Magnetic resonance imaging of tumor response to stroma-modifying pegvorhyaluronidase alpha (PEGPH20) therapy in early-phase clinical trials.

Pre-clinical and clinical studies have shown that PEGPH20 depletes intratumoral hyaluronic acid (HA), which is linked to high interstitial fluid pressures and poor distribution of chemotherapies. 29 patients with metastatic advanced solid tumors received quantitative magnetic resonance imaging (qMRI) in 3 prospective clinical trials of PEGPH20: HALO-109-101 (NCT00834704), HALO-109-102 (NCT01170897), and HALO-109-201 (NCT01453153). Apparent Diffusion Coefficient of water (ADC), T1, ktrans, vp, ve, and iAUC maps were computed from qMRI acquired at baseline and ≥ 1 time point post-PEGPH20. Tumor ADC and T1 decreased, while iAUC, ktrans, vp, and ve increased, on day 1 post-PEGPH20 relative to baseline values. This is consistent with HA depletion leading to a decrease in tumor extracellular water content and an increase in perfusion, permeability, extracellular matrix space, and vascularity. Baseline parameter values predictive of pharmacodynamic responses were: ADC > 1.46 × 10-3 mm2/s (Balanced Accuracy (BA) = 72%, p < 0.01), T1 > 0.54 s (BA = 82%, p < 0.01), iAUC < 9.2 mM-s (BA = 76%, p < 0.05), ktrans < 0.07 min-1 (BA = 72%, p = 0.2), ve < 0.17 (BA = 68%, p < 0.01), and vp < 0.02 (BA = 60%, p < 0.01). A low ve at baseline was moderately predictive of response in any parameter (BA = 65.6%, p < 0.01 averaged across patients). These qMRI biomarkers are potentially useful for guiding patient pre-selection and post-treatment follow-up in future clinical studies of PEGPH20 and other tumor stroma-modifying anti-cancer therapies.

A Comparison of the Effect of Kegel Exercises and Conventional Therapy versus Conventional Therapy Alone in the Treatment of Functional Constipation in Children: A Randomized Clinical Trial.

Background: There have been few studies on the effect of Kegel exercises on the treatment of functional constipation in children. Hence, the present study investigated the add-on role of Kegel exercises in children with functional constipation. Methods: This clinical trial was conducted on children with functional constipation, according to Rome IV, who were referred to the pediatric department of Imam Reza Clinic (Shiraz, Iran) in 2022. The sample consisted of 64 children who were randomly assigned to either the intervention or the control groups. In the control group, a pediatrician administered conventional therapy, including diet training, defecation training, and polyethylene glycol (PEG) syrup (0.7 g/Kg daily). In the treatment group, in addition to conventional therapy, a pediatrician taught Kegel exercises to the child both verbally and in writing in the presence of their parents. To investigate the effectiveness of the intervention, frequency of defecation, defecation time, assistance used for defecation, incomplete emptying, unsuccessful defecation, abdominal pain, and painful defecation were selected as the outcomes. Independent sample t test was used for continuous variables. Categorical variables were reported as frequency and percentages. To examine the difference in categorical outcome variables, Wilcoxon (pre and post), Chi square, and Fisher exact tests were used. Data were analyzed using SPSS software version 21. P<0.05 were considered statistically significant. Results: Twenty-seven (88.4%) patients in the Kegel exercise group reported a defecation time of less than 5 min, while only 12 (37.5%) patients in the control group reached this time, and this difference was statistically significant (P=0.001). Moreover, patients in the treatment group showed significant improvements in terms of incomplete emptying of stool, unsuccessful defecation, abdominal pain, and painless defecation (P=0.001, P=0.001, P=0.001, P=0.037, respectively). After intervention, the use of laxatives, digits, or enemas to assist defecation was not significantly different between the groups (P=0.659). Conclusion: Kegel exercise was an effective adjunctive treatment for pediatric functional constipation.Trial Registration Number: IRCT20230424057984N1.

Clinical profile of functional constipation in Saudi children.

