6-month Phase Research Articles

A phase I study of a mutant KRAS-targeted long peptide vaccine combined with ipilimumab/nivolumab in resected pancreatic cancer and MMR-proficient metastatic colorectal cancer.

TPS814 Background: Novel strategies are needed to improve immune responses in “cold” tumors such as pancreatic ductal adenocarcinoma (PDAC) and mismatch repair-proficient colorectal cancer (MMRp CRC). As a frequent oncogenic driver, mutant KRAS (mKRAS) neoantigens are attractive targets to augment anti-tumor immunity in both diseases. Recently, adoptive transfer of mKRAS G12D-specific T cells has shown durable tumor regressions in patients with metastatic CRC and PDAC (Tran et. al., 2020; Leidner et. al., 2022). Furthermore, our preclinical work has demonstrated that combining a mKRAS neoantigen vaccine with immune-modulating agents prevents progression of premalignant lesions to PDAC in mice (Keenan et. al., 2014). Based on this rationale, our study pairs a pooled synthetic long peptide (SLP) mKRAS vaccine with dual checkpoint blockade to assess safety and immunogenicity in patients with resected PDAC and chemorefractory MMRp CRC. Methods: This is a first-in-human, single-arm, open-label phase I trial evaluating a pooled SLP mKRAS vaccine combined with ipilimumab/nivolumab (ipi/nivo) in patients with resected PDAC (Cohort A, n = 12) and MMRp metastatic CRC (Cohort B, n = 12) The vaccine consists of poly-ICLC adjuvant admixed with SLPs corresponding to six common mKRAS subtypes: G12D, G12R, G12V, G12A, G12C, and G13D. In priming phase, the mKRAS vaccine is given on days 1, 8, 15, and 22 along with ipi/nivo. In boost phase, the mKRAS vaccine is given on weeks 13, 21, 29, 37, and 45 along with nivo alone. Cohort A patients who remain disease-free can continue to receive boost vaccines in a 12-month extended treatment phase. Eligible patients must have molecular tumor testing that demonstrates one of the six KRAS mutations listed above. Cohort A patients must be disease-free following completion of adjuvant chemotherapy within 6 months prior to study entry. Cohort B patients must have confirmed MMRp status, exposure to ≥ 2 prior lines of standard chemotherapy, and measurable disease amenable to biopsies at baseline and week 7. The co-primary endpoints of this study are safety and T cell response. Adverse events will be graded per NCI CTCAE v5.0. T cell response will be determined by the maximal percent change in IFNγ-producing mKRAS-specific T cell density within 16 weeks post-vaccination compared to baseline. Secondary endpoints include disease control and objective response rates at 16 weeks per RECIST v1.1/iRECIST (Cohort B only) as well as disease-free/progression-free and overall survival. Correlative studies will examine treatment-associated changes in T cell receptor (TCR) repertoire diversity by next-generation TCR sequencing of peripheral blood and tumor specimens. Patient accrual began in May 2020 and is completed for Cohort A. Enrollment is currently ongoing for Cohort B. Study drug support provided by Bristol Myers Squibb. Clinical trial information: NCT04117087 .

Peer-led recovery groups for people with psychosis in South Africa (PRIZE): protocol for a randomised controlled feasibility trial

BackgroundThe available care for people with psychosis in South Africa is inadequate to support personal recovery. Group peer support interventions are a promising approach to foster recovery, but little is known about the preferences of service users, or the practical application of this care model, in low- and middle-income countries (LMIC). This study aims to assess the acceptability and feasibility of integrating peer-led recovery groups for people with psychosis and their caregivers in South Africa into existing systems of care, and to determine key parameters in preparation for a definitive trial.MethodsThe study is set in Nelson Mandela Bay Metropolitan district of the Eastern Cape Province, South Africa. The design is an individually randomised parallel group feasibility trial comparing recovery groups in addition to treatment as usual (TAU) with TAU alone in a 1:1 allocation ratio. We aim to recruit 100 isiXhosa-speaking people with psychosis and 100 linked caregivers. TAU comprises anti-psychotic medication-focused outpatient care. The intervention arm will comprise seven recovery groups, including service users and caregiver participants. Recovery groups will be delivered in two phases: a 2-month phase facilitated by an auxiliary social worker, then a 3-month peer-led phase. We will use mixed methods to evaluate the process and outcomes of the study. Intervention acceptability and feasibility (primary outcomes) will be assessed at 5 months post-intervention start using qualitative data collected from service users, caregivers, and auxiliary social workers, along with quantitative process indicators. Facilitator competence will be assessed with the GroupACT observational rating tool. Trial procedures will be assessed, including recruitment and retention rates, contamination, and validity of quantitative outcome measures. To explore potential effectiveness, quantitative outcome data (functioning, unmet needs, personal recovery, internalised stigma, health service use, medication adherence, and caregiver burden) will be collected at baseline, 2 months, and 5 months post-intervention start.DiscussionThis study will contribute to the sparse evidence on the acceptability and feasibility of peer-led and recovery-oriented interventions for people with psychosis in LMIC when integrated into existing care systems. Results from this feasibility trial will inform preparations for a definitive trial and subsequent larger-scale implementation.Trial registrationPan-African Clinical Trials Register PACTR202202482587686. Registered on 28 February 2022. https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=21496.

