Prospective Clinical Trial Research Articles

1040P Chemotherapy remodels the tumor immune microenvironment to increase the pCR rate of anti-PD-1 neoadjuvant therapy in MSS/pMMR locally advanced colon cancer: A prospective clinical trial and translational study

1040P Chemotherapy remodels the tumor immune microenvironment to increase the pCR rate of anti-PD-1 neoadjuvant therapy in MSS/pMMR locally advanced colon cancer: A prospective clinical trial and translational study

Evaluation of pulpal blood flow during orthodontic space closure: Prospective clinical trial

Orthodontic tooth movement (OTM) is a biological process that can affect the vascularization of the dental pulp. The forces exerted on the teeth may increase periapical pressure that could compress the arterioles, which in turn affects pulpal blood flow (PBF). The study aimed to investigate how OTM affects PBF during orthodontic space closure. A total of 22 adolescent participants who required orthodontic space closure in mandibular posterior sectors were enrolled in a prospective clinical study. The same sliding mechanics, wires, and active elements were used. Patients were observed before OTM, after leveling before space closure, and at the 4th, 7th, 21st, and 28th during active space closure. PBF was measured with laser Doppler (LD) flowmetry. Dental models were obtained with an intraoral scanner. The LD flow values decreased significantly during the observation period (2-way repeated measures analysis of variance, P<0.001). There was a significant difference in LD flow between tooth categories (2-way repeated measures analysis of variance, P<0.001). During space closure, the most pronounced LD flow reduction was observed in single-rooted teeth closest to the residual space. A higher speed of OTM was associated with a greater decrease in LD flow on day 4 of OTM (Pearson correlation, P= 0.0299). Orthodontic space closure reduced PBF; it was lowest in the early stages of space closure and showed a tendency to increase during the first month. Anterior teeth closer to the interdental space that experiences more OTM and teeth that move faster during initial OTM had a higher risk of reduced blood flow.

Outcomes of a Novel Single Branched Aortic Stent Graft for Treatment of Type B Aortic Dissection

Intervention on Type B dissection frequently requires landing the proximal edge of the stent graft between the left common carotid artery and left subclavian artery (LSA). The Gore® TAG® Thoracic Branch Endoprosthesis (TBE) is a technology which allows LSA preservation with a single internal branch. This study was a prospective non-randomized single-arm clinical trial of patients with type B aortic dissection that were treated with the single branched device. Patients with operative indications for acute, chronic or residual Type B dissections that originated distal to the origin of a left subclavian artery suitable for branch graft placement were eligible for the study. Native aortic and surgical graft proximal landing zones were eligible. Among the 132 patients, there were 25 (18.9%) acute type B dissections, 79 (59.8%) of chronic type B dissections and 28 (21.1%) of residual dissections after previous open Type A repair. Percutaneous access was used in 105 (79.5%) patients. Overall, 30-day mortality occurred in 6 patients (4.5%). The overall 30 day stroke rate was 2/132(1.5%) and the one-year freedom from stroke was 96.8%. Device Technical Success and Procedural Success was achieved in 129/132(97.7%) and 110/132(83.3%) of subjects, respectively and there was one instance of loss of side branch patency. There was no persistent antegrade false lumen flow observed. In this study of a novel branched endograft device to preserve the LSA in patients with type B dissection undergoing TEVAR, we demonstrate acceptable safety and efficacy outcomes at one year.

Amplitude Parameters Are Predictive of Hearing Preservation in a Randomized Controlled Trial of Intracochlear Electrocochleography During Cochlear Implant Surgery.

