Prospective Nonrandomized Trial Research Articles

Results of the study of factors predicting the risk of the development of grade III radiation-induced mucositis during radiation or chemoradiation therapy in patients with oral cavity and oropharynx cancer.

Today, a number of methods and ways of prevention and treatment of radiation- -induced mucositis of the oral cavity and oropharynx have been developed, but the represented approaches are still not effective enough. Therefore, to increase the effectiveness of the prevention and treatment of radiation-induced mucositis, it is necessary to approach this problem comprehensively and individually, and to evaluate the factors affecting the development of mucositis. In this single-center prospective controlled non-randomized clinical trial, the results of clinical observation of the development of complications of radiation and chemoradiation therapy in 105 patients with a newly diagnosed squamous cell cancer of the oral cavity and oropharynx were analyzed. Factors affecting the risk of the development of grade III radiation-induced mucositis including the age, gender of the patients, their general condition before the treatment according to World Health Organisation scales, type of the treatment and its doses, additional use of immunotherapy with alpha/beta defensins, characteristic signs of the tumor process and all indices of the immune status of the patients before the treatment have been analyzed. The method of construction and analysis of one-factor logistic regression models, where 24 indices were analyzed as factorial features, showed that the reduction of the risk of the development of grade III radiation-induced mucositis is predicted by several factors: immunotherapy, gender, serum concentrations of IgG and IgA. A decrease (P < 0.001) in the risk of the development of grade III radiation-induced mucositis was revealed if immunotherapy with alpha/beta defensins (with a total dose of 40 mg) was included into the treatment scheme (relative odds (RO) 0.05; 95% reference interval (RI) 0.02-0.18), in comparison with patients of the groups where it was not present or this immune agent was used in a total dose of 60 mg (P = 0.001, RO 0.06; 95% RI 0.01-0.30). The next factorial sign was gender, namely the risk of the development of grade III radiation-induced mucositis was lower for men (P = 0.003; RO 0.15; 95% RI 0.04-0.53) compared to women. An increase (P = 0.024) in the risk of the development of grade III radiation-induced mucositis with an increase in the initial level of IgG serum concentration was revealed, (RO 1.08; 95% RI 1.01-1.16) for each 1 mg/mL, as well as an increase (P = 0.044) in the possibility of the appearance of grade III radiation-induced mucositis with an increase in the serum concentration of IgA (RO 1.23; 95% RI 1.01-1.50) for every 1 mg/mL also before the beginning of the treatment. Multifactorial analysis has also confirmed that the risk of the development of grade III radiation-induced mucositis increases (P = 0.008) with a high serum IgG concentration before the treatment or with an increase in this index during therapy (RO 1.13; 95% RI 1.03-1.09) for every 1 mg/mL (when standardized by other risk factors). It was determined that when standardizing according to other factors (gender, IgG level), the risk of the development of grade III radiation-induced mucositis in the use of the immune agent alpha/beta defensins in a total dose of 40 mg per course decreases (P < 0.001; RO 0.08; 95% RI 0.02-0.27) compared to patients with oral cavity and oropharynx cancer who were not treated with immunotherapy. The risk of the development of grade III radiation-induced mucositis also decreases (P = 0.001) in the use of immunotherapy in a higher dose, i.e. 60 mg per course (RO 0.03; 95% RI 0.004-0.24 compared to patients whose treatment did not include immunotherapy (when standardized by other factors). As a result of this controlled clinical study, some factors were determined in addition to the radiation as those affecting the risk of the development of grade III radiation-induced mucositis in patients with oral cavity and oropharynx cancer during special treatment. These factors comprise the inclusion of immunotherapy with alpha/beta defensins into the specific treatment; gender, and baseline levels of serum IgG and IgA concentrations suggest a pattern in which the higher the serum IgG and IgA concentrations are before the start of the treatment, the greater is the likelihood of severe radiation-induced mucositis degree during special therapy. The results of the study of humoral state of the immune system in patients with oral cavity and oropharynx cancer before the beginning of chemoradiation therapy can be used as prognostic risk factors for the development of severe gamma-irradiation-induced mucositis of the oropharyngeal area, as well as an indication for the use of immunotherapeutic agents (in particular, alpha/beta defensins) that are able to polarize the immune response towards type 1 T-helpers through their immunomodulatory action.

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non−Small Cell Lung Cancer

Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. This prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. The findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. ClinicalTrials.gov Identifier: NCT03046316.

SPEctacle Correction for the TReatment of Amblyopia (SPECTRA): study protocol for a prospective non-randomised interventional trial in adults with anisometropic/mixed mechanism amblyopia

IntroductionAmblyopia is a neurodevelopmental vision disorder typically affecting one eye, resulting in compromised binocular function. While evidence-based treatments exist for children, there are no widely accepted treatments for adults. This...

