeta-potential value of 38.5mV and size of 37.5nm. The supernatant of lymphocytes treated with supernatant from Ct26 transfected pIL12 with DMP could inhibit Ct26 cells growth ex vivo. Treatment of tumor-bearing mice with DMP-pIL12 complex has significantly inhibited tumor growth at both the subcutaneous and peritoneal model in vivo by inhibiting angiogenesis, promoting apoptosis and reducing proliferation. The IL-12 plasmid and DMP complex may be used to treat the colorectal cancer in clinical as a new drug.

Efficacy of pegylated interferon α2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy.

BACKGROUND: Improving the HBe seroconversion rate of patients without HBeAg loss after long-term lamivudine therapy has become an urgent clinical problem that we have to face. Unfortunately, there is no consensus on the mananement of these patients. The aim of this study was to evaluate the efficacy of pegylated interferon (PEG-IFN) α2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy. METHODS: Fifty patients with chronic hepatitis B without the loss of HBeAg after ≥96 weeks of lamivudine treatment were enrolled to withdraw from treatment to induce a biochemical breakthrough. Patients who achieved a biochemical breakthrough within 24 weeks received 48-weeks of PEG-IFN α2a therapy, and were then assessed during a subsequent 24-week follow-up period. RESULTS: Forty-three (86.0%) patients achieved a biochemical breakthrough within 24 weeks of lamivudine withdrawal. The rates of combined response (both undetectable HBV DNA and HBeAg loss) and HBsAg loss were alone 51.2% and 20.9%, respectively after 48 weeks of PEG-IFN α2a therapy, and 44.2% and 18.6%, respectively, at 24 weeks after treatment cessation. The end-of-treatment combined response rate was 65.4% among patients with a baseline HBsAg <20,000 IU/mL, which was significantly higher than 29.4% of patients with HBsAg ≥20,000 IU/mL (P=0.031). For patients with HBsAg levels <1,500 IU/mL at 12 and 24 weeks therapy, the end-of-treatment combined response rate was 68.2% and 69.0%, which were both significantly higher than patients with HBsAg ≥1,500 IU/mL (33.3% and 14.3%; P=0.048 and 0.001). The end-of-treatment combined response rate was significantly higher among patients with HBV DNA<105 copies/mL (76.2%) compared to patients with HBV DNA ≥105 copies/mL (27.3%) after 24 weeks of therapy (P=0.004). CONCLUSION: Retreatment with PEG-IFN α2a was effective and safe for patients without HBeAg loss after the withdrawal of long-term lamivudine therapy. HBsAg levels at the baseline, 12 and 24 weeks of therapy, and HBV DNA levels at 24 weeks of therapy, can predict the effect of PEG-IFN α2a after 48 weeks of therapy.

Severe acute exacerbation of chronic hepatitis B during pegylated interferon treatment and early intervention with corticosteroid.

Severe acute exacerbation or liver failure induced by standard interferon-α(IFN-α) therapy had been reported to occur in few patients with chronic hepatitis B. However, no report showed that pegylated interferon-α therapy was able to induce severe acute exacerbation of chronic hepatitis B. Here, we describe three patients with severe acute exacerbation of chronic hepatitis B during pegylated interferon-α2a (Pegasys) treatment. One patient progressed into acute-on-chronic liver failure (ACLF) at the second week of Pegasys treatment. Two patients progressed into acute-on-chronic pre-liver failure (pre-ACLF) at the second and eighth week of Pegasys treatment, respectively. Three patients recovered after early combined intervention with corticosteroid and lamivudine. Our data indicated that there was a risk of severe acute exacerbation among patients with chronic hepatitis B during receiving Pegasys treatment. Importantly, early combined intervention with corticosteroid and lamivudine should be introduced to prevent the disease progression and improve their prognosis once severe acute exacerbation was diagnosed.

Rapidly decreased HBV RNA predicts responses of pegylated interferons in HBeAg-positive patients: a longitudinal cohort study.

