Maximum Grade Research Articles

Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer.

Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy. In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded. A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = 0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = 0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group. Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.).

Bio-mediated enhancement of supergene copper mineralization: Evidence from Cu isotope geochemistry

The relationship between microbial activity and the supergene modification of ore systems has been a major subject of debate. Here, we present isotopic evidence of microbial-driven secondary copper mineralization in the active cementation zone of the Las Cruces deposit, a volcanogenic massive sulfide deposit located in Iberian Pyrite Belt, Spain. Copper isotopic data show that the lower isotopic ratios (δ65Cu ≈ −9.2 ± 0.11 ‰, the lowest value measured worldwide in a supergene environment) are found in the upper part of the cementation zone, the same zone where the maximum copper grades are found and where there is direct evidence of extremophilic microbial activity. There is a tendency towards higher values downwards through the cementation zone (−9.2 ± 0.11 ‰ to + 1.67 ± 0.11 ‰ δ65Cu) and upwards into the former Cu-depleted gossan that originally capped the cementation zone (−7.79 ± 0.11 ‰ to −1.32 ± 0.11 ‰ δ65Cu). As microbes preferentially sequester the lighter isotope when incorporating intracellular Cu, this distribution indicates that microbes played a major role in the formation of the high-grade zones. Water arrives to the deposit enriched in isotopically heavy copper, likely because it has leached other ore bodies upstream. δ65Cu values of water currently flowing into the system are remarkably more positive than those in the ore, indicating that microbial activity is a major cause of copper isotope fractionation. At least half of the copper transported by the incoming waters remains within the ore body. Our best interpretation is that the large and high-grade cementation zone at Las Cruces is of biogenic origin, and that the primary mineralization acted as a trap for copper transported by groundwater, leading to the formation of an exotic mineralization distal to sub-eroded massive sulfides located upstream.

A Pilot Study of UM171-Expanded Cord Blood Grafts for Tandem Auto/Allogeneic Hematopoietic Cell Transplant in High and Ultra-High-Risk Myeloma Patients

Multiple myeloma (MM) remains associated with a poor outcome, particularly in patients with advanced disease and high-risk (HR) cytogenetics. To date, the only curative treatment is allogeneic (allo) hematopoietic cell transplantation (HCT), but high incidences of graft versus host disease (GVHD), non-relapse mortality (NRM) and disease progression remain important obstacles. Cord blood (CB) transplantation has been associated with low rates of relapse and chronic (c) GVHD, but its use has declined because of high incidences of infections, severe acute GVHD and high NRM. In other hematologic malignancies, UM171-expanded CB transplants have led to improved outcomes, allowing for the selection of smaller, better HLA-matched units. We aimed to investigate the safety and feasibility of single UM171-expanded single CB unit transplantation in frontline tandem auto/allo HCT for HR/ultra-HR MM patients. Newly diagnosed MM patients ≤ 65 years with an ISS stage II/III and del17p, t4,14, t14,16, t14,20, del1p or +1q, R-ISS 3, ≥ 2 cytogenetic abnormalities, or plasma cell leukemia without a sibling donor and availability of a 5-7/8 matched CB graft with ≥ 0.5 x 105 CD34+/kg and ≥ 1.5 x 107 TNCs/kg were eligible to this phase I/II prospective study (ClinicalTrials.gov NCT03441958). After induction and autologous HCT, patients received a reduced intensity conditioning regimen and were infused with 7-day UM171-expanded CD34+ cells, along with the lymphocytes contained in the CD34-negative fraction. The primary endpoints were feasibility of UM171 expansion, safety, kinetics of engraftment, incidences and maximum grades of acute and cGVHD at 1 and 2 years, assessment of measurable residual disease (MRD) and quality of life (QoL). Between 05/2018 and 11/2021, 20 patients were enrolled. One patient had an unsuccessful CB expansion with UM171, leaving 19 patients with a median age of 56 years. Median CD34+ cell dose infused after expansion was 4.62 x 106/kg (range: 0.79-5.76). Median times to achieve absolute neutrophil counts of 0.1 and 0.5 x 109/L were D+6 and D+10.5; median time to reach ≥ 20 x 109/L platelets was D+36. Full donor chimerism was achieved in all cell lineages by D+120 in recipients of reduced intensity conditioning. Cumulative incidences of grade II-IV, grade III-IV acute GVHD and moderate/severe cGVHD at 12 months were 68.4% (95% CI: 46-90), 5.3% (95% CI: 0-16%), and 10.5% (95% CI: 0-25%), respectively. With a median follow-up of 2.9 years (range: 0.46-5.3), cumulative incidences of relapse, PFS, OS and NRM at 3 years were 36.8% (95% CI: 14-59), 47.4% (95% CI: 29-76), 68.4% (95% CI: 50-93) and 15.8% (95%CI: 0-33), respectively. Median time to complete immunosuppression discontinuation was D+238. No unexpected adverse events were observed. Only one of 7 patients alive at 2 years with negative MRD at transplant has relapsed. Non-relapsing patients had a QoL after transplant similar to the general population. UM171-expanded CB transplant in HR/ultra-HR myeloma patients is feasible and allows the use of single CB units with a low risk of cGVHD. Patients with negative pre-transplant MRD might benefit most from a UM171-expanded CB transplant.

