Nonrandomized Clinical Trial Research Articles

Study of the Relative Frequency of Spontaneous Pneumothorax Recurrence with Two Policy Therapies: A Clinical Trial.

Spontaneous pneumothorax is a potentially fatal condition with a high risk of recurrence. The purpose of this study is to compare two different approaches to SP management. In the first group, patients underwent only chemical pleurodesis; in the second group, CT-scan, VATS, and then chemical pleurodesis was performed. This study is a non-randomized clinical trial conducted on 65 patients admitted to Al-Zahra Hospital in Isfahan with a primary complaint of sudden dyspnea and a definitive diagnosis of spontaneous pneumothorax. Two studies compared the main outcomes of recurrence within six months and the time until recurrence. Age, sex, and BMI were matched between the two study groups. The side of the pneumothorax, smoking history, and pulmonary disease history did not differ significantly (P > 0.05). Pneumothorax recurrence did not differ significantly between the two groups (P: 0.477). This study demonstrated no distinction between VATS and chemical pleurodesis when using only chemical pleurodesis. However, because numerous studies have suggested that one of these techniques may be beneficial for patients with SP, it is recommended to conduct additional randomized controlled trials (RCTs) with a more detailed plan and more comparable procedures, although it appears that meta-analysis design may be effective given the abundance of available RCT studies.

Impact of Oral Health Programmes on the Oral Health-Related Quality of Life among Children: A Systematic Review

Background: Over the last two decades, health professionals and researchers have become increasingly interested in understanding the sociodental approach to improving oral care quality, which focuses more on individuals’ subjective well-being and is guided by Oral Health-Related Quality of Life (OHRQoL) measures. Objectives: (1) To critically review published literature on the impact of oral health programmes upon OHRQoL among children and (2) to provide an evidence-based approach on research regarding the impact of oral health programmes upon OHRQoL. Methodology: This systematic review is being conducted as per the Joanna Briggs Institute Guidelines and reported as per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. An initial literature yielded 359 abstracts/manuscripts which were tested for eligibility. A total of 10 full length articles satisfying inclusion/exclusion criteria were retrieved and were included for qualitative synthesis. Studies were categorized as interventional (7) and observational (3). Four independent reviewers critically assessed the included studies based on CONSORT and STROBE guidelines, respectively. Risk of bias was assessed using ROBINS-I tool for nonrandomized clinical trial, RoB 2.0 tool for randomized clinical trial. Preventive fraction and levels of evidence were calculated for all the studies using the available data. Results: A total of 10 studies published over a period of 15 years were considered for qualitative synthesis. Analysis revealed that different types of oral health programmes (curative programs – 5 studies, curative and preventive programs – 4 studies and comprehensive programs – 1 study) were conducted over a duration of 2 weeks to 3 years. The age group of the subjects in various studies ranged from 4 to 14 years. Most of the studies were reported from Brazil (5) (55%). The outcome measures in all the studies were OHRQoL and the tools that were used to measure it were Child Perception Questionnaire (6 studies), Child Oral Impact on Daily Performance (3 studies), and Early childhood Oral Health Impact Scale (1 studies). A wide range of preventive fraction was obtained ranging from 8% to 90%. The risk of bias assessment for nonrandomized studies mostly showed moderate bias, whereas risk of bias assessment for randomized studies showed low bias. Conclusion: The results of this systematic review revealed that oral health programs does have a positive impact on OHRQoL among children.

Перспективы микроволновой радиотермометрии в ранней диагностике эндометрита и несостоятельности шва на матке после абдоминального родоразрешения

Aim: To assess the capabilities of microwave radiothermometry (MRTM) in early diagnosis of Postpartum endometritis and uterine suture failure after caesarean section. Design: Prospective non-randomized clinical trial. Materials and methods. A comparative analysis of the sensitivity of ultrasound (ultrasound) with dopplerometry and MRTM in the diagnosis of endometritis and suture failure on the uterus after cesarean section was carried out. The study included puerperal women after abdominal delivery (n = 90): 24 patients with a puerperia complication in the form of endometritis (group I), 16 — with suture failure on the uterus (group II), 50 — with a physiologically occurring postoperative period (control group). Assessment of the condition of the uterus and the postoperative suture on it was carried out on the 3–4th day after the operation. Results. Despite the fact that ultrasound with dopplerometry assessment of blood flow in the branches of the uterine arteries makes it possible to assess the structure of the myometrium and with a fairly high degree of probability to identify its inflammatory changes and defects in the suture, the sensitivity of this method in the early (3–4th day of the postoperative period) diagnosis of endometritis after abdominal delivery reaches an average of 54.2 ± 23.5%, and in the insolvency of the suture on the uterus — 31.25 ± 14.65%. At the same time, the MRTM study revealed indirect signs of endometritis in 66.7 ± 7.9% (if the conclusion is based on only one parameter — the thermoassymetry index, ITA) and 87.5 ± 8.3% (taking into account the combination of three signs), and for the insolvency of the suture on the uterus, the sensitivity of the method is 81.25 ± 4.75% for both ITA and three thermogram parameters, which is 2.6 times higher, than with ultrasound. Conclusion. Despite the rather high diagnostic effectiveness of the ultrasound method for assessing the condition of the scar on the uterus after cesarean section, the MRTM method has advantages in the form of higher sensitivity, ease of implementation, no need for expensive equipment and specialized medical qualifications. The greatest effectiveness of the diagnosis of postpartum purulent-septic complications can be achieved only with an integrated approach with clinical and laboratory tests and functional diagnostics, and timely prevention and an integrated approach to the treatment of purulent-inflammatory diseases of postoperative puerperia contribute to a significant reduction in the frequency of severe forms of postpartum infection. Keywords: caesarean section, endometritis, uterine suture failure, ultrasound, microwave radiothermometry, hysteroscopy.