The feasibility of implementing a cultural mentoring program alongside pain management and physical rehabilitation for chronic musculoskeletal conditions: results of a controlled before-and-after pilot study

BackgroundCulturally diverse communities face barriers managing chronic musculoskeletal pain conditions including navigation challenges, sub-optimal healthcare provider engagement and difficulty adopting self-management behaviours.ObjectivesTo explore the feasibility and trends of effectiveness of implementing a cultural mentoring program alongside clinical service delivery.MethodsThis quasi-experimental controlled before-and-after multiple case study was conducted in three hospital-based services that provide treatment for patients with musculoskeletal pain. Two prospective cohorts, a pre-implementation and a post-implementation cohort, of adults with chronic musculoskeletal pain who attended during the 6-month recruitment phase, were eligible if they self-identified with one of the cultures prioritised for mentoring by the clinic. The pre-implementation cohort received routine care for up to 3-months, while the post-implementation cohort received up to 3-months of cultural mentoring integrated into routine care (3 to 10 sessions), provided by a consumer (n = 6) with lived experience. Feasibility measures (recruitment and completion rates, attendance, satisfaction), and trends of effectiveness (Patient Activation Measure and Health Literacy Questionnaire items one and six) were collated over 3-months for both cohorts. Outcomes were presented descriptively and analysed using Mann-Whitney U-tests for between-group comparisons. Translation and transcription of post-treatment semi-structured interviews allowed both cohorts’ perspectives of treatment to be analysed using a Rapid Assessment Process.ResultsThe cultural mentor program was feasible to implement in clinical services with comparable recruitment rates (66% pre-implementation; 61% post-implementation), adequate treatment attendance (75% pre-implementation; 89% post-implementation), high treatment satisfaction (97% pre-implementation; 96% post-implementation), and minimal participant drop-out (< 5%). Compared to routine care (n = 71), patients receiving mentoring (n = 55) achieved significantly higher Patient Activation Measure scores (median change 0 vs 10.3 points, p < 0.01) at 3-months, while Health Literacy Questionnaire items did not change for either cohort over time. Three themes underpinned participant experiences and acceptability of the mentoring intervention: ‘expectational priming’, ‘lived expertise’ and ‘collectivist orientation’ to understand shared participant experiences and explore the potential differential effect of the mentoring intervention.ConclusionParticipant experiences and observations of improved patient activation provide support for the acceptability of the mentoring intervention integrated into routine care. These results support the feasibility of conducting a definitive trial, while also exploring issues of scalability and sustainability.

The Beneficial Effect of Three-month Induction Therapy with High-dose Prednisone and Mycophenolate Mofetil Followed by Maintenance Therapy in Acute Non-crescentic Nephritis Associated with Immunoglobulin A Deposition Disease in Adults.

The data available on immunoglobulin A (IgA) deposition disease indicate an inherited predisposition to the disease with autoimmune triggering. Hence, we prospectively evaluated the role of a new autoimmune regimen in the treatment of severe nephrotic or nephritic flares associated with noncrescentic nephritis in adult patients. Thirty-six patients were included, and the regimen consisted of an initial 3-month induction phase of prednisone and mycophenolate mofetil (MMF), followed by a maintenance phase of MMF alone for 21 months. Complete remission (CR) (normalization of creatinine clearance [CrCl] and a decrease in protein output to <500 mg/day) was achieved in 29 of 36 patients, and a partial response (no further decline in CrCl and a decrease in proteinuria to <50%) was seen in seven patients. CrCl was maintained in patients with CR but was mildly reduced in partially responsive ones. Our study showed the short- and longterm safety and efficacy of this autoimmune regimen directed toward the autoimmune triggering factors in severe forms of noncrescentic IgA nephritis.

NJGWEP RESUSCITATING THE VA COGNITIVE CLINIC: REBUILDING COMMUNITY PARTNERSHIPS DURING A PANDEMIC

Abstract The New Jersey Geriatrics Workforce Enhancement Program (NJGWEP), in collaboration with the Wilmington Veteran’s Administration Community-Based Outpatient Clinic (VA-CBOC) in Vineland, NJ, implemented a multi-disciplinary comprehensive, evidence-based geriatric care program to assess cognitive health and geriatric syndromes as well as offer caregiver support, dementia disease education and referrals to VA and community resources. The “Cognitive Clinic” evaluated 15 veterans during a 3-month pilot phase before suspension due to COVID-19 in March 2020. To maintain momentum established prior to COVID-19, NJGWEP/VA clinical providers routinely met virtually to update each other on their organizations’ status, policies, and progress providing clinical care during the pandemic. These meetings offered opportunities to retain rapport and brainstorm strategies to modify the cognitive clinic.NJGWEP/VA providers successfully pivoted to include a telehealth model of care when appropriate and feasible; also helping to reduce barriers that limited the number of in-person contacts allowed on any given day. Implementation of telehealth proved successful at capturing caregivers who otherwise cannot attend appointments. The VA suggested de-coupling the back-to-back social work/physician appointments to ease scheduling concerns for VA providers. The Cognitive Clinic resumed employing a hybrid model of in-person physician assessments with referrals to social work for caregiver support offered via telehealth. From 1/19/22-3/2/22, 10 veterans were evaluated by a physician; 5 were diagnosed with dementia, all of whom identified a caregiver and received education, resources and referrals. In the upcoming year, the plan is to evaluate 4 veterans per month and train a VA geriatric APN to support program sustainability.