Evaluation of Clinical Performance of Ponto Implantation Using a Minimally Invasive Surgical Technique-A Prospective Multicenter Study.

To investigate the clinical outcomes of bone-anchored hearing implant surgery using the MONO procedure. Multicenter, multinational, single-arm, prospective trial with a 12-month follow-up. Seven European university hospitals from the United Kingdom, Sweden, Denmark, and The Netherlands. Fifty-one adult patients requiring surgical intervention for bone conduction hearing. Bone-anchored hearing implant surgery using the MONO procedure. The primary endpoint assessed implant usability 3 months after surgery. Implant status, soft tissue reactions, pain and numbness, postoperative events, and sound processor usage were assessed at all follow-up visits. Hearing-related quality of life was evaluated using the Glasgow Benefit Inventory (GBI). At 3 months, 94.2% of the implant/abutment complexes provided reliable anchorage for sound processor usage. No severe intraoperative complications occurred. Sixty-nine percent of surgeries were performed under local anesthesia, with surgery lasting 10 minutes on average. Four implants were lost due to trauma (n = 2), spontaneous loss of osseointegration (n = 1), or incomplete insertion (n = 1). Adverse soft tissue reactions occurred in 2.6% of visits, with a maximum Holgers grade of 3 (n = 1) and grade 2 (n = 5) across patients. Hearing-related quality of life at 3 months improved in 96% of patients. The MONO procedure provides a safe and efficient surgical technique for inserting bone-anchored hearing implants with few and minor intra- and postoperative complications.

Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA-targeting therapies

AbstractTeclistamab is a B-cell maturation antigen (BCMA)–directed bispecific antibody approved for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma (R/RMM). In the phase 1/2 MajesTEC-1 study, a cohort of patients who had prior BCMA-targeted therapy (antibody-drug conjugate [ADC] or chimeric antigen receptor T-cell [CAR-T] therapy) was enrolled to explore teclistamab in patients previously exposed to anti-BCMA treatment. At a median follow-up of 28.0 months (range, 0.7-31.1), 40 patients with prior BCMA-targeted therapy had received subcutaneous 1.5 mg/kg weekly teclistamab. The median prior lines of treatment was 6 (range, 3-14). Prior anti-BCMA therapy included ADC (n = 29), CAR-T (n = 15), or both (n = 4). The overall response rate was 52.5%; 47.5% of patients achieved very good partial response or better, and 30.0% achieved complete response or better. The median duration of response was 14.8 months, the median progression-free survival was 4.5 months, and the median overall survival was 15.5 months. The most common treatment-emergent adverse events (TEAEs) were neutropenia, infections, cytokine release syndrome, and anemia; cytopenias and infections were the most common grade ≥3 TEAEs. Infections occurred in 28 patients (70.0%; maximum grade 3/4, n = 13 [32.5%]; grade 5, n = 4 [10%]). Before starting teclistamab, baseline BCMA expression and immune characteristics were unaffected by prior anti-BCMA treatment. The MajesTEC-1 trial cohort C results demonstrate favorable efficacy and safety of teclistamab in patients with heavily pretreated R/RMM and prior anti-BCMA treatment. This trial was registered at www.ClinicalTrials.gov as #NCT03145181 and #NCT04557098.

Single-center analysis of a real-world cohort of patients with metastatic urothelial carcinoma evaluated by NGS: molecular landscape and efficacy of targeted therapies.

To describe the molecular profile of a real-world cohort of patients with metastatic urothelial carcinoma (mUC) and to evaluate the benefit of next-generation sequencing (NGS) panels in guiding therapy in patients with mUC and the outcomes of DNA-matched treatments recommended by a multidisciplinary molecular tumor board (MMTB). This was a single-center analysis of a real-world cohort of adult patients with mUC included in an ongoing trial that aimed to evaluate the clinical utility of NGS for solid tumors. Genomic analysis was performed for each patient, most of them using the Ion Torrent Oncomine Focus Assay. Genomic results were discussed during MMTB meetings. We included 43 patients with mUC treated with platinum-based combinations and immunotherapy. Twenty-five patients (58.1%; 95% CI 43.4-72.9) had at least one tumor pathogenic alteration. The MMTB classified 16 (48.5%) of the 33 tumor pathogenic alterations found in our real-world cohort of mUC patients as ESCAT I, which is the maximum grade of actionability. After excluding patients who were not candidates for targeted therapies, the MMTB provided guidance on matched therapy for seven patients. Among these patients, three achieved a partial response for an overall response rate of 42.9%, a median progression-free survival of 7.3months (95% CI 6.7-7.9) and a median overall survival of 10.9months (95% CI 2.4-19.5). We recommend that all patients with mUC undergo NGS at diagnosis given the high percentage of patients with pathogenic alterations in our real-world cohort and the efficacy data of patients treated with targeted therapies.