Biometric recognition of newborns and young children for vaccinations and health care: a non-randomized prospective clinical trial

Although universal biometrics have been broadly called for, and there are many validated technologies to recognize adults, these technologies have been ineffective in newborns and young children. The present work describes the development and clinical testing of a fingerprint capture system for longitudinal biometric recognition of newborns and young children to support vaccination and clinical follow-up. The reader consists of a high-resolution monochromatic imaging system with an ergonomic industrial design to comfortably support and align infant fingers for imaging without a platen. This imaging approach without a platen, also called free-space imaging, reduces fingerprint distortion and ensures a more consistent finger placement. This system was tested in a newborn ward and immunization clinic at an urban hospital in Baja, California, Mexico, from 2017 to 2019. Nearly five hundred children were enrolled and followed for up to 24 months. With a protocol of imaging all ten fingers, the failure to enroll (FTE) rate was < 1% when acquiring at least two fingers for all ages and < 2% when enrolling at least four fingers. The verification (1:1) true accept rate (TAR) was 77% for newborns enrolled at ≤ 3 days of age and 96% for those enrolled at ≥ 4 days of age, both at a time gap of 15–30 days after enrollment at a false accept rate (FAR) of 0.1%. Using the top-ranked match score, the identification rate (1:many) was 86% for the ≤ 3 days enrollment age and 97% for age ≥ 4 days for a single finger at 15–30 days after enrollment. The enrollment protocol and the frequency of updating will increase for infants compared to adults. However, these data suggest that a high-resolution, free space imaging technique may fill the final gap for universal biometrics across all populations called for by the United Nations Sustainable Development Goal 16.9.

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C

BackgroundAdagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.MethodsIn this phase 1–2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety.ResultsAs of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed.ConclusionsAdagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.)

Evaluation of the effect of low-intensity rhythmic transcranial magnetic stimulation on motor and non-motor manifestations of Parkinson's disease

BACKGROUND: The use of repetitive transcranial magnetic stimulation as a method of non-drug therapy of Parkinson's disease has been actively studied over the past decades. The prevailing number of repetitive transcranial magnetic stimulation protocols in Parkinson's disease use a high intensity of stimulation (80120% of the value of the threshold of the evoked motor threshold from the muscles of the hand), while the choice of the stimulation intensity parameter was carried out empirically.&#x0D; AIM: to study the effectiveness of low-intensity unilateral repetitive transcranial magnetic stimulation on motor and non-motor symptoms of Parkinson's disease.&#x0D; MATERIAL AND METHODS:An open prospective non-randomized clinical trial included 37 patients with stage IIII Parkinson's disease according to HoehnYahr (1967), akinetic-rigid and mixed (akinetic-rigid-tremor) forms. All patients underwent repetitive transcranial magnetic stimulation according to the protocol: M1 stimulation zone, frequency 5 Hz, intensity 40% of the cortical motor threshold, on 6s, off 8s, total number of pulses per session 3000. The course of treatment is 10 procedures with 2 days (weekend) off.&#x0D; RESULTS: All patients completed the study in accordance with the protocol. When analyzing the results of the UPDRS scale (Unified Parkinson's disease rating scale), positive dynamics was noted in all parts of the questionnaire: part I ― from 2 (0; 3) to 0 (0; 1) points, p 0.05; part II ― from 9 (5.5; 12.5) to 4 (2; 6.5) points, p 0.05; part III ― with 11 (7; 14.5) to 6 (2; 7.5) points, p 0.05; part IV (Schwab and England scale) ― from 80% (70; 95) to 90% (85; 100), p 0.05. There was also a selective effect on non-motor symptoms.&#x0D; CONCLUSION: Low-intensity exposure (40% of the motor threshold) has a significant clinical effect on motor and non-motor symptoms of Parkinson's disease; stimulation of the primary motor cortex can have an antidepressant effect; repetitive transcranial magnetic stimulation has a selective effect on non-motor symptoms of Parkinson's disease: a predominant effect has been demonstrated with respect to olfactory, emotional, cognitive disorders, sleep disorders and hypersalivation; when assessing the dynamics of motor disorders, a more pronounced effect was noted with respect to rigidity, postural disorders, walking speed, and to a lesser extent, the effect on tremor was noted.