CUPCOMP: A multi-site UK trial in carcinoma of unknown primary: A comparison across tissue and liquid biomarkers.

3059 Background: Cancer of Unknown Primary (CUP) is a difficult to treat cancer entity for which the tumour origins remain elusive. There is emerging evidence to support a precision medicine approach to aid treatment decisions, however scarcity of tumour tissue for molecular profiling remains a challenge. CUPCOMP sought to compare the feasibility of molecular profiling from both tissue and blood in patients (pts) diagnosed with CUP. Methods: A non-randomised prospective feasibility clinical trial conducted across 7 UK sites between 06/2021-02/2023. Eligible pts had a histological confirmed diagnosis of favourable/unfavourable CUP based on clinical, radiological, and pathological review at a CUP Multi-Disciplinary Team meeting and ESMO Guidelines for CUP. Pts had mutation profiling performed from circulating tumour DNA (ctDNA) (FoundationOne Liquid CDx) and tumour tissue (FoundationOne CDX or whole genome sequencing (WGS)). All results were discussed at a dedicated Molecular Tumour Board (MTB) to evaluate the activation state of oncogenic pathways. Results: Baseline characteristics of the 117 pts recruited are shown (Table). 114/117 (97%) pts had successful blood (109/117; 93% pts) or tissue (69/117; 59% pts) molecular profiling; both methods were performed in 64/117 (55%) pts. WGS was only successful in 15/21 pts where repeat biopsy was obtained. Where targeted tissue and blood profiling was performed using the same panel (49/117; 42%): 421/550 (77%) Single Nucleotide Variants (SNVs) found in tissue were concordant in ctDNA. ctDNA tumour fraction was ≥10% in 41/109 (35%) pts. In ctDNA, 1556 SNVs, across 271 genes, and 42 rearrangements were identified. 73/114 (64%) of cases carried an actionable alteration in blood or tissue, as determined by MTB. The most frequently reported actionable gene alterations were: KRAS (n=11; 10%); ATM (n=9; 8%); ARID1A (n=9; 8%); PIK3CA (n=10; 9%); NF2 (n=7; 6%); BRAF (n=7; 6%); FGFR2-fusion (n=7; 6%). A tumour mutational burden (TMB) of ≥10 mutations/Mb was detected in 25/117 (22%) of pts. Potential germline variants were found in 8% of pts. 80/114 (70%) pts were alive 6 months after consent to trial. Conclusions: Successful tissue-based molecular profiling is challenging in pts with CUP; achieved in only 59% of pts in this cohort. ctDNA analysis was feasible (93% successful) and reliably concordant with tissue. Potentially actionable alterations were found in 64% of pts. ctDNA molecular profiling should be considered as a reliable alternative to tissue-based testing in pts diagnosed with CUP. Clinical trial information: NCT04750109 . [Table: see text]

Comparing Magnetic Resonance Imaging and Prostate-Specific Membrane Antigen-Positron Emission Tomography for Prediction of Extraprostatic Extension of Prostate Cancer and Surgical Guidance: A Prospective Nonrandomized Clinical Trial.

Survivors of surgically managed prostate cancer may experience urinary incontinence and erectile dysfunction. Our aim was to determine if 68Ga-prostate-specific membrane antigen-11 positron emission tomography CT (PSMA-PET) in addition to multiparametric (mp) MRI scans improved surgical decision-making for nonnerve-sparing or nerve-sparing approach. We prospectively enrolled 50 patients at risk for extraprostatic extension (EPE) who were scheduled for prostatectomy. After mpMRI and PSMA-PET images were read for EPE prediction, surgeons prospectively answered questionnaires based on mpMRI and PSMA-PET scans on the decision for nerve-sparing or nonnerve-sparing approach. Final whole-mount pathology was the reference standard. Sensitivity, specificity, positive predictive value, negative predictive value, and receiver operating characteristic curves were calculated and McNemar's test was used to compare imaging modalities. The median age and PSA were 61.5 years and 7.0 ng/dL. The sensitivity for EPE along the posterior neurovascular bundle was higher for PSMA-PET than mpMRI (86% vs 57%, P = .03). For MRI, the specificity, positive predictive value, negative predictive value, and area under the curve for the receiver operating characteristic curves were 77%, 40%, 87%, and 0.67, and for PSMA-PET were 73%, 46%, 95%, and 0.80. PSMA-PET and mpMRI reads differed on 27 nerve bundles, with PSMA-PET being correct in 20 cases and MRI being correct in 7 cases. Surgeons predicted correct nerve-sparing approach 74% of the time with PSMA-PET scan in addition to mpMRI compared to 65% with mpMRI alone (P = .01). PSMA-PET scan was more sensitive than mpMRI for EPE along the neurovascular bundles and improved surgical decisions for nerve-sparing approach. Further study of PSMA-PET for surgical guidance is warranted in the unfavorable intermediate-risk or worse populations. NCT04936334.