Stereotactic Magnetic Resonance–Guided Daily Adaptive Radiation Therapy for Localized Prostate Cancer: Acute and Late Patient-Reported Toxicity Outcomes

ObjectiveTo report acute and late bowel, urinary and sexual dysfunction patient reported outcome measures (PROMS), amongst localised prostate cancer patients who underwent Stereotactic MRI-guided daily adaptive radiotherapy (SMART). MethodsAll patients who completed a baseline 12 item Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), before undergoing 36.25 Gy in 5 fractions by SMART, were subsequently followed up with the same graded questionnaire at set time points. Latest PSA levels were recorded. The percentage of patients who reported no change from their baseline AE or reported a new ≥ ‘frequent’ or’ severe’ AE grade during follow up was calculated. The maximum PRO-CTCAE grade for each item was recorded for each patient. The percentage of toxicity levels for each separate AE item at set time points were calculated. ResultsThe total number of patients was 69 with a median follow-up of 27 months. Median age of cohort 73 (range 54-85). The median pre-treatment PSA, T stage and Gleason score was 7.5 mmol/l (4.5-32 mmol/l), T2b (T2-T3b) and Gleason Score of 7 (3+4, range: 6-9) respectively. No patient had biochemical failure during follow up. Regarding bowel symptoms, >80% of men reported no change from baseline toxicity during follow up. New ≥ frequent diarrhoea was reported in 9% of patients. ‘Almost constant’ diarrhoea peaked at 1 month but was absent at >33 months. Regarding urinary symptoms, increased urinary urgency was the most common complaint (39%). 20% of men reported new ≥ frequent urinary urgency incidence peaking at 1 month but absent at >33 months. New “severe” sexual dysfunction was seen in 26% of patients and was persistent at >33 months. ConclusionOur study is one the largest patient reported outcomes study post prostate SMART. It shows acceptable levels of toxicity even up to 2 years post treatment.

Maximizing food equivalent unit yield for forage maize production without notably compromising dry matter yield and feed quality in a semi-arid region

Food equivalent unit (FEU) is a vector used to measure the value of food based on its calorie and protein content and their digestibility. However, the optimal planting density and N application rate for maximizing the FEU yield (FEUY) of forage maize (Zea mays L.) is still poorly understood in the fast-growing animal husbandry regions of the Chinese Loess Plateau. Here, a 2-year consecutive field experiment was conducted to explore the impacts of planting density, N application rate, and their interactions on growth, dry matter yield (DMY), forage quality, and FEUY of a dominant forage maize cultivar. Planting density significantly affected the stem diameter, LAI, DMY, and dry matter allocation (DMA) of the leaf. Initially, increasing the N rate increased the stem diameter, LAI, FEUY, and DMY of forage maize and then decreased. The stem diameter, LAI, FEUY and above-ground DMY peaked under 180 kg∙ha−1 N in both years. Moreover, N application significantly increased the crude protein content of the whole plant and decreased the acid detergent fiber content. The surface fittings of the 2-year study indicated that 110,000 plants∙ha−1 (plant density) and 171.2 kg∙ha−1 (N rate) obtained the greatest DMY (19.0 t∙ha−1). The grade index (a comprehensive evaluation index for forage quality) peaked at 15.4 MJ∙d−1 under 94,000 plants ha−1 and 270 kg∙ha−1. The 110,000 plants∙ha−1 plant density and 181.5 kg∙ha−1 N rate jointly maximized the FEUY (11,125.4 FEU∙ha−1), maintaining 99.9 % of the maximum DMY and 97.5 % of the maximum grade index. Thus, 110,000 plants∙ha−1 plant density and 181.5 kg∙ha−1 N rate are recommended for high-productivity forage maize production, without notably compromising dry matter yield and feed quality. This research is conducive to advancing the coordinated development of forage crop cultivation and herbivorous livestock farming in semi-arid rainfed areas.

ADRIATIC: Durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC).