To prospectively evaluate the association between hearing preservation after cochlear implantation (CI) and intracochlear electrocochleography (ECochG) amplitude parameters. Multi-institutional, prospective randomized clinical trial. Ten high-volume, tertiary care CI centers. Adults (n = 87) with sensorineural hearing loss meeting CI criteria (2018-2021) with audiometric thresholds of ≤80 dB HL at 500 Hz. Participants were randomized to CI surgery with or without audible ECochG monitoring. Electrode arrays were inserted to the full-depth marker. Hearing preservation was determined by comparing pre-CI, unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to LF-PTA at CI activation. Three ECochG amplitude parameters were analyzed: 1) insertion track patterns, 2) magnitude of ECochG amplitude change, and 3) total number of ECochG amplitude drops. The Type CC insertion track pattern, representing corrected drops in ECochG amplitude, was seen in 76% of cases with ECochG "on," compared with 24% of cases with ECochG "off" ( p = 0.003). The magnitude of ECochG signal drop was significantly correlated with the amount of LF-PTA change pre-CI and post-CI ( p < 0.05). The mean number of amplitude drops during electrode insertion was significantly correlated with change in LF-PTA at activation and 3 months post-CI ( p ≤ 0.01). ECochG amplitude parameters during CI surgery have important prognostic utility. Higher incidence of Type CC in ECochG "on" suggests that monitoring may be useful for surgeons in order to recover the ECochG signal and preventing potentially traumatic electrode-cochlear interactions.

857P Safety and efficacy of neoadjuvant immunochemotherapy in patients with locally advanced head and neck squamous cell carcinoma: A prospective single-arm clinical trial

857P Safety and efficacy of neoadjuvant immunochemotherapy in patients with locally advanced head and neck squamous cell carcinoma: A prospective single-arm clinical trial

Effect of oral or subcutaneous administration of cyanocobalamin in hypocobalaminemic cats with chronic gastrointestinal disease or exocrine pancreatic insufficiency.

No prospective study has evaluated the efficacy of oral supplementation with cobalamin in hypocobalaminemic cats. To investigate the efficacy of oral or SC supplementation with cyanocobalamin in normalizing serum cobalamin and methylmalonic acid (MMA) concentrations in hypocobalaminemic cats with chronic gastrointestinal disease (CGID) or exocrine pancreatic insufficiency (EPI). Forty-eight client-owned hypocobalaminemic (<290 ng/L) cats with normal or abnormally high serum MMA concentrations. This study was conducted based on the prospective randomized clinical trial method. Cats with CGID or EPI were randomly assigned to 2 groups that received either oral or SC supplementation with cobalamin (250 μg/cat) for 12 and 10 weeks, respectively, in addition to other medical and dietary interventions. Each cat was evaluated 3 times (baseline, 6-week postsupplementation, and 1-week postcompletion) by measuring serum cobalamin and MMA concentrations. In cats with CGID or EPI, cobalamin concentrations were normalized in all cats that received either oral or SC supplementation (mean 100% [95% CI: 80.6%-100%] in both groups in cats with CGID and 100% [67.6%-100%] in both groups in cats with EPI). Among 37 cats with elevated MMA concentrations at baseline (21 cats with CGID and 16 cats with EPI), MMA concentrations were normalized in most cats with CGID (70% in oral and 82% in SC group) or EPI (88% in both groups). In hypocobalaminemic cats with CGID or EPI, in conjunction with other medical and dietary interventions, both oral and SC supplementation are effective at normalizing serum cobalamin and MMA concentrations.

New Ultherapy method: Utilizing novel surgical and anatomical concepts yields outstanding results.

Micro-focused ultrasound (MFU) is a technique for skin rejuvenation and lifting, targeting the facial SMAS-a fibrous network encompassing the platysma muscle and parotid fascia. This study aims to propose a novel and cost-effective method (suggested by Fatemi) for Ultherapy, comparing its effectiveness with the conventional approach. A prospective double-blind clinical trial was conducted with 30 female volunteers randomly assigned to two groups: The control group (conventional method) and the experimental group (new method). Ultherapy procedures utilized MFU technology with low energy and a higher frequency. Statistically significant differences in lifting effects and improvement in skin laxity were observed between the two groups. The new method, with a focus on the parotideal area of the SMAS, demonstrated superior outcomes and higher patient satisfaction. The parotideal region's accessibility, increased thickness, and safety profile make it an ideal target for Ultherapy. This not only reduces the risk of nerve injury but also yields effective collagen remodeling and skin-lifting results.