BACKGROUND: Functional constipation (FC) is a common condition in children, and information on the clinical characteristics of FC in Saudi children is scarce. OBJECTIVE: Describe the clinical profile of FC in Saudi children. DESIGN: Retrospective. SETTING: Hospital that provides primary, intermediate and tertiary care. PATIENTS AND METHODS: All children diagnosed with FC according to the Rome IV criteria were included and had at least one follow-up clinic visit. Demographic and clinical data collected from medical records included the age at onset, duration of constipation, clinical features, treatment modalities, and factors associated with clinical response. Descriptive statistics and Pearson's chi-squared test were used in the statistical analysis to see how categorical study variables were linked to clinical response. A P value of ≤.05 was used to report statistical significance. MAIN OUTCOME MEASURE: Compliance and clinical response to polyethylene glycol (PEG) compared with lactulose. SAMPLE SIZE: 370 children from 0.1 to 13 years of age. RESULTS: The median (IQR) age of onset was 4 (5) years and less than one year in 14%. The median (IQR) duration of constipation was 4 months (11) and less than two months in 93/370 (25%). Abdominal pain was the most commonly associated feature (44%). Screening for celiac disease and hypothyroidism was negative. A Fleet enema was the most common disimpaction method (54%) and PEG was the most common maintenance medication (63.4%). PEG was significantly better tolerated (P=.0008) and more effective than lactulose (P<.0001). Compliance was the only variable significantly associated with clinical response. CONCLUSIONS: PEG was better tolerated and more effective than lactulose in our study, a finding in agreement with the literature. Therefore, PEG should be the drug of choice in the initial management of FC in Saudi children. Prospective studies on the causes of noncompliance are needed to improve the response to treatment. LIMITATIONS: The limitations of retrospective design are missing data, recall bias, and hospital-based limitation, such as missing milder cases treated at the outpatient level. However, the sample size of 370 may have minimized these limitations.

Liposome Nanomedicine Based on Tumor Cell Lysate Mitigates the Progression of Lynch Syndrome-Associated Colon Cancer.

Treatment with immune checkpoint inhibitors (ICIs) has shown efficacy in some patients with Lynch syndrome-associated colon cancer, but some patients still do not benefit from it. In this study, we adopted a combination strategy of tumor vaccines and ICIs to maximize the benefits of immunotherapy. Here, we obtained tumor-antigen-containing cell lysate (TCL) by lysing MC38Mlh1 KD cells and prepared liposome nanoparticles (Lipo-PEG) with a typical spherical morphology by thin-film hydration. Anti-PD-L1 was coupled to the liposome surface by the amidation reaction. As observed, anti-PD-L1/TCL@Lipo-PEG was not significantly toxic to mouse intestinal epithelial cells (MODE-K) in the safe concentration range and did not cause hemolysis of mouse red blood cells. In addition, anti-PD-L1/TCL@Lipo-PEG reduced immune escape from colon cancer cells (MC38Mlh1 KD) by the anti-PD-L1 antibody, restored the killing function of CD8+ T cells, and targeted more tumor antigens to bone marrow-derived dendritic cells (BMDCs), which also expressed PD-L1, to stimulate BMDC antigen presentation. In syngeneic transplanted Lynch syndrome-associated colon cancer mice, the combination of anti-PD-L1 and TCL provided better cancer suppression than monoimmunotherapy, and the cancer suppression effect of anti-PD-L1/TCL@Lipo-PEG treatment was even better than that of the free drug. Meanwhile anti-PD-L1/TCL@Lipo-PEG enhanced the immunosuppressive tumor microenvironment. In vivo fluorescence imaging and H&E staining showed that the nanomedicine was mainly retained in the tumor site and had no significant toxic side effects on other major organs. The anti-PD-L1/TCL@Lipo-PEG prepared in this study has high efficacy and good biosafety in alleviating the progression of Lynch syndrome-associated colon cancer, and it is expected to be a therapeutic candidate for Lynch syndrome-associated colon cancer.

Interim analysis of the PARADISE study: Benefits of add-on peginterferon-α in NA-treated patients with CHB.

This study aimed to investigate whether peginterferon-α (IFN) add-on nucleos(t)ide analogs(NAs) can further reduce hepatocellular carcinoma(HCC) risk compared with NAs monotherapy in NA-treated patients with chronic hepatitis B(CHB). In this multi-center randomized controlled trial "PARADISE study" (NCT05671315), CHB patients with intermediate to high risk of HCC after more than 24-week NAs pretreatment were recruited, randomized to two groups at a ratio of 1:2 and followed up for 240 weeks. NAs group maintained NAs monotherapy, while IFN + NAs group received IFN add-on NAs therapy for 48 weeks, then switched to NAs monotherapy. Totally, 196 patients were included in interim analysis (NAs group 68, IFN + NAs group 128). The 96-week cumulative HCC incidence was lower in IFN + NAs group than NAs group (0% vs. 4.5%, p < 0.05). Compared with NAs group, IFN + NAs group had significantly higher rates of HBsAg loss at week 48 and 96 (22.7% vs. 0%; 16.7% vs. 0%, both p < 0.05). A new scoring system was established to predict HBsAg decline >2log10 IU/ml, HBsAg <10 IU/ml or HBsAg loss at the end of 48-week IFN treatment. The area under ROC curve was 0.914, 0.922 or 0.905 in the original cohort (n = 128) and 0.896, 0.896 or 0.864 in the external validation cohort (n = 162) for the aforementioned three outcomes, respectively. IFN add-on NAs therapy may suggest the dual benefits of reducing HCC development and facilitating HBsAg loss among NA-treated CHB patients with intermediate to high risk of HCC. The new scoring system helps to make the most of IFN treatment for a higher cost-effectiveness in healthcare.