Effect of Intrauterine Perfusion of Granulocyte Colony-Stimulating Factor on Endometrium and Blood Flow Parameters in Patients With Thin Endometrium: A Prospective Controlled Clinical Trial

To investigate the effects of intrauterine perfusion with granulocyte colony-stimulating factor (G-CSF) on the endometrial thickness, volume, and blood flow parameters of patients with thin endometrium and their clinical outcomes. We designed a prospective non-randomized synchronous controlled trial and recruited patients with thin endometrium who underwent frozen-thawed embryo transfer (FET) at Mianyang Central Hospital between September 1, 2021 and September 1, 2023. They were divided into two groups, an experimental group of patients who received the experimental treatment of intrauterine perfusion with G-CSF and a control group of patients who did not receive the experimental treatment. The general data and the clinical outcomes of the two groups were analyzed and compared. The endometrial thickness, volume and blood flow parameters of patients in the experimental group before and after intrauterine perfusion with G-CSF were analyzed. The clinical data of 83 patients were included in the study. The experimental group included 51 cases, while the control group included 31 cases. There were no significant differences in the baseline data between the two groups. The clinical pregnancy rate of the experimental group (56.86%) was higher than that of the control group (50.00%) and the rate of spontaneous abortion in the experimental group (27.59%) was lower than that in the control group (37.50%), but the differences were not statistically significant (P>0.05). In the experimental group, the postperfusion endometrial thickness ([0.67±0.1] cm) was greater than the preperfusion endometrial thickness ([0.59±0.09] cm), the postperfusion ([1.84±0.81] cm3) was greater than the preperfusion endometrial volume ([1.54±0.69] cm3), and the postperfusion vascularization flow index (VFI) (1.97±2.82) was greater than the preperfusion VFI (0.99±1.04), with all the differences being statistically significant (P<0.05). Intrauterine perfusion with G-CSF can enhance the endometrial thickness, volume, and some blood flow parameters in patients with thin endometrium.

Standardizing Integrated Oncology and Palliative Care Across Service Levels: Challenges in Demonstrating Effects in a Prospective Controlled Intervention Trial.

Patients with cancer often want to spend their final days at home. In Norway, most patients with cancer die in institutions. We hypothesized that full integration of oncology and palliative care services would result in more time spent at home during end-of-life. A prospective non-randomized intervention trial was conducted in two rural regions of Mid-Norway. The hospitals' oncology and palliative care outpatient clinics and surrounding communities participated. An intervention including information, education, and a standardized care pathway was developed and implemented. Adult non-curative patients with cancer were eligible. Proportion of last 90days of life spent at home was the primary outcome. We included 129 patients in the intervention group (I) and 76 patients in the comparison group (C), of whom 82% of patients in I and 78% of patients in C died during follow-up. The mean proportion of last 90days of life spent at home was 0.62 in I and 0.72 in C (p = 0.044), with 23% and 36% (p = 0.073), respectively, dying at home. A higher proportion died at home in both groups compared to pre-study level (12%). During the observation period the comparison region developed and implemented an alternative intervention to the study intervention, with the former more focused on end-of-life care. A higher proportion of patients with cancer died at home in both groups compared to pre-study level. Patients with cancer in I did not spend more time at home during end-of-life compared to those in C. The study intervention focused on the whole disease trajectory, while the alternative intervention was more directed towards end-of-life care. "Simpler" and more focused interventions on end-of-life care may be relevant for future studies on integration of palliative care into oncology. ClinicalTrials.gov Identifier: NCT02170168.

Preliminary clinical observation and analysis of structural changes of optic nerve head in glaucoma patients after visual training

Objective: To investigate the effect of virtual reality visual training on remodeling optic nerve structures of glaucoma patients and analyze the influencing factors of visual training effect. Methods: A prospective non-randomized controlled trial was conducted. Glaucoma patients who presented to the Department of Ophthalmology, Beijing Shijitan Hospital between October 2021 and October 2022 were collected and divided into the training group or the control group according to their intentions. The training group accepted 3 months of visual training, while the control group did not. Optical coherence tomography was used to examine the disc edge area, cup volume, disc area, cup-to-disc ratio, and other parameters of the optic disc of both eyes of the patients at enrollment and after 3 months, and the changes of each parameter in the two groups were analyzed. Multivariate analysis was performed in the training group to investigate the effects of sex, age, visual field index, and mean defect on visual disc structure changes during visual training. Results: A total of 53 glaucoma patients (101 eyes) were included in the final analysis, among which the training group consisted of 27 cases (51 eyes), with 19 males and 8 females, and the age range was 48.0 (40.0, 61.0) years old. The control group comprised 26 cases (50 eyes), with 26 males and 11 females, and the age range was 54.0 (38.0, 63.0) years old. Compared with the control group, the deviation of cup volume was -0.006(-0.050, 0.015)mm3 (P<0.05), and the deviation of disc edge area was 0.00(-0.04, 0.05)mm2 (P<0. 05)in the visual training group after 3 months of visual training. The gender (OR=4.217, 95%CI=1.188-14.966) may be the influence factor of rim area. While,the mean defect (OR=1.526, 95%CI=0.245-9.491) was not that influential on rim area change. Conclusions: Visual training can increase the disc area and decrease the optic cup volume of the optic nerve in glaucoma patients. The rim area may be increased more easily after visual training in male glaucoma patients.