LBA5 Background: The standard of care (SoC) for pts with LS-SCLC is concurrent platinum-based chemoradiotherapy (cCRT) ± prophylactic cranial irradiation (PCI). ADRIATIC (NCT03703297), a phase 3, randomized, double-blind, placebo (PBO)-controlled, multicenter, global study, assessed D ± tremelimumab (T) as consolidation tx for pts with LS-SCLC who had not progressed after cCRT. Here we report results for D vs PBO from the first planned interim analysis (IA). Methods: Eligible pts had stage I–III LS-SCLC (stage I/II inoperable) and WHO performance status 0/1, and had not progressed after cCRT. PCI was permitted before randomization. Pts were randomized 1–42 days after cCRT to D 1500 mg + PBO, D 1500 mg + T 75 mg, or PBO + PBO every 4 weeks (Q4W) for 4 cycles, followed by D (D±T arms) or PBO Q4W until investigator-determined progression or intolerable toxicity, or for a maximum of 24 months (mo). The first 600 pts were randomized in a 1:1:1 ratio; subsequent pts were randomly assigned 1:1 to D or PBO. Randomization was stratified by stage (I/II vs III) and receipt of PCI (yes vs no). The dual primary endpoints were OS and PFS (blinded independent central review per RECIST v1.1) for D vs PBO. OS and PFS for D+T vs PBO were alpha-controlled secondary endpoints. Results: 730 pts were randomized, including 264 to D and 266 to PBO. Baseline characteristics and prior tx were well balanced between arms. Radiation schedule in the D vs PBO arms was once daily in 73.9% vs 70.3% of pts and twice daily in 26.1% vs 29.7%; 53.8% of pts in each arm received PCI. At this IA (data cutoff 15Jan2024), median (range) duration of follow-up for OS and PFS in censored pts was 37.2 (0.1–60.9) and 27.6 (0.0–55.8) mo, respectively. OS was significantly improved with D vs PBO (HR 0.73 [95% CI 0.57–0.93]; p=0.0104; median OS 55.9 [95% CI 37.3 – not estimable] vs 33.4 [25.5–39.9] mo; 24-mo OS rate 68.0% vs 58.5%; 36-mo OS rate 56.5% vs 47.6%). PFS was also significantly improved with D vs PBO (HR 0.76 [95% CI 0.61–0.95]; p=0.0161; median PFS 16.6 [95% CI 10.2–28.2] vs 9.2 [7.4–12.9] mo; 18-mo PFS rate 48.8% vs 36.1%; 24-mo PFS rate 46.2% vs 34.2%). Tx benefit was generally consistent across predefined pt subgroups for both OS and PFS. With D vs PBO, maximum grade 3/4 all-cause adverse events (AEs) occurred in 24.3% vs 24.2% of pts; AEs led to tx discontinuation in 16.3% vs 10.6% of pts and to death in 2.7% vs 1.9%. Any-grade pneumonitis/radiation pneumonitis was reported in 38.0% vs 30.2% of pts with D vs PBO (maximum grade 3/4 in 3.0% vs 2.6%). The D+T arm remains blinded until the next planned analysis. Conclusions: D as consolidation tx after cCRT demonstrated a statistically significant and clinically meaningful improvement in OS and PFS compared with PBO in pts with LS-SCLC. D was well tolerated and AEs were consistent with the known safety profile, with no new signals observed. These data support consolidation D as a new SoC for pts with LS-SCLC who have not progressed after cCRT. Clinical trial information: NCT03703297 .

VERIFY: A randomized controlled phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera (PV).

TPS6592 Background: PV is a myeloproliferative neoplasm characterized by overproduction of red blood cells and increased risk of thrombosis. Patients may require frequent therapeutic phlebotomies (TP) alone or in combination with cytoreductive therapy to maintain hematocrit (HCT) <45%. Hepcidin regulates iron homeostasis but is downregulated in PV, increasing iron availability for erythropoiesis, which complicates TP optimization. In a phase 2 study (REVIVE, NCT04057040), rusfertide led to rapid, sustained, and durable HCT control with over 90% of patients achieving TP independence in part 2.1 It was well tolerated; majority (77.1%) of treatment-emergent adverse events (TEAEs) had a maximum grade of 2. There were no Grade 4 or 5 TEAEs. The phase 3 study VERIFY (NCT05210790) aims to confirm efficacy and safety of rusfertide in patients with PV. Methods: VERIFY is a multicenter, global, randomized trial comparing efficacy and safety of rusfertide (starting dose: 20 mg subcutaneously once weekly) vs. placebo when added to ongoing therapy for PV. Patients with PV who require frequent TP with or without concurrent cytoreductive therapy to control HCT are included in this 3-part study: Part 1a: 1:1 randomized, double-blind, placebo-controlled, add-on parallel-group period lasting 32 weeks (Week 0-32); Part 1b: open-label treatment phase with cross-over for previous placebo-treated patients. During this phase, all patients who completed Part 1a successfully will receive rusfertide for 20 weeks (Week 32-52); and Part 2: long term extension phase where all patients who complete Part 1b will continue to receive rusfertide for 104 weeks (Week 52-156). Results: Major inclusion criteria prior to randomization include PV diagnosis by 2016 WHO criteria; ≥3 TP in the previous 28 weeks or ≥5 in the previous 12 months due to inadequate HCT control; HCT <45%, white blood cells 4-20 × 109/L and platelets 100-1000 × 109/L at Week 0; stable PV therapy regimen in patients receiving cytoreduction at randomization; and cessation of cytoreductive therapy 2-6 months before screening in patients treated with TP alone. Major exclusion criteria are thrombosis or bleeding (active and/or chronic) within 2 months before randomization and a history of invasive malignancy within the previous 5 years. Primary endpoint is the proportion of patients achieving a response in Part 1a from Week 20-32. A response is defined as absence of TP eligibility. TP eligibility: HCT ≥45% and ≥3% higher than baseline HCT or HCT ≥48%. Secondary endpoints are mean number of TPs from Week 0-32; proportion of patients with HCT <45% from Week 0-32; mean change from baseline to Week 32 in total fatigue score measured by PROMIS Short Form and in total symptom score measured by MFSAF v4.0. Conclusions: VERIFY opened in January 2022 and aims to enroll approximately 250 patients globally. Reference: 1. Ritchie EK, et al. Blood.2023;142(Suppl 1):745. Clinical trial information: NCT05210790 .