Analgesic Characteristics of Ultrasound-guided Great Auricular Nerve Block in Middle Ear Surgery: A Prospective Randomized Controlled Preliminary Trial

PurposeTo explore the analgesic characteristics of ultrasound-guided great auricular nerve (GAN) block to further improve pain management. DesignSingle-center, prospective, randomized, controlled, and double-blind preliminary clinical trial. MethodsThirty-seven patients who underwent middle ear surgery were included in this study: 15 in the GAN block group (the large ear nerve block [NB] group) and 22 in the traditional anesthesia group (control [CON] group). After induction of anesthesia, the NB group was given an ultrasound-guided GAN block (0.25 % Ropivacaine 2 mL), while the CON group was exempt from the GAN block. The patient’s basic information, perioperative information, the region, and numeric rating scale of postoperative pain (at 1 hour, 6 hours, 12 hours, and 24 hours), and adverse reactions were recorded. Repeated measurement analysis, t test, and Fisher exact probability method were used for statistical analysis. FindingsCompared with the CON group, the numeric rating scale in the NB group was lower after surgery (1 hour: 1.18 ± 0.35 vs 0.27 ± 0.20, P = .023; 6 hours: 1.82 ± 0.37 vs 1.13 ± 0.39, P = .203; 12 hours: 1.05 ± 0.19 vs 0.20 ± 0.10, P < .001; 24 hours: 0.55 ± 0.17 vs 0.13 ± 0.09, P = .029). In the NB group, the region of pain was merely concentrated in the ear canal. In the CON group, the pain extended to areas outside the ear canal, such as tragus and mastoid (at 12 hours, P = .006). There was no significant difference in the risk of postoperative adverse reactions between the two groups. ConclusionsUltrasound-guided GAN block can relieve patients’ pain after middle ear surgery, especially in the area outside the ear canal.

Predicting non-small cell lung cancer lymph node metastasis: integrating ctDNA mutation/methylation profiling with positron emission tomography-computed tomography (PET-CT) scan: protocol for a prospective clinical trial (LUNon-invasive Study).

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and remains a leading cause of cancer-related death. Lymph node metastasis (LNM) significantly affects recurrence, survival rates, and treatment options. While lymph node sampling is standard for surgically removing operable NSCLC, it can lead to complications. Positron emission tomography-computed tomography (PET-CT) helps assess preoperative LNM despite false positive or negative rates. Additionally, circulating tumor DNA (ctDNA) detects minimal residual disease with high sensitivity and specificity. Whether ctDNA can predict LNM in operable NSCLC remains uncertain. Our goal is to develop a precise model for predicting NSCLC LNM using non-invasive ctDNA/methylation profiling combined with PET-CT imaging. This is a prospective study conducted in three stages. We will enroll patients with clinical stage I-IIIB [8th tumor, node, metastasis (TNM) staging] NSCLC requiring lobectomy plus lymph node sampling/dissection. The distribution of clinical stages in the enrolled population is as follows: clinical stage cN0 (n=100) and cN1/cN2 (n=100). During Stage 1, we will establish LNMs-specific ctDNA methylation signatures and compare negative predictive value (NPV) rates of LNMs using preoperative blood ctDNA somatic mutation/methylation alone or combined with PET-CT across different groups. For Stage 2, we will compare detection rates between ctDNA somatic mutation/methylation profiles alone or combined with PET-CT and traditional mediastinoscopy/endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). As for Stage 3, ctDNA-free interval (CFI) and disease-free survival between systematic lymph node presence and absence in patients will be compared with preoperative negative ctDNA profiling and/or PET-CT. In Stage 3, patients will be followed up for 5 years to collect recurrence and survival data. Post-surgery follow-up ctDNA tests will be conducted every 3 months for the first 2 years, every 6 months for years 3-4, and annually in year five. Demographics and baseline data will be summarized with mean, standard deviation, median, max, and min values. Tests will include t-tests, Welch/Behren-Fisher test, and Wilcoxon rank-sum test for continuous variables. Categorical data will be presented as counts/percentages and compared using χ2 test or Fisher's exact test. By utilizing preoperative ctDNA/methylation profiling in conjunction with PET-CT, this study is expected to yield substantial evidence for accurately predicting LNM before surgery. This will help inform surgeons in selecting the appropriate intraoperative lymph node dissection strategy for operable NSCLC patients. This study is registered on www.clinicaltrials.gov (NCT06358222).

