Synergistic anti-tumor efficacy by combination therapy of a self-assembled nanogel vaccine with an immune checkpoint anti-PD-1 antibody

Therapeutic strategies for cancer involving immune checkpoint inhibitors (ICIs) have been gaining widespread attention, but their efficacy remains limited. Thus, combination of ICI therapies with other therapeutic modalities may be required to improve their outcomes. In this study, we examined the improved efficacy of a CHP nanogel-based vaccine delivery system after combination with ICI therapy. For this, we evaluated the therapeutic efficacy of combining an anti-PD-1 antibody as an ICI with an OVA antigen-complexed CHP nanogel vaccine delivery system in a mouse E.G7-OVA tumor model. Mice were subcutaneously inoculated with E.G7-OVA tumor cells on one side of the back, and subcutaneously injected with OVA or the OVA/CHP nanogel vaccine on the other side of the back. Anti-PD-1 antibody was administered at defined intervals. Tumor volume, immune responses, and tumor-infiltrating cells were evaluated. Mice treated with OVA vaccine alone showed weak tumor suppression compared with untreated control mice. Mice receiving combined OVA/CHP nanogel vaccine and anti-PD-1 antibody therapy exhibited strong tumor growth suppression and markedly improved survival, suggesting that PD-1 signaling blockade by the anti-PD-1 antibody enhanced the anti-tumor efficacy of the OVA vaccine. Furthermore, tumor-infiltrating cells and immune responses were increased in the combined therapy group. No serious side effects were observed for any of the treatments. Taken together, the immune system activation induced by the CHP nanogel vaccine was synergistically enhanced by the anti-PD-1 antibody. The present findings suggest the potential for enhanced therapeutic efficacy by combining the CHP nanogel vaccine delivery system with ICI therapy for various cancer types.

Combination therapy of OVA/CHP nanogel vaccine with anti-PD-1 antibody synergistically improved anti-tumor effect and survival rate without side effects.     

Comparison of Pentax-AWS Airwayscope, Airtraq and Miller laryngoscope for tracheal intubation by novice doctors during infant cardiopulmonary resuscitation simulation: a randomized crossover trial

Recent guidelines for infant cardiopulmonary resuscitation emphasize that all rescuers should minimize interruption of chest compressions, even for endotracheal intubation. We compared the utility of the Pentax-AWS Airway Scope (AWS) with an infant-sized Intlock (AWS-I), Airtraq laryngoscope (ATQ) and Miller laryngoscope during chest compressions on an infant manikin. Twenty-three novice doctors performed tracheal intubation on an infant manikin using the AWS-I, ATQ and Miller laryngoscope, with or without chest compressions. In Miller laryngoscope trials, one participant failed to secure the airway without chest compressions, while nine failed with compressions (P < 0.05). In ATQ trials, none of the participants failed without compressions, while six failed with compressions (P < 0.05). In AWS-I trials, all participants succeeded regardless of chest compressions. Intubation time was significantly longer with chest compressions with the Miller laryngoscope and ATQ, but not with the AWS-I. The AWS-I is an effective device for endotracheal intubation during chest compressions in infant simulations managed by novice doctors.     

Cervical Lymph Node Dissection for Clinically Submucosal Carcinoma of the Thoracic Esophagus

Background

The purposes of this study were to clarify the risk factors for supraclavicular lymph node (SCLN) metastasis and the survival benefit from cervical lymph node (LN) dissections in patients with clinically submucosal (cT1b) carcinoma of the thoracic esophagus.

Methods

A total of 86 patients with this disease who underwent esophagectomy with 3-field lymph node dissection were retrospectively reviewed. Multivariate logistic regression and Cox proportional hazard model were used to identify the independent risk factors for SCLN metastasis and prognostic factors, respectively. An index calculated by multiplying the frequency of metastasis at nodal basin and the 5-year overall survival rate of patients with metastasis at that basin were used to assess the therapeutic outcomes.

Results

A total of 40 patients (47 %) were found to have pathological LN metastasis. Also, 13 patients (15 %) had cervical LN metastasis: 6 and 7 with carcinoma of the upper and mid-thoracic esophagus, respectively. SCLN metastasis was found in 6 patients (7 %); however, there was no independent risk factor for SCLN metastasis. The 5-year overall survival rate was 72.5 %. Cervical LN metastasis was an independent prognostic factor (p = .04; odds ratio 2.55; 95 % confidence interval 1.03–6.31); however, there was no significant difference in survival between patients with SCLN metastasis and those without (p = .06). The calculated index of estimated benefit from cervical LN dissections was 6.9, following upper mediastinal LN of 15.6 and perigastric LN of 8.3.

Conclusions

We could not identify risk factors to predict SCLN metastasis. Cervical LN dissection should not be omitted in patients with cT1b carcinoma, especially of the upper and mid-thoracic esophagus.     

Patient-prosthesis mismatch in patients with aortic valve replacement

Objective

Patient-prosthesis mismatch (PPM) may affect clinical outcomes in patients with aortic valve replacement (AVR). We retrospectively examined the PPM in patients with isolated AVR in the Japan Adult Cardiovascular Surgery Database (JACVSD).

