Τετάρτη 31 Αυγούστου 2022

VG161 activates systemic anti‐tumor immunity in pancreatic cancer models as a novel oncolytic herpesvirus expressing multiple immunomodulatory transgenes

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Abstract

The VG161 represents the first recombinant oncolytic herpes simplex virus type 1 carrying multiple synergistic anti-tumor immuno-modulating factors. Here, we report its anti-tumor mechanisms and thus provide firm theoretical foundation for the upcoming clinical application in pancreatic cancer. Generally, the VG161-mediated anti-tumor outcomes were analyzed by a collaboration of techniques, namely the single cell sequencing, airflow-assisted desorption electrospray ionization-mass spectrometry imaging (AFADSI-MSI) and Nanostring techniques. In vitro, the efficacy of VG161 together with immune checkpoint inhibitors (ICIs) has been successfully shown to grant a long-term anti-tumor effect by altering tumor immunity and remodeling tumor microenvironment (TME) metabolisms. Cellular functional pathways and cell subtypes detected from patient samples before and after the treatment had undergone distinctive changes including upregulated CD8+ T and NK cells. More importantly, significant antitumor signals have emerged since the administration of VG161 injection. In conclusion, VG161 can systematically activate acquired and innate immunity in pancreatic models, as well as improve the tumor immune microenvironment, indicative of strong anti-tumor potential. The more robusting anti-tumor outcome for VG161 monotherapy or in combination with other therapies on pancreatic cancer is worth of being explored in further clinical trials.

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Long‐Term Binaural Hearing Improvements for Cochlear Implant Users with Asymmetric Hearing Loss

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Long-Term Binaural Hearing Improvements for Cochlear Implant Users with Asymmetric Hearing Loss

Cochlear implant (CI) recipients with unilateral hearing loss reached early asymptote for binaural hearing abilities, and CI recipients with asymmetric hearing loss continued to improve out to 5-years post-activation for spatial release from masking when the masker was presented toward the better hearing ear. There was a significant correlation with improvement and age at implantation and contralateral hearing thresholds which may influence these differences.


Objective

To assess long-term binaural hearing abilities for cochlear implant (CI) users with unilateral hearing loss (UHL) or asymmetric hearing loss (AHL).

Methods

A prospective, longitudinal, repeated measures study was completed at a tertiary referral center evaluating adults with UHL or AHL undergoing cochlear implantation. Binaural hearing abilities were assessed with masked speech recognition tasks using AzBio sentences in a 10-talker masker. Performance was evaluated as the ability to benefit from spatial release from masking (SRM). SRM was calculated as the difference in scores when the masker was presented toward the CI-ear (SRMci) or the contralateral ear (SRMcontra) relative to the co-located condition (0°). Assessments were completed pre-operatively and at annual intervals out to 5 years post-activation.

Results

Twenty UHL and 19 AHL participants were included in the study. Linear Mixed Models showed significant main effects of interval and group for SRMcontra. There was a significant interaction between interval and group, with UHL participants reaching asymptotic performance early and AHL participants demonstrating continued growth in binaural abilities to 5 years post-activation. The improvement in SRM showed a significant positive correlation with contralateral unaided hearing thresholds (p = 0.050) as well as age at implantation (p = 0.031).

Conclusions

CI recipients with UHL and AHL showed improved SRM with long-term device use. The time course of improvement varied by cohort, with the UHL cohort reaching asymptotic performance early and the AHL cohort continuing to improve beyond 1 year. Differences between cohorts could be driven by differences in age at implantation as well as contralateral unaided hearing thresholds.

Level of Evidence

Level III Laryngoscope, 2022
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Endoscopic pituitary surgery: A national database review

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Abstract

Background

Pituitary tumors surgery is increasingly performed via endoscopic transsphenoidal approach (TSP). This study describes outcomes of TSP surgery in the United States.

Methods

A retrospective cross-sectional analysis of adult patients with pituitary adenoma was performed using the Nationwide Readmissions Database, 2010–2015.

Results

A total of 5891 patients were identified. The average age was 51.29 ± 0.29 years. The risk of postoperative epistaxis, diabetes insipidus, cerebrospinal fluid (CSF) leak, and other general postoperative complications was 0.71%, 10.20%, 8.35%, and 2.37%, respectively. Independent risk factors of CSF leak included: age <65-year, male, body mass index ≥25, and multiple comorbidities (p < 0.001 each). The prevalence of CSF leak was not associated with hospital TSP volume and teaching status.