Ecological restoration effects of the Beijing–Tianjin Sandstorm Source Control Project in China since 2000

The Beijing–Tianjin Sandstorm Source Control Project (BTSSCP) has been implemented for more than 20 years (2001–2022), and a scientific, accurate, and complete evaluation of its implementation effect is of great significance for the study of ecosystem evolution. In this study, we present a vegetation–water–soil–environment system comprising the net ecosystem productivity (NEP), water conservation (WC), soil erosion (SE), and habitat quality (HQ) to evaluate the spatiotemporal changes and future trends. The results showed that: (1) In areas with high vegetation coverage, only WC was significantly and negatively correlated with SE (−0.68, p less than 0.01). In areas with low vegetation coverage, NEP, WC, and HQ were all significantly negatively correlated with SE. This indicates that SE is a basic function that affects the performance of other ecological services. (2) From 2000 to 2020, the annual maximum average vegetation coverage increased by about 10 %; the annual average NEP increased by about 60 g C/km2, and the annual average SE decreased by about 500 t/km2. Compared with Phase I (2000–2010), the vegetation condition (coverage, NEP) in summer (July–August) was improved by about 10 %, and SE in winter (December–January) decreased by 3 t/km2 per month in Phase II (2010–2020). (3) In terms of future trends, NEP may continue to increase in the grassland area, especially in the Mu Us Sandland, but it may not change significantly in the forest area. Similarly, SE may continue to decrease in grassland-covered areas, but not in forest-covered areas. Most areas of WC could continue to increase, but the HQ will not change significantly. In general, the ecological restoration effects of the BTSSCP have improved significantly. This paper is intended to provide some key information for the management of ecological projects and regional ecological security.

Experiences of Health Care Professionals Working Extra Weekends to Reduce COVID-19-Related Surgical Backlog: Cross-sectional Study.

During the quiescent periods of the COVID-19 pandemic in 2020, we implemented a weekend-scheduled pediatric surgery program to reduce COVID-19-related backlogs. Over 100 staff members from anesthesiologists to nurses, surgeons, and administrative and supporting personnel signed up to work extra weekends as part of a novel weekend elective pediatric surgery program to reduce COVID-19-related backlog: Operating Room Ramp-Up After COVID-19 Lockdown Ends-Extra Lists (ORRACLE-Xtra). In this study, we sought to evaluate staff perceptions and their level of satisfaction and experiences with working extra scheduled weekend elective surgical cases at the end of the 3-month pilot phase of ORRACLE-Xtra and identify key factors for participation. Following the pilot of ORRACLE-Xtra, all perioperative staff who worked at least 1 weekend list were invited to complete an online survey that was developed and tested prior to distribution. The survey collected information on the impact of working weekends on well-being, overall satisfaction, and likelihood of and preferences for working future weekend lists. Logistic regression was used to estimate the association of well-being with satisfaction and willingness to work future weekend lists. A total of 82 out of 118 eligible staff responded to the survey for a response rate of 69%. Staff worked a median of 2 weekend lists (IQR 1-9). Of 82 staff members, 65 (79%) were satisfied or very satisfied with working the extra weekend elective lists, with surgeons and surgical trainees reporting the highest levels of satisfaction. Most respondents (72/82, 88%) would continue working weekend lists. A sense of accomplishment was associated with satisfaction with working on the weekend (odds ratio [OR] 19.97, 95% CI 1.79-222.63; P=.02) and willingness to participate in future weekend lists (OR 17.74, 95% CI 1.50-200.70; P=.02). Many (56/82, 68%) were willing to work weekend lists that included longer, more complex cases, which was associated with a sense of community (OR 0.12, 95% CI 0.02-0.63; P=.01). Staff participating in the first 3 months of the ORRACLE-Xtra program reported satisfaction with working weekends and a willingness to continue with the program, including doing longer, more complex cases. Institutions planning on implementing COVID-19 surgical backlog work may benefit from gathering key information from their staff.

Perbandingan Kadar C-Reactive Protein Terhadap Fase Pemberian Obat Anti Tuberkulosis

Pulmonary tuberculosis is a disease caused by Mycobacterium tuberculosis. C-Reactive Protein (CRP) is produced in the body by the liver in response to inflammation caused by Mycobacterium tuberculosis infection. CRP as the main mediator of the non-specific immune system, and the concentration will increase to 1000 times higher than normal value in the event of tissue injury or infection. The aim of this study was to determine the comparison of CRP levels to the phase of anti-tuberculosis drug administration in pulmonary tuberculosis patients. The study was conducted by cross sectional study with a semi-quantitative method in June - July 2020 in Purwokerto Community Lung Health Center. The number of samples as much as 24 TB patients which is 12 TB patients in 0 month and 12 TB patients in 6 months. Data were analyzed by Mann Whitney Test. The mean rank in 0 month was 18.08 with median (min-max) 12 (12-24) mg / dL, whereas mean rank for 6 months was 6.92 with median (mix-max) was 0 (0- 12) mg / dL. Serum CRP levels in pulmonary TB patients in the 0-month treatment phase are higher than CRP levels in the 6-month treatment phase (p = 0,000).

