Citations

OBJECTIVE Achieving submillimetric accuracy in stereotactic neurosurgery remains critical for safely targeting deep brain structures. Current workflows rely on intraoperative CT to register stereotactic frames to preoperative imaging, but this introduces additional radiation exposure, cost, and workflow complexity. Three-dimensional surface scanning (3DSS) potentially offers a fast radiation-free alternative capable of capturing detailed craniofacial anatomy and frame geometry. Therefore, the aim of this cadaveric study was to evaluate the feasibility, accuracy, and navigational compatibility of integrating 3DSS into stereotactic workflows as a potential replacement for intraoperative CT. METHODS A human cadaveric head was imaged with both thin-slice CT and structured-light 3DSS after mounting stereotactic frame components. CT, 3DSS, and computer-aided design (CAD) models were registered using a multistep point cloud alignment pipeline involving the fast point feature histogram, the random sample consensus method, and the iterative closest point algorithm. Accuracy was assessed using surface deviation error, root mean square error (RMSE), and fiducial registration error within a commercial neuronavigation platform. RESULTS Fusion of the 3D facial scan with CT provided a mean surface deviation error of approximately 0.4 mm. Registration of the 3DSS-derived N-bar localizer to its CAD reference model produced a frame alignment RMSE of 1.3 mm. Within the navigation system, the 3DSS-based workflow achieved a mean fiducial registration error of 0.14 mm (range 0.02–0.20 mm), outperforming the conventional CT-based method (mean error 0.20 mm, range 0.09–0.40 mm). CONCLUSIONS The 3DSS-based method enabled precise submillimetric stereotactic registration without the need for intraoperative CT, reducing radiation exposure and operative complexity. This workflow is fully compatible with existing navigation systems and could serve as a practical radiation-free alternative in stereotactic neurosurgery. Future work will focus on automating frame detection, incorporating artificial intelligence–driven fusion methods, and validating this approach in live surgical settings.

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is a deadly disease with a complex tumor microenvironment (TME). How chemotherapy alters the TME, and whether these changes drive chemoresistance, is poorly understood. We examined matched pre- and post-treatment tissue specimens and found near-universal enrichment of axonal guidance genes in cancer-associated fibroblasts (CAFs) after treatment. These CAFs were enriched near sites of perineural invasion, coinciding with regions of increased tumor cell proliferation, and were enriched in tumor areas distant from nerves after chemotherapy. Metastatic recurrence lesions had the highest prevalence of these CAFs versus primary tumors and untreated metastasis. These CAFs showed elevated non-canonical Wnt mediators and axonal guidance genes, which complemented matching cognate binding partners in tumor epithelial cells, suggesting a role in tumor-stroma crosstalk. Our findings implicate fibroblast-derived axonal-guidance genes in promoting PDAC invasion and point to a promising target for this disease. Statement of Significance Therapeutic resistance remains a major challenge in pancreatic cancer. Our findings shed light on the changes in the complex tumor microenvironment in response to chemotherapy and identify fibroblasts high in axonal-guidance genes that may drive tumor progression and chemoresistance, thus uncovering a potential avenue for targeting pancreatic cancer.

Abstract Valvular heart disease represents a significant global health burden, with an estimated prevalence of 2.5% in high-income countries and projected increases due to population ageing. Randomized controlled trials in valvular heart disease have undergone substantial evolution, shifting from mortality-focused endpoints toward comprehensive assessments integrating imaging parameters and patient-centered outcomes. Cardiovascular imaging modalities, including echocardiography, cardiac computed tomography, and cardiac magnetic resonance, have become pivotal in trial design, patient selection, and endpoint definition. Recent landmark trials in aortic stenosis, including EARLY-TAVR and EVOLVED, have challenged traditional symptom-based intervention thresholds by incorporating imaging biomarkers of subclinical myocardial dysfunction and cardiac damage staging. In aortic regurgitation, the paucity of randomized controlled trials evidence contrasts with emerging transcatheter technologies, highlighting critical knowledge gaps. Mitral regurgitation trials have demonstrated the importance of patient phenotyping, with divergent outcomes between COAPT and MITRA-FR emphasizing the role of imaging in optimal patient selection. The recent TRILUMINATE and TRISCEND trials have transformed tricuspid regurgitation management through transcatheter interventions, prioritizing quality-of-life improvements alongside traditional clinical endpoints. Future directions include standardization of imaging protocols across modalities, development of artificial intelligence-enhanced analysis, and integration of multiparametric biomarkers for personalized risk stratification. The paradigm shift toward imaging-guided, patient-centered trial design represents a fundamental reimagining of therapeutic success in valvular heart disease, moving beyond procedural outcomes toward comprehensive assessment of clinical benefit and improved patient care.