Is the retromandibular approach a suitable approach to anatomical reduction of unilateral subcondylar fracture? A non-randomized clinical trial

The aim of this study was to evaluate the efficacy of the retromandibular approach (RMA) to produce three-dimensional (3-D) reduction of the unilateral subcondylar fracture and Temporomandibular Joint (TMJ) functional implication.Methods: A prospective cohort study was designed. Twenty-nine patients with unilateral subcondylar fracture underwent consecutively Open Reduction, and Internal Fixation. The cohorts were divided into two groups; RMA group (n = 16, 55.17%) and submandibular approach SMA group (n = 13, 44.82%). The primary outcome was the anatomical 3-D reduction of the condyle. The secondary outcome was to compare the condyle position and inclination finding with TMJ outcomes. Helkimo Index score was used to evaluate the TMJ outcome at six months postoperatively.Result: There was a significant difference between the mediolateral condylar inclination, condylar medial and vertical positions when RMA compared with SMA groups (P < 0.05). The medial joint space was correlated with the medial condylar position in both groups (P < 0.05). The Helkimo Ai and Di was associated with mediolateral condylar inclination in SMG; however, Helkimo Ai was found to be correlated with the RMA group.Conclusion: The current study demonstrates that the RMA could re-establish the anatomical position of the unilateral subcondylar fracture in patients undergoing ORIF. The clinical outcome of the TMJ with RMA was better than SMA.

Breast shells for pain and nipple injury prevention: A non-randomized clinical trial.

This study aimed to analyze the effectiveness of breast shells in preventing pain and nipple injury during breastfeeding. A non-randomized clinical trial was carried out with blinding to the evaluators of the study results. The study included women with ≥35 weeks of singleton pregnancy, no nipple changes, and a desire to breastfeed. Resulting in 62 lactating women. The experimental group used breast shells and health education with clinical demonstration (n = 29), whereas the control group used no breast shells (n = 33). Pain and nipple injury were assessed three times, twice prenatally and once up to 14 days postpartum. Nipple injury (50.0%) and nipple pain (67.7%) presented with similar frequency in both groups (p = 1). Breast engorgement (35,5%) was associated with nipple pain (p = 0.019) and its onset was delayed in the experimental group (p = 0.001). Health education contributes to breast and nipple care and increases favorable breastfeeding patterns. Breast shells do not prevent nipple pain or injury. As far as we know, this is the first clinical research evaluating the use of breast shells since the antenatal care to prevent the occurrence of nipple pain and injury.

A Cost-Effectiveness Analysis of Prehabilitation for High-Risk Surgical Patients in Canada: Results from a Nonrandomized Clinical Trial

<h3>Research Objectives</h3> To evaluate the cost-effectiveness of a pragmatic model of prehabilitation for high-risk surgical candidates from a hospital perspective. <h3>Design</h3> A cost-effectiveness analysis (CEA) from a hospital perspective was performed using data from a nonrandomized clinical trial of a pragmatic model of prehabilitation compared to usual care (UC) for high-risk surgical patients. <h3>Setting</h3> A large academic hospital in Toronto, Ontario, Canada. <h3>Participants</h3> High-risk surgical candidates referred by their physician at the time of surgical planning. <h3>Interventions</h3> The prehabilitation group underwent baseline assessments from a multidisciplinary healthcare team followed by shared-decision making concerning allocation to facility-based, home-based, or virtual prehabilitation. Prehabilitation modalities included individualized exercise, nutrition, psychological support, and smoking cessation over the preoperative period. The control group received UC. <h3>Main Outcome Measures</h3> The primary endpoint was an incremental cost-effectiveness ratio (ICER) with surgical complications as the effect measure. Nonparametric bootstrapping methods were employed to investigate the joint distribution of incremental costs and incremental effects, estimate ICER uncertainty, and generate cost-effectiveness acceptability curves (CEACs). Results were presented for overall prehabilitation and stratified by each prehabilitation delivery strategy. <h3>Results</h3> Sixty-seven patients were included (prehabilitation n=49; UC n=18). Prehabilitation was associated with averting more surgical complications but came at greater costs compared to UC. Results indicate the potential cost-effectiveness of prehabilitation for reducing surgical complications, although data limitations and point-estimate uncertainty preclude conclusive recommendations. When stratified by prehabilitation delivery strategy, estimated cost-effectiveness varied considerably, and beckon future research to clarify economically optimal prehabilitation protocols within an implementation context. <h3>Conclusions</h3> This was the first CEA of a pragmatic model of prehabilitation for high-risk surgical patients, contributing an increasingly relevant economic perspective regarding the potential role of prehabilitation implementation from a hospital perspective. Future economic evaluations of prehabilitation are necessary to clarify optimal prehabilitation protocols and definitively inform implementation decisions. <h3>Author(s) Disclosures</h3> No disclosures.