Evidence-Based High-Loading Tendon Exercise for 12 Weeks Leads to Increased Tendon Stiffness and Cross-Sectional Area in Achilles Tendinopathy: A Controlled Clinical Trial

BackgroundAssuming that the mechanisms inducing adaptation in healthy tendons yield similar responses in tendinopathic tendons, we hypothesized that a high-loading exercise protocol that increases tendon stiffness and cross-sectional area in male healthy Achilles tendons may also induce comparable beneficial adaptations in male tendinopathic Achilles tendons in addition to improving pain and function.ObjectivesWe investigated the effectiveness of high-loading exercise in Achilles tendinopathy in terms of inducing mechanical (tendon stiffness, maximum strain), material (Young’s modulus), morphological (tendon cross-sectional area (CSA)), maximum voluntary isometric plantar flexor strength (MVC) as well as clinical adaptations (Victorian Institute of Sports Assessment—Achilles (VISA-A) score and pain (numerical rating scale (NRS))) as the primary outcomes. As secondary outcomes, drop (DJ) and counter-movement jump (CMJ) height and intratendinous vascularity were assessed.MethodsWe conducted a controlled clinical trial with a 3-month intervention phase. Eligibility criteria were assessed by researchers and medical doctors. Inclusion criteria were male sex, aged between 20 and 55 years, chronic Achilles tendinopathy confirmed by a medical doctor via ultrasound-assisted assessment, and a severity level of less than 80 points on the VISA-A score. Thirty-nine patients were assigned by sequential allocation to one of three parallel arms: a high-loading intervention (training at ~ 90% of the MVC) (n = 15), eccentric exercise (according to the Alfredson protocol) as the standard therapy (n = 15) and passive therapy (n = 14). Parameters were assessed pre- and-post-intervention. Data analysis was blinded.ResultsPrimary outcomes: Plantar flexor MVC, tendon stiffness, mean CSA and maximum tendon strain improved only in the high-loading intervention group by 7.2 ± 9.9% (p = 0.045), 20.1 ± 20.5% (p = 0.049), 8.98 ± 5.8% (p < 0.001) and −12.4 ± 10.3% (p = 0.001), respectively. Stiffness decreased in the passive therapy group (−7.7 ± 21.2%; p = 0.042). There was no change in Young’s modulus in either group (p > 0.05). The VISA-A score increased in all groups on average by 19.8 ± 15.3 points (p < 0.001), while pain (NRS) dropped by −0.55 ± 0.9 points (p < 0.001). Secondary outcomes: CMJ height decreased for all groups (−0.63 ± 4.07 cm; p = 0.005). There was no change in DJ height and vascularity (p > 0.05) in either group.ConclusionDespite an overall clinical improvement, it was exclusively the high-loading intervention that induced significant mechanical and morphological adaptations of the plantar flexor muscle–tendon unit. This might contribute to protecting the tendon from strain-induced injury. Thus, we recommend the high-loading intervention as an effective (alternative) therapeutic protocol in Achilles tendinopathy rehabilitation management in males.Clinical Trials Registration Number: NCT02732782.

Individualized anemia management enhanced by ferric pyrophosphate citrate protocol

The optimal use of erythropoiesis-stimulating agents (ESAs) and parenteral iron in managing anemia in end-stage renal disease (ESRD) remains controversial. One-size-fits-all rule-based algorithms dominate dosing protocols for ESA and parenteral iron. However, the Food & Drug Administration (FDA) guidelines for using ESAs in chronic kidney disease recommend individualized therapy for the patient. This prospective quality assurance project was at a single hemodialysis (HD) center comprising three 6-month phases (A, B, C) separated by 3-month washout periods. Standard bi-weekly ESA dose titration and intravenous (IV) iron sucrose protocols were used in baseline Phase A, and ferric pyrophosphate citrate (FPC) augmented iron in Phase B. In Phase C, an FPC protocol and weekly, individualized ESA management were used. We examined clinic-level mean differences in hemoglobin (Hb) and ESRD-related outcomes by phase with repeated ANOVA. To examine the Hb at the patient level, we used multi-level mixed-effect regression adjusting for phase, month, and other relevant confounders at each month over time to derive the mean marginal effects of phase. There were 54, 78, and 66 patients in phases A, B, and C, respectively, with raw mean Hb values of 9.9, 10.2, and 10.3 g/dL. The percentage of Hb values < 9 g/dL declined from 14.3% in Phase A to 7.6% in Phase C (p = 0.007). The multivariable mixed-effect regression results showed mean marginal Hb was higher by 0.3 mg/dL and 0.4 mg/dL in Phases B and C, respectively, compared to Phase A. We also observed reduced ferritin (p = 0.003) and transferrin saturation (TSAT) (p = 0.008) levels from Phase A to Phase C with the repeated ANOVA analysis. Ferric pyrophosphate citrate (FPC) appears to support more efficient ESA-stimulated erythropoiesis. Moreover, individualized ESA management combined with FPC (Phase C) was associated with further improvement in efficiency as we observed the fewest patients with Hb values < 9 g/dL concurrent with greater decreases in ferritin levels and reduced ESA doses. However, future prospective studies to confirm these findings on a larger, more diverse cohort of ESRD patients are warranted.