Thalidomide and Hydroxyurea in Transfusion-Dependent Thalassemia: Efficacy, Safety Profile and Impact on Quality of Life

Transfusion-dependent thalassemia (TDT) is a major public health concern in India, requiring regular transfusions for survival. There is also significant morbidity caused by iron overload and transfusion related infections. Novel therapies targeting fetal hemoglobin induction are the need of the hour in resource-poor institutions for patients where transplant is not feasible for various reasons. This single arm, non-randomised prospective trial evaluated the efficacy and safety of a combination of low dose thalidomide and hydroxyurea in TDT along with the impact on quality of life (QoL). It included 41 TDT patients, who failed a reasonable trial of hydroxyurea. Complete response (CR) was defined as transfusion independence and partial response (PR) denoted at least a 50% reduction in transfusion requirement. The rest were defined as non-responders (NR). The mean age of the cohort was 20.78 years (range 12–45 years). There were 13 males and 28 females. Nineteen (46.3%), 7 (17.1%), and 15 (36.6%) patients achieved CR, PR, and no response respectively. The overall response rate (CR + PR) was 63.4%. There was a significant increase in hemoglobin levels with decrement in transfusion burden and ferritin levels. There were no significant adverse reactions. No significant predictors of response were found including amongst genetic modifiers. It improved the health related QoL amongst responders. The combination of thalidomide and hydroxyurea appear safe and effective in the reduction in transfusion requirement of TDT patients. The judicious use of these drugs can improve the quality of life and pave the way for patients not eligible for a stem cell transplant.

Efficacy of single-dose versus triple-doses perioperative antimicrobial prophylaxis in patients undergoing laparoscopic cholecystectomy

Introduction: Although debatable, prophylactic antibiotics may be required for patients undergoing cholecystectomy for symptomatic gallstone disease with certain associated risk factors. Our study aimed to perform a non-randomised prospective comparative trial evaluating a single-dose pre-operative antibiotic versus a triple-dose prophylactic post-operative antibiotic in patients with symptomatic uncomplicated cholelithiasis undergoing laparoscopic cholecystectomy. Methodology: This study was a non-randomised prospective comparative study in a single institution. Two hundred patients were enrolled and allocated to two groups. Group A patients were given a single dose of pre-operative prophylactic antibiotic, and Group B patients received a triple dose of prophylactic antibiotic therapy. We also studied the bacteriological profile of bile in all the patients using bile culture and antibiotic sensitivity, and we analysed their association with post-operative surgical site infection (SSI). Results: All the patients were followed up on post-operative days 7 and 30. On post-operative day 7, 2% of patients in Group A and 1% of patients in Group B were found to have SSI, and no statistically significant difference in SSI between the two groups was noted (P = 0.558). On post-operative day 30, no patient was found to have a SSI in either of the two groups. Moreover, post-operative bile culture was obtained in all the cases, and 6% of patients had a positive bile culture. However, none of them developed SSIs on post-operative day 7. Conclusion: A single-dose pre-operative antibiotic is as effective as three perioperative doses in preventing SSI in laparoscopic cholecystectomy for symptomatic, uncomplicated gallstone disease. Our study did not associate port-site SSI with a positive bile culture.

