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Introduction: Splenic marginal zone lymphoma (SMZL) is a rare, indolent disease. There is no universally accepted standard therapy and long-term outcome data are limited. Rituximab monotherapy is increasingly used over splenectomy in the first-line setting despite a paucity of comparative studies. In the absence of randomized trials, large-scale international real-world data studies are critical to evaluate outcomes of different treatment interventions and to understand the natural history of SMZL in the rituximab-era. Methods: Adult patients with SMZL diagnosed between Jan 1 st 2000 and Dec 31 st 2018 were identified using regional/nationwide population-based registries or hospital registries in Europe, the UK, North America, and Australia. Medical records and pathology reports from eligible patients were reviewed locally by clinicians with specialty experience in hemato-oncology. SMZL cases were required to meet the diagnostic criteria by Matutes et al. Detailed data on clinico-pathological features, comorbidities, treatments (including treatment intention), treatment responses and survival outcomes were entered in a central study database. Overall survival (OS) was defined as time from diagnosis until death from any cause or censoring at last follow-up unless stated otherwise. Event-free survival (EFS) was defined as the time from diagnosis until histological transformation, initiation of new chemotherapy or death from any cause. Survival probabilities were estimated using the Kaplan-Meier estimator. Cumulative risk of transformation was estimated with death as a competing risk. Primary endpoints were 10-year OS and 5-year EFS respectivly. Results: A total of 934 patients from 25 sites were included. Median age at diagnosis was 68 years (IQR 60-76) and 54% were female. Bone marrow involvement was present in 96% (564/590) of those assessed, anemia (Hb <12g/dL for women or <13g/dL for men) in 58%, LDH >UNL in 46%, lymphocytosis (>5 x10 9/L) in 34%, and B-symptoms in 34%. Treatment data were available for 97% of patients. Median follow-up was 9.1 years (range 0-23). Watch and wait was the initial strategy in 28% and 88% of patients received at least one line of treatment during follow-up with the most common being splenectomy (45%), immuno-chemotherapy (19%) or rituximab monotherapy (8%). Fifteen percent received “other” treatments (i.e., combinations of listed therapies and/or radiation). The overall response rate to first-line treatment was 88% (95%CI: 85-90%) with 61% (95%CI: 57-64%) achieving CR. Second line (2L) therapy was needed in 34% during follow-up, 3L in 20% and 4L+ in 9%. The 5-year EFS and OS for all patients were 61% (95%CI: 57-65%) and 77% (95%CI: 74-80%) respectively. The 10-year OS and lymphoma-specific mortality (with non-SMZL deaths as competing risk) estimates were 60% (95%CI: 57-64%) and 11% (95%CI: 9-14%) respectively. The 5-year OS after 2L and 3L were 61% (95%CI: 55-68%) and 51% (95%CI: 42-61%) respectively (figure 1). The 10-year cumulative risk of histological transformation was 17% (95%CI: 13-21%), with 5-year post-transformation OS of 42% (32-54%). At the time of transformation, 60% were chemo-naive and 52% had never been treated for SMZL. The 5-year OS for chemo-naive patients with transformation was 54% (95%CI: 41-71%) versus 24% (95% CI: 13-44%) for transformations after (immuno)chemotherapy (p = 0.01). When comparing patients intended for treatment in first line with splenectomy (n=312) versus rituximab (n=70), patients treated with splenectomy more frequently presented with extra-hilar lymphadenopathy (35% vs 18%), splenomegaly (92% vs 87%) and anemia (64% vs 48%). OS was similar for the two groups (Figure 2, p = 0.53). The 5-year EFS were 63% (95%CI: 57-68%) and 64% (95%CI: 54-77%), respectively (p = 0.31). Conclusions: To date, this is the largest real-world study of SMZL with detailed treatment and outcome data. The study shows that histological transformation was not uncommon with 10-year risk of 17%. However, outcomes for the entire cohort were excellent irrespective of initial treatment and both OS and EFS were similar after first line rituximab versus splenectomy. Long-term survival remained relatively high even following multiple lines of therapy.