A Pilot Study of the CD38 Antagonist Daratumumab in Patients with Metastatic Renal Cell Carcinoma or Muscle-Invasive Bladder Cancer.

We performed a pilot study of daratumumab (an mAb directed against CD38) in muscle-invasive bladder cancer (MIBC) and treatment-refractory metastatic renal cell carcinoma (mRCC). Patients with MIBC underwent baseline transurethral resection of the bladder tumor followed by four weekly doses of daratumumab prior to cystectomy. Patients with mRCC underwent baseline and sequential biopsies after eight weekly doses. The primary endpoint was safety. The secondary endpoints were pathologic complete response rate for the MIBC cohort and objective response rate and progression-free survival for the mRCC cohort. Exploratory analyses included immune monitoring and overall survival. A Bayesian sequential monitoring design for toxicity was used for excessive toxicity. In both the MIBC (n = 8) and mRCC (n = 8) cohorts, no toxicity events were encountered. In the MIBC cohort, one patient experienced pathologic complete response rate. In the mRCC cohort, no objective responses were reported, and the median progression-free survival was 1.5 months (95% confidence interval, 1.1-1.8 months). Immune monitoring found significant reductions in NK cells in circulation in both cohorts after treatment. In the tissue analysis, IHC found evidence of diminished CD38 presence in mRCC with treatment, whereas the baseline levels in MIBC were low. Treatment with daratumumab was safe. No signal of efficacy was detected in mRCC, and conclusions on the activity in MIBC were limited. Evidence of daratumumab targeting CD38 was detected in circulating immune cells and within the tumor microenvironment of mRCC and MIBC. In this prospective clinical trial of daratumumab, treatment in patients with MIBC and mRCC was safe. Limited efficacy was observed. Treatment with daratumumab resulted in CD38-expressing immune cell subsets to be targeted both in circulation and within the tumor microenvironment.

Head-to-head comparison of 18F-sodium fluoride coronary PET imaging between a silicon photomultiplier with digital photon counting and conventional scanners

BackgroundWe compared silicone photomultipliers with digital photon counting (SiPM) and photomultiplier tubes (PMT) PET in imaging coronary plaque activity with 18F-sodium fluoride (18F-NaF) and evaluated comprehensively SiPM PET reconstruction settings. MethodsIn 25 cardiovascular disease patients (mean age 67±12 years), we conducted 18F-NaF PET on a SiPM (Biograph Vision) and conventional PET (Discovery 710) on the same day as part of a prospective clinical trial (NCT03689946). Following administration of 250 MBq of 18F-NaF, patients underwent a contrast-enhanced CT angiography and a 30-min PET acquisition in list mode on each PET consecutively. Image noise was defined as mean standard deviation of blood pool activity within the left atria. Target-to-background ratio (TBR) and signal-to-noise ratio (SNR) were measured within the whole-vessel tubular 3-dimensional volumes of interest on the cardiac motion and attenuation corrected 18F-NaF PET images using dedicated software. ResultsThere were significant differences in image noise and background activity between the two PETs (Image noise (%), PMT: 7.6±3.7 vs. SiPM: 4.0±2.3, p<0.001; background activity, PMT: 1.4±0.4 vs. SiPM: 1.0±0.3, p<0.001). Similarly, the SNR and TBR were significantly higher in vessels scanned with the SiPM PET (SNR, PMT: 16.3±11.5 vs. SiPM: 32.7±29.8, p<0.001; TBR, PMT: 0.8±0.4 vs. SiPM: 1.1±0.6, p<0.001). SiPM PET image reconstruction with a 256 matrix, 1.4 mm pixel, and 2 mm Gaussian filter provided best tradeoff in terms of maximal SNR, TBR and clinically practical file size. ConclusionsIn 18F-NaF coronary PET imaging, the SiPM PET showed superior image contrast and less image noise compared to PMT PET.