Intravitreal Aflibercept vs Laser Therapy for Retinopathy of Prematurity

Prospective long-term data after retinopathy of prematurity (ROP) treatment with anti-vascular endothelial growth factor injections vs laser therapy are scarce. The FIREFLEYE (Aflibercept for ROP IVT Injection vs Laser Therapy) next trial is prospectively evaluating the long-term efficacy and safety outcomes following ROP treatment with intravitreal aflibercept vs laser therapy. To evaluate 2-year ophthalmic and safety outcomes after 0.4-mg aflibercept injection or laser therapy in the 24-week randomized (2:1) FIREFLEYE trial (FIREFLEYE outcomes previously reported). This prospective nonrandomized controlled trial performed in 24 countries in Asia, Europe, and South America (2020-2025) follows up participants treated in the FIREFLEYE randomized clinical trial (2019-2021) through 5 years of age. Participants included children born very or extremely preterm (gestational age ≤32 weeks) or with very or extremely low birth weight (≤1500 g) who were previously treated with a 0.4-mg injection of aflibercept compared with laser therapy for severe acute-phase ROP. Data for the present interim analysis were acquired from March 18, 2020, to July 25, 2022. Complications of ROP treated at investigator discretion (no study treatment). Efficacy end points included ROP status, unfavorable structural outcomes, ROP recurrence, treatment for ROP complications, completion of vascularization, and visual function. Safety end points included adverse events and growth and neurodevelopmental outcomes. Overall, 100 children were enrolled (median gestational age, 26 [range, 23-31] weeks; 53 boys and 47 girls). Of these, 21 were Asian, 2 were Black, 75 were White, and 2 were of more than 1 race. At 2 years of age, 61 of 63 children (96.8%) in the aflibercept group vs 30 of 32 (93.8%) in the laser group had no ROP. Through 2 years of age, 62 of 66 (93.9%) in the aflibercept group and 32 of 34 (94.1%) in the laser group had no unfavorable structural outcomes. No new retinal detachment occurred during the study. Four children in the aflibercept group (6.1%) were treated for ROP complications before 1 year of age (2 had preexisting end-stage disease and total retinal detachment; 1 had reactivated plus disease; and 1 had recurrent retinal neovascularization not further specified). Most children were able to fix and follow a 5-cm toy (aflibercept group, 118 of 122 eyes [96.7%] among 63 children; laser group, 62 of 63 eyes [98.4%] among 33 children). High myopia was present in 9 of 115 eyes (7.8%) among 5 children in the aflibercept group and 13 of 60 eyes (21.7%) among 9 children in the laser group. No relevant differences in growth and neurodevelopmental outcomes by Bayley Scales of Infant and Toddler Development, Third Edition and Vineland Adaptive Behavior Scales, Second Edition were identified. In this nonrandomized follow-up of a randomized clinical trial comparing treatment of severe acute-phase ROP with 0.4-mg injection of aflibercept and laser, disease control was stable and visual function was appropriate in children through 2 years of age. No adverse effects on safety, including growth and neurodevelopment, were identified. These findings provide clinically relevant long-term information on intravitreal aflibercept injection therapy for ROP. ClinicalTrials.gov Identifier: NCT04015180.

Does the Use of Intraoperative Neuromonitoring during Thyroid and Parathyroid Surgery Reduce the Incidence of Recurrent Laryngeal Nerve Injuries? A Systematic Review and Meta-Analysis.

Injury to the recurrent laryngeal nerve (RLN) can be a devastating complication of thyroid and parathyroid surgery. Intraoperative neuromonitoring (IONM) has been proposed as a method to reduce the number of RLN injuries but the data are inconsistent. We performed a meta-analysis to critically assess the data. After applying inclusion and exclusion criteria, 60 studies, including five randomized trials and eight non-randomized prospective trials, were included. A meta-analysis of all studies demonstrated an odds ratio (OR) of 0.66 (95% CI [0.56, 0.79], p < 0.00001) favoring IONM compared to the visual identification of the RLN in limiting permanent RLN injuries. A meta-analysis of studies employing contemporaneous controls and routine postoperative laryngoscopy to diagnose RLN injuries (considered to be the most reliable design) demonstrated an OR of 0.69 (95% CI [0.56, 0.84], p = 0.0003), favoring IONM. Strong consideration should be given to employing IONM when performing thyroid and parathyroid surgery.

THE EFFECT OF INTERNAL LIMITING MEMBRANE PEELING ON THE INNER RETINAL LAYERS IN PATIENTS WITHOUT MACULAR PATHOLOGIC CONDITION.

To examine the effect of internal limiting membrane peeling on the inner retinal layers in patients without macular pathological condition. A prospective nonrandomized trial of patients undergoing pars plana vitrectomy with internal limiting membrane peeling for pathologic condition outside the macula was performed. Optical coherence tomography including macular ganglion cell layer, inner plexiform layer, and peripapillary retinal nerve fiber layer imaging was performed before surgery, 1, 3, and 6 months postoperatively, and at the end of follow-up (ranges between 4 and 17 months). Patients with any macular pathological condition on optical coherence tomography before surgery were excluded. The main outcome measure was change in thickness of the ganglion cell layer and inner plexiform layer. Ten patients who underwent pars plana vitrectomy with internal limiting membrane peeling for macula-on retinal detachment were included in the analysis. The mean age was 55 years, and the mean follow up was 10.8 months. All patients completed at least two postoperative follow-up visits that included an optical coherence tomography as per the protocol (range 2-6 months). There was an immediate reduction in the global (G), inferotemporal, superotemporal, and superior (S) ganglion cell layer thickness at the first follow up as compared with the preoperative state ( P = 0.028, P = 0.027, P = 0.026, and P = 0.027 respectively). From the first follow-up visit onward until the final follow-up, the thinning persisted, although there was no further statistically significant thinning. Peeling of the internal limiting membrane causes significant ganglion cell layer thinning in maculae without pathologic condition before surgery. At up to 17 months of follow-up, this effect seems to be immediate and nonprogressive.