Multiple Myeloma (MM) progresses from monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM). Despite similar primary genetic events as MM, MGUS and SMM PCs are non- or low-proliferative. Since oncogene activation and DNA damage drive senescence growth arrest to promote immune clearance of potentially malignant cells, we hypothesized that MGUS and SMM pre-malignant PCs exhibit senescence features. To test this, we performed gene set enrichment analysis (GSEA) of a published human PC gene array dataset (GSE5900) comparing normal, MGUS, and SMM PCs for custom senescence phenotyping gene sets (Senescence Up, SenUp; Senescent Cell Anti-Apoptosis Pathways, SCAPs; Senescence Growth Arrest, SenGA; Inflammatory Senescence Associated Secretory Phenotype, iSASP; Interferon SASP, IFN-SASP) versus biological aging gene sets (SenMayo; CellAge). MGUS and SMM PCs exhibited significant enrichment (NES>1.5, q<0.05) for senescence gene sets SenUp, SenGA, and SCAPs compared to normal PCs, with no enrichment for aging gene sets. MGUS PCs were also enriched for iSASP (NES=1.4, q=0.11), whereas SMM PCs were enriched for IFN-SASP (NES=2.3, q<0.05), characteristic of late-senescence. Thus, both MGUS and SMM PCs show enrichment of senescence gene sets compared to normal PCs with differential SASP profiles. Next, we evaluated MGUS, SMM, and MM patient PCs isolated by magnetic sorting for histological senescence features. PCs were immunostained for LMNB1 and HMGB1, and fluorescent in situ hybridized for α-satellite. Cellular senescence was defined as loss of ≥50% nuclear membrane LMNB1, loss of HMGB1, and ≥2 senescence-associated distensions of satellite (SADS) per nuclei. PCs from MGUS patients (N=12) exhibited increased percentage of senescent PCs (26.9±4.1%, Mean±SEM, p<0.0001) compared to SMM (11.0±1.9%, N=19, p<0.0001) and MM (11.6±1.5%, N=11, p<0.001). A subset analysis of SMM patients for which disease stability was known (≥2 years, N=6-8) showed no differences. These results demonstrate that the percentage of senescent PCs is increased in MGUS but not SMM PCs compared to proliferative disease. To assess PC senescence in the native bone marrow microenvironment (BMME), we evaluated trephine bone biopsies from MGUS and SMM patients that progressed or not to MM ≤10 years, as well as newly diagnosed MM. Biopsies were immunostained for CD138, LMNB1, and HMGB1. Whole biopsy images were analyzed using the artificial intelligence-based software HALO. Cells were classified as senescent if they were double negative and non-senescent if they were double positive for LMNB1 and HMGB1. The percentage of non-senescent PCs increased with progression to MM and positively correlated with total PC burden (R=0.52, p<0.0001), reflective of proliferative disease. Senescent PCs correlated with total senescent BMME (R=0.87, p<0.0001), consistent with a role for senescent cells to drive paracrine senescence. We performed proximity analysis to evaluate the cellular composition within 25um of senescent and non-senescent PCs. As expected, non-senescent PCs exhibited a significantly greater percentage of proximate non-senescent BMME in all groups (p<0.0001). In contrast, senescent PCs in stable MGUS (N=16) and SMM (N=14) were equally surrounded by senescent and non-senescent BMME. In progressing MGUS (N=21) and SMM (N=20), as well as MM (N=18), senescent PCs exhibited significantly reduced senescent BMME in their proximate environment (p<0.05). This suggests that senescent PCs in progressive disease, in contrast to stable disease, fail to drive local paracrine senescence responses. These data demonstrate that PCs from stable MGUS and SMM patients exhibit senescence features, with isolated PCs from stable MGUS showing increased senescence gene expression and histologic features. While stable SMM also exhibits senescence gene expression, they lose morphological features of senescence and show a preferential IFN SASP. Within the bone compartment, senescent PCs in stable MGUS and SMM exhibit the expected proximity to senescent BMME. In contrast, progressing MGUS and SMM, as well as NDMM, show a loss of proximate senescent BMME. Given the role of senescence to drive inflammation to clear potentially tumorigenic cells, these data support that failure to drive paracrine senescence may be key to the immune escape of pre-malignant cells in MGUS and SMM.