Conclusion

This study provides a national epidemiological perspective on TSP in the United States. The risk of postoperative CSF leak appears to be associated with intrinsic patient factors rather than resource and expertise availability.
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Mini‐hyper CVD + CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab) for refractory pediatric B‐acute lymphoblastic leukemia

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Abstract

Relapsed or refractory pediatric patients with B-acute lymphoblastic leukemia (B-ALL) have high rates of toxicities and relapse, and novel therapy is needed. We present a case of a 5-year-old male child with high-risk B-ALL that was refractory to several re-induction regimens. He was put into minimal residual disease-negative remission after re-induction with chemotherapy plus overlapping rituximab, inotuzumab ozogamicin, and blinatumomab, termed mini-hyper-CVD (cyclophosphamide, vincristine, and dexamethasone) plus CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab). This regimen was well tolerated, and he received his transplant and engrafted with no significant infections, toxicities, or sinusoidal obstruction syndrome. This is the first reported use of a condensed sequential immunotherapy/chemotherapy regimen in a pediatric leukemia patient.
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Survival Outcomes of Patients with Mycosis Fungoides Involving the External Ear and Ear Canal

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Survival Outcomes of Patients with Mycosis Fungoides Involving the External Ear and Ear Canal

This manuscript reports our retrospective review of 40 patients with mycosis fungoides, and it demonstrates a comparison in outcomes of patients with ear involvement with those without ear involvement. Overall survival was shorter when the ear canals were involved.


Objectives/Hypothesis

Mycosis Fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. Disease involvement of specific locations may be more significant than simply the symptoms associated with that site; it is possible that involvement of certain sites could be associated with poor prognosis. We aimed to evaluate the outcomes of patients with MF with documented involvement of the EAC and external ear.

Study Design

Retrospective analysis.

Methods

We retrospectively reviewed 40 patients with MF that were treated by otologists between 2012 and 2021.

Results

We report the largest series of patients with MF involving the external ear and EAC. Of the 40 patients included in this study, 17 presented with Mycosis Fungoides in the otologic region (MFO). Of these 17 MFO patients, 2/17 had involvement of the external ear only, 3/17 of the EAC only, 11/17 of both the external ear and EAC, and 1/17 of the periauricular skin. Of note, 11/14 (79%) patients presenting with EAC disease died compared to11/26 (42%) of patients without involvement. In addition, eight of the 13 (62%) patients with external ear involvement died compared to 14/27 (52%) of patients without involvement. Ear canal involvement was associated with a statistically significant shorter overall survival duration in patients with MF (p = 0.03). Furthermore, disease in the EAC was found to have a hazard ratio value of 2.565 (CI 1.102–5.970).

Conclusions

Involvement of the EAC by MF portends a poor prognosis. This finding highlights the need for a more in-depth otologic evaluation of patients with MF.

Level of Evidence

Level 4 Laryngoscope, 2022
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Τρίτη 30 Αυγούστου 2022

Asthma inflammatory phenotypes on four continents: most asthma is non-eosinophilic

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Abstract
Background
Most studies assessing pathophysiological heterogeneity in asthma have been conducted in high-income countries (HICs), with little known about the prevalence and characteristics of different asthma inflammatory phenotypes in low-and middle-income countries (LMICs). This study assessed sputum inflammatory phenotypes in five centres, in Brazil, Ecuador, Uganda, New Zealand (NZ) and the United Kingdom (UK).
Methods
We conducted a cross-sectional study of 998 asthmatics and 356 non-asthmatics in 2016–20. All centres studied children and adolescents (age range 8–20 years), except the UK centre which involved 26–27 year-olds. Information was collected using questionnaires, clinical characterization, blood and induced sputum.
Results
Of 623 asthmatics with sputum results, 39% (243) were classified as eosinophilic or mixed granulocytic, i.e. eosinophilic asthma (EA). Adjusted for age and sex, with NZ as ba seline, the UK showed similar odds of EA (odds ratio 1.04, 95% confidence interval 0.37–2.94) with lower odds in the LMICs: Brazil (0.73, 0.42–1.27), Ecuador (0.40, 0.24–0.66) and Uganda (0.62, 0.37–1.04). Despite the low prevalence of neutrophilic asthma in most centres, sputum neutrophilia was increased in asthmatics and non-asthmatics in Uganda.
Conclusions
This is the first time that sputum induction has been used to compare asthma inflammatory phenotypes in HICs and LMICs. Most cases were non-eosinophilic, including in settings where corticosteroid use was low. A lower prevalence of EA was observed in the LMICs than in the HICs. This has major implications for asthma prevention and management, and suggests that novel prevention strategies and therapies specifically targeting non-eosinophilic asthma are required globally.
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A rare case of facial asymmetry caused by simultaneous development of osteochondroma and synovial chondromatosis at the temporomandibular joint