Clonal Hematopoiesis is Associated With Severe Cytokine Release Syndrome in Patients Treated With Chimeric Antigen Receptor T-Cell (CART) Therapy

Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR T therapy, inflammation pre- and post-CAR T infusion is implicated in the development of toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and likely contributes to prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells harboring somatic mutations, has been associated with inflammasome upregulation. Herein, we examined the prevalence of pre-CAR T CH in a predominantly transplant-naïve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between the presence of CH mutations and CAR T-related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS). This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR T therapy from 2017 to 2022 at City of Hope and had available pre-CAR T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected <30d of CART infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] ≥2%). Multivariable logistic regression was used to examine the association between CH and absolute neutrophil count (ANC) recovery at day +30 and +60, maximum grade CRS and ICANS, grade <2 versus 2+, and OS and PFS at 1y. Covariates considered were age at CART, baseline ANC, sex, race, CAR-HEMATOTOX, LDH, bridging therapy (Y/N), and number of prior lines of therapy. Fifteen (24%) patients had at least one pathogenic CH mutation; 2 (13%) had ≥2 CH mutations concurrently. DMT3A mutations were the most common; 29% of mutations had VAFs >10%. Patients with CH were significantly more likely to develop grade ≥2 CRS (60% versus 28%, p = .03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p = .027). Accounting for baseline ANC (which was higher among the CH cohort and associated with delayed ANC recovery, p = .02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p = .17). There was no association between CH and ICANS, nor with 1y PFS or OS. CH was frequent (24%) in this cohort of CAR T recipients and was associated with a higher risk of development of grade ≥2 CRS after CAR T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis. Translational studies could aim to prove a direct relationship between CH-mutated myeloid cells and CRS.

Prevalence and Precipitants of Hepatic Encephalopathy in Hospitalized Children With Chronic Liver Disease

ObjectiveHepatic encephalopathy (HE) is a marker of poor prognosis in adults with chronic liver disease (CLD). We prospectively studied the prevalence and precipitants of HE in children with CLD as there is a paucity of literature on the same. MethodsChildren (1-18years) admitted with CLD were examined daily for the presence and grading of HE (West Haven/ Whitington grading). Precipitants were classified as infection, dyselectrolytemia, gastrointestinal bleeding, constipation, and dehydration. Changes in grades of HE and outcome were noted. ResultsOne hundred and sixty children (age 120[84-168] months) were enrolled. HE was present in 50(31.2%) patients with a total of 61 episodes. Maximum grade of HE was grade I (n=16), II (n=23), III (n=11) and IV (n=11). Forty-two cases had single and 8 had recurrent (2-5) episodes. Median duration of HE episodes was 96 (72-192) hours. Precipitants were identified in 55/61(90.2%) episodes with infection (45/61, 73.7%) and dyselectrolytemia (33/61,54%) being most common. Lower albumin and sodium, higher INR and presence of infection were significantly associated with presence of HE. Overall, HE resolved in 33(54%) episodes, while it progressed and persisted in 28(45.9%) episodes. Patients with HE had a poorer outcome (25/50 vs 13/110; p <0.01) with both higher in-hospital (11/50 vs 9/110; p=0.02) and 1month post discharge (14/39 vs 4/101; p<0.01) mortality than those without HE. ConclusionOne third of admitted CLD children have HE, with identifiable precipitants in 90% cases. Children with HE have poorer liver functions, higher rate of infections and worse outcome than those without HE.

Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study

In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]). Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. AstraZeneca.

Treatment-Responsive Acute Graft-versus-Host Disease after Post-Transplantation Cyclophosphamide-Based Prophylaxis: Incidence and Clinical Outcomes