Effects of stannous fluoride dentifrice on gingival health and oxidative stress markers: a prospective clinical trial

BackgroundPeriodontal disease results in oral dysbiosis, increasing plaque virulence and oxidative stress. Stannous fluoride (SnF2) binds lipopolysaccharides to reduce plaque virulence. This study prospectively assessed SnF2 effects on oxidative stress in adults with gingivitis.MethodsThis was a 2-month, single-center, single-treatment clinical trial. Twenty “disease” (> 20 bleeding sites with ≥ 3 pockets 3 mm-4 mm deep) and 20 “healthy” (≤ 3 bleeding sites with pockets ≤ 2 mm deep) adults were enrolled. All participants were instructed to use SnF2 dentifrice twice daily for 2 months. An oral examination, Modified Gingival Index (MGI) examination and Gingival Bleeding Index (GBI) examination were conducted at baseline, 1 month and 2 months. Gingival crevicular fluid (GCF), saliva, oral lavage and supragingival plaque were collected at each visit to evaluate: Endotoxins, Protein Carbonyls, L-lactate dehydrogenase (LDH), Ferric reducing antioxidant power (FRAP), Oxidized low density lipoproteins (oxi-LDL), IL-6 and C-reactive protein (CRP). A subset-analysis examined participants considered at higher risk of cardiovascular disease. Change-from-baseline analyses within each group were of primary interest.ResultsThe disease group showed statistically significant reductions in GBI at Month 1 (67%) and Month 2 (85%) and in MGI at Month 1 (36%) and Month 2 (51%) versus baseline (p < 0.001). At baseline, the disease group showed greater LDH in GCF and oxi-LDL levels in saliva versus the healthy group (p ≤ 0.01). Total antioxidant capacity (FRAP) in saliva increased versus baseline for the disease group at Months 1 and 2 (p < 0.05), and levels for the disease group were greater than the healthy group at both timepoints (p < 0.05). SnF2 treatment reduced endotoxins (lavage) for both disease and healthy groups at Month 2 (p ≤ 0.021) versus baseline. There was a reduction in oxidative stress markers, namely protein carbonyl in saliva, at Months 1 and 2 (p < 0.001) for both groups and a reduction in cytokine IL-6 (lavage) in the disease group at Month 2 (p = 0.005). A subset analysis of participants at higher coronary disease risk showed reductions in endotoxins in lavage, oxi-LDL, and CRP in saliva at Month 2 (p ≤ 0.04).ConclusionSnF2 dentifrice use reversed gingival inflammation, suppressed endotoxins and reduced some harmful oxidant products in saliva and gingiva.Clinical trial registrationClinicaltrials.gov NCT05326373, registered on 13/04/2022.

Rationale and design of RESILIENCE: A prospective randomized clinical trial evaluating remote ischaemic conditioning for the prevention of anthracycline cardiotoxicity.

There is a lack of therapies able to prevent anthracycline cardiotoxicity (AC). Remote ischaemic conditioning (RIC) has shown beneficial effects in preclinical models of AC. REmote iSchemic condItioning in Lymphoma PatIents REceiving ANthraCyclinEs (RESILIENCE) is a multinational, prospective, phase II, double-blind, sham-controlled, randomized clinical trial that evaluates the efficacy and safety of RIC in lymphoma patients receiving anthracyclines. Patients scheduled to undergo ≥5 chemotherapy cycles including anthracyclines and with ≥1 AC-associated risk factors will be randomized to weekly RIC or sham throughout the chemotherapy period. Patients will undergo three multiparametric cardiac magnetic resonance (CMR) studies, at baseline, after the third cycle (intermediate CMR), and 2 months after the end of chemotherapy. Thereafter, patients will be followed up for clinical events over an anticipated median of ≥24 months. The primary endpoint is the absolute change from baseline in CMR-based left ventricular ejection fraction (LVEF). The main secondary outcome is the incidence of AC events, defined as (1) a drop in CMR-based LVEF of ≥10 absolute points, or (2) a drop in CMR-based LVEF of ≥5 and <10 absolute points to a value <50%. Intermediate CMR will test the ability of T2 mapping to predict AC versus classical markers (left ventricular strain and cardiac injury biomarkers). A novel CMR sequence allowing ultrafast cine acquisition will be validated in this vulnerable population. The RESILIENCE trial will test RIC (a novel non-invasive intervention to prevent AC) in a cohort of high-risk patients. The trial will also test candidate markers for their capacity to predict AC and will validate a novel CMR sequence reducing acquisition time in a vulnerable population.