Abstract Introduction Benign prostatic hyperplasia (BPH) is an age-related condition affecting many men. Emerging evidence highlights a strong relationship between BPH, lower urinary tract symptoms (LUTS) and sexual dysfunction, including erectile dysfunction (ED), reduced sexual desire, hormonal imbalances, and ejaculatory dysfunction, warranting a comprehensive approach to diagnosis and management. Objectives This report aims to provide recommendations for identifying and managing sexual dysfunction associated with BPH and LUTS. Methods Based on guidelines from the International Consultation on Sexual Medicine, a literature review was conducted. Recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation system. Results The association between BPH, LUTS, and sexual dysfunction is significant, with ED, ejaculatory dysfunction, and hypogonadism being common complications. Lifestyle modifications, medical therapies, minimally invasive surgical therapies, prostate artery embolization, and surgeries (eg, Transurethral resection of the prostate, HoLEP, Aquablation) are among the recommended treatments. Each intervention carries varying risks of sexual dysfunction, requiring specific tailored treatment plans. Conclusions BPH/LUTS significantly affect sexual health, emphasizing the need for a multidisciplinary approach to management. Future research should refine diagnostic criteria and develop treatments that minimize sexual side effects. Enhanced education for patients and their partners could improve quality of life and coping mechanisms.

Abstract Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare blood disorder associated with human T-cell leukemia virus type 1 (HTLV-1) infection. It is generally categorized into four subtypes: smoldering, chronic, lymphoma, and acute. Given the heterogeneity of these subtypes, there is a significant difference in outcomes. Robust and contemporary epidemiological data are lacking for this rare disorder. We present a retrospective cohort study of patients with ATLL, utilizing the National Cancer Database (NCDB) to better characterize the epidemiology and survival trends in the United States. Methods: This is a retrospective cohort study using the NCDB to identify ATLL cases diagnosed from 2004-2020. Descriptive statistics summarized baseline characteristics, while chi-square tests assessed group differences. Overall survival (OS) was estimated using Kaplan-Meier analysis and compared using log-rank tests. Multivariable Cox proportional hazards models identified independent prognostic factors (p < 0.05 considered significant). Results: A total of 635 patients were identified with ATLL, including 344 (54%) males and 291 (46%) females, with a median age at diagnosis of 59 years (range: 19-90). Most patients came from the Middle Atlantic (NY, NJ, PA) region (33%), followed by the South Atlantic (DC, DE, FL, GA, MD, NC, SC, VA, WV) region (20%) and the East North Central (IL, IN, MI, OH, WI) region (8%). Of the 635 patients, 335 (52%) were Black, 247 (39%) White, and 26 (4%) Asian. Sixty-five (10%) patients were of Hispanic origin. Over half of patients with ATLL (54%) had a median income below $46,000. International Prognostic Index (IPI) score was only available for 16 patients: three (19%) patients were in the high-risk group, 7 (43%) in the high-intermediate group, and 6 (37.5%) in the low-intermediate group. Treatment groups included 357 (56%) patients treated with chemotherapy and 29 (4.5%) who received radiation therapy. Thirty-three (5%) patients underwent hematopoietic stem cell transplant (HSCT), including 27 autologous and 16 allogeneic transplants. The median survival time in the cohort was 9 months (95% CI 7.3-10.7). One-year OS rate in the cohort was 43%, while 2-year and 5-year OS rates were 