BACKGROUND: As an important anti-HBV drug, pegylated interferon α (PegIFNα) offers promising clinical efficacy, but biomarkers that accurately forecast treatment responses are yet to be elucidated. Here, we evaluated whether HBV RNA could act as an early monitor of pegylated interferon responses. METHODS: We analyzed a phase 3, multicenter, randomized cohort of 727 HBeAg-positive non-cirrhotic patients receiving a 48-week treatment of PegIFNα-2a or PegIFNα-2b and a 24-week treatment-free follow-up. Serum levels of HBV RNA, HBV DNA, HBeAg, and HBsAg were measured at weeks 0, 12, 24, 48, and 72. RESULTS: HBeAg seroconversion and HBsAg loss at week 72 were observed in 217 (29.8%) and 21 (2.9%) patients, respectively. During the 48-week treatment, HBV RNA decreased more rapidly than HBV DNA and HBsAg, but HBV RNA and HBeAg shared similar dynamics with positive correlations. Multivariate regression analyses consistently revealed the significance of HBV RNA at weeks 0, 12, 24, and 48 to monitor HBeAg seroconversion but not HBsAg loss. Although baseline HBV RNA only showed a modest AUC performance, HBV RNA with a significant increase of AUC at week 12 outperformed other HBV biomarkers to forecast HBeAg seroconversion (p value < 0.05). HBV RNA ≤ 1000 copies/mL was an optimized cutoff at week 12 that offered better prediction than other HBV biomarkers. This optimized cutoff plus patient age, HBV genotype B, and HBeAg offered a strong estimation of HBeAg seroconversion (accuracy 95.2%, true negative rate 99.8%). CONCLUSION: HBV RNA at week 12 is an effective monitor of HBeAg seroconversion in HBeAg-positive patients treated with pegylated interferons.

Tolvaptan in Chinese cirrhotic patients with ascites: A randomized, placebo-controlled phase 2 trial.

OBJECTIVE: To evaluate tolvaptan as a novel therapeutic option for Chinese patients with liver cirrhosis-associated ascites in a phase 2 clinical trial. METHODS: This randomized, double-blind, placebo-controlled, multicenter trial was conducted in patients with insufficient responses to combination therapies of an oral loop diuretic and an aldosterone antagonist. Reduction in body weight and abdominal circumference, increase in 24-h cumulative urine volume and improvement in serum sodium level from baseline to the end of treatment in the tolvaptan groups (15 mg/day or 30 mg/day orally) were compared with those in the placebo group. Drug safety was also assessed. RESULTS: Sixty-two patients were allocated to the placebo group, 56 to the tolvaptan 15-mg group and 63 to the tolvaptan 30-mg group. Their mean changes in body weight were -0.5 ± 1.6 kg, -2.1 ± 2.0 kg and -1.9 ± 2.0 kg, respectively. Body weight reductions in both tolvaptan groups were significantly greater than that in the placebo group (difference -1.6, 95% confidence interval [CI] -2.5 to -0.8, and difference -1.4, 95% CI, -2.2 to -0.7, both P < 0.0001). The administration of tolvaptan also significantly reduced the abdominal circumference, increased 24-h cumulative urine volume and serum sodium level compared with placebo. The most common adverse events in the tolvaptan groups were constipation, diarrhea, dry mouth and thirst, with no severe adverse events observed. CONCLUSION: Tolvaptan at 15 mg/day significantly reduced the body weight and abdominal circumference in patients with liver cirrhosis-associated ascites, which needs to be confirmed in a phase 3 trial.

Enhancing the anti-glioma therapy of doxorubicin by honokiol with biodegradable self-assembling micelles through multiple evaluations.

Combination chemotherapy is an important protocol in glioma therapy and honokiol shows synergistic anticancer effects with doxorubicin. In this paper, honokiol (HK) and doxorubicin (Dox) co-loaded Methoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) nanoparticles were prepared with a assembly method. The particle size (about 34 nm), morphology, X-ray Powder Diffraction (XRD), in vitro release profile, cytotoxicity and cell proliferation effects were studied in detail. The results indicated that honokiol and doxorubicin could be efficiently loaded into MPEG-PCL nanoparticles simultaneously, and could be released from the micelles in an extended period in vitro. In addition, honokiol and doxorubicin loaded in MPEG-PCL nanoparticles could efficiently suppress glioma cell proliferation and induce cell apoptosis in vitro. Furthermore, Dox-HK-MPEG-PCL micelles inhibited glioma growth more significantly than Dox-MPEG-PCL and HK-MPEG-PCL in both nude mice and zebrafish tumor models. Immunohistochemical analysis indicated that DOX-HK-MPEG-PCL micelles improved Dox's anti-tumor effect by enhancing tumor cell apoptosis, suppressing tumor cell proliferation, and inhibiting angiogenesis. Our data suggest that Dox-HK-MPEG-PCL micelles have the potential to be applied clinically in glioma therapy.