Frailty in People With Multiple Sclerosis Who Use Wheelchairs Or Scooters

<h3>Research Objectives</h3> To evaluate frailty through the deficit accumulation model and to explore the relationship of frailty with multiple sclerosis (MS) clinical subtypes, disease duration and fall-history in people with MS who use wheelchairs or scooters. <h3>Design</h3> Secondary analysis of baseline data collected as part of a multi-center non-randomized clinical trial focusing on a personalized fall prevention intervention. <h3>Setting</h3> University research laboratories in the United States. <h3>Participants</h3> Forty-five people with MS who use wheelchairs or scooters (median age=60.0 [16.0] years, 82.2% female, patient determined disease steps score=7.0). <h3>Interventions</h3> Not applicable. <h3>Main Outcome Measures</h3> A frailty index was calculated by following standard validated procedures. Information on demographics, MS clinical subtypes, disease duration, and six-month fall-history were collected as part of a standardized medical survey. <h3>Results</h3> The mean frailty index score was 0.54 (SD=0.13). Overall, 91.1% and 8.9% of participants met objective diagnostic criteria for severe and moderate frailty, respectively. A one-way ANOVA revealed no significant differences (F=0.054, p=0.948) in the frailty index among participants with relapsing-remitting MS, primary progressive, and secondary progressive MS. No relationship between frailty and disease duration (r=-0.058, p=0.706) was found. A univariable negative binomial regression analysis revealed a significant association between frailty index scores and the number of falls experienced in the previous six months (IRR=1.75, 95% CI [1.06-2.91], p=0.030). <h3>Conclusions</h3> The current study suggests that individuals with MS with advanced disability also live with coexisting frailty. The significant overlap observed between severe disability and severe frailty highlights the emerging need to untangle this bi-directional relationship to identify appropriate therapeutic pathways in the MS population living with advanced disability. <h3>Author(s) Disclosures</h3> Nothing to disclose.

Safety and Potential Efficacy of Selective Dorsal Rhizotomy in Adults with Spinal Cord Injury-Induced Spasticity: An Open-Label, Non-Randomized, Single-Arm Trial

Despite the abundant literature on the use of selective dorsal rhizotomy (SDR) in spastic cerebral palsy, no investigation has evaluated its use in adult patients with chronic spinal cord injury (SCI)-induced spasticity. The present investigation aimed to evaluate the safety and potential efficacy of SDR in chronic SCI-induced spasticity for the first time. In this open-label, single-arm, non-randomized clinical trial, all patients were assigned to the single study intervention arm and underwent SDR. The primary outcome measure was the safety profile of SDR. Secondary outcome measures were Modified Ashworth Scale, Penn Spasm Frequency Scale, visual analog scale for spasticity, Spinal Cord Injury Spasticity Tool, Spinal Cord Independence measure version III, and Short Form 36 Health Survey Questionnaire. Six patients with cervical SCI and 4 with thoracic SCI were allocated to the single study intervention arm. No adverse event attributable to the SDR was found. Moreover, all secondary outcome measures of the study improved significantly over the study period (P < 0.001). Multiple regression analysis also found a significant association between level of injury and changes in average Modified Ashworth Scale scores (P= 0.041), Spinal Cord Injury Spasticity Tool score (P= 0.013), and Spinal Cord Independence measure version III total (P= 0.002) and mobility domain scores (P= 0.004) at 12-month postoperatively. This clinical trial indicated that SDR is a safe and potentially effective procedure in patients with severe and intractable SCI-induced spasticity. However, future clinical trials with larger sample sizes and adequate power are required to validate our findings regarding efficacy.

Assessment of Blue Light Phototherapy for Grover Disease

This nonrandomized clinical trial assesses treatment of patients diagnosed with Grover disease with blue light phytotherapy for several weeks.

Five-year follow-up of corneal endothelial cell density after transscleral ab interno glaucoma gel stent implantation

PurposeThis study investigates the course of the endothelial cell density over a period of 5 years after XEN45 implantation (XEN45µm, Allergan Plc., USA) with or without combined cataract surgery.MethodsThis is a prospective, cross-sectional, monocentric, non-randomized clinical trial with the intention to treat a population of the University Eye Clinic Glaucoma Service Salzburg. One hundred and fifty-five eyes with preoperative central corneal endothelial cell counts were subjected to XEN45 implantation with (combined surgery group) or without (solo surgery group) combined cataract surgery. Endothelial cell density was measured at 3 corneal positions. XEN45 location parameters were determined with anterior segment OCT and gonioscopy.ResultsIn the combined surgery group, a significant reduction of central endothelial cell count was found at years 2 and 4 when compared to baseline (p = 0.001 and p = 0.02, n = 86), whereas at years 1, 3, and 5, no change was detected (all p > 0.09). The median reduction of endothelial cell count was − 79 (95% CI: − 183 to − 9) and − 93 (95% CI: − 220 to 23) cells at years 2 and 4, respectively. In the solo surgery group (n = 69), no significant change in endothelial cell counts was detected at any time during the 5-year evaluation period (all p > 0.07). Explorative data analyses revealed that XEN45 location parameters did not significantly influence the course of endothelial cell count over time.ConclusionsEndothelial cell loss after XEN45 implantation seems to be low. The present data suggest no impact on the position of the implant with regard to central endothelial cell counts in this study.

Effectiveness of Physiotherapy in the Treatment of Temporomandibular Joint Dysfunction and the Relationship with Cervical Spine.