31% and 23.5%, respectively. Patients over the age of 65 had a significantly shorter median OS than those under 65 (4 vs. 11 months, p=0.001) and were significantly less likely to undergo HSCT (p< 0.001). Black patients had significantly shorter median OS compared to White patients (7.8 months vs 13.3 months, p=0.014), despite similar treatment rates with chemotherapy and HSCT. Median OS appeared to improve over time, from 8 months in patients diagnosed between 2004-2009 to 10 months for those diagnosed between 2016-2020, although this was not statistically significant (p=0.145). Treatment with allogeneic HSCT was associated with significantly prolonged median survival, compared to those who did not receive transplant (50 months vs. 7 months, p<0.05). Additionally, receiving chemotherapy and/or radiation compared to not receiving treatment was also associated with significantly prolonged median survival (p<0.05). Patients treated in the Middle Atlantic region had a median survival of 8.8 months, compared to 23.2 months in the West South Central (AR, LA, OK, TX) region (p< 0.001). Increased education and income levels were not significantly associated with improved survival. There were no significant differences in survival between males and females. Conclusions: We provide contemporary estimates on the epidemiology of ATLL. Factors associated with improved prognosis included undergoing HSCT, radiation, or chemotherapy. We report that increased age and Black race are negative prognostic factors. Regional differences in incidence and survival persist in the US. Our study findings underscore the need for increasing access to treatment, including HSCT for those who are good candidates. Additionally, there remains work to be done to address racial disparities in the care of patients with ATLL.

Abstract Introduction The International Prognostic Index (IPI) is widely used to stratify risk in large B-cell lymphoma (LBCL) across all ages, with age-adjusted (aa)IPI applied to younger patients. While there have been efforts to develop prognostic indices (PIs) tailored to older patients, few are adopted in clinical practice due to their complexity and reliance on functional assessments, which are not routinely collected in real-world registry datasets. Recently proposed SENIOR-IPI (Dubois, ASH 2024) was developed for older patients with LBCL receiving anthracycline (A)-based therapy. We assessed the performance of standard and novel PIs in patients aged 80+ years and externally validated the SENIOR-IPI. Methods We harmonized and pooled data of patients aged 80+ years with newly diagnosed LBCL from a national registry and two prospective cohorts: NiHiL (Czech Republic, enrolled 2010–2023), LEO (USA; n=222, 2015–2020), and MER (USA; n=77, 2010–2015), forming a cohort of 819 individuals. We included 536 individuals with complete data on IPI components and albumin, including 485 treated with chemotherapy and 397 with A-based regimens (primary cohort). Following PIs were evaluated: IPI, NCCN-IPI, (aa)IPI, and SENIOR-IPI (age per year, aaIPI components, LDH >3x ULN as extra point, and albumin, all weighted six-fold; extranodal involvement excluded due to lack of prognostic significance). Multivariable hazard ratios (HR) were estimated using Cox proportional hazards models; discriminative ability was assessed using C-index and calibration plots. The primary endpoint was overall survival (OS); event-free survival results were consistent (230/357 events were deaths) and are not reported here. Results Among the 397 A-treated patients (median age 82 years, range 80–99), ECOG performance status (PS) 2–4 was observed in 35% of patients, clinical stage III–IV in 67%, elevated LDH in 65% (8% with >3x ULN), >1 extranodal (EN) site in 32%, and albumin levels < 3.5 