Post-transplantation cyclophosphamide (PTCy) following hematopoietic cell transplantation (HCT) has emerged as standard of care for graft-versus-host disease (GVHD) prevention in adult patients without increasing malignant relapse. We previously defined acute GVHD (aGVHD) treatment response categories as corticosteroid-sensitive (SS), -dependent (SD), or -resistant (SR) based on response to first-line corticosteroids and reported their clinical outcomes following non-PTCy-based prophylaxis. More than one-third of patients developed aGVHD necessitating systemic therapy. Cases were predominantly SR, with a 14% overall incidence of SR aGVHD. The incidence and clinical outcomes of these 3 distinct aGVHD treatment response groups following PTCy-based prophylaxis have not been well described. The objective of this retrospective single-institution cohort study was to assess the incidence and clinical outcomes of SS, SD, and SR aGVHD following HCT with PTCy-based prophylaxis using a prophylactic regimen of PTCy, tacrolimus, and mycophenolate mofetil (MMF). We included 196 consecutive adult and pediatric patients undergoing allogeneic HCT for malignant and non-malignant disorders at the University of Minnesota between 2017 and 2021. Patients received PTCy on days +3 and +4 plus tacrolimus and MMF prophylaxis. Bone marrow and peripheral blood stem cell graft sources and related and unrelated donors were included. Recipients received myeloablative or reduced-intensity conditioning regimens. Of the 196 allografts, 54 (28%) developed aGVHD before day +180, with a median time to onset of 50 days (interquartile range, 34 to 71 days). Of those, 32 patients (16% overall) developed maximum grade II-III aGVHD necessitating systemic corticosteroids, with the following response: 13 SS (41%), 10 SD (31%), and 9 SR (28%). The overall incidence of SR aGVHD was 4.6%. Only 12 patients (6%) developed maximum grade III aGVHD, and none had grade IV aGVHD. The 2-year overall survival analyzed from 80 days after initiation of systemic treatment was similar in the SS and SD groups (77 and 75%, respectively), comparable to those without aGVHD (81%), and was lowest in the SR group (20%), with GVHD the primary cause of death. Nonrelapse mortality was highest in the SR group. MN high-risk and higher GVHD grade at onset were risk factors for developing SR aGVHD. Overall, we report a low incidence (16%) of aGVHD requiring systemic corticosteroids with PTCy-based prophylaxis. aGVHD cases were predominantly SS aGVHD, with lower incidences of SD and SR aGVHD. Our findings suggest that PTCy-based prophylaxis reduces the rate of treatment-resistant aGVHD. Patients with SR aGVHD had the worst clinical outcomes and poorest survival. Those with SS and SD aGVHD had similar clinical outcomes, both better than seen with SR aGVHD.

Pelaksanaan Pembelajaran Seni Budaya Musik Tradisional (Talempong Pacik) Siswa Kelas VIII-1 SMP Negeri 43 Padang

. This study aims to describe the process of implementing Talempong Pacik Music learning in grades VIII-1 at SMP Negeri 43 Padang. This type of research is qualitative research with descriptive methods. This research instrument is the researcher himself and is assisted by supporting instruments in the form of stationery and cameras. This research data uses primary data and secondary data. Data are collected through literature study, observation, interviews, documentation. The steps of analyzing data are data classification, analyzing data, and inferring data. The results showed that the implementation of learning Traditional Music Culture Arts (Talempong Pacik) in Grades VIII-1 SMP Negeri 43 Padang consisted of 4 meetings, namely initial activities, core activities and closing activities. The scores of students after the implementation of Traditional Music Culture (Talempong Pacik) learning activities are still many who have not reached KKM, there are 15 students who have not reached KKM and 8 students can only achieve predetermined KKM standard scores and there are 9 students who get scores that exceed KKM. The learning process has not fully obtained satisfactory learning results. Teacher limitations in using teaching aids and limited time in practical activities, teachers continue to try to motivate students, so that students continue to be enthusiastic in the process of learning activities, students still look rigid in carrying out learning activities including in the process of traditional music learner practice activities, so that there are still many student scores below KKM, and the rest only reach the KKM limit. So it is known that students have not received maximum grade results.

Value of perilesional biopsies in multiparametric magnetic resonance imaging-targeted biopsy and systematic biopsy in detection of prostate cancer: results of a prospective, non-randomized, surgeon-blinded study

PurposeThe goal of this study is to address if detection rates of clinically significant prostate cancer (csPCa) can be increased by additional perilesional biopsies (PB) in magnetic resonance (MR)/ultrasound fusion prostate biopsy in biopsy-naïve men.MethodsThis prospective, non-randomized, surgeon-blinded study was conducted between February 2020 and July 2022. Patients were included with PSA levels < 20 ng/ml and ≥ one PI-RADS lesion (grades 3–5) per prostate lobe. Prostate biopsy was performed by two urologists. The first performed the MR-fusion biopsy with 3–5 targeted biopsies (TB) and 6 PB in a standardized pattern. The second performed the systematic (12-fold) biopsy (SB) without knowledge of the MR images. Primary outcome of this study is absence or presence of csPCa (≥ ISUP grade 2) comparing TB, PB and SB, using McNemar test.ResultsAnalyses were performed for each PI-RADS lesion (n = 218). There was a statistically significant difference in csPC detection rate of TB + SB between PI-RADS 3, 4 and 5 lesions (18.0% vs. 42.5% vs. 82.6%, p < 0.001) and TB + PB (19.7% vs. 29.1% vs. 78.3%). Comparing only maximum ISUP grade per lesion, even SB plus TB plus PB did not detect more csPCa compared to SB plus TB (41.3% vs. 39.9%, p > 0.05).ConclusionWe present prospective study data investigating the role of perilesional biopsy in detection of prostate cancer. We detected no statistically significant difference in the detection of csPCa by the addition of PB. Therefore, we recommend continuing 12-fold bilateral SB in addition to TB.