Comparative study of clinical manifestation, plain-film radiography, and computed tomographic scan in arteriovenous malformations of the jaws.

OBJECTIVE: The purpose of this study was to summarize the clinical manifestation, plain-film radiography, and computed tomographic (CT) scan features of arteriovenous malformations (AVMs) of the jaws on the basis of a series of 12 patients. STUDY DESIGN: This study group comprised twelve patients with AVM of the jaws from February 1996 to February 2001. Seven cases were located in the mandible, and 5 in the maxilla. Both plain-film radiography and CT scan were available for all cases. For the patients with lesions in the mandible, panoramic, posterioanterior, and lateral mandibular views were applied. Waters' position view and panoramic radiography were indicated for AVMs of the maxilla. RESULTS: Each patient with AVM of the maxillary bone had involvement of adjacent soft tissues. Various radiographic signs were noted, including erosion, coarse trabeculae, and apparent lack of any radiographic change, and CT scans featured cystic expansion of alveolar process with broken cortex. The radiographic signs and CT scan features of AVMs in the mandible were related to involvement of surrounding soft tissues. If involvement of the adjacent soft tissues was found, "soap bubble" radiolucency was shown radiographically and osteolytic expansion with perforation of cortex was present on CT scan. In cases without surrounding soft tissue involvement, the various radiographic signs included multilocular or unilocular radiolucency or coarse trabeculae; osteolytic expansions with intact cortex were found on CT scan. CONCLUSION: AVMs of the jaws showed intraosseous osteolytic expansion on CT scan but had variable appearance on plain-film radiographs.

Direct-puncture embolization of intraosseous arteriovenous malformation of jaws.

PURPOSE: Our goal was to report our experience with direct-puncture embolization of intraosseous arteriovenous malformations (AVMs). PATIENTS AND METHODS: Three cases of AVM in the mandible and 2 cases of AVM in the maxilla comprised this study group. The patients were embolized with fiber coils through direct puncture, and the coils were placed directly into the center of the intraosseous lesion, in some cases in conjunction with polyvinyl alcohol foam and N-butyl-2-cyanoacrylate through vascular access. RESULTS: The acute arterial bleeding was controllable in 3 patients. The other 2 patients had pericoronal oozing bleeding and a warm soft pulsative mass on the left face, respectively; their symptoms and signs improved greatly. The pericoronal oozing of blood in all patients disappeared during a 3- to 13-month follow-up, and new bone formation was found on the follow-up radiography. CONCLUSIONS: The embolization of the AVM of jaws by direct percutaneous puncture in conjunction with endovascular therapy is effective and safe, but longer follow-up is required to determine the true efficacy of this method of treatment.

Embolization of the AVM of jaws by direct percutaneous puncture combined with endovascular route.

OBJECTIVE: To report our experience to embolize the AVM of jaws by direct puncture in conjunction with endovascular treatment. METHODS: 5 cases of AVM of mandible and 2 cases of AVM of maxilla comprised this study group. The patients were embolized with coils with wool strands and PVA. The coils were placed directly into the center of the intraosseous lesion. The procedure was under the guidance of DSA machine (PHILIPS V3000). RESULTS: The acute arterial bleeding of 4 patients was controllable. The chronic oozing bleeding in the other 3 cases disappeared in the 3 - 24 months follow-up and new bone formation was found in the follow-up radiography. CONCLUSIONS: The embolization of the AVM of jaws by direct puncture in conjunction with endovascular therapy is effective and safe, however the longer follow-up is expected.

[Staging and management of extracranial arteriovenous malformations].

OBJECTIVE: Congenital arteriovenous malformations(AVM) are considered to be the most difficult and challenging problems in the treatment of hemangiomas and vascular lesions. This study focused on the natural history, the clinical classification, the choice and effectiveness of various treatments. METHODS: This retrospective review included 83 patients with extracranial arteriovenous malformations, who were referred to our department over the past 6 years. The anatomic patterns, clinical staging, respective treatments, influential factors of endovascular treatment, causes of recurrence were analyzed. RESULTS: According to clinical manifestations, arteriovenous malformations were categorized as three clinical stages: the quiescence, the expansion and the decompensation stages. Most AVMS in the quiescence stage only require endovascular treatment while those in the decompensation stage require surgical resection. Angiography was performed not only for diagnosis of AVM but also as an initial therapeutic step in the form of embolization, which might be the only means to some AVM without surgical possibility or necessity. CONCLUSION: The new concept of staging and management is expected to be helpful for diagnosis and treatments of AVM.