Preparation of etoposide liposomes for enhancing antitumor efficacy on small cell lung cancer and reducing hematotoxicity of drugs.

Etoposide (VP16) is commonly used in the treatment of small cell lung cancer (SCLC) in clinical practice. However, severe adverse reactions such as bone marrow suppression toxicity limit its clinical application. Although several studies on VP16 liposomes were reported, no significant improvement in bone marrow suppression toxicity has been found, and there was a lack of validation of animal models for in vivo antitumor effects. Therefore, we attempted to develop a PEGylated liposomal formulation that effectively encapsulated VP16 (VP16-LPs) and evaluated its therapeutic effect and toxicity at the cellular level and in animal models. First, we optimized the preparation process of VP16-LPs using an orthogonal experimental design and further prepared them into freeze-dried powder to improve storage stability of the product. Results showed that VP16-LPs freeze-dried powder exhibited good dispersibility and stability after redispersion. In addition, compared to marketed VP16 injection, VP16-LPs exhibited sustained drug release characteristics. At the cellular level, VP16-LPs enhanced the cellular uptake of drugs and exhibited strong cytotoxic activity. In animal models, VP16-LPs could target and aggregate in tumors and exhibit a higher anti-tumor effect than VP16-injection after intravenous injection. Most importantly, hematological analysis results showed that VP16-LPs significantly alleviated the bone marrow suppression toxicity of drug. In summary, our study confirmed that PEGylated liposomes could enhance therapeutic efficacy and reduce toxicity of VP16, which demonstrated that VP16-LPs had enormous clinical application potential.

Bushen Formula promotes the decrease of HBsAg levels in patients with CHB by regulating Tfh cells and B-cell subsets.

ETHNOPHARMACOLOGICAL RELEVANCE: Bushen Formula (BSF) is the effective traditional Chinese medicine (TCM) for chronic hepatitis B (CHB) according to our previous researches. However, the special effectiveness of BSF treating CHB patients in different stages and the immunoregulatory mechanisms remain to be explored. AIM OF THE STUDY: To compare the therapeutic effects of BSF in both treatment-naive patients and Peg-IFN-α-treated patients, and explore the potential mechanism of immunomodulation. MATERIALS AND METHODS: Ultra-high performance liquid chromatography-quadrupole electrostatic field-orbital trap high resolution mass spectrometry and the TCMSP database were used to determine the main components of BSF. Two hundred and sixty-six patients were enrolled in the retrospective study, and they were divided into the treatment group (T-Group, BSF plus Peg-IFN-α) and the control group (C-Group, Peg-IFN-α monotherapy). Within each group, patients were further grouped into subgroups, namely T1/C1 groups (treatment-naive patients, T1 = 34, C1 = 94) and T2/C2 groups (Peg-IFN-α-treated patients, T2 = 56, C2 = 82). Serum HBV markers, serum HBV DNA levels, serum ALT/AST and TCM symptoms were obtained from the record. Bioinformatics analysis was employed to obtain the potential immunoregulatory mechanisms of BSF treating CHB patients. Among patients in T2 and C2 group, peripheral mononuclear cells from 36 patients were used to analyze the characteristics of peripheral follicular helper T (Tfh) cells and B-cell subtypes by flow cytometry. Preparation of BSF-containing serum in rats. In vitro, the co-culture system of CXCR5+ cells and HepG2.2.15 cells was built to investigate the immunoregulatory effects of BSF. RESULTS: A total of 14 main active compounds were detected in BSF, which were deemed critical for the treatment of CHB. Our findings indicated that the T2-Group exhibited the higher percentage of HBsAg decline ≥ 1-log10 IU/ml and rate of HBeAg seroclearance compared to the C2-Group (35.7% vs. 15.9%, P = 0.033; 33.9% vs. 11.0%, P = 0.002). Additionally, the T2-Group demonstrated the higher percentage of HBsAg decline ≥ 1-log10 IU/ml and rate of HBeAg seroclearance compared to the T1-Group (35.7% vs. 14.7%, P = 0.031; 33.9% vs. 2.9%, P = 0.000). The total effective rate based on TCM clinical syndrome in T1-Group and T2-Group were significantly greater than those in C1-Group and C2-Group (85.3% vs. 61.7%, P = 0.012; 89.1% vs. 63.4%, P = 0.000). Bioinformatics analysis indicated that the immunoregulatory mechanisms of BSF treating CHB patients were mainly linked to the growth and stimulation of B-cell, T-cell differentiation, and the signaling pathway of the B-cell receptor. Furthermore, the frequencies of Tfh cells and its IL-21 level, and the IL-21R expressed by B-cell were all increased after BSF treatment. Additionally, in the co-culture system of CXCR5+ cells and HepG2.2.15 cells, HBsAg and HBeAg levels were decreased after BSF-containing serum treatment，as well as the up-regulating of Tfh cell frequencies and down-regulating of B-cell frequencies. CONCLUSIONS: BSF have the higher percentage of HBsAg decline and HBeAg seroclearance in Peg-IFN-α-treated patients compared with treatment-naive patients. The potential immunoregulatory mechanism may correlate with promoting the interaction between Tfh cells and B-cell through IL-21/IL-21R signaling pathway.