Abstract PO2-22-05: A prospective phase I-II study of hypofractionated accelerated breast and nodal intensity modulated radiation therapy delivered in the prone position

Abstract Background In patients with breast cancer, prone radiotherapy (RT) has been shown to reduce heart and lung dose. Routinely used for whole breast (WB) RT, its use to treat regional lymph nodes (LNs) is not widespread. Methods In this phase I-II study (NCT02308488) patients treated with lumpectomy or mastectomy with 1-5 pathologically involved LNs underwent WBRT or post-mastectomy RT plus regional nodal RT using IMRT to the supraclavicular and level III axillary LNs. The prescription was 40.5Gy in 15 daily 2.7Gy fractions with a daily concomitant 0.5Gy tumor bed boost. Patients who underwent sentinel LN biopsy (SLNB) alone (no axillary dissection) had the level I-II axilla included in the RT field. The primary endpoints were incidence of &amp;gt;grade 2 acute toxicity per CTCAE v 3.0 and dosimetric feasibility. The secondary endpoint was late toxicity. Clinical outcomes were local recurrence (LR), disease free survival (DFS), distant recurrence free survival (DRFS) and overall survival (OS). Coverage constraints included planning target volume [PTV] V48Gy ≥ 98%, PTV breast V40.5Gy ≥ 95% and PTV nodes V38.5Gy ≥ 95%. Normal tissue constraints included heart V5Gy &amp;lt; 5%, ipsilateral lung V10Gy &amp;lt; 20%, contralateral lung V5Gy &amp;lt; 15%, ipsilateral brachial plexus (BP) maximal dose (Dmax) &amp;lt; 42Gy, spinal cord Dmax ≤ 3 7.5Gy, thyroid contralateral lobe Dmax ≤ 15Gy, esophagus V30Gy &amp;lt; 50% and Dmax ≤ 40.5Gy. Results From 2011-2016, 97 patients with stage IB-IIA breast cancer were enrolled. 66 underwent lumpectomy and 31 underwent mastectomy. 16 had SLNB alone. There were no grade 3 acute toxicities meeting the primary toxicity endpoint. Common acute low-grade toxicities included fatigue (grade 1: 65 [66.3%]; grade 2: 7 [7.1%]), esophagitis (grade 1: 7 [7.1%]; grade 2: 10 [10.2%]), dermatitis (grade 1: 82 [83.7%]; grade 2: 7 [7.1%]). At median and maximum follow up of 8.02 (IQR: 3.31) and 13.3 years, respectively, there were 2 LRs (2.1%). 8-year DRFS, DFS and OS were 88.1% (95% CI 81.3%, 95.4%), 85.7% (95% CI 78.4%, 94.6%) and 90.5% (95% CI 84%, 97.6%), respectively. Clinician-rated cosmesis (n=64) was excellent/good in 67.2% of cases and fair/poor in 6.3%. Patient- rated cosmesis (n=47) was excellent/good in 91.5% and fair/poor in 8.5%, with patients rating themselves more favorably than their physicians (p=0.0014). The incidence of maximum grade 1, 2 and 3 late toxicities were 49 (62.8%), 15 (19.2%), and 3 (3.8%), respectively. This included 2 grade 3 asymmetries,1 grade 3 pigmentation change, and 1 grade 2 pneumonitis. There was no brachial plexopathy. Among the 28 patients who underwent reconstruction, 17 were implant-based and 11 were autologous. Of the implant-based, 9 underwent RT to the tissue expander and 8 to the permanent implant. 11/28 patients had long-term plastic surgery follow up. There were 3 hospitalizations with reoperation post-RT (1 unplanned revision, 1 implant removal for threatened exposure, and 1 excision of fat necrosis). There was 1 incident of wound infection/cellulitis. With regard to dosimetric constraints, 54.3% of plans (95% CI 43.6%, 64.8%) met all constraints. 92% (95% CI 83%, 97%), 98% (95% CI 93%, 100%) and 89% (95% CI 80%, 94%) met the PTV tumor V48Gy, PTV breast V40.5Gy, and PTV nodes V38.5Gy coverage constraints, respectively. Heart, contralateral lung, spinal cord, and esophagus constraints were met by all patients. 95% (95% CI 88.6%, 98.4%) met the ipsilateral lung V10Gy and 99% (95% CI 94%, 100%) met the thyroid contralateral lobe constraint. The BP constraint was met in 73% (95% CI 63.0%, 81.0%) of plans with a mean increase of 1.61 Gy (SD 1.96 Gy) over target. Conclusion Toxicity was low and outcomes were excellent in this prospective trial of hypofractionated regional nodal RT in the prone position. Dosimetric constraints were only met in 54% of plans with the nodal coverage and the BP constraint as the most frequently unmet. These constraints may need to be modified and/or techniques refined to optimize hypofractionated prone nodal RT. Citation Format: Juhi Purswani, Olivier Maisonet, Julie Xiao, Jose R Teruel, Christine Hitchen, Xiaochun Li, Judith D. Goldberg, Carmen A. Perez, Silvia C. Formenti, Naamit K. Gerber. A prospective phase I-II study of hypofractionated accelerated breast and nodal intensity modulated radiation therapy delivered in the prone position [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-22-05.