Safety profile and effects on the peripheral immune response of fecal microbiota transplantation in clinically healthy dogs.

Fecal microbiota transplantation (FMT) is increasingly used for gastrointestinal and extra-gastrointestinal diseases in veterinary medicine. However, its effects on immune responses and possible adverse events have not been systematically investigated. Determine the short-term safety profile and changes in the peripheral immune system after a single FMT administration in healthy dogs. Ten client-owned, clinically healthy dogs as FMT recipients, and 2 client-owned clinically healthy dogs as FMT donors. Prospective non-randomized clinical trial. A single rectal enema of 5 g/kg was given to clinically healthy canine recipients. During the 28 days after FMT administration, owners self-reported adverse events and fecal scores. On Days 0 (baseline), 1, 4, 10, and 28 after FMT, fecal and blood samples were collected. The canine fecal dysbiosis index (DI) was calculated using qPCR. No significant changes were found in the following variables: CBC, serum biochemistry, C-reactive protein, serum cytokines (interleukins [IL]-2, -6, -8, tumor necrosis factor [TNF]-α), peripheral leukocytes (B cells, T cells, cluster of differentiation [CD]4+ T cells, CD8+ T cells, T regulatory cells), and the canine DI. Mild vomiting (n = 3), diarrhea (n = 4), decreased activity (n = 2), and inappetence (n = 1) were reported, and resolved without intervention. Fecal microbiota transplantation did not significantly alter the evaluated variables and recipients experienced minimal adverse events associated with FMT administration. Fecal microbiota transplantation was not associated with serious adverse events, changes in peripheral immunologic variables, or the canine DI in the short-term.

Analysis of mandibular jaw movements to assess ventilatory support management of children with obstructive sleep apnea syndrome treated with positive airway pressure therapies.

The polysomnography (PSG) is the gold-standard for obstructive sleep apnea (OSA) syndrome diagnosis and assessment under positive airway pressure (PAP) therapies in children. Recently, an innovative digital medicine solution, including a mandibular jaw movement (MJM) sensor coupled withautomated analysis, has been validated as an alternative to PSG for pediatric application. This study aimed to assess the reliability of MJMautomated analysis for the assessment of residual apnea/hypopnea events during sleep in children with OSA treated with noninvasive ventilation (NIV) or continuous PAP(CPAP). In this open-label prospective non-randomized multicentric trial, we included children aged from 5 to 18 years with a diagnosis of severe OSA. The children underwent in-laboratory PSG with simultaneous MJM monitoring and at-home recording with MJM monitoring 3 months later. Agreement between PSG and MJM analysis in measuring the residual apnea-hypopnea index (AHI) was evaluated by the Bland-Altman method. The treatment effect on residual AHI was estimated for both PSG and MJM analysis. Fifteen (60% males) children were included with a median age of 12 years [interquartile range 8-15]. Two (17%) were ventilated with NIV and 13 (83%) with CPAP. There was a good agreement between MJM-AHI and PSG-AHI with a median bias of -0.25 (95% CI: -3.40 to +2.04) events/h. The reduction in AHI under treatment was consistently significant across the three measurement methods: in-laboratory PSGand MJM recordings in the laboratory and at home. Automated analysis of MJM is a highly reliable alternative method to assess residual events in a small population treated with PAP therapies.