Purpose: Improved predictive tools are desired in classic Hodgkin lymphoma (cHL) to improve prognostication and to better risk stratify patients (pts) for clinical trials. In younger pts who tolerate intensive therapies, focus has been on limiting late treatment toxicity through risk-adapted, PET-guided treatment strategy. In older pts, acute treatment toxicities are limiting factors for optimal disease control. Due to these fundamental differences, predictive tools may perform differently in younger and older pts. In particular, tools developed in younger pts may be suboptimal in older populations and vice versa. The primary objective of this study was to assess the performance of the A-HIPI (development was limited to 18-65 years of age) against the international prognostic score (IPS) for modelling overall survival (OS) and progression-free survival (PFS) in younger and older pts with cHL. Methods: This study utilized data from the population-based, nationwide Danish National Lymphoma registry. Pts with advanced-stage cHL (Ann Arbor stage III-IV or IIB with extra nodal disease) were included and categorized by age in two groups: ages ≤65 years vs. >65 years. In the primary analysis, all pts regardless of therapy were included. A sensitivity analysis restricting to pts starting on BEACOPP or ABVD was performed (Only ABVD in the >65 cohort). Concordance index (C-index) and calibration were used to assess model performance and generalizability. Calibration was visualized using calibration plots and quantified by calibration in the large (CITL) and calibration slope (CS) at 5-years post diagnosis. Results: A total of 893 advanced-stage HL pts fulfilled the inclusion criteria (634 in the ≤65 cohort and 259 in the >65 cohort). The 5-year OS and PFS in the >65-year cohort were 44% (Confidence intervals (CI); 37-51%) and 35% (CI; 30-42%), respectively. Fifty-six pts in the >65 cohort were classified as low-intermediate-risk (IPS; 1-2), 128 intermediate-risk (IPS; 3-4), and 75 high-risk (IPS; 5-7). For the ≤65 cohort, the 5-year OS and PFS was 88% (CI; 85-90%) and 76% (CI; 73-80%), respectively. Twenty-three pts were classified as low-risk (IPS; 0), 244 low-intermediate-risk, 286 intermediate-risk, and 81 high-risk. The A-HIPI had a C-index of 0.74 and 0.63 for OS and PFS, respectively in the ≤65 years cohort vs. 0.65 and 0.64 for OS and PFS, respectively, in the >65 cohort. The IPS had a C-index in the ≤65 cohort of 0.66 and 0.60 for OS and PFS, respectively, vs. 0.58 and 0.59 for OS and PFS, respectively, in the >65 cohort (i.e., the IPS performed better in the ≤65 cohort in terms of OS and PFS but was inferior to the A-HIPI). When restricting to pts treated with ABVD or BEACOPP, the A-HIPI C-index in the >65 cohort (116 pts) were reduced to 0.55 for OS and 0.54 for PFS. For the ≤65 cohort (595 pts), the A-HIPI C-index was stable at 0.75 and 0.62 for OS and PFS, respectively. In terms of A-HIPI calibration in the >65 cohort, CITL and CS were -0.78 and 0.39 for OS vs. -0.98 and 0.80 for PFS. In the ≤65 cohort, CITL and CS were -0.06 and 0.99 for OS vs. 0.21 and 1.18 for PFS. Visual inspection of the calibration plot (Figure 1) for the >65 cohort showed that the A-HIPI underestimated the observed proportion for both OS and PFS (i.e., the observed events were higher than the predicted). Calibration plot for the ≤65 cohort (Figure 2) indicated that the A-HIPI accurately modelled the observed proportion for both OS and PFS (i.e., the predicted probability was consistent with the observed proportion). Conclusion: The newly developed A-HIPI was validated in a large population-based cohort of Danish pts with advanced-stage cHL. Performance of the A-HIPI was high in the ≤65 cohort and superior to the IPS for OS prediction. Calibration of A-HIPI was excellent in pts ages ≤65 years. However, A-HIPI performed significantly worse among pts >65 years and attained poor performance in pts receiving ABVD or BEACOPP, which is not surprising since patients older than 65 were not included in the development. This study emphasizes the importance of further efforts to develop or update models that apply specifically in older individuals. The inclusion of additional variables reflecting comorbidities and pts fitness into a prognostic model may be necessary to effectively deliver accurate prognoses and risk assessments for the older pt.