POTENTIAL IMPACT OF EXERCISE UPON SYMPTOM BURDEN IN ADOLESCENTS AND YOUNG ADULTS UNDERGOING CANCER TREATMENT

INTRODUCTION Adolescents and young adults (AYAs) experience vast symptom burden resulting from cancer treatment-related toxicities (TRTs). Evidence supports exercise to mitigate several TRTs in other cohorts, however evidence in AYAs is lacking. Conventional reporting of TRTs adopts a maximum grade approach failing to recognise the trajectory over time or lower grade toxicities. Alternatively, longitudinal analysis of toxicities over time (ToxT) may provide clinically meaningful summaries of this data. We evaluated the longitudinal impact of an exercise intervention on TRTs in AYAs undergoing cancer treatment. METHODS A prospective, randomised trial allocated participants to a 10-week exercise intervention (EG) or control group (CG) undergoing usual care. Detailed information on TRTs was collected throughout the intervention. All TRTs were graded per the Common Terminology Criteria for Adverse Events (CTCAE v5.0). RESULTS Forty-three (43) participants (63% male, mean age 21.1 years) were enrolled. When categorised to reflect the maximal worst grade experienced (Grade 0, Grade 1-2 and ≥Grade 3), the CG reported an increased incidence of severe fatigue (≥Grade 3) compared with the EG (p=0.05). No other differences between groups were evident (p&amp;gt;0.05). ToxT analysis of the four most common toxicities (fatigue, pain, nausea and mood disturbances) demonstrated no difference in the mean grade of each over time (p&amp;gt;0.05). Additionally, area under the curve (AUC) analysis revealed trends towards a higher magnitude of fatigue (mean AUC 12.5 vs 11.1 p=0.11) and mood disturbances (mean AUC 7.2 vs 5.7 p=0.28) over time in the CG. No differences were evident for pain and nausea between groups (p&amp;gt;0.05). CONCLUSION A 10-week exercise intervention reduces the severity of fatigue in AYAs undergoing treatment. While the ToxT approach provided insight into the toxicity profile, adequately powered studies are needed to better understand these differences within a homogeneous sample

The potential impact of exercise upon symptom burden in adolescents and young adults undergoing cancer treatment

PurposeAdolescents and young adults (AYAs) experience vast symptom burden resulting from cancer treatment-related toxicities (TRTs). Evidence supports integrated exercise to mitigate several TRTs in other cohorts; however, evidence in AYAs is lacking. Conventional reporting of TRTs adopts a maximum grade approach failing to recognise the trajectory over time, of persistent, or lower grade toxicities. Alternatively, longitudinal analysis of toxicities over time (ToxT) may provide clinically meaningful summaries of this data. We evaluated the longitudinal impact of an exercise intervention on TRTs in AYAs undergoing cancer treatment.MethodsA prospective, randomised trial allocated participants to a 10-week exercise intervention (EG) or control group (CG) undergoing usual care. Detailed information on TRTs was collected throughout the intervention. All TRTs were graded per the Common Terminology Criteria for Adverse Events (CTCAE v5.0).ResultsForty-three (43) participants (63% male, mean age 21.1 years) were enrolled. When categorised to reflect the maximal worst grade experienced (Grade 0, Grade 1–2 and ≥ Grade 3), the CG reported an increased incidence of severe fatigue (≥ Grade 3) compared with the EG (p = 0.05). No other differences between groups were evident (p > 0.05). ToxT analysis of the four most common toxicities (fatigue, pain, nausea and mood disturbances) demonstrated no difference in the mean grade of each over time (p > 0.05).ConclusionA 10-week exercise intervention reduces the severity of fatigue in AYAs undergoing treatment. While the ToxT approach provided insight into the toxicity profile, adequately powered studies are needed to better understand these differences within a homogenous sample.Trial registration(ACTRN12620000663954) 10th June 2020.

Impact of baseline yellow plaque assessed by coronary angioscopy on vascular response after stent implantation

BackgroundThe relationship between baseline yellow plaque (YP) and vascular response after stent implantation has not been fully investigated. MethodsThis was a sub-analysis of the Collaboration-1 study (multicenter, retrospective, observational study). A total of 88 lesions from 80 patients with chronic coronary syndrome who underwent percutaneous coronary intervention were analyzed. Optical coherence tomography (OCT) and coronary angioscopy (CAS) were serially performed immediately and 11 months after stent implantation. YP was defined as the stented segment with yellow or intensive yellow color assessed by CAS. Neoatherosclerosis was defined as a lipid or calcified neointima assessed by OCT. OCT and CAS findings at 11 months were compared between lesions with baseline YP (YP group) and lesions without baseline YP (Non-YP group). ResultsBaseline YP was detected in 37 lesions (42 %). OCT findings at 11 months showed that the incidence of neoatherosclerosis was significantly higher in the YP group (11 % versus 0 %, p = 0.028) and mean neointimal thickness tended to be lower (104 ± 43 μm versus 120 ± 48 μm, p = 0.098). CAS findings at 11 months demonstrated that the dominant and minimum neointimal coverage grades were significantly lower (p = 0.049 and P = 0.026) and maximum yellow color grade was significantly higher (p < 0.001) in the YP group. ConclusionsBaseline YP affected the incidence of neoatherosclerosis as well as poor neointimal coverage at 11 months after stent implantation.