Evaluation of the nation-wide implementation of ALS home monitoring & coaching: an e-health innovation for personalized care for patients with motor neuron disease

BackgroundTo improve the care for patients with motor neuron disease an e-health innovation for continuous monitoring of disease progression and patients’ well-being (ALS H&C) was implemented in 10 multidisciplinary rehabilitation settings. The first aim was to evaluate the implementation of ALS H&C by assessing several implementation outcomes, technology acceptance and usability of the innovation according to the end users. The secondary aim was to explore differences in these outcomes between the teams with sustainable and unsustainable implementation.MethodsThe chosen implementation strategy was a combination of the implementation process model by Grol & Wensing and a participatory action research approach. In three meetings with multidisciplinary project groups the innovation was introduced, the expected barriers/facilitators identified, and action plans to resolve each barrier developed. After a 3-month pilot phase, patients and their healthcare providers were asked to complete an online evaluation survey to assess implementation outcomes, based on Proctor’s evaluation framework (i.e., acceptability, feasibility, fidelity, sustainability). Telemedicine technology acceptance was assessed according the technology acceptance model of Chau, and user experiences with the System Usability Scale (SUS). Implementation outcomes of teams with sustainable implementation (continuation after completion of the pilot phase) and unsustainable implementation (discontinuation after the pilot phase) were compared.ResultsThe implementation outcomes from the patients’ perspective (N = 71) were positive; they found ALS H&C to be an acceptable and feasible care concept. Patients’ technology acceptance was high, with positive attitudes towards ALS H&C, and positive views on perceived technology control, usefulness, and ease of use. Patients rated their satisfaction with the (web) app on a scale from 1 (not satisfied at all) to 10 (very satisfied) with a 7.0 (median; IQR 1.0). Healthcare providers (N = 76) also found ALS H&C acceptable and appropriate as well, but were less positive about the feasibility and usability of ALS H&C (mean SUS 58.8 [SD 11.3]). ALS H&C has largely been implemented as intended and the implementation was sustainable in 7 teams. Teams who discontinued ALS H&C after the pilot phase (N = 2) had more fidelity issues.ConclusionsA participatory action research approach supported by theoretical approaches used in implementation science led to a sustainable implementation of ALS H&C in 7 of the participating teams. To improve implementation success, additional implementation strategies to increase feasibility, usability and fidelity are necessary.Trial registrationTrial NL8542 registered at Netherlands Trial Register (trialregister.nl) on 15th April 2020.

Efficacy and Safety of Donor-Derived CD7 CAR T Cells for r/r T-Cell Acute Lymphoblastic Leukemia/Lymphoma: Interim Analysis from a Phase 2 Trial

Background: Results of a phase I trial of donor-derived CD7 chimeric antigen receptor (CAR) T cells for relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) (Pan et al. J ClinOncol 2021;39:3340-3351) have been reported previously. Herein, we report interim findings of the phase 2 trial on the efficacy and safety of donor-derived CD7 CAR T cells for relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma. Methods: The subjects in phase 2 were screened from the similar I/E criteria of phase 1 trial. Patients with prior stem cell transplantation (SCT) received CAR T cells from prior SCT donors, while patients without SCT history received CAR T cells from new donors who also provided stem cells for transplantation post CAR T therapy. The phase 2 trial was using Bayesian optimal phase 2 (BOP2) design to evaluate the efficacy and safety of the target dose of 1 × 106 (±20%) CD7 CAR T cells per kg of body weight in refractory/relapsed T-cell acute lymphoblastic leukemia/lymphoma (NCT04689659). The primary endpoint was efficacy with safety secondary. An interim analysis of phase 2 trial could be performed when the first 20 patients who receive CD7 CAR T cells have completed 3 months from infusion or discontinued earlier. Survival status were continuously followed up while severe adverse events (SAEs) were recorded until receiving other anti-leukemia therapy. Results: Eighteen (90%) of twenty enrolled patients responded in phase 2 trial and were followed up with a median time of 11.0 months (range 7.6-14.6) until May, 14th, 2022. Patients in phase 1 and 2 trial had similar baseline characteristics, whereas phase 2 trial included more patients with mediastinal malignancies.(Fig. A) The best overall response (BOR) rate was 90% at 3 months. The objective response rate (ORR) were 90% and 90% at 1 and 3 months post-infusion, which were similar to 95% and 95% at 1 and 3 months in phase 1 trial. The 3-months complete remission (CR) rate in patients with mediastinal tumors was lower than that in patients without mediastinal tumors, although there was no significant statistical difference (p=0.07, Fig. B) Of total 18 responders that were followed up, 12 (67%) patients who received no further therapy, all had continuously detectable CAR T cells until the last visit, three remained in remission, seven had a relapse (three CD7+, and three CD7-, one unknown), and two died of infection; 8 (44%) patients proceeded to SCT and no CAR T cells were detectable after SCT, and among them five remained in remission, two had a relapse (CD7-), and one died of infection. Patients relapsed at a median time of 4 (range 1.6-10.5) months. The one-year progressive-free survival (PFS) and overall survival (OS) rates were 62.3% (95% CI, 38.3-86.3) and 60.0% (95% CI, 38.5-81.5). Patients without mediastinal mass had longer OS than patients with mediastinal mass. (p<0.05, Fig. C) Updated phase 1 data at a median 1.5-year follow-up, shows PFS and OS rates of 60.0% (95%CI, 38.4-81.6) and 70.0% (95%CI, 50.0-90.0) Short-term adverse events included grade 3 or higher cytokine release syndrome (10%) and grade 1-2 graft-versus-host disease (GVHD, 40%), which were all reversible. Three late-onset (> 30 days post-infusion) SAEs occurred in 3 responders, including 1 grade 5 sepsis at month 2, 1 grade 5 fulminant hepatitis at month 2, and 1 grade 5 pneumonia at month 5. Severe infections occurred in 2/3 patients with no further therapy, and the total T cells in them reached a median count of 654.34/μL (range 41.87-1210.46), which were substantially lower than normal levels despite steadily increasing. The safety analysis was similar to the phase 1 trial of donor-derived CD7 CAR T cells. (Fig. D) Conclusions: Interim results from a phase 2 trial of donor-derived CD7 CAR T cell therapy showed similar encouraging activity in treating r/r T-ALL with phase 1 trial. Relapse emerges as major issues impeding long-term outcomes. CD7-negative relapse was commonly observed under CAR T cell surveillance. Late onset GVHD and infections may occur and should be carefully managed. Patients with mediastinal mass had poor overall survival and needed been further investigated. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Stimulus MDS-US Trial in Progress: Evaluating Sabatolimab in Combination with Hypomethylating Agents (HMAs) in Patients with Intermediate-, High-, or Very High-Risk Myelodysplastic Syndrome (MDS)