Background: Event-free survival at 24 months (EFS24) after frontline immunochemotherapy (IC) is an important endpoint in diffuse large B-cell lymphoma and follicular lymphoma, and patients who achieve EFS24 have similar survival compared to age- and sex-matched general population. The role of EFS24 in predicting subsequent survival has not been established in mantle cell lymphoma (MCL), possibly due to perceived poor survival historically. In the last decade, the outcomes of MCL are improving in the evolving treatment landscape. In this international multicenter study, we investigated conditional survival and cause of death in patients with MCL who achieved EFS24 after frontline IC in the older and more recent eras. Methods: Outcomes after frontline IC were evaluated in 5 independent cohorts that included over 3000 patients in total: Mayo/Iowa MER prospective cohort, BC Cancer retrospective population-based cohort, US 12-center retrospective cohort, Swedish Lymphoma Registry, and Danish National Lymphoma Registry. For each cohort, 2 treatment eras were defined based on cohort-specific shifts in treatment patterns (Table 1). Overall survival (OS) after diagnosis and after achieving EFS24 were compared to the background age- and sex-matched general population using a standardized mortality ratio (SMR). Cumulative incidences of cause-specific deaths were analyzed using a competing risk model. Results: In the MER cohort, patients treated in Era M1 (2002-2009; n=147) and Era M2 (2010-2015; n=153) both had inferior OS compared to the general US population. A lower SMR in Era M2 vs M1 (2.25 vs 3.46) suggests a narrower gap in OS compared to the general US population. Lymphoma was the leading cause of death in both eras. In Era M1, patients who achieved EFS24 still had inferior OS compared to the general US population (SMR=2.40, 95% CI 1.76-3.19), and lymphoma remained the leading cause of death. For patients in Era M2 who achieved EFS24, the difference in OS compared to the general US population was not statistically significant with current follow-up (SMR=1.43, 95% CI 0.93-2.09), and lymphoma was no longer the leading cause of death (Table 2). In the BC cohort, patients treated in Era B2 (6/2013-2019; n=188) vs Era B1 (2003-5/2013; n=250) had a narrower gap in OS compared to the general British Columbia population (SMR 4.53 vs 6.69). Lymphoma was the leading cause of death in both eras. For patients achieving EFS24, the gap in OS was narrower in Era B2 vs B1 (SMR 3.56 vs 4.99). After achieving EFS24, lymphoma was the single leading cause of death for patients in Era B1 but not in Era B2 (Table 2). In the US 12-center cohort, patients treated in Era U1 (2002-2011; n=312) and Era U2 (2012-2016; n=417) both had inferior OS compared to the general US population (SMR 2.68 and 2.92, respectively). In patients who achieved EFS24, with current follow up, the difference in OS compared to the general US population was statistically significant in Era U1 (SMR=2.01, 95% CI 1.50-2.64) but not in Era U2 (SMR=1.44, 95% CI 0.82-2.34). Lymphoma was not the leading cause of death after achieving EFS24 (Table 2). In the Swedish cohort, the gap in OS compared to the general Swedish population was narrower in Era S2 (2013-2018; n=439) vs S1 (2006-2012; n=442), both after frontline IC (SMR 4.8 vs 5.4) and after achieving EFS24 (SMR 2.6 vs 3.4). After achieving EFS24, lymphoma was the leading cause of death for patients in Era S1 but not in Era S2 (Table 2). In the Danish cohort, patients treated in Era D2 (2014-2020; n=370) vs Era D1 (2004-2013; n=461) had a slightly narrower gap in OS compared to the general Danish population (SMR 1.90 vs 2.10). For patients who achieved EFS24, those in Era D1 still had inferior OS compared to the general Danish population (SMR=1.44, 95% CI 1.22-1.68), but the OS difference compared to the general Danish population in Era D2 was not statistically significant (SMR=1.27, 95% CI 0.92-1.72) with current follow-up (Table 2). Cause of death data were not available in this cohort. Conclusion: Survival in patients with MCL who achieved EFS24 after frontline IC improved in the more recent treatment era and moved closer to the background expected survival. After achieving EFS24, lymphoma-related mortality was no longer the leading cause of death in the more recent era. EFS24 following frontline treatment may become a critical endpoint for predicting subsequent outcomes in patients with MCL in the modern era.