g/dL in 27%. In multivariable modeling, only age per year (HR=1.07, P<0.01), and clinical stage (HR=1.36, P=0.048) were independent predictors of OS, whereas ECOG PS (HR=1.27, P=0.12), trichotomized LDH by ULN (HR=1.23, P=0.08) and albumin (HR=1.17, P=0.35) were not significant. SENIOR-IPI had the highest discrimination (C-index 0.631) in A-treated patients, outperforming IPI (0.617), NCCN-IPI (0.591), and aaIPI (0.620), with consistent results across cohorts: NiHiL (0.633), LEO (0.619), and MER (0.621). SENIOR-IPI stratified patients into low- (L-Risk, 0–9 points, 28%), low-intermediate (L-Int, 10–19 points, 42%), high-intermediate (H-Int, 20–29 points, 23%), and high-risk (H-Risk, 30–40 points, 7%) categories, with OS medians of 6.3, 3.8, 2.4, and 1.4 years, respectively (P<0.01), and significant separation between L-Int and H-Int (HR=1.47, P=0.02). By comparison, IPI categorized patients as L-Risk (12%), L-Int (24%), H-Int (27%), and H-Risk (37%), with median OS of 8.7, 4.6, 4.8, and 1.9 years, resp. (P<0.01). aaIPI yielded following distributions: 13%, 29%, 37%, and 21%; and median OS: 8.7, 5.3, 3.4, and 1.5 years; P<0.01. NCCN-IPI stratified patients into three groups: L-Int (13%), H-Int (49%), and H-Risk (39%), with respective OS medians of 8.7, 4.1, and 2.5 years (P<0.01). All PIs showed modest overestimation of mortality (calibration slopes: SENIOR-IPI 1.36; IPI 1.24; aaIPI 1.30; NCCN-IPI 1.26; intercept: -0.97, -0.87, -0.92, -0.87, resp.). In the entire cohort (n=536), SENIOR-IPI showed highest C-index (0.651 vs IPI 0.622, aaIPI 0.631, NCCN-IPI 0.606), and stratified patients into L-Risk (26%, 2-year OS: 6.4 years), L-Int (40%, 3.2 years), H-Int (24%, 1.5 years), and H-Risk (10%, 0.6 years). Calibration slope was 1.18 (intercept -0.33). Among patients not receiving chemotherapy, SENIOR-IPI also performed best (C-index 0.759 vs IPI 0.738, aaIPI 0.757, NCCN-IPI 0.728). Conclusion SENIOR-IPI enables effective risk stratification of patients aged 80+ years with LBCL into four prognostically distinct groups, outperforming traditional indices (IPI, NCCN-IPI, aaIPI) in patients receiving A-based therapy, as well as in the entire cohort and in patients not receiving chemotherapy. While its discrimination is superior, modest miscalibration suggests that future recalibration may improve precision. These findings support SENIOR-IPI as a clinically relevant prognostic tool for the elderly LBCL patient population. Funding: NU21-03-00411, P50 CA97274, U01 CA195568.

Abstract Background: Despite advances in LBCL treatment, 35–45% of patients relapse or have refractory disease highlighting an unmet clinical need. Clinical trials are essential to advancing lymphoma treatment, yet participation remains low – especially among certain populations. We hypothesized that participation in clinical trials as part of first-line therapy is associated with improved survival outcomes and conducted this retrospective study in a multi-center cohort. Methods: The LEO cohort prospectively enrolled newly diagnosed patients with LBCL between 2015 and 2020 at 8 academic medical centers in the United States. LBCL histology's included T-cell/histiocyte rich LBCL, Primary mediastinal LBCL, high grade B-cell lymphoma and DLBCL NOS. Pathology was reviewed and classified by a LEO pathologist. Clinical and treatment data (including trial participation) were abstracted from medical records. The primary outcome endpoint is overall survival (OS) defines as the time from diagnosis to death from any cause or last follow up. Univariable and multivariable Cox proportional hazards models were used to evaluate the association between OS and therapeutic trial participation. Univariable models assessed each baseline covariate, with and without interaction with trial participation. The