Methods

We examined all patients with isolated AVR between January 1, 2008 and December 31, 2009. The JACVSD data collection form has a total of 255 variables. We defined PPM as an effective orifice area index of ≤0.85 m²/cm².

Results

PPM was observed in 306 of 3,609 cases analyzed, PPM rate was 8.5 %. Body surface area was larger and body mass index was higher in the PPM group than the non-PPM group (P < 0.001). Patients with PPM were older (P = 0.001) and had a higher prevalence of diabetes (P = 0.004), dyslipidemia (P < 0.001), hypertension (P < 0.001), cerebrovascular disease (P = 0.031), old myocardial infarction (P = 0.006), previous percutaneous coronary artery intervention (P = 0.001), coronary artery disease (P = 0.018), and aortic valve stenosis (P < 0.001). Perioperative blood transfusion (P < 0.001) and dialysis (P = 0.005) were more frequent in the PPM group. Postoperative ventilation (P = 0.004) and intensive care unit stay (P = 0.004) were significantly longer in the PPM group.

Conclusions

Age, aortic valve stenosis, dyslipidemia, hypertension, old myocardial infarction, previous percutaneous coronary artery intervention, diabetes mellitus, cerebrovascular disease, and high body mass index were the risk factors for PPM. PPM was not an independent risk factor for short-term mortality.     

Effect of VA-045, a novel apovincaminic acid derivative,on closed head injury-induced neurological dysfunction in aged rats

Abstract

Objective: The strength–duration time constant (SDTC) is a measure of axonal excitability and it can provide information about Na⁺ channel function. In this study, we sought to examine the changes in the SDTCs of motor and sensory fibers of the median nerve in patients taking colchicine, which affects axoplasmic flow and may result in axonal neuropathy.

Methods and results: The SDTCs of motor and sensory fibers of 29 patients who had been taking colchicine were measured following stimulation of the right median nerve at the wrist. The results were compared with ten healthy age-matched subjects. No significant differences were found between the groups.

Conclusions: The lack of any effect on the SDTC by colchicine might have been due to the fact that axonal degeneration caused by colchicine affects the Na⁺–K⁺ ATP pump or that it affects internodal channels other than nodal channels.     

Isolated pyramidal tract impairment in the central nervous system of adult-onset Krabbe disease with novel mutations in the GALC gene

This report describes a 60-year-old female patient with Krabbe disease who presented with slowly progressive gait disturbance due to mild spastic paraplegia. Brain magnetic resonance imaging showed high-intensity lesions along the upper parts of the bilateral pyramidal tracts in fluid-attenuated inversion recovery images. Central motor conduction time was prolonged both in the upper and the lower extremities, while central sensory conduction time was normal. The reduced lymphocyte galactocerebrosidase (GALC) activity and two novel mutations in the GALC gene, p.G496S and p.G569S, proved the diagnosis of Krabbe disease. Our findings show that adult-onset Krabbe disease is characterized by isolated pyramidal tract impairment in the central nervous system, both neurophysiologically and radiologically.     

Effect of polyglycolic acid sheets with fibrin glue (MCFP technique) on the healing of wounds after partial resection of the border of the tongue in rabbits: a preliminary study

The aim of this study was to examine the effectiveness of covering wounds to the tongue with a polyglycolic acid (PGA) sheet and fibrin glue. Eighteen mature male Japanese white rabbits had a unilateral glossectomy involving an area 10mm×10mm×2mm. After glossectomy the tongues were covered with PGA sheets 8mm×8mm in size and fibrin glue (mucosal defect covered with fibrin glue and polyglycolic acid sheet=MCFP) 1 week after the operation (n=3), after 2 weeks (n=3), and after 4 weeks (n=3). In control groups, after 1, 2, and 4 weeks (n=3 in each group), the partially resected tongues were closed with absorbable sutures (polyglactin 910). One week (experimental and control groups 1), 2 weeks (experimental and control groups 2) and 4 weeks (experimental and control groups 3) after operation the tongues were harvested and stained for microscopic examination. Histological examination showed that the covered wound surface had not epithelialised and the basal layer had yet to form in experimental group 1, but had formed in experimental group 2. However, in control group 1, epithelialisation of the sutured wound had begun. Immunohistochemical examination showed that, in experimental group 1, the non-uniform epithelial layer of the covered wound surface expressed cytokeratin AE1/AE3, and the epithelial and connective tissue layers stained strongly for FGF-2. Similar results were obtained in experimental group 2, whereas in experimental group 3, FGF-2 was expressed only in the connective tissue layer, and epithelialisation was complete. However, in control group 1, AE1/AE3 was expressed in the epithelial layer, and FGF was expressed in the connective tissue layer beneath the basal layer. In control groups 2 and 3, AE1/AE3 and FGF-2 were expressed in patterns similar to those in experimental groups 2 and 3. We suggest that this method is useful and the operation is simple. However, further testing of the method is needed and it should be widely used clinically before it is recommended.