4-week results of “Linni Slim” synbiotic in patients with metabolic syndrome

The purpose of the study is to evaluate the efficacy and safety of a synbiotic in a short-term course (4 weeks), including an extract of garcinia cambogia, probiotics and prebiotics in patients with MS Materials and methods. The pilot, observational, open-label, non-randomized prospective clinical trial included 20 patients with metabolic syndrome (13 males and 7 females, Me age 42 years). A biologically active food supplement (synbiotic) “LINNI SLIM” (PharmlandBIO, Republic of Belarus) was used, including an extract of garcinia cambogia (containing 60% hydroxycitric acid, 0.03 g/g), probiotic strains of the genus Bifidobacterium (B. bifidum, B. animalis ssp lactis, B. longum ssp longum) CFU/g) - 0.066x 109 CFU/g and Lactobacillus (L. Acidophilus, L. Plantarum, L. Rhamnosus, L. Casei, L. Crispatus, L. Reuteri, L. Gasseri) - 0,134 x 109 CFU/g; prebiotics (psyllium husk, microcrystalline cellulose, linseed fiber, inulin, fenugreek). The daily dose of garcinia cambogia is 0.3 g, dietary fiber is 5.16 g. The parameters of nutritional (including bioimpedance analysis) and metabolic status, safety (hepatotoxic effects) and tolerability (gastrointestinal symptoms, 2H-breath test with lactulose and glucose) were evaluated. Results. There was a significant decrease in serum concentrations of insulin (15.2 [9.7; 23.0] Vs 10.9 [6.6; 16.4] mcU/ml; p=0.002), triglycerides (2.1 [1.4; 2.3] Vs 1.2 [1.2; 1.9] mmol/l; p=0.002), values of the HOMA-IR index (3.77 [2.54; 6.08] Vs 2.50 [1.44; 3.65]; p=0.003) without deviation of serum biomarkers of liver damage. Good tolerability and safety of “LINNI SLIM” was established: the appearance of symptoms of dyspepsia, stool disorders requiring the abolition of dietary supplements, deviations in the results of the 2H-breath test were not registered. Conclusion. A 4-week course of using the “LINNI SLIM” synbiotic at a daily dose of 10 grams has a positive effect on the metabolic status of the body (reduction of insulin, triglycerides, HOMA-IR - insulin resistance index) with satisfactory safety parameters. The effectiveness and improvement of “metabolic health” allows the use of the “LINNI SLIM” synbiotic in the initial therapy for reducing (controlling) body weight in people suffering from metabolic syndrome on the background of obesity.

Effectivity and safety of trifocal intraocular lenses and capsular tension rings implantation for cataract patients with axial high myopia.

To assess effectivity and safety of trifocal intraocular lenses (IOLs) and capsular tension rings in treating cataract patients with axial high myopia. A prospective nonrandomized controlled clinical trial was conducted. Totally 98 eyes (74 patients) who underwent femtosecond laser-assisted cataract surgery (FLACS) with trifocal IOLs were enrolled in the study and followed up for 2y after surgery: 46 eyes (33 patients) with capsular tension ring implantation in the long axial lengths (AL) group (26<AL<29 mm) and 52 eyes (41 patients) in the normal AL group (22<AL<24.5 mm). Postoperative outcomes about effectivity and safety, including the subjective and objective visual quality, and postoperative complications were assessed. Uncorrected distance visual acuity at 5 m and uncorrected intermediate visual acuity at 60 and 80 cm in the long AL group were significantly worse than those in the normal AL group at 3mo postoperatively (P<0.05). The differences in reading speed, spectacle independence and potential visual complaints between the two groups were not statistically significant (P>0.05). The dysfunctional lens index and total modulation transfer function (MTF) average height were similar between the two groups. The postoperative internal coma aberrations in the axial high myopia eyes were significantly higher than that in the normal AL group (P<0.05). The total satisfaction score in the long AL group (91.32±2.76) was slightly higher than that in the normal AL group (90.36±3.47), but there was no difference (P=0.136). A statistically negative correlation was found between corrected distance visual acuity (CDVA) and dysfunctional lens index (r=-0.382, P=0.009), and between CDVA and the total MTF average height (r=-0.374, P=0.01). But there was no significant correlation between CDVA and total satisfaction score (r=0.059, P=0.696). Postoperative complications mainly presented as posterior capsular opacity (PCO), retinal detachment and cystoid macular edema. There was no difference in the incidence of fundus disease (6.5% vs 3.8%, P=0.663) or PCO (17.4% vs 7.7%, P=0.217) between the two groups at two years. The utilization of trifocal IOL and capsular tension ring implantation is beneficial for cataract patients with axial high myopia undergoing FLACS. This approach not only ensures excellent subjective feelings and objective visual quality, but also does not increase the incidence of postoperative complications.

Lumpectomy without radiation for ductal carcinoma in situ of the breast: 20-year results from the ECOG-ACRIN E5194 study

We report the 20-year rate of ipsilateral breast event (IBE) for patients with ductal carcinoma in situ (DCIS) treated with lumpectomy without radiation on a non-randomized prospective clinical trial. Patients were enrolled in cohort 1: low- or intermediate-grade DCIS, size ≤ 2.5 cm (n = 561); or cohort 2: high-grade DCIS, size ≤ 1 cm (n = 104). The Kaplan–Meier method was used to estimate time-to-event distributions. Cox proportional hazard methods were used to estimate hazard ratios (HRs) and tests for significance for event times. 561 patients were enrolled in cohort 1 and 104 in cohort 2. After central pathology review, 26% in cohort 1 were recategorized as high-grade and 26% in cohort 2 as low- or intermediate-grade. Mean DCIS size was similar at 7.5 mm in cohort 1 and 7.8 mm in cohort 2. Surgical margin was ≥3 mm in 96% of patients, and about 30% received tamoxifen. Median follow-up was 19.2 years. There were 104 IBEs, of which 54 (52%) were invasive. The IBE and invasive IBE rates increased in both cohorts up to 15 years, then plateaued. The 20-year IBE rates were 17.8% for cohort 1 and 28.7% for cohort 2 (p = 0.005), respectively. Invasive IBE occurred in 9.8% and 15.1% (p = 0.09), respectively. On multivariable analysis, IBE risk increased with size and was higher in cohort 2, but grade and margin width were not significantly associated with IBE. For patients with DCIS treated with excision without radiation, the rate of IBE increased with size and assigned cohort mostly in the first 15 years.