Temporomandibular dysfunctions are a heterogeneous group of conditions involving the temporomandibular joints (TMJs) and periarticular musculoskeletal structures. This study aimed to evaluate the effectiveness of a physiotherapy program for TMJ dysfunctions and the relationship with cervical spine. The study design was a non-randomized clinical trial with two parallel treatment groups: 33 subjects in the experimental group that underwent conservative drug treatment and physiotherapy treatment, and 31 subjects in the control group that underwent only conservative drug treatment. The participants were examined at baseline and re-examined after 3 months. In this study there was a higher incidence of female subjects. After 3 months of treatment of the TMJs and cervical spine, pain decreased in both groups (p = 0001). Muscle testing at the cervical spine and temporomandibular level showed a decrease in pain and muscles spasms. The average percentage values of the Neck Disability Index (NDI) and the Jaw Functional Limitation Scale 8 (JFLS 8) decreased significantly in both groups, but especially in the experimental group (p = 0.001). Physiotherapy treatments could maintain the functional state at the temporomandibular and cervical levels, thus contributing to increasing the quality of daily life.

Tvt CAR7: Phase 1 Clinical Trial of Base-Edited "Universal” CAR7 T Cells for Paediatric Relapsed/Refractory T-ALL

Background Genome editing can overcome HLA barriers to generate 'off-the-shelf’ CAR T cell therapies. Despite the success of CAR-T cell therapies in B-cell malignancies, the expression of shared T cell antigens has constrained the development of CAR T cells targeting T-cell malignancies, due to T cell fratricide. Targeted base editing using CRISPR guided cytidine deamination mediates highly precise C→U→T conversion which can directly disrupt gene expression without DNA breaks. This Phase I study will investigate the feasibility and safety of base edited (BE) allogeneic CAR T cells against CD7, disrupted for TCR, CD7 and CD52. The cells are used to secure remission ahead of allogeneic stem cell transplantation (allo-SCT). Investigational medicinal product (IMP) Two allogeneic healthy donor derived BE-CAR7 T cell banks were manufactured from steady state apheresis harvests using a semi-automated process under compliant conditions. Cells were activated with an anti-CD3/CD28 reagent (Transact) and electroporated with codon optimised base editor (coBE) mRNA and three single guide RNAs targeting TRBC, CD52 and CD7. Subsequent lentiviral transduction delivered CAR7 (59-62% efficiency) and magnetic bead processing depleted residual TCRαβ+ T cells (residual 0.1-0.3%). Highly efficient disruption of CD7 and CD52 (98-99%) was confirmed by sequencing. Cells were cryopreserved and QC tested by flow cytometry, ddPCR for copy number (3.1-3.6) and replication competent lentivirus was excluded. Anti-leukemic potency was confirmed in vitro and in human:murine chimera experiments. Trial sponsorship & approvals The TvT CAR7 study (ISRCTN15323014) is an open label, single centre, single arm and non-randomised clinical trial. The trial is sponsored by Great Ormond Street Hospital NHS trust and is supported by MRC, Wellcome Trust and NIHR. Clinical trial authorisation was provided by MHRA and ethical approval by a gene therapy advisory committee (GTAC) ahead of site initiation. Study aims and Objectives The study aims to establish the safety and feasibility of BE-CAR7 to induce molecular remission in children with relapsed/refractory (r/r) CD7-positive T-ALL, ahead of a planned allo-SCT. Assessments include incidence of adverse events, duration of remission, disease-free survival and overall survival. Expansion, persistence and elimination of BE-CAR7 cells and immune recovery after allo-SCT are monitored. Eligibility, treatment and recruitment The study opened on 14th April 2022 at Great Ormond Street Hospital recruiting children across the UK aged between 6 months and 16 years with r/r CD7+ T-cell malignancies quantifiable in bone marrow (>10-4 by flow or PCR). Exclusions include active uncontrolled infections, pre-existing GvHD or the detection of anti-HLA antibodies against the IMP. Eligible patients receive lymphodepletion with fludarabine (150 mg/sqm), cyclophosphamide (120 mg/kg) and alemtuzumab (1 mg/kg), followed by infusion of 0.2-2.0x106 BE-CAR7 T cells (maximum 5x104/kg TCRαβ T cells). Patients in molecular remission at day +28 proceed to allo-SCT, to remove BE-CAR 7 cells and promote immune reconstitution. The first subject was infused on 4th May 2022. Grade 2 CRS and grade 1 ICANS were observed, but no GvHD. Bone marrow assessment at d+28 revealed morphological remission without count recovery and with PCR-MRD <10-4 and the patient proceeded to reduced intensity allo-SCT as planned. This Phase 1 study aims to treat 10 children in the UK. Conclusion The study has demonstrated the feasibility of manufacturing "off-the-shelf” GMP-compliant base edited CAR7 T cells and is investigating their safety and efficacy against paediatric r/r T-ALL.