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Publication date: Available online 30 August 2022

Source: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology

Author(s): Ichiro Kaneko, Masaaki Karino, Rie Osako - Sonoyama, Shinji Ishizuka, Erina Toda, Junichi Kanayama, Satoe Okuma, Hiroto Tatsumi, Tatsuo Okui, Takahiro Kanno
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Transmission pattern of measles virus circulating

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Abstract
Background
To provide useful insights into the measles elimination progress in China, measles surveillance data was reviewed, and the transmission patterns of measles viruses circulating in China during 1993–2021 were analyzed.
Methods
Measles incidence data from the National Notifiable Disease Reporting System of the China Center for Disease Control and Prevention was analyzed. A total of 17,570 strains were obtained from 30 of 31 provinces in mainland China during 1993–2021. The recommended genotyping window was amplified. Genotyping analysis was conducted in comparison with the reference strains. Furthermore, phylogenetic analyses were performed to identify genetic relationships among different lineages within the genotypes.
Results
With high coverage of routine immunization and intensive supplementary immunization activities, measles incidence has shown a downward trend since 1993, despite two resurgences, reac hing a historic low level in 2020–2021 (average 0.5 per million). During 1993–2021, nine genotypes including domestic genotype H1, imported genotypes B3, D4, D8, D9, D11, G3, and H2, and vaccine-associated genotype A were identified. Among them, genotype H1 strain circulated endemically in China for over 25 years; the last strain was detected in Yunnan province in September 2019. Multiple imported genotypes were identified since 2009 showing different transmission patterns. Since April 2020, no imported strains have been detected, while vaccine-associated genotype A continues to be detected.
Conclusions
The evidence of low incidence during 2020–2021 and virological surveillance data in this study confirmed that China is currently approaching measles elimination.
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Rifapentine with and without moxifloxacin for pulmonary tuberculosis in people with HIV (S31/A5349)

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Abstract
Background
Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 non-inferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had non-inferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the pre-specified subgroup of people with HIV (PWH).
Methods
PWH and CD4 + counts ≥100 cells/μL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months post-randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% non-inferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV-status. PWH were e nrolled in a staged fashion, to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz.
Results
2,516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4 + count was 344 cells/μL (interquartile range: 223–455). The rifapentine-moxifloxacin regimen was non-inferior to control (absolute difference in unfavorable outcomes -7.4% [95% CI –20.8% to +6.0%]); the rifapentine regimen was not non-inferior to control (+7.5% [95% CI -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%).
Conclusions
In people with HIV-associated DS-PTB with CD4 + counts ≥100 cells/μL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was non-inferior to the 6-month control regimen and was safe.
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Δευτέρα 29 Αυγούστου 2022

Curcumin reduces inflammation in rat apical periodontitis

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Abstract

Aim

To evaluate the effect of systemic curcumin administration on the severity of apical periodontitis (AP).

Methodology

Forty male Wistar rats weighing 250-280g each, age 2.5 months, were distributed into four groups (n=10): control untreated rats (C), control rats treated with curcumin (CUR), rats with pulp exposure-induced apical periodontitis (AP), and rats with pulp exposure-induced apical periodontitis treated with curcumin (AP-CUR). Curcumin treatment was administered orally once daily for 15 days before pulp exposure and continued for 30 days after pulp exposure. The rats were sacrificed at 30 days, and the jaws were collected and reconstructed in a program specific for micro-CT. The jaws were processed for analysis of the inflammatory process using Haemotoxylin and Eosin staining and immunohistochemical assays for interleukin tumour necrosis factor alpha (TNF-α), interleukin (Il)-6, and Il-1β. Tartrate-resistant acid phosphatase (TRAP) and osteocalcin (OCN) staining were used to analyze the resorptive process on the bone surface of periapical area. Kruskal–Wallis with Dunn's test was performed for nonparametric data, and ANOVA with Tukey's test for parametric data, p < .05.

Results

Micro-CT revealed no statistically significant differences in bone resorption between the AP and AP-CUR groups (p > .05). The levels of inflammatory cell infiltration and immunoreactivity for the proinflammatory cytokines TNF-α, Il-6, and Il-1β were significantly higher in the periapical lesions of the AP group than in the AP-CUR group (p < .05). The number of TRAP-positive multinucleated cells was higher in the AP group than in the AP-CUR group (p < .05). In OCN-positive cells, no differences were observed between the AP and AP-CUR groups (p > .05).

Conclusions

Oral supplementation with curcumin had a significant effect on the AP severity in rats, suggesting an anti-inflammatory effect of curcumin on AP development.
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