Pharmacologic Management of Hepatic Encephalopathy.

Hepatic encephalopathy is a common cause of morbidity and mortality among patients with decompensated liver cirrhosis. In this article, we review the history, mechanism, and evidence for first-line pharmacologic therapies for hepatic encephalopathy including nonabsorbable disaccharides, antibiotics, and electrolyte management. We also review newer, second-line therapies including polyethylene glycol, albumin, branched-chain amino acids, probiotics and fecal microbiota transplant, zinc, and l-ornithine-l-aspartate.

Does a Preoperative Bowel Regimen Change Time to Bowel Movement? A Randomized Clinical Trial.

IMPORTANCE: This study is important because it aimed to assess an intervention to decrease patient discomfort after a robotic sacral colpopexy. OBJECTIVE: Our primary outcome was to determine whether preoperative use of polyethylene glycol decreases time to first bowel movement postoperatively. Secondary outcomes include degree of pain with first bowel movement and stool consistency. STUDY DESIGN: This was a randomized controlled trial. The experimental group was assigned polyethylene glycol daily for 7 days before surgery and the control group was not. All patients received polyethylene glycol postoperatively. RESULTS: There was no statistically significant reduction in the time to first postoperative bowel movement when preoperative polyethylene glycol was used (mean [SD] in days for the control and experimental groups of 2.32 [0.99] and 1.96 [1.00], P = 0.21). There was a statistically significant reduction in pain levels with the first postoperative bowel movement in the experimental group (median [IQR] of 4 [2-5] vs 1 [0-2], P = 0.0007). Postoperative day 1 pain levels were also significantly lower in the experimental group (median [IQR] of 4 [3-6] vs 2 [0-4], P = 0.0484). In addition, patients had decreased average postoperative pain levels over 7 days with an estimated difference in the median pain levels of 1.88 units (95% confidence interval, 0.64-3.12; P = 0.0038). CONCLUSIONS: Preoperative administration of polyethylene glycol did not decrease time to first postoperative bowel movement. Patients in the experimental group exhibited less pain with their first postoperative bowel movement and had improved pain levels on postoperative day 1.