multivariable model adjusted for age, sex, race/ethnicity, diagnosis to treatment interval [DTI], and IPI, including an interaction between IPI and trial participation which was justified per minimal Akaike information criteria. All models clustered on institution. Results: Among the 2636 patients with LBCL, the median age was 63 (range 18 – 99), 57% were male, 75% non-Hispanic white (NHW), 12% Hispanic (H) and 7.3% African American (AA), 62% had Stage III/IV disease, and 214 (8.0%) participated in a clinical trial as part of first line therapy. Overall, between ages 18 – 80, clinical trial participation increased with age (55 % in ages 18-30 vs 11% in ages 71-80) but dropped significantly for patients > 80 (3.4%). There were no significant differences in the rate of trial participation by sex (male 8.6 % vs female 7.5%; p=0.35), race/ethnicity (NHW 8.9% vs H 5.5% vs AA 6.3%; p=0.061), body mass index (underweight [<18.5] 4.5% vs normal [18.5-24.9] 7.7% vs overweight [25-29] 8.3% vs obese (>30) 8.5; p = 0.75) or Rural-Urban Continuum Codes (Metro[1-3] 8.5% vs non-metro Urban [4-6] 7.6% vs non-metro Rural [7-9] 5.4 %; p=0.49). Patients with advanced disease more commonly participated in a trial. Most patients received systemic treatment (98%), with 94% of patients receiving an anti-CD20 antibody and 91% of patients receiving anthracycline-based therapy. Importantly, there was no difference in anthracycline use in trial participants vs nonparticipants (92 vs 91%; p=0.53). Patients with high IPI scores [3-5] were more likely to participate on trials compared to those with low scores [1-2] (8% vs 5.9% respectively, p= 0.012). Patients who participated in clinical trials had significantly longer median DTI (26 days vs 21 days; p <0.0001) and had a significantly lower number of comorbidities compared to non-participants (mean 0.55 vs. 0.69; p=0.032). Among patients with low IPI (0–2), 5-year OS was 89% trial participants (CTP) compared to 82% for non-participants (CTNP). Among patients with high IPI (3–5), 5-year OS was 78% for CTP vs 60%for CTNP. The multivariable Cox model demonstrated a significant interaction between trial participation and IPI, with trial participation with low IPI having a non-significant hazard ratio (HR) of 0.87 with 95% CI (0.57,1.32), while trial participation with high IPI had a significant HR of 0.57 (0.44, 0.74). Additionally, increased age, male sex, black race, and lower DTI were associated with increased hazard. Conclusion: Patients at high risk of poor outcomes such as those with advanced age (80+), higher comorbidities burden, and those needing more urgent therapy (shorter DTI) were less likely to participate in clinical trials. In this multi-institutional cohort of patients with LBCL treated at academic centers, frontline trial participants had outcomes that were equivalent or better than those receiving standard care. These finding underscore the value of clinical trial participation even in the frontline setting and support trial designs that expand inclusion- allowing participation of patients who are older, medically complex or in need urgent therapy.

Abstract Introduction: THRLBCL is a rare disease accounting for less than 10% of all diffuse large B-cell lymphoma (DLBCL) subtypes. THRLBCL was associated with poor outcomes in the pre-rituximab era, with limited contemporaneous data. Optimal frontline treatment remains unclear with some studies advocating for intensive regimens. The goal of this international study is to analyze the survival and treatment-related outcomes in patients with newly diagnosed THRLBCL treated with rituximab-containing chemotherapy and to compare with a DLBCL, not otherwise specified (NOS) cohort. Methods: THRLBCL and DLBCL patients prospectively enrolled in the Lymphoma