436: Heel spur radiotherapy: prospective randomized clinical trial

436: Heel spur radiotherapy: prospective randomized clinical trial

Prognostic significance of a negative PSMA PET/CT in biochemical recurrence of prostate cancer

BackgroundProstate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is becoming standard of care for men with biochemical recurrence (BCR) of prostate cancer. The implications of a negative PSMA PET/CT scan in this population remain unclear. This study aims to assess the outcome of patients with BCR post radical prostatectomy (RP) who have negative [18F]DCFPyL PET/CT scan at relapse.MethodsThis is a post-hoc subgroup analysis of a prospective non randomized clinical trial. One hundred and one patients (median age, 75 years) with BCR after RP, who tested negative on [18F]DCFPyL PET/CT and subsequently either underwent salvage radiotherapy (sRT) with or without androgen deprivation therapy (ADT) or were followed without active treatment, were included. Freedom from progression (FFP) after negative PSMA PET/CT was determined based on follow-up imaging selected as per clinical practice. Uni- and multivariate Cox regression analyses were performed to examine the association of patients' characteristics, tumor-specific variables, and treatment with clinical progression at the last follow-up. FFP at 1-, 2-, and 3-year were reported using Kaplan Meier analysis.ResultsThe median PSA level at PET/CT was 0.56 ng/mL (range, 0.4–11.3). Sixty five (64%) patients were followed without receiving further treatment, and 36 (36%) received sRT (18% to the prostate bed only and 18% to the prostate bed and pelvic lymph nodes) within 3 months of the PSMA PET. Seventeen of the sRT patients (17 of 36, 47%) received concomitant androgen deprivation therapy (ADT). Median follow-up was 39 months. Subsequent clinical progression was detected in 21 patients (21%), with 52% in pelvic lymph nodes, 52% in the prostatic fossa, 19% in distant lymph nodes, 14% in lungs, and 10% in bones. The FFP was 95% (95% CI: 91%-99%) at 12 months, 87% (95% CI: 81%-94%) at 24 months, and 79% (95% CI: 71%-88%) at 36 months. Multivariate Cox regression analysis revealed that an initial International Society of Urological Pathology (ISUP) grade 5 was significantly associated with clinical progression at the last follow-up (hazard ratio, 5.1, P value, 0.04). Furthermore, the receipt of sRT correlated significantly with lower clinical progression at the last follow-up (hazard ratio, 0.2, P value, 0.03), whereas other clinical and tumor-specific parameters did not. Following surveillance-only and sRT, 29% (19 of 65) and 6% (2 of 36) of patients, respectively, showed clinical progression. In the sRT group, no significant difference was observed in FFP between patients who underwent sRT to the prostatic fossa versus those who received sRT to the prostatic fossa and pelvic lymph nodes, although the numbers in these groups were small.ConclusionsThis study suggests that salvage radiotherapy is associated with a decreased or delayed clinical progression in patients with biochemical recurrence following radical prostatectomy who have negative PSMA PET/CT scan results. The analysis also underscores the prognostic significance of the initial ISUP grade, with ISUP grade 5 being associated with worse outcomes.Trial registrationRegistered September 14, 2016; NCT02899312.