First-line sintilimab with pegaspargase, gemcitabine, and oxaliplatin in advanced extranodal natural killer/T cell lymphoma (SPIRIT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitor sintilimab is effective in relapsed and refractory extranodal natural killer/T cell lymphoma (ENKTL), nasal type. We aimed to assess the safety and activity of sintilimab plus P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) in the first-line setting for advanced ENKTL. METHODS: The multicentre, single-arm, phase 2 trial was done at three medical centres in China. Patients aged 18-75 years with treatment-naive pathologically confirmed advanced ENKTL and an with Eastern Cooperative Oncology Group performance status score of 0-2 were eligible. Patients received intravenous sintilimab (200 mg on day 1), intramuscular pegaspargase (2000 U/m2 on day 1), intravenous gemcitabine (1 g/m2 on days 1 and 8), and intravenous oxaliplatin (130 mg/m2 on day 1) every 3 weeks for six cycles, followed by intravenous sintilimab (200 mg) every 3 weeks for up to 2 years or until disease progression or unacceptable toxicities. The primary endpoint was the complete response rate in the intention-to-treat population. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), disease-free survival (DFS), and overall survival. This trial is registered with ClinicalTrials.gov, NCT04127227. Enrolment has been completed, and follow-up is ongoing. FINDINGS: Between Nov 29, 2019, and Sept 7, 2022, 34 eligible patients were enrolled (median age 39 years [IQR 32-55]; 25 [74%] of 34 patients were male; nine [26%] were female; and all were of Asian ethnicity). At the data cutoff (July 20, 2023), the median follow-up was 21 months (IQR 13-32). The complete response rate was 85% (29 of 34 patients, 95% CI 70-94). Five patients (15%; 95% CI 7-30) attained partial response and the ORR was 100% (34 of 34 patients). 24-month PFS was 64% (95% CI 48-86), 24-month DFS was 72% (54-95), and 36-month overall survival was 76% (52-100). The most common grade 3 or 4 treatment-related adverse events were neutropenia (17 [50%] of 34 patients), anaemia (10 [29%] patients), and hypertriglyceridemia (10 [29%] patients). Hypothyroidism was the most frequent immune-related adverse event (18 [53%]), including grade 3 hypothyroidism in one (3%) patient that caused treatment termination. No severe adverse events occurred. There were three deaths: one due to haemophagocytic syndrome, one due to disease progression, and one due to unknown cause, which were not considered to be treatment related. INTERPRETATION: Combination of sintilimab with P-GEMOX seems to be an active and safe first-line regimen for patients with advanced ENKTL. FUNDING: National Key Research and Development Program and National Natural Science Foundation of China, Guangzhou Science and Technology Program and the Clinical Oncology Foundation of Chinese Society of Clinical Oncology.

Recombinant interferon alfa in BCR/ABL-negative chronic myeloproliferative neoplasms.

The treatment landscape for BCR/ABL-negative myeloproliferative neoplasms (MPNs), driven by JAK2, CALR, and MPL mutations, has evolved significantly over the last decade. Recent regulatory approvals in polycythemia vera (PV) include the JAK inhibitor ruxolitinib, and more recently, a novel recombinant interferon alfa-2 (IFN-α) therapeutic agent. Many clinical trials have documented the safety and efficacy of IFN-α therapy in PV and essential thrombocythemia, the classical BCR/ABL-negative MPNs. Used off-label for more than 30 years as a cytoreductive agent, IFN-α therapy promotes significant clinical, hematologic, and molecular responses. In some IFN-α-treated patients, partial or complete reduction of the mutant JAK2 allele burden may lead to a durable measurable residual disease state, owing to the ability of long-term IFN-α therapy to selectively deplete mutant JAK2-harboring hematopoietic stem cells. Pegylated IFN-α forms were developed to improve the drug stability and tolerability of first-generation IFN-α therapeutics. More recently, a novel pegylated IFN-α, ropeginterferon alfa-2b, received approval for PV by the European Medicines Agency and the US Food and Drug Administration in 2019 and 2021, respectively. This article reviews the clinical research and recent advances that led to the first regulatory approval of IFN-α in a BCR/ABL-negative MPN and its future promise as a disease-modifying therapeutic agent.

Pharmacological prevention and treatment of opioid-induced constipation in cancer patients: A systematic review and meta-analysis.