Background Patients with intermediate-, high-, or very-high-risk myelodysplastic syndrome (I/H/vHR-MDS) need durable treatment options with favorable tolerability. Sabatolimab (MBG453) is a novel immunotherapy targeting TIM-3, an immuno-myeloid regulator expressed on immune and leukemic stem cells, but not on normal hematopoietic stem cells. Patients with higher-risk MDS experience poor outcomes and limited treatment options. HMAs are approved for the frontline management of higher-risk MDS, but 50% of HMA-treated patients experience primary failure, and most responders progress within 2 years. Novel therapies that provide improved durable outcomes with favorable safety profiles are needed for these patients. In a phase Ib study (NCT03066648), sabatolimab+HMAs demonstrated an encouraging safety-tolerability profile and emerging durable responses in patients with higher-risk MDS (64% overall response rate and approximately 84% of patients still in response after 6 months). Sabatolimab is being studied in multiple phase I-III trials within the STIMULUS program. We present the STIMULUS MDS-US trial, designed to further assess the safety and efficacy of sabatolimab+HMAs, including an oral HMA. Study Design and Methods: STIMULUS MDS-US (NCT04878432) is a nonrandomized, single-arm, open-label, phase II study evaluating the safety and efficacy of sabatolimab in combination with FDA-approved HMAs of the investigator's choice in patients with MDS in the United States. A 12-month extension phase will continue investigating safety and efficacy after 24 months of treatment. The planned enrollment is estimated to be 90 patients. The trial is currently enrolling. Eligible patients are aged ≥18 years and have treatment-naive, higher-risk MDS (IPSS-R intermediate- or high/very high-risk) not suitable for intensive chemotherapy or hematopoietic stem cell transplant. Patients will receive IV sabatolimab 800 mg on day 8 (D8; or once between D5-8 to coincide with partner HMA administration) of each 28-day cycle for 24 months plus the investigator's choice of the following HMAs: oral decitabine (Inqovi®, decitabine 35 mg and cedazuridine 100 mg, D1-5); IV decitabine (20 mg/m2, D1-5); or IV or subcutaneous azacitidine (75 mg/m2, D1-7 or D1-5+8-9). Primary end points are incidence and severity of adverse events (AEs) and serious AEs. Secondary endpoints are complete remission (CR) rate (according to International Working Group for the Prognosis for MDS), progression-free survival, overall survival, leukemia-free survival, percentage of patients with CR, marrow CR and/or partial remission, duration of CR, time to CR, and percentage of patients with improvement in red blood cell/platelet transfusion independence. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

RF13 | PMON159 Long-term Efficacy and Safety Data for Oral Octreotide Capsules in Acromegaly: MPOWERED Trial Open-Label Extension Phase

Abstract Background Oral octreotide capsules (OOC) are a treatment option for patients with acromegaly in the United States. The MPOWERED trial (NCT02685709) showed that OOC were noninferior to injectable somatostatin receptor ligands (iSRLs; octreotide or lanreotide) in maintenance of biochemical control in patients previously responding to both treatments, as well as demonstrated improvements in patient-reported outcomes among patients receiving OOC. Objective Report long-term safety and efficacy outcomes with OOC from the open-label extension (OLE) of MPOWERED. Methods Patients were eligible for and could voluntarily enroll into the OLE if they had completed the 15-month core treatment phase of MPOWERED (6-month Run-in phase plus 9-month randomized controlled treatment [RCT] phase or, for OOC nonresponders during/at end of Run-in at participating sites, combination sub-study evaluating OOC in combination with cabergoline) and were adequately biochemically controlled per investigator assessment. Maintenance of response (definition: IGF-I &amp;lt;1.3×ULN; single timepoint) was assessed in each year of the OLE in patients responding at the start of that year. Additional analyses were performed on patients switching to OOC in the OLE from iSRLs in the core study. Results Sixty patients elected to enroll in the OLE (35 who received OOC and 19 who received iSRLs in the RCT phase, 6 from the combination sub-study). Median and maximal OOC exposure durations in the OLE were 2.2 and 3.5 years, respectively. A total of 94%, 90%, and 93% of patients receiving OOC monotherapy maintained biochemical response at the end of years 1, 2, and 3 of the OLE, respectively (using last observation carried forward imputation). Of patients switching from iSRLs to OOC during the OLE, 79% reported very good (47%) or excellent (32%) symptom control at the end of the OLE, compared with 47% (42% very good, 5% excellent) at the end of the RCT phase while receiving iSRLs. Patients switching from iSRLs also experienced significant improvements in the treatment convenience and treatment satisfaction domains (both P&amp;lt;0.05) of the Acromegaly Treatment Satisfaction Questionnaire. Median OOC compliance rate during the OLE was 99%. OOC safety during the OLE was consistent with that observed during the core study, with no new safety signals observed with long-term exposure. Conclusions The OLE of MPOWERED demonstrated a high percentage (≥90%) of patients maintaining biochemical response while receiving OOC monotherapy with a favorable long-term safety profile of OOC. Those who switched from iSRLs to OOC demonstrated improvements in symptom control, treatment convenience, and treatment satisfaction. Presentation: Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Effect of progressive resistance training with weight loss compared with weight loss alone on the fatty liver index in older adults with type 2 diabetes: secondary analysis of a 12-month randomized controlled trial