Impact of occlusal stabilization splints on global body posture: a prospective clinical trial

ObjectivesBody posture of patients with temporomandibular disorders (TMD) has been investigated using different methods, whereas outcome and conclusions were controversial. The present clinical trial aimed to investigate the effects of splint therapy on global body posture.Materials and methods24 subjects (20 females, 4 males; age 24.2 ± 4.0 years) with TMD symptoms were examined clinically (RDC/TMD) and subsequently, splint fabrication was initiated. Along with routine therapy, all subjects underwent three-dimensional pre- and post-treatment full body scans in standing and upright sitting posture using a Vitus Smart XXL 3D scanner. Each scan was acquired in triplicate and evaluated in duplicate, measuring twelve standing and nine sitting postural parameters. Influencing factors were analyzed using analysis of variance (ANOVA), and additional Bland-Altman analyses verified the significance of the ANOVA results.ResultsThe increase of Forward Head angles and the decrease of Round Shoulders angles were consistent for both positions and sides. Forward Head angles were significantly influenced by limited mandibular mobility and myofascial pain. Round Shoulders angles showed a significant correlation with myofascial pain, joint noises and the absence of limited mandibular mobility.ConclusionThe influence of occlusal splints on global posture is limited and only small effects on cervicocranial parameters were found. In the present study, the average head position of post treatment measurements was more centered on the body’s core, whereas the shoulders were tilted more anteriorly.Clinical relevanceUnderstanding the limited influence of occlusal splints on cervicocranial parameters underscores the need for multimodal treatment strategies for TMD patients.

Tumor microenvironment biomarkers predicting pathological response to neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma: post-hoc analysis of a single center, phase 2 study

BackgroundNeoadjuvant chemoimmunotherapy has a promising effect on locally advanced esophageal squamous cell carcinoma (ESCC). However, reliable biomarkers robustly predicting therapeutic response are still lacking.MethodsFormalin-fixed and paraffin-embedded pre-neoadjuvant chemoimmunotherapy biopsy samples...

Prognostic algorithm for early diagnosis of subcritical conditions as predictors of sudden cardiac death

Aim. To develop a method for early diagnosis of subcritical homeostasis disorders leading to sudden cardiac death (SCD). The basis is to improve the efficiency of predictive algorithms.Material and methods. This pilot, controlled, open-label, randomized, prospective clinical trial included 220 patients at risk of SCD and 150 patients without risk of SCD. Main and control groups was formed according to the global cardiovascular risk score. Based on the informative features proposed by specialized experts using multivariate statistics methods (discriminant analysis), two condition classes were formed. The conducted exploratory analysis confirmed the significance of diagnostic criteria in relation to SCD manifestation (manifestation of cardiac arrest — MCA), which is an integral assessment of a fatal complication. The development of decision rules was carried out on the basis of soft computing technology.Results. Taking into account the priority of clinical research, namely, the identification of subcritical stages of MCA, a classifier is proposed according to basic severity of patients — the severity of critical condition risk (SCCR). The discriminant function and intersection areas between MCA subclasses in the conditions of early SCD diagnosis determine the transition to soft computing technology. Membership functions for severe MCA are formed, followed by their iteration according to E. Shortliffe. The final decision rule, using a fuzzy classifier, differentiates the MCA into stages with different SCCR. In parallel with standard protocols for the management of severe somatic patients (chronic obstructive pulmonary disease, chronic kidney disease, hepatocellular failure), based on the proposed algorithm with an integral assessment of critical conditions, using the MCA decision rule in the main group in 30,5% of cases, subcritical stage was revealed, followed by targeted treatment and preventive support. In the first group, a subcritical condition was detected in 67 patients (30,5%); a critical condition without SCD — in 3 patients (1,4%). In all noted cases, early prevention of SCD was successfully carried out (these patients were transferred to a class with a lower SCD degree). Using conventional prognostic scores in this group, 46 patients (20,9%) were identified with a subcritical condition and 1 (0,4%) with a critical condition. In the control group, subcritical condition was determined in 35 patients (23,3%), of which 17 patients (11,3%) had a moderate risk of SCD. Using conventional prognostic scores, 23 patients (15,3%) with subcritical condition were identified.Conclusion. In the conditions of intensive care unit, general medicine departments, hemodialysis department, cardiac surgery, and organ transplantation department, an algorithm for early diagnosis and risk stratification of SCD with an integral assessment (MCA) should be used. The fuzzy classifier MCA according to SCCR makes it possible to carry out timely correction of treatment measures in addition to standard protocols.