BACKGROUND: Cancer-related pain often requires opioid treatment with opioid-induced constipation (OIC) as its most frequent gastrointestinal side-effect. Both for prevention and treatment of OIC osmotic (e.g. polyethylene glycol) and stimulant (e.g. bisacodyl) laxatives are widely used. Newer drugs such as the peripherally acting µ-opioid receptor antagonists (PAMORAs) and naloxone in a fixed combination with oxycodone have become available for the management of OIC. This systematic review and meta-analysis aims to give an overview of the scientific evidence on pharmacological strategies for the prevention and treatment of OIC in cancer patients. METHODS: A systematic search in PubMed, Embase, Web of Science and the Cochrane Library was completed from inception up to 22 October 2022. Randomized and non-randomized studies were systematically selected. Bowel function and adverse drug events were assessed. RESULTS: Twenty trials (prevention: five RCTs and three cohort studies; treatment: ten RCTs and two comparative cohort studies) were included in the review. Regarding the prevention of OIC, three RCTs compared laxatives with other laxatives, finding no clear differences in effectivity of the laxatives used. One cohort study showed a significant benefit of magnesium oxide compared with no laxative. One RCT found a significant benefit for the PAMORA naldemedine compared with magnesium oxide. Preventive use of oxycodone/naloxone did not show a significant difference in two out of three other studies compared to oxycodone or fentanyl. A meta-analysis was not possible. Regarding the treatment of OIC, two RCTs compared laxatives, of which one RCT found that polyethylene glycol was significantly more effective than sennosides. Seven studies compared an opioid antagonist (naloxone, methylnaltrexone or naldemedine) with placebo and three studies compared different dosages of opioid antagonists. These studies with opioid antagonists were used for the meta-analysis. Oxycodone/naloxone showed a significant improvement in Bowel Function Index compared to oxycodone with laxatives (MD -13.68; 95 % CI -18.38 to -8.98; I2 = 58 %). Adverse drug event rates were similar amongst both groups, except for nausea in favour of oxycodone/naloxone (RR 0.51; 95 % CI 0.31-0.83; I2 = 0 %). Naldemedine (NAL) and methylnaltrexone (MNTX) demonstrated significantly higher response rates compared to placebo (NAL: RR 2.07, 95 % CI 1.64-2.61, I2 = 0 %; MNTX: RR 3.83, 95 % CI 2.81-5.22, I2 = 0 %). With regard to adverse events, abdominal pain was more present in treatment with methylnaltrexone and diarrhea was significantly more present in treatment with naldemedine. Different dosages of methylnaltrexone were not significantly different with regard to both efficacy and adverse drug event rates. CONCLUSIONS: Magnesium oxide and naldemedine are most likely effective for prevention of OIC in cancer patients. Naloxone in a fixed combination with oxycodone, naldemedine and methylnaltrexone effectively treat OIC in cancer patients with acceptable adverse events. However, their effect has not been compared to standard (osmotic and stimulant) laxatives. More studies comparing standard laxatives with each other and with opioid antagonists are necessary before recommendations for clinical practice can be made.

Peg-IFNα combined with hepatitis B vaccination contributes to HBsAg seroconversion and improved immune function.

PURPOSE: The purpose of this study was to investigate immunological variations between a group that received the hepatitis B vaccine and a non-vaccine group. We focused on a cohort that achieved HBsAg seroclearance after Peg-IFNα treatment of CHB. METHODS: We enrolled twenty-eight individuals who achieved HBsAg seroclearance after Peg-IFNα treatment. They were divided into two groups: a vaccine group (n = 14) and a non-vaccine group (n = 14). We assessed lymphocyte subpopulations, B cell- and T cell-surface costimulatory/inhibitory factors, cytokines and immunoglobulin levels were detected at different time points to explore immune-function differences between both groups. RESULTS: The seroconversion rate in the vaccine group at 24 weeks post-vaccination was 100%, which was significantly higher (p = 0.006) than that of the non-vaccine group (50%). Additionally, more individuals in the vaccine group exhibited anti-HBs levels exceeding 100 IUs/L and 300 IUs/L compared to the non-vaccine group (p < 0.05). The vaccine group demonstrated significantly increase total B cells and class-switched B cells at 24 weeks and plasma cells, CD80+B cells, Tfh cells, and ICOS+Tfh cell at 12 weeks, compared with baseline levels (p < 0.05). Conversely, Bregs (CD24+CD27+ and CD24+CD38high) decreased significantly at 24 weeks (p < 0.05). None of the above changes were statistically significance in the non-vaccine group (p > 0.05). Total IgG increased significantly in the vaccine group, and IL-2, IL-5, and IL-6 concentrations increased significantly at week 24 (p < 0.05). Differences in various types of cytokines and immunoglobulins in the plasma of the non-vaccine group were not significant (p > 0.05). Anti-HBs titers positively correlated with Th1/Th2 cells at 24 weeks (r = 0.448 and 0.458, respectively, p = 0.022 and 0.019, respectively), and negatively with CD24+CD38highBreg cells (r = -0.402, p = 0.042). CONCLUSIONS: After achieving HBsAg seroclearance through Peg-IFNα treatment for CHB, administering the hepatitis B vaccine significantly increased anti-HBs-seroconversion rates and antibody levels. We also observed significant immunological differences between the vaccine and non-vaccine groups. Specifically, the vaccine group exhibited significant increases in B cells, plasma cells, and Tfh cells, while Breg levels was significantly lower. These immunological changes are likely conducive to the production of anti-HBs antibodies. However, in the non-vaccine group, the observed changes were not significantlly significant.

Withaferin A-Encapsulated PEGylated Nanoliposomes Induce Apoptosis in B16F10 Melanoma Cells by Regulating Bcl2 and Bcl xl Genes and Mitigates Murine Solid Tumor Development.