Epidemiology of Outcomes (LEO) (NCT02736357) (7/2015 to 5/2020), Molecular Epidemiology Resource (1/2010 to 6/2015), and Czech Lymphoma Study Group project (NiHiL) (NCT03199066) (2/2010 to 11/2023) were analyzed. Diagnosis was made in dedicated hematopathology centers in both registries. We excluded patients with prior nodular lymphocyte-predominant Hodgkin lymphoma, central nervous system involvement, and not treated with rituximab-containing therapy. Event-free survival (EFS) and overall survival (OS) were estimated by Kaplan-Meier.Univariate associations were derived via Cox model and multivariate models were constructed by forward selection of significant variables with P≤0.05. Propensity score matching (1:5, caliper 0.2) between THRLBCL and DLBCL NOS patients was performed using IPI score components and treatment as covariates. Results: We identified 158 patients (LEO: 67 and NiHiL: 91) with THRLBCL. Among them, 140 patients received rituximab-containing regimens and were included in this analysis. Median age was 58 years (range, 19-89) with 57% aged ≤60 years. Most patients were male (n= 88; 63%) and had ECOG performance status (PS) of 0-1 (n= 111; 79%), stage III-IV (n= 111; 79%), elevated LDH (n= 92; 66%), and B symptoms (n= 84; 60%). Fifty (36%) patients had ≥2 extranodal (EN) sites, mostly liver (n= 39; 28%) and lung (n= 16; 11%), bone marrow (BM) involvement was observed in 26% (n= 37). Bulky disease (≥7.5cm) was present in 50 (36%) and IPI score ≥3 in 68 (48%) patients. The median diagnosis-to-treatment interval was 23 days (IQ range, 13-38.5). Frequent regimens were R-CHOP (n= 106; 75.7%), followed by intensive regimens such as R-MegaCHOP/ESHAP, R-HyperCVAD/MA, and R-CODOX-M/IVAC (n= 15; 10.7%), and R-CHOEP/EPOCH-R (n= 10; 7.14%). With a median follow-up of 3.92 years, the 4-year EFS & OS were 71% and 80%, respectively. Lymphoma was the main cause of death (n= 15; 11%) among 30 events. No difference in 4-year EFS (70% vs. 76%; P= 0.55) & OS (80% vs 82%; P= 0.96) were observed between R-CHOP and intensive regimens. Factors associated with shorter EFS and OS in univariate analysis for THRLBCL were ECOG PS 2-4: (HR= 3.3; P<.001 & HR= 5.97, P<.001, respectively); ≥2 EN sites (HR= 1.85, P= 0.043 & HR= 2.54, P= 0.014, respectively); B symptoms (HR= 2.35, P= 0.014 & HR= 2.84, P= 0.023) and IPI score (HR= 1.5, P= 0.002 & HR= 2.16, P<.001). Stage III-IV and BM involvement were associated with shorter OS only (HR= 7.36, P= 0.05 & HR= 2.18, P= 0.036, respectively). Among them, only ECOG PS 2-4 (OS: HR= 3.6, P= 0.003) and B symptoms (EFS: HR= 2.3, P= 0.046) were independent predictors of survival in multivariate analysis. Finally, we compared baseline characteristics and survival between THRLBCL (n= 140) and DLBCL NOS (n= 6099; LEO/MER: 2069 & NiHiL: 4030) treated with rituximab-containing regimens. Patients with THRLBCL were younger (≤60 years: 57% vs. 38%; P<.001), more frequently had ECOG PS 0-1 (79% vs 76%; P= 0.012), stage III-IV (79% vs 63%; P<.001), B symptoms (60% vs 38%; P<.001), and liver involvement (28% vs 7%; P<.001), compared to DLBCL NOS. Subtype was not associated with survival (OS HR= 0.79, P= 0.262 & EFS HR= 0.93, P= 0.662) when adjusted for IPI score. With a median follow-up of 4.89 years in the DLBCL NOS cohort, we observed similar 4-year EFS (71% vs 67%; P= 0.197) & OS between histologies (80% vs 77%; P= 0.125). These results were confirmed in propensity matching for EFS (HR= 0.98, P= 0.897) and OS (HR= 1.07, P= 0.732). Conclusions: In this large international analysis of patients with newly diagnosed THRLBCL contemporaneously treated, we observed similar survival rates compared to DLBCL NOS treated with R-CHOP and intensive regimens. ECOG PS and the presence of B symptoms were independent factors associated with survival.