IntroductionNon-alcoholic fatty liver disease (NAFLD) is highly prevalent (~75%) in people with type 2 diabetes (T2D). Since exercise and weight loss (WL) are recommended for the management of both NAFLD...

MPN-546 A Single-Arm Multicenter Study to Assess the Efficacy, Safety, and Tolerability of Ropeginterferon alfa-2b-njft (P1101) in North American Adults With Essential Thrombocythemia.

There is an unmet need for treatment options for patients with essential thrombocythemia (ET) who require cytoreduction who may or may not have been treated with hydroxyurea (HU) or anagrelide (ANA), which is commonly used outside of North America. In addition to the reduction of thrombotic risk, treatment options for ET should reduce all blood cell types, prevent disease progression, and modify the disease. To assess the efficacy of ropeginterferon alfa-2b-njft (P1101) in adults with ET who live in the US or Canada. Single-arm, open-label study includes a 28-day screening period, a 12-month treatment phase, and a 28-day follow-up period, for a total trial duration of 14 months. P1101 will be administered every 2 weeks during the treatment phase at each study visit, and once a maintenance dose is identified for a patient, bi-weekly minor assessment visits may be replaced with phone visits. A subsequent extension phase will supply P1101 to patients deriving benefit for a total of 3 years of treatment. Study results will impact the general management of patients with ET. Adults diagnosed with ET according to the WHO 2016 criteria with a platelet count at screening >4 50 × 109/L, cytoreductive treatment naïve or with prior HU and/or ANA may participate. Patients with a history or presence of clinically relevant depression, risk of suicide, or autoimmune disease may not participate. P1101 will be administered subcutaneously every 2 weeks at the starting dose of 250 mcg (Week 0), 350 mcg (Week 2), and target optimal dose of 500 mcg (Week 4) and remain fixed for the 12-month treatment period. Subjects currently on HU or ANA will follow a pre-specified dose-tapering schedule. All subjects will receive low-dose aspirin unless contraindicated. The primary endpoint is a durable response defined as the proportion of subjects who achieve simultaneous peripheral blood count remission (platelets ≤400×109/L and WBC <10 × 109/L) for at least 80% of bi-weekly measurements consecutively between weeks 32-52. This study is being sponsored by PharmaEssentia USA.

Comparison of TSH Levels Pulmonary Tuberculosis Patients at The Phase 0 and 6 Months Treatment

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. Pulmonary TB has become a health problem worldwide, including in Indonesia, because the sufferers' prevalence is increasing every year. The increase in TB drug resistance will pose a severe health threat. The continuous consumption of drugs in large quantities and high doses can affect the function of the thyroid gland. This study aimed to determine the levels of thyroid stimulating hormone (TSH) in pulmonary tuberculosis patients with treatment phases of 0 months and six months. This research is analytical observational research with a cross-sectional research design. The sampling method uses accidental sampling. A total of 42 respondents participated in this study to determine the levels of TSH in pulmonary TB. The results of the Mann-Whitney U test showed no difference in TSH levels in pulmonary TB patients with different treatment phases of 0 months and six months (p = 0.3). There was no significant difference between TSH levels in pulmonary TB patients in the 0 and 6-month treatment phases.

Comparison of Ureum and Creatinine Levels in Patients with Pulmonary Tuberculosis in the Treatment Phase 0 and 6 Months

Pulmonary tuberculosis is a disease caused by Mycobacterium tuberculosis. Treatment for tuberculosis patients is given in the intensive and advanced stages. Anti-tuberculosis drugs can be nephrotoxic to cells in the kidneys. This research is an analytic observational study to know the comparison of urea and creatinine levels in pulmonary tuberculosis patients in the 0 and 6-month treatment phases at the Community Lung Health Center Purwokerto. The samples studied were 42 respondents who were taken by accidental sampling. This study was conducted from December 2021 to January 2022. Out of the 42 pulmonary tuberculosis patients who received treatment at 0 and 6 months, the majority of pulmonary tuberculosis patients were 28 patients (66.7%) had normal urea levels, and 38 patients (90.5 %) had normal creatinine levels. Urea levels in pulmonary tuberculosis patients during the 0-month treatment phase were 9 (2-24) mg/dL, while in the 6-month treatment phase, it was 8 (1-37) mg/dL. The creatinine level of pulmonary tuberculosis patients with 0-month treatment phase was 0.98 (0.64-1.62) mg/dL, while in the 6-month treatment phase it was 0.88 (0.62-1.92) mg/dL. There was no significant comparison of urea and creatinine levels in pulmonary tuberculosis patients with treatment phases 0 and 6 months (p&gt;0.05).