Hemophagocytic Lymphohistiocytosis Patients Need Intensive Care Can be Successfully Rescued By Timely Using Etoposide-Based HLH Regimens

Objectives:Hemophagocytic lymphohistiocytosis (HLH) patients who need life support and intensive care usually have multiple organ failure and high mortality. However, the clinical characteristics, therapeutic efficacy and outcome in these critically ill HLH patients have remained unclear. Methods: In the study, we analyzed the data of 41 critically ill HLH patients treated in a prospective, non-randomized clinical trial (ChiCTR1800015283). Results: 41 secondary HLH patients need life support and intensive care, the median age was 47 years (9-79 years), 22 males and 19 females. The median sequential organ failure assessment (SOFA) score at diagnosis was 8 (4-17). 70.73% of critically ill HLH patients had septic shock, followed by disseminated intravascular coagulation (DIC, 58.54%) , acute respiratory distress syndrome (53.66%). 22 patients (53.66%) needed invasive or non-invasive positive pressure mechanical ventilation, 26 patients (63.41%) needed vasoactive drugs, and 4 patients (9.76%) needed continuous renal replacement therapy (CRRT). Among 10 patients treated with DEP regimen, the median time to remove ECG monitoring, respiratory support, stop using vasoactive drugs, converting from dominant DIC to non dominant DIC was respectively 8.5 days, 8 days, 6.5 days and 4 days. After 4 weeks, 5 patients achieved PR, and 3 patients were evaluated as NR. However, among 4 patients treated with HLH-94/2004, the median time to remove ECG monitoring, respiratory support, converting from dominant DIC to non dominant DIC was respectively 30 days, 14 days and 4 days. After 4 weeks, 3 patients were evaluated as NR. Up to the last follow-up, the OS rate of 14 patients receiving DEP/ HLH-94/2004 regimens was 78.6%. In contrast, all 27 untreated HLH patients died. Univariate analysis showed that PCT>0.5 ug/l, respiratory failure, renal failure and liver failure were the negative factors affecting survival (p=0.018, 0.003, 0.001, 0.006). Multivariate analysis showed that respiratory failure (P=0.014), renal failure (P=0.019) and liver failure(P=0.049) were independent adverse factors. Conclusion: HLH patients need intensive care timely used etoposide-based HLH regimens especially DEP regimen which might successfully rescue the critically ill patients.

Genetically Undetectable and Negative Minimal Residual Disease after Induction Therapy Are Equally Crucial for Survival in Multiple Myeloma

Introduction Cytogenetic abnormalities (CA) identified by interphase fluorescence in situ hybridization (iFISH) has been served as the cornerstone for risk stratification at diagnosis. However, iFISH analyses were generally performed in newly diagnosed and relapsed multiple myeloma (MM) patients, but CA architecture has received little attention in patients after induction therapy. Since it is not the be-all and end-all for everyone to achieve minimal residual disease (MRD)-negativity. iFISH assay may be a good tool to explore the nature of residual plasma cells (PCs) and has proven to be a reliable complementary technique for MRD detection. We thus performed iFISH analyses after proteasome inhibitor (PI) or immunomodulatory drugs (IMiDs) induction in our prospective clinical trial. Methods A total of 396 patients with NDMM between January 2014 and March 2020 who had cytogenetic analysis by iFISH both at diagnosis and within 6 months from the start of induction therapy were included in this study. All of the participants in this study were enrolled in the prospective, non-randomized clinical trial (BDH 2014/03), which was a part of the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). A cohort of 269 patients with iFISH results after induction therapy were analyzed, with 252 of them were immunophenotyped by multiparameter flow cytometry. The median follow-up time was 41.5 months (25th/75th, 26.5/61.4 months) for the 269 patients who underwent post-induction iFISH analyses. Kaplan-Meier method was used to plot survival curves and compared by the 2-sided log-rank test. We also investigated the interaction between post-induction flow-MRD and iFISH status concerning patient outcomes. Multivariable Cox proportional hazard regression was used to assess the impact of variables on PFS and OS. Results Persistent high frequencies of CA were observed in residual PCs, survival of patients decreased with the increasing clonal size of unique CA. iFISH-positive (iFISH+) was observed in 118 (43.9%) patients whose any clonal size was more than 10%. FISH-positive patients or MRD-positive (MRD+) patients experienced significantly inferior survival than those without CA or undetectable (< 10-4) MRD. Patients were clustered into four groups according to the iFISH and flow-MRD status: (1) iFISH-negative (iFISH-) & MRD-negative (MRD-) (100/252, 39.7%), (2) iFISH+ & MRD- (42/252, 16.6%), (3) iFISH- & MRD+ (45/252, 17.9%) and (4) iFISH+ & MRD+ (65/252, 25.8%). iFISH+ & MRD- patients achieved deeper response depth than iFISH- & MRD+ patients, but this did not translate into better survival, regardless of response depth or treatment regimens. An adjusted survival analysis was performed and showed that the survival outcomes of the 4 clusters in the adjusted analysis and the crude analysis were identical, and that outcomes were similar between patients with iFISH+ & MRD- and those with iFISH- & MRD+ (mPFS: 49.49 months vs. 41.49 months; mOS: 75.33 vs. 70.74 months). Follow-up suggested that persistent CA in residual PCs facilitated the conversion of MRD- to MRD+. The MRD- conversion rate was slightly higher in patients with iFISH+ & MRD- than iFISH- & MRD- (49% vs. 36%, p = 0.139), and the duration of MRD- was also shortened by persistent CA. Longitudinal iFISH examinations were available for 21 patients with MRD- conversion at 3 time points: at diagnosis, post-induction, and at relapse. Notably, a more adverse clonal evolution pattern was observed among patients with iFISH+ & MRD-, with 5 cases of linear evolution at relapse. Conclusions In summary, our study underscores the importance of tumor cell biological characteristics examinations post-induction among patients with NDMM. We demonstrated that patients continued to have high frequencies of CA after therapy. iFISH examination after induction therapy not only provided a complementary tool to flow-MRD but also deciphered the cytogenetic profiles of residual PCs based on the quantification of these residual PCs. This comprehensive approach of combining flow-MRD and iFISH examination leverages common tests. Therefore, it may be practical to adapt in clinical practice to help identify the resistant clones and guide risk-adapted treatment strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Belantamab Mafodotin in Combination with Vrd for the Treatment of Newly Diagnosed Transplant Eligible Multiple Myeloma Patients: Results from the Phase II, Open Label, Multicenter, GEM-BELA-Vrd Trial