Abstract Introduction: The real-world outcomes in patients (pts) with PCALCL in the era of targeted therapies like Brentuximab Vedotin (BV) is not well defined due to lack of large multicenter studies. We conducted a multicenter retrospective analysis (RWA) to assess patient and disease characteristics, treatment patterns, survival outcomes and impact of novel therapies in this rare type of cutaneous T cell lymphoma (CTCL). Methods: The analysis included 167 adult (≥18 years) patients (pts) with PCALCL across 9 academic institutions in the United States diagnosed between 01/2012 to 06/2022. The study was approved by the Institutional Review Boards at the respective sites. Demographic and disease factors were summarized using descriptive statistics. Overall survival (OS) and relapse-free survival (RFS) were estimated using Kaplan-Meier method and compared via log rank tests. Prognostic models included factors such as age, sex, race, performance status (PS), disease stage, type of initial lesion, presence of B symptoms, previous history of lymphomatoid papulosis and prior transplant. Prognostic factors for survival were assessed using both univariable and multivariable Cox proportional hazard models. Results: The median age at diagnosis was 61 (range 18-93) years. The majority of pts were male (55%) and white (82%), with good PS as indicated by an ECOG 0-1 (71%). The initial skin presentation consisted of tumors in 62% of the pts, while 34% presented with plaques or patches. Notably, no pts presented with erythroderma. Most pts underwent PET scan for staging at initial diagnosis (83%) with the majority having early-stage (IA-IIA) disease (86%). Furthermore, palpable lymph nodes (11%) and the presence of B symptoms (4%) were rare at diagnosis, and no pts had blood involvement. The most common sites of involvement were extremities (33%) followed by the head and neck (H&N) and trunk (31% each). Immunophenotyping revealed CD4 positivity in 59% of pts and CD8 positivity in 25%. The T cell receptor (TCR) rearrangement was positive in 28% of pts, though it was not completed in the majority of cases (72%). Most common initial treatments included localized radiation (61%) and surgical excision (19%). A small subset of pts received frontline systemic chemotherapy regimens such as cytotoxic chemotherapy (11%), BV (8%) and oral methotrexate (MTX) (8%). Approximately 7% of the pts had a stem cell transplant. Overall response rate (ORR) for radiation, oral MTX, BV and cytotoxic chemotherapy were 78% (CR:78% 74/100), 42% (CR:63% 6/12) and 39% (CR:67% 6/12), 89% (CR: 88% 15/18) respectively. At a median follow-up of 3.8 years (range 0.04-10.23), the median RFS and OS were 2.7 years (95% CI:1.86, 3.43) and 12 years (95% CI:10.6- NA) respectively. The estimated 3- and 5-year RFS are 46% (95% CI:0.38, 0.55) and 37% (95% CI:0.28, 0.46) respectively. The estimated 3- and 5-year OS were 89% (95% CI:0.82, 0.93) and 82% (95% CI:0.73, 0.88) respectively. At the time of the last follow-up, 79% were alive, while 21% were deceased. The cause of death (COD) was unknown in 50% of the cases and only 10% (3/of deaths were attributed to lymphoma. Other known CODs included infection (20%) and second malignancies 7%. On univariate analysis (UVA), age (p=.007), female sex (p=.04), ECOG PS 1-2 compared to 0 (p=.007) and prior transplant (p=.009) predicted for worse RFS. On multivariate analysis (MVA), only ECOG PS 1-2 (HR 2.31, 95 CI:1.06, 1.18, p=.009) and prior transplant (HR 5.38, 95 CI:2.30, 12.57, p=.0001) had a significant impact on RFS. Age and presence of B symptoms were strong predictors of OS on both UVA (age p=<.0001; B symptoms p=<.0001) and MVA (age: HR 1.12, 95 CI:1.06, 1.18, p=<.0001; B symptoms: HR 16.48, 95 CI: 3.69, 73.60, p=.0002). However, the impact of B symptoms should be interpreted with caution as only 4% of pts presented with this at baseline. On UVA, each one-year increase in age was associated with an 8.5% rise in the risk of death. ECOG PS 1-2 was associated with worse OS on univariate analysis (HR 2.62, 95% CI 0.99, 6.93, p=.05), but was not significant on MVA (HR 1.05, 95% CI 0.368, 2.974, p=.93). Conclusions: In this large RWA of PCALCL, excellent long-term survival was observed with predominantly skin directed frontline therapies. The use of systemic treatments, including BV, was infrequent as first line therapy. Older age and poor PS were significant predictors for reduced survival.