Withaferin A (WA) is a natural steroidal lactone with promising pharmacological activities, but its poor solubility and bioavailability hinder its clinical application. The liposomal drug delivery system has attracted considerable attention to overcome the delivery limitations of pharmacological agents. The present study investigated the effect of WA-loaded pegylated nanoliposomes (LWA) on in vitro and in vivo B16F10 melanoma tumor models. In vitro results showed that LWA had significantly (P < 0.01) higher cytotoxicity than free WA and induced ROS-mediated apoptosis in B16F10 cells. Transwell cell migration and invasion studies demonstrated that LWA treatment significantly (P < 0.01) decreased the migratory and invasive capacities of melanoma cells compared with WA. In vivo study revealed that treatment significantly (P < 0.01) reduced tumor growth in experimental animals compared with WA or tumor control. Also, LWA administration remarkably inhibited tumor cell proliferation by downregulating the expression of Ki-67 and Cyclin D1 and induced apoptosis by regulating the expression of Bax, Bcl2, and Bcl xl levels. Our results strongly suggest that LWA could be a promising therapeutic formulation for treating malignant melanoma.

Management of autoimmune hepatitis induced by hepatitis delta virus.

Approximately 12-72 million people worldwide are co-infected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). This concurrent infection can lead to several severe outcomes with hepatic disease, such as cirrhosis, fulminant hepatitis, and hepatocellular carcinoma, being the most common. Over the past few decades, a correlation between viral hepatitis and autoimmune diseases has been reported. Furthermore, autoantibodies have been detected in the serum of patients co-infected with HBV/HDV, and autoimmune features have been reported. However, to date, very few cases of clinically significant autoimmune hepatitis (AIH) have been reported in patients with HDV infection, mainly in those who have received treatment with pegylated interferon. Interestingly, there are some patients with HBV infection and AIH in whom HDV infection is unearthed after receiving treatment with immunosuppressants. Consequently, several questions remain unanswered with the challenge to distinguish whether it is autoimmune or "autoimmune-like" hepatitis being the most crucial. Second, it remains uncertain whether autoimmunity is induced by HBV or delta virus. Finally, we investigated whether the cause of AIH lies in the previous treatment of HDV with pegylated interferon. These pressing issues should be elucidated to clarify whether new antiviral treatments for HDV, such as Bulevirtide or immu-nosuppressive drugs, are more appropriate for the management of patients with HDV and AIH.

Efficacy of Bleomycin-Lauromacrogol Foam in Pediatric Macrocystic Lymphatic Malformations With and Without Intracapsular Hemorrhage.

BACKGROUND: Sclerotherapy is purportedly less effective in patients with hemorrhagic than with non-hemorrhagic lymphatic malformations (LMs). We aimed to compare the efficacy of bleomycin-lauromacrogol foam (BLF) sclerotherapy in the treatment of macrocystic LMs with and without intralesional hemorrhage. METHODS: Fifty-five children with macrocystic LMs admitted to the Pediatric Surgery Department were retrospectively included. The patients were allocated into a hemorrhage group (23 cases) or a non-hemorrhage group (32 cases) based on the occurrence of an intracapsular hemorrhage. The diagnosis was confirmed by physical examination, color ultrasound, magnetic resonance imaging, and puncture findings. BLF was injected into the capsule after draining the cystic fluid under color ultrasound guidance. Patients whose lesions were unchanged or showed minor change after 1 month were treated again using the same method. Changes in lesion size and the number of treatments were recorded. Effectiveness was classified as excellent (volume reduction ≥90%), good (50%≤volume reduction<90%), or poor (volume reduction <50%). RESULTS: In the hemorrhage group, 17, 6, and 0 patients' outcomes were classified as excellent, good, and poor, respectively. The overall efficacy rate was 100%. In the non-hemorrhage group, 23, 7, and 2 patients' outcomes were classified as excellent, good, and poor, respectively. The overall efficacy rate was 93.8%. There was no significant difference in efficacy rate between groups (P = 0.767). CONCLUSIONS: BLF is an effective and safe treatment for macrocystic LMs with bleeding. The results were similar in patients with and without bleeding. LEVEL OF EVIDENCE: Treatment, Level III.

[A cross-sectional survey on the types of antiviral treatment plans for patients with chronic hepatitis B].