Introduction: The use of bortezomib, lenalidomide and dexamethasone (VRd) as induction triplet has resulted in deep and durable responses in newly diagnosed transplant-eligible multiple myeloma (NDTE MM) patients, as shown by the Spanish group in the GEM2012 trial. The addition of anti-CD38 monoclonal antibodies to VRd deepen responses without impairing safety. The BCMA antibody-drug conjugated belantamab mafodotin (belamaf) is approved for relapsed and refractory MM, but its role in the frontline setting is not established. Patients and methods: 50 patients (pts) were planned to be recruited in this phase II, open label, multicenter, non-randomized single arm clinical trial (GEM-BELA-VRd). Treatment consisted of six induction cycles with VRd every 4 wks and belamaf 2.5 mg/kg iv every 8 wks (on day 1 of cycles 1, 3 and 5), followed by high dose melphalan (200mg/m2) and autologous stem cell transplant. Patients also receive two consolidation cycles with VRd (Q4W) and belamaf (Q8W), and maintenance with R until progression/toxicity and belamaf (Q8W) for 2 yrs. Primary endpoint was safety, evaluated in terms of incidence of adverse events (AEs) [according to CTCAE v. 4.0], of ocular events (OEs) [according to Visual Acuity - KVA scale] and of deaths. Main key secondary endpoints were overall response rate (ORR), complete response rate (CR), and progression-free survival (PFS). Cut-off date: July 7th 2022. Here, we report the initial safety and efficacy results of patients included after 4 cycles of induction with Belamaf-VRd. Results: Forty pts had already completed the four induction cycles and were included in this analysis. Half of them were women and the median age at diagnosis was 58 years old (27-74). Ocular toxicity was the most frequent AE. Thirty-eight pts (95%) presented any eye symptom, the most frequent one was blurred vision (77.5%; G3-4: 27.5%); followed by eye irritation (57.5%; G3-4: 10%) and dry eye (50%; G3-4: 10%). Four wks from first belamaf dose (C2 of VRD), 24 pts (60%) had any grade of keratopathy related to belamaf (mild: 50.0%; moderate: 45.8%, and severe: 4.2%); that persisted 4 wks later (C3), as 21 pts (52.5%) still had keratopathy (mild: 47.6%; moderate: 47.6%, and severe: 4.8%). Seven pts (17.5%) did not receive the second planned belamaf dose, 9 (22.5%) received reduced dose (1.9 mg/kg) and the remaining 24 pts received the full planned dose. At C4D1, four wks after the second planned belamaf dose, 32 pts (80%) had keratopathy (mild: 37.5%; moderate: 53.1%, and severe: 9.4%) and, after 8 wks, 27 pts (67.5%) (mild: 48.1%; moderate: 37.0%, and severe: 14.8%). In addition, hematological toxicity was reported in 24 pts (60%). Neutropenia and thrombocytopenia were the most frequent hematological AEs (both 20%; G3-4 in 12.5 and 7.5%, respectively). Twenty-two patients (55%) had any infection during this induction period, with respiratory infection as the most frequent one, in 20 pts (50%; G3-4: 22.5%). Pneumonia was registered in 8 patients (20%), in 7 of them was considered as a serious adverse event, 3 were caused by SARS-CoV-2 and 2 pts died. Skin toxicity, like maculo-papular rash, was reported in 35% of pts, G3-4 was present in 6 pts (15%). Peripheral neuropathy (PN) occurred in 27.5% of pts, none of them had G3-4 PN. With a median follow-up of 6 mo (3-12), 2 pts died, both due to COVID pneumonia and 1 progressed resulting in 6-mo PFS of 89.3%. After 4 cycles, ORR was 82.1%; VGPR or better was achieved in 69.2% of pts, and CR in 5 patients (12.8%), all of them with MRD negativity (except one that was not evaluable). Conclusions: The results of adding belamaf to VRD seem encouraging, although ocular toxicity is a concern. The study is ongoing with belamaf as part of the maintenance and longer follow-up will confirm whether the combination improves outcomes in NDTE MM patients. "Funding and product for this study was provided by GSK [NCT04802356]. GSK was provided the opportunity to review a preliminary version of this manuscript for factual accuracy, but the authors are solely responsible for final content and interpretation".