Safety and Tolerability of ADR-001 Therapy for Immunoglobulin A Nephropathy.

Immunoglobulin A nephropathy often requires kidney replacement therapy because of its refractoriness and because corticosteroids pose infection risks. However, mesenchymal stem cells offer clinical benefits because of their regenerative and immunomodulatory properties. This prospective clinical trial assessed the safety and tolerability of adipose-derived mesenchymal stem cell therapy and evaluated its therapeutic efficacy. This phase 1 study included adult patients with refractory immunoglobulin A nephropathy that was difficult to treat with traditional therapies. Adipose-derived mesenchymal stem cell therapy comprising one intravenous dose of 1 × 108 cells was administered to three to six patients in cohort 1. The same intravenous dose was administered twice with a 2-week interval to six patients in cohort 2. Heparin was administered simultaneously. This study continued for 52 weeks, and the primary endpoints were safety and tolerability during the 6-week period after treatment administration. Secondary endpoints included adverse events and efficacy measures such as clinical remission, partial remission, urine protein remission, hematuria remission, time to remission, changes in the urine protein and hematuria levels, and changes in the estimated glomerular filtration rate. The three patients in cohort 1 and six patients in cohort 2 who received adipose-derived mesenchymal stem cell therapy achieved the primary endpoints. No severe adverse clinical events were observed. Therefore, the safety and tolerability of adipose-derived mesenchymal stem cells were confirmed. Improvements such as significantly decreased kidney damage markers and urinary protein levels were observed immediately after adipose-derived mesenchymal stem cell administration. The safety and tolerability of adipose-derived mesenchymal stem cells are acceptable for patients with immunoglobulin A nephropathy. This trial was registered with the Japan Registry of Clinical Trials (jRCT2043200002; registration date: April 14, 2020) and ClinicalTrials.gov (NCT04342325; registration date: April 13, 2020).

A 6-month randomized controlled trial for vitamin E supplementation in pediatric patients with Gaucher disease: Effect on oxidative stress, disease severity and hepatic complications.

Enzymatic deficiency in Gaucher disease (GD) may induce oxidative stress. Vitamin E is the nature's most effective lipid-soluble antioxidant. This prospective clinical trial assessed the oxidant-antioxidant status in Egyptian patients with GD and the efficacy and safety and of vitamin E as an adjuvant antioxidant therapy. Forty children and adolescents with GD on stable doses of enzyme replacement therapy (ERT) were enrolled. Abdominal ultrasonography and transient elastography were performed. Malondialdehyde (MDA), vitamin E, and antioxidant enzymes (reduced glutathione [GSH], superoxide dismutase [SOD], glutathione peroxidase [GPx], and peroxiredoxin 2 [PRDX2]) were assessed. Patients were compared with 40 age- and sex-matched healthy controls. Patients with GD were randomized either to receive oral vitamin E for 6 months or not. All patients with GD had significantly higher MDA levels with lower levels of vitamin E and antioxidant enzymes compared with healthy controls (p < 0.001). Vitamin E and PRDX2 were negatively correlated to severity score index (SSI), lyso GL1, and MDA. After 6 months of vitamin E supplementation, SSI and liver and spleen volumes and liver stiffness were significantly lower. Lyso GL1 and MDA were significantly decreased post-vitamin E therapy while antioxidant enzymes were significantly higher compared with baseline levels and with patients without vitamin E therapy. Oxidative stress is related to disease severity in pediatric patients with GD. A 6-month vitamin E supplementation for those patients represents a safe therapeutic adjuvant agent increasing the efficacy of ERT, reducing oxidative stress, and improving outcomes.