Background Inconsistent nomenclature and anatomical descriptions of regional anesthetic techniques hinder scientific communication and engender confusion; this in turn has implications for research, education and clinical implementation of regional anesthesia. Having produced standardized nomenclature for abdominal wall, paraspinal and chest wall regional anesthetic techniques, we aimed to similarly do so for upper and lower limb peripheral nerve blocks. Methods We performed a three-round Delphi international consensus study to generate standardized names and anatomical descriptions of upper and lower limb regional anesthetic techniques. A long list of names and anatomical description of blocks of upper and lower extremities was produced by the members of the steering committee. Subsequently, two rounds of anonymized voting and commenting were followed by a third virtual round table to secure consensus for items that remained outstanding after the first and second rounds. As with previous methodology, strong consensus was defined as ≥75% agreement and weak consensus as 50%–74% agreement. Results A total of 94, 91 and 65 collaborators participated in the first, second and third rounds, respectively. We achieved strong consensus for 38 names and 33 anatomical descriptions, and weak consensus for five anatomical descriptions. We agreed on a template for naming peripheral nerve blocks based on the name of the nerve and the anatomical location of the blockade and identified several areas for future research. Conclusions We achieved consensus on nomenclature and anatomical descriptions of regional anesthetic techniques for upper and lower limb nerve blocks, and recommend using this framework in clinical and academic practice. This should improve research, teaching and learning of regional anesthesia to eventually improve patient care.

In this paper we report on the inaugural meetings of the Musical Care International Network held online in 2022. The term “musical care” is defined by Spiro and Sanfilippo (2022) as “the role of music—music listening as well as music-making—in supporting any aspect of people's developmental or health needs” (pp. 2–3). Musical care takes varied forms in different cultural contexts and involves people from different disciplines and areas of expertise. Therefore, the Musical Care International Network takes an interdisciplinary and international approach and aims to better reflect the disciplinary, geographic, and cultural diversity relevant to musical care. Forty-two delegates participated in 5 inaugural meetings over 2 days, representing 24 countries and numerous disciplines and areas of practice. Based on the meetings, the aims of this paper are to (1) better understand the diverse practices, applications, contexts, and impacts of musical care around the globe and (2) introduce the Musical Care International Network. Transcriptions of the recordings, alongside notes taken by the hosts, were used to summarise the conversations. The discussions developed ideas in three areas: (a) musical care as context-dependent and social, (b) musical care's position within the broader research and practice context, and (c) debates about the impact of and evidence for musical care. We can conclude that musical care refers to context-dependent and social phenomena. The term musical care was seen as useful in talking across boundaries while not minimizing individual disciplinary and professional expertise. The use of the term was seen to help balance the importance and place of multiple disciplines, with a role to play in the development of a collective identity. This collective identity was seen as important in advocacy and in helping to shape policy. The paper closes with proposed future directions for the network and its emerging mission statement.

Background: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS). Objectives: We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels. Methods: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) ( n = 3), progressive MS ( n = 3), neuromyelitis optica spectrum disorder (NMOSD) ( n = 2), and controls ( n = 9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients: 49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and 19 isolated optic neuritis (ION). Results: MFAP4 localized to meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 14.3, MOGAD 9.7, and ION 14.6 relative to HC 17.9. ( p = 0.013, p = 0.000, and p = 0.019, respectively). Patients with acute ON ( n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = −0.41, p = 0.017). Conclusion: MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity.