Interim Report of Bendamustine Plus Rituximab As First-Line Induction Therapy with or without Lenalidomide Maintenance Therapy in Chinese Patients with Indolent Non-Hodgkin's Lymphoma or Elderly Mantle Cell Lymphoma: Data from a Multi-Center Prospective Trial

Background: Bendamustine plus rituximab (BR) was established as a preferred first line therapy for patients with previously untreated indolent non-Hodgkin's lymphoma (iNHL) and elderly MCL (eMCL) based on the BRIGHT and STiL trials. But the data is rare from Chinese patients because the unavailability of bendamustine. Furthermore, the safety and efficacy of maintenance therapy with rituximab remained contradictory after BR induction therapy, due partly to the durable immuno-supression of bendumustine. On the other hand, lenalidomide, as a proven effective agent for iNHL and MCL, have immune modulatory function. So, as maintenance therapy after BR induction, lenalidomide may increase response rate and prolong progression free survival (PFS) for iNHL and eMCL. Aims: To assess the efficacy and safety of BR regimen for Chinese patients with iNHL and eMCL. And more importantly, to assess the efficacy and tolerability of lenalidomide as maintenance therapy after BR. Methods: We conducted a multi-institutional, prospective, non-randomized clinical trial for patients with iNHL and eMCL. The patients received standard six cycles of BR regimen as induction therapy, and then received lenalidomide (10 mg, qd) maintenance vs. no maintenance, from December 2020 to July 2022. Patients with iNHL and elderly MCL who received at least two cycles of BR were evaluated. The primary endpoint of the study was progression-free survival (PFS). Results: Overall, 72 patients enrolled in the study, baseline characteristics of cohort were shown in Table 1. Median age at BR initiation was 55 years (range 24-74), 76.4% had ECOG 0-1, and 23.6% ECOG 2. Follicular lymphoma (FL) (55.6%) and marginalzone lymphoma (MZL) (30.6%) were the main subtypes of iNHL. The proportion of elderly MCL was 9.7%. Most patients were in stage 3 (16.7%) and stage 4 (65.3%). All patients have indication for systemic therapy. Till the date of July 10, 2022, a total of 91.7% completed 4 cycles induction therapy. Overall response was 98.6%, with 84.7% complete response (CR) and 13.9% partial remission (PR), (Figure 1). Progression during induction occurred only in one MCL patient. And another two patients with FL was suspected progressive disease during observation. After 4 cycles induction therapy, PET/CT detected in 59 patients (81.9%), while CT or MRI detected in 13 patients (18.1%). Among the 39 patients with complete remission assessed by PET-CT, 10 patients (25.6%) of them had residual lymph nodes with diameter > 1cm. So the CRR by CT is 69.4%, which is much higher than that reported in STiL study and BRIGHT study. The safety profile of BR regimen was shown in Table 2. Hematological toxicities was the main adverse events, with grade 3-4 neutropenia was recorded in 27.8%, febrile neutropenia in 8.3%, grade 3-4 anemia in 5.6%, and grade 3-4 thrombocytopenia in 4.2% of patients. The rate of fatigue, nausea/vomiting, skin rash and infections were less than 20%. A total of 52.1% patients proceeded to lenalidomide maintenance. However, 11% patients discontinued because of rash or other adverse reaction to lenalidomide. Conclusion:BR regimen was feasible, safety and got high CRR for Chines iNHL and eMCL patients by our clinical trial. The efficacy and safety of maintenance lenalidomide after BR induction are still under follow-up. This trial was registered at http://www.chictr.org.cn. Clinical trial information: ChiCTR2200056288. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

POWERbreathe® Inspiratory Muscle Training in Amyotrophic Lateral Sclerosis.

Inspiratory muscle training may benefit respiratory function, cardiocirculatory parameters, quality of life and functionality in neuromuscular diseases. This pilot study aimed to demonstrate the POWERbreathe® inspiratory muscle training effects on maximum inspiratory pressure (PImax), heart rate (HR) and HR variability, as well as the quality of life impairment and functionality in patients with Amyotrophic Lateral Sclerosis (ALS). A pilot single-blinded, non-randomized controlled clinical trial was carried out. A total of 20T ALS patients were enrolled and divided into experimental (n = 10) and control (n = 10) groups. The experimental group received POWERbreathe® inspiratory muscle training in conjunction with usual care, and the control group received only usual care for 8 weeks. PImax (measured by POWERbreathe® KH1), HR and HR variability (evaluated by Polar H7), quality of life impairment [measured by the Amyotrophic Lateral Sclerosis Assessment Questionnaire—40 items (ALSAQ-40)] and functionality [assessed by the ALS Functional Rating Scale Revised (ALSFRS-R)] were collected at baseline and after 8 weeks of intervention. We detected statistically significant differences (p < 0.05) with an effect size ranging from medium to large (Cohen’s d = 0.72−1.37); relative to the control group, the experimental group had an increased PImax (mean difference = 10.80 cm H2O; 95% CI = 3.42−18.17) and ALSFRS-R score (mean difference = 5.30 points; 95% CI = −0.03−10.63) and reduced HR (mean difference = −8.80 beats-per-minute; 95% CI = −20.27−2.67) and R-R interval (mean difference = 78.30 ms; 95% CI = 2.89−153.70). POWERbreathe® inspiratory muscle training, in addition to usual care, may improve inspiratory strength and heart rate in patients with ALS. These results encourage larger and longer trials investigating potential clinically relevant benefits of inspiratory muscle training to these patients over the disease course.