Video-urodynamics efficacy of sacral neuromodulation for neurogenic bladder guided by three-dimensional imaging CT and C-arm fluoroscopy: a single-center prospective study

To assess the efficacy of sacral neuromodulation (SNM) for neurogenic bladder (NB), guided by intraoperative three-dimensional imaging of sacral computed tomography (CT) and mobile C-arm fluoroscopy through video-urodynamics examination. We enrolled 52 patients with NB who underwent conservative treatment with poor results between September 2019 and June 2021 and prospectively underwent SNM guided by intraoperative three-dimensional imaging of sacral CT and mobile C-arm fluoroscopy. Video-urodynamics examination, voiding diary, quality of life questionnaire, overactive bladder symptom scale (OABSS) scoring, and bowel dysfunction exam were completed and recorded at baseline, at SNM testing, and at 6-month follow-up phases. Finally, we calculated the conversion rate from period I to period II, as well as the treatment efficiency and the occurrence of adverse events during the testing and follow-up phases. The testing phase of 52 NB patients was 18–60 days, with an average of (29.3 ± 8.0) days. Overall, 38 patients underwent SNM permanent electrode implantation, whose follow-up phase was 3–25 months, with an average of (11.9 ± 6.1) months. Compared with baseline, the voiding times, daily catheterization volume, quality of life score, OABSS score, bowel dysfunction score, maximum detrusor pressure before voiding, and residual urine volume decreased significantly in the testing phase. The daily voiding volume, functional bladder capacity, maximum urine flow rate, bladder compliance, and maximum cystometric capacity increased significantly in the testing phase. Besides, the voiding times, daily catheterization volume, quality of life score, OABSS score, bowel dysfunction score, maximum detrusor pressure before voiding, and residual urine volume decreased further from the testing to follow-up phase. Daily voiding volume, functional bladder capacity, maximum urine flow rate, bladder compliance, and maximum cystometric capacity increased further from testing to follow-up. At baseline, 10 ureteral units had vesicoureteral reflux (VUR), and 9 of them improved in the testing phase. Besides, there was 1 unit that further improved to no reflux during the follow-up phase. At baseline, 10 patients had detrusor overactivity (DO), and 8 of them improved in the testing phase. Besides, 1 patient’s symptoms further improved during the follow-up phase. At baseline, there were 35 patients with detrusor-bladder neck dyssynergia (DBND); 14 (40.0%) of them disappeared during the testing phase. Among 13 cases who had DBND in the testing phase, 6 (46.2%) disappeared during the follow-up phase. Of the 47 patients with detrusor-external sphincter dyssynergia (DESD) at baseline, 8 (17.0%) disappeared during the testing phase. Among 26 cases who had DESD in the testing phase, 6 (23.1%) disappeared during the follow-up phase. The effective rate of this study was 88.5% (46/52), and the conversion rate from phase I to phase II was 73.1% (38/52). Additionally, the efficacy in a short-term follow-up was stable. SNM guided by intraoperative three-dimensional imaging of sacral CT and mobile C-arm fluoroscopy is an effective and safe treatment option for NB in short time follow-up. It would be well improved in the bladder storage function, sphincter synergetic function and emptying efficiency by video-urodynamics examination in this study.Trial registration: Chinese Clinical Trial Registry. ChiCTR2100050290. Registered August 25 2021. http://www.chictr.org.cn/index.aspx.

Modulation of resting-state functional connectivity in default mode network is associated with the long-term treatment outcome in major depressive disorder.

Treatment non-response and recurrence are the main sources of disease burden in major depressive disorder (MDD). However, little is known about its neurobiological mechanism concerning the brain network changes accompanying pharmacotherapy. The present study investigated the changes in the intrinsic brain networks during 6-month antidepressant treatment phase associated with the treatment response and recurrence in MDD. Resting-state functional magnetic resonance imaging was acquired from untreated patients with MDD and healthy controls at baseline. The patients' depressive symptoms were monitored by using the Hamilton Rating Scale for Depression (HAMD). After 6 months of antidepressant treatment, patients were re-scanned and followed up every 6 months over 2 years. Traditional statistical analysis as well as machine learning approaches were conducted to investigate the longitudinal changes in macro-scale resting-state functional network connectivity (rsFNC) strength and micro-scale resting-state functional connectivity (rsFC) associated with long-term treatment outcome in MDD. Repeated measures of the general linear model demonstrated a significant difference in the default mode network (DMN) rsFNC change before and after the 6-month antidepressant treatment between remitters and non-remitters. The difference in the rsFNC change over the 6-month antidepressant treatment between recurring and stable MDD was also specific to DMN. Machine learning analysis results revealed that only the DMN rsFC change successfully distinguished non-remitters from the remitters at 6 months and recurring from stable MDD during the 2-year follow-up. Our findings demonstrated that the intrinsic DMN connectivity could be a unique and important target for treatment and recurrence prevention in MDD.