PURPOSE CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. PATIENTS AND METHODS Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti–CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). RESULTS Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, –1.5 to 4.4; all-pts) and 1.4% (95% CI, –1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. CONCLUSION In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Abstract Disclosure: B. Clarke: Advisory Board Member; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. Consulting Fee; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. Grant Recipient; Self; Ascendis Pharma, Takeda. Research Investigator; Self; Ascendis Pharma, Takeda. Other; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. A.A. Khan: Advisory Board Member; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, Takeda, Ultragenyx. Consulting Fee; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Amolyt, Ascendis Pharma, Ultragenyx. Grant Recipient; Self; Amolyt. Research Investigator; Self; Radius Health, Inc, Takeda, Ultragenyx, Amolyt, Ascendis Pharma, Chugai. Speaker; Self; Amgen Inc. Other; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, Takeda, Ultragenyx. M.R. Rubin: Research Investigator; Self; Chugai Pharma. P.E. Schwarz: Stock Owner; Self; Novo Nordisk, Genmab. T.J. Vokes: Consulting Fee; Self; Takeda, Ascendis Pharma. Research Investigator; Self; Ascendis Pharma, Radius Health, Inc. D.M. Shoback: Research Investigator; Self; Bone Health Tech. C. Gagnon: Advisory Board Member; Self; Novo Nordisk. Grant Recipient; Self; Shire, Takeda, Ascendis Pharma. Research Investigator; Self; Novo Nordisk. Other; Self; Amgen Inc. A. Palermo: Consulting Fee; Self; Theramex, Bruno, Farmaceutici, Amgen Inc. Grant Recipient; Self; Amgen Inc. Research Investigator; Self; Amgen Inc, Shire, Ascendis Pharma. Speaker; Self; UCB, Amgen Inc. L.G. Abbott: Advisory Board Member; Self; Ascendis. Research Investigator; Self; Takeda, Shire, Ascendis Pharma. Speaker; Self; Abbott Laboratories, Clarus. Other; Self; Ascendis. L.C. Hofbauer: Advisory Board Member; Self; Amgen Inc, UCB. Other; Self; Amgen Inc, UCB. L. Kohlmeier: Advisory Board Member; Self; Alexion Pharmaceuticals, Inc., Ascendis Pharma. Research Investigator; Self; Ascendis Pharma. Speaker; Self; Amgen Inc, Radius Health, Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma. Other; Self; Amgen Inc, Radius Health, Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, MediMaps. F. Cetani: None. S. Phil: Employee; Self; Ascendis Pharma. X. An: Employee; Self; Ascendis Pharma. A.R. Smith: Employee; Self; Ascendis Pharma. B. Lai: Employee; Self; Ascendis Pharma. J. Le: Employee; Self; Ascendis Pharma. J. Ukena: Employee; Self; Ascendis Pharma. C. Sibley: Employee; Self; Ascendis Pharma. A. Shu: Employee; Self; Ascendis Pharma. L. Rejnmark: Advisory Board Member; Self; Takeda, Amolyt. Research Investigator; Self; Takeda, Kyowa Kirin International, Ascendis Pharma, Calcilytix Therapeutics. Other; Self; Calcilytix Therapeutics. Objective: Evaluate the long-term efficacy and safety of TransCon PTH as a potential hormone replacement therapy for hypoparathyroidism. Methods: PaTHway is a phase 3 trial of TransCon PTH with a placebo (PBO)-controlled 26-week blinded period and a 156-week open-label extension (OLE) period. Results through Week 52 (26 weeks blinded + 26 weeks OLE) are reported. Three-component efficacy endpoint: normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D). Other endpoints: Hypoparathyroidism Patient Experience Scale (HPES); 36-Item Short Form Survey (SF-36); bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA); bone turnover markers (BTM) procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTx). Safety was assessed by 24-hour urine calcium and reported treatment-emergent adverse events (TEAEs). Results: Of the 82 participants given study drug, 79 completed blinded treatment and entered the OLE, and 78 (59 TransCon PTH/TransCon PTH, 19 PBO/TransCon PTH) completed Week 52. Overall at Week 52, 81% (63/78) met the efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. Mean albumin-adjusted serum calcium was within the normal range at all time points in the OLE (8.9 mg/dL at Week 52). Mean Week 52 HPES scores showed sustained improvement from baseline in disease-related symptoms and the impact of hypoparathyroidism on physical functioning and daily life. Mean Week 52 SF-36 physical functioning scores also remained above baseline. In the TransCon PTH/TransCon PTH group, mean BMD corrected Z-scores trended toward norms from baseline to Weeks 26 and 52:1.5, 0.7, 0.7 at the lumbar spine (L1-L4); 0.8, 0.3, 0.3 at femoral neck; 0.9, 0.5, 0.4 at total hip; and 0.3, 0.3, 0.3 at distal 1/3 radius; P1NP peaked at Week 26 and CTx at Week 12. Smaller incremental changes were seen in BMD and BTM from Weeks 26 to 52 than baseline to Week 26. In the PBO/TransCon PTH group, changes in BMD and BTM from Week 26 to 52 resembled those in the TransCon PTH/TransCon PTH group from baseline to Week 26. Mean 24-hour urine calcium excretion decreased from 376 mg/day at baseline to 195 mg/day at Week 52. Most TEAEs were mild or moderate and none led to discontinuation of the study drug or trial. Conclusions: At Week 52 of the PaTHway trial, TransCon PTH showed a similar sustained efficacy, safety, and tolerability profile to that of Week 26, demonstrating its potential as a hormone replacement therapy for adults with hypoparathyroidism. Indices of skeletal dynamics trended toward age- and sex-matched norms in the TransCon/TransCon PTH group. TransCon PTH treatment in the PBO/TransCon PTH group showed rapid improvement in all outcomes in the first 26 weeks of the OLE consistent with the pattern in the TransCon PTH group during the blinded period. Presentation: Saturday, June 17, 2023