Objective: To understand the current antiviral treatment status and various clinical types of treatment plans in Xiamen City so as to explore ways to improve and optimize the diagnosis and treatment standards for chronic hepatitis B. Methods: A cross-sectional survey method was used to study the antiviral treatment status and treatment plans for chronic hepatitis B patients who visited and were diagnosed in the Department of Infectious Diseases and Hepatology of all tertiary hospitals in Xiamen City at 0:00~23:59 on May 25, 2022. Results: A total of 665 cases were surveyed in this study, with an antiviral treatment rate of 81.2%(540/665). The antiviral treatment rate of patients who accorded with the current guidelines for antiviral treatment indications was 85.8%(507/591). The antiviral treatment rate for 362 outpatients was 72.9%(264/362). Among them, the antiviral treatment rates were 80.1%, 89.3%, and 25.0%(226/282, 25/28, 13/52), respectively, for patients diagnosed with chronic hepatitis B, hepatitis B cirrhosis, and hepatitis B surface antigen-carrying status. The treatment plan for all outpatient patients was mainly oral nucleos(t)ide analogues, accounting for 59.1%(214/362). The antiviral treatment rate for 303 inpatients was 91.1%(276/303). The various clinical types of antiviral therapy rates among all patients were 70%~95%. The antiviral treatment plan for inpatients was mainly based on pegylated interferon alpha treatment, accounting for 72.6%(220/303). Conclusion: Antiviral treatment for chronic hepatitis B in Xiamen City can still be strengthened to meet the current demand for expanding antiviral treatment indications. Antiviral treatment rates and various types of treatment plans differ between outpatients and inpatients; thus, further awareness and acceptance of the goal of improving antiviral therapy, especially in outpatients, and the possibility for a clinical cure based on pegylated interferon alpha treatment are needed to maximize the benefit to more patients.

Prophylactic pegfilgrastim reduces febrile neutropenia in ramucirumab plus docetaxel after chemoimmunotherapy in advanced NSCLC: post hoc analysis from NEJ051.

Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p < 0.001). The frequency of FN was 25 patients (10.1%) in the pegfilgrastim group and 10 (24.4%) in the control group (p = 0.018). The objective response rate was 31.2% and 14.6% in the pegfilgrastim and control groups (p = 0.039), respectively. The disease control rate was 72.9% in the pegfilgrastim group and 51.2% in the control group (p = 0.009). Median progression free survival was 4.3 months in the pegfilgrastim group and 2.5 months in the control group (p = 0.002). The median overall survival was 12.8 and 8.1 months in the pegfilgrastim and control groups (p = 0.004), respectively. Prophylactic pegfilgrastim for RD reduced the frequency of grade 3/4 neutropenia and febrile neutropenia and did not appear to be detrimental to patient outcome RD.Clinical Trial Registration Number: UMIN000042333.

Deguelin and Paclitaxel Loaded PEG-PCL Nano-Micelles for Suppressing the Proliferation and Inducing Apoptosis of Breast Cancer Cells.

BACKGROUND: Deguelin (DGL) is a natural flavonoid reported to exhibit antitumor effects in breast cancer (BC). PEG-PCL (Polyethylene Glycol- Polycaprolactone), as polymeric micelles, has biodegradability and biocompatibility. The aim of this study was to investigate whether the nanoparticular delivery system, PEG-PCL could improve the bioavailability of DGL for suppressing proliferation of BC cells. METHODS: PEG-PCL polymers were first prepared by ring-opening polymerization, and DGL and paclitaxel (PTX)-loaded PEG-PCL nano-micelles were formulated via the film dispersion method. The composition and molecular weight of PEG-PCL were analyzed by nuclear magnetic resonance and fourier Transform infrared spectroscopy (FTIR) spectra. Particle size, surface potential and hemolytic activity of micelles were assessed by dynamic light scattering, transmission electron microscopy and hemolysis assay, respectively. Then proliferation and apoptosis of MDA-MB-231 and MDA-MB-468 cells were tested with Edu staining, CCK-8, TUNEL staining, and Flow cytometer. Caspase 3 expression was also assessed by Western blot. RESULTS: Our results first indicated that PEG2000-PCL2000 was successfully synthesized. DGL and PTX-loaded PEG-PCL nano-micelles were rounded in shape with a particle size of 35.78 ± 0.35 nm and a surface potential of 2.84 ± 0.27 mV. The micelles had minimal hemolytic activity. Besides, we proved that DGL and PTX-loaded PEG-PCL nano-micelles could suppress proliferation and induce apoptosis in BC cells. The DGL and PTX-loaded PEG-PCL nano-micelles constructed in this study had a prominent inhibitory role on proliferation and a remarkable promotional role on apoptosis in BC cells. CONCLUSIONS: This study proposes that nano-micelles formed by PEG-PCL can enhance the cytotoxicity of Paclitaxel against breast cancer cells, and concurrently, the loading of Deguelin may further inhibit cell proliferation. This presents a potential for the development of a novel therapeutic strategy.