Effectiveness of hybrid digital breast tomosynthesis/digital mammography compared to digital mammography in women presenting for routine screening at Maroondah BreastScreen: Study protocol for a co-designed, non-randomised prospective trial

BackgroundDigital breast tomosynthesis (DBT) for breast cancer screening has been shown in international trials to increase cancer detection compared with mammography; however, results have varied across screening settings, and currently there is limited and conflicting evidence on interval cancer rates (a surrogate for screening effectiveness). Australian pilot data also indicated substantially longer screen-reading time for DBT posing a barrier for adoption. There is a critical need for evidence on DBT to inform its role in Australia, including evaluation of potentially more feasible models of implementation, and quantification of screening outcomes by breast density which has global relevance. MethodsThis study is a prospective trial embedded in population-based Australian screening services (Maroondah BreastScreen, Eastern Health, Victoria) comparing hybrid screening comprising DBT (mediolateral oblique view) and digital mammography (cranio-caudal view) with standard mammography screening in a concurrent group attending another screening site. All eligible women aged ≥40 years attending the Maroondah service for routine screening will be enrolled (unless they do not provide verbal consent and opt-out of hybrid screening; are unable to provide consent; or where a ‘pushback’ image on hybrid DBT cannot be obtained). Each arm will enrol 20,000 women. The primary outcomes are cancer detection rate (per 1000 screens) and recall rate (percentage). Secondary outcomes include ‘opt-out’ rate; cohort characteristics; cancer characteristics; assessment outcomes; screen-reading time; and interval cancer rate at 24-month follow-up. Automated volumetric breast density will be measured to allow stratification of outcomes by mammographic density. Stratification by age and screening round will also be undertaken. An interim analysis will be undertaken after the first 5000 screens in the intervention group. DiscussionThis is the first Australian prospective trial comparing hybrid DBT/mammography with standard mammography screening that is powered to show differences in cancer detection. Findings will inform future implementation of DBT in screening programs world-wide and provide evidence on whether DBT should be adopted in the broader BreastScreen program in Australia or in subgroups of screening participants.

Real-Time Machine Learning Alerts to Prevent Escalation of Care: A Nonrandomized Clustered Pragmatic Clinical Trial.

Machine learning algorithms can outperform older methods in predicting clinical deterioration, but rigorous prospective data on their real-world efficacy are limited. We hypothesized that real-time machine learning generated alerts sent directly to front-line providers would reduce escalations. Single-center prospective pragmatic nonrandomized clustered clinical trial. Academic tertiary care medical center. Adult patients admitted to four medical-surgical units. Assignment to intervention or control arms was determined by initial unit admission. Real-time alerts stratified according to predicted likelihood of deterioration sent either to the primary team or directly to the rapid response team (RRT). Clinical care and interventions were at the providers' discretion. For the control units, alerts were generated but not sent, and standard RRT activation criteria were used. The primary outcome was the rate of escalation per 1000 patient bed days. Secondary outcomes included the frequency of orders for fluids, medications, and diagnostic tests, and combined in-hospital and 30-day mortality. Propensity score modeling with stabilized inverse probability of treatment weight (IPTW) was used to account for differences between groups. Data from 2740 patients enrolled between July 2019 and March 2020 were analyzed (1488 intervention, 1252 control). Average age was 66.3 years and 1428 participants (52%) were female. The rate of escalation was 12.3 vs. 11.3 per 1000 patient bed days (difference, 1.0; 95% CI, -2.8 to 4.7) and IPTW adjusted incidence rate ratio 1.43 (95% CI, 1.16-1.78; p < 0.001). Patients in the intervention group were more likely to receive cardiovascular medication orders (16.1% vs. 11.3%; 4.7%; 95% CI, 2.1-7.4%) and IPTW adjusted relative risk (RR) (1.74; 95% CI, 1.39-2.18; p < 0.001). Combined in-hospital and 30-day-mortality was lower in the intervention group (7% vs. 9.3%; -2.4%; 95% CI, -4.5% to -0.2%) and IPTW adjusted RR (0.76; 95% CI, 0.58-0.99; p = 0.045). Real-time machine learning alerts do not reduce the rate of escalation but may reduce mortality.