Citations

505 Background: Increased TILs are associated with better prognosis in triple-negative BC, including in patients (pts) age < 40. However, the role of TILs remains unclear in HR+/HER2- BC and little data exist in young pts, in whom immune microenvironment could be altered by age-related host/tumor differences. We assessed the extent and composition of immune infiltration in HR+ tumors of young women and correlated with clinicopathologic features and survival outcomes. Methods: From a prospective cohort study of women with BC diagnosed age ≤40, we identified those with stage I-III HR+/HER2- BC and available pre-treatment (tx) tumor tissue. Multiplexed immunofluorescence was used to quantify cytotoxic T (CD8+), T helper (Th, CD3+CD8-), T regulatory (Tregs, FOXP3+CD3+) and exhausted T (PD1+CD8+) cells in stroma and tumor. Univariate analyses tested associations between clinicopathologic variables and immune markers by high or low expression, divided based on median. High vs. low TILs were evaluated in Cox regression analyses for invasive breast cancer-free survival (iBCFS), distant disease-free survival (DDFS) and overall survival (OS). Results: In 390 pts, median age was 37 years (21-40), most had grade 2 (51%), T1 (65%), N0 (63%) tumors and 67% received adjuvant chemotherapy. Black pts (n = 17) had higher expression of stromal CD8+ ( P= .010), FOXP3+CD3+ ( P= .027) and PD1+CD8+ TILs ( P= .043); intratumoral TILs did not differ by race. Older age (36-40) was associated with high expression of CD8+ ( P= .033) and PD1+CD8+ TILs ( P= .031) within stroma and CD3+CD8- TILs within tumor ( P= .046). Grade 3 tumors had higher stromal and intratumoral expression of CD3+CD8- ( P= .002; P< .001) and FOXP3+CD3+ TILs ( P= .020; P< .001). No differences in TILs were seen according to recency of pregnancy, BRCA1/2 status or T/N stage. Over a median follow up of 8 years, 85 iBCFS events, 64 DDFS events and 37 deaths occurred. High stromal expression of CD3+CD8- TILs was associated with better iBCFS (HR 0.49, P= .002) and DDFS (HR 0.57, P= .046), which remained significant when adjusted for T/N stage, grade and chemotherapy (iBCFS HR 0.41, P< .001; DDFS HR 0.45, P= .008). High stromal expression of CD3+CD8- and FOXP3+CD3+ TILs was associated with better OS (HR 0.47, P= .038) and iBCFS (HR 0.58, P= .018), respectively, on adjusted analyses only. High intratumoral expression of CD3+CD8- and FOXP3+CD3+ TILs was associated with better iBCFS (HR 0.59, P= .025; HR 0.63, P= .043) after adjustment only. Conclusions: The distribution of TIL subtypes in young women’s HR+ BC varied according to race, age and grade. High stromal and intratumoral expression of Th and Tregs was associated with improved BC outcomes. Characterization of immune cell subsets could help refine the prognostic value of TILs in HR+ BC, particularly in young pts who may benefit from individualized escalated/de-escalated tx strategies.

AimsThe benefit of MRI in the preoperative assessment of scaphoid proximal fragment vascularity remains controversial. The purpose of this study is to compare preoperative MRI findings to intraoperative bleeding of the proximal scaphoid.MethodsA retrospective review of 102 patients who underwent surgery for scaphoid nonunion between January 2000 and December 2020 at a single institution were identified. Inclusion criteria were: isolated scaphoid nonunion; preoperative MRI assessing the proximal fragment vascularity; and operative details of the vascularity of the proximal fragment with the tourniquet deflated. MRI results and intraoperative findings were dichotomized as either ‘yes’ or ‘no’ for the presence of vascularity. A four-fold contingency table was used to analyze the utility of preoperative MRI with 95% confidence intervals. Relative risk was calculated for subgroups to analyze the association between variables and MRI accuracy.ResultsPreoperative MRI identified 55 proximal scaphoid fragments with ischaemia and 47 with vascularized proximal fragments. After the proximal fragment was prepared, the tourniquet was deflated and assessed for bleeding; 63 proximal fragments had no bleeding and 39 demonstrated bleeding. MRI was not reliable or accurate in the assessment of proximal fragment vascularity when compared with intraoperative assessment of bleeding. No patient or MRI factors were identified to have a statistical impact on MRI accuracy.ConclusionCurrent preoperative MRI protocols and diagnostic criteria do not provide a high degree of correlation with observed intraoperative assessment of proximal fragment bleeding. While preoperative MRI may assist in surgical planning, intraoperative assessment remains the best means for assessing proximal fragment vascularity in scaphoid nonunion. Future efforts should focus on the development of objective measures of osseous blood flow that may be performed intraoperatively.Cite this article: Bone Joint J 2023;105-B(6):657–662.

Objective(s): PIK3CA-related overgrowth spectrum (PROS) is a group of disorders caused by somatic variants in the PIK3CA gene. We aimed to update recommendations on the severity classification, testing, and medical management of patients with PROS. Methods: Using validated consensus methodology, we convened a 13-member panel in 2020 and reviewed current evidence on how to diagnose and treat PROS. The panel was asked to rate the level of disease severity, and the appropriateness of whether to test for a mutation and medical therapy in 217 patient scenarios before a virtual meeting. Panelists discussed areas of disagreement and completed ratings following the meeting. Results: The panel developed clinical presentations and endorsed the disease severity framework defined by functional impairment, a reduction in quality of life, and risk of death. Panelists agreed it is appropriate to test for a PIK3CA gene variant in every moderately/severely affected patient. Panelists agreed it may be appropriate to consider an mammalian (mechanistic) target of rapamycin inhibitor in some severely affected patients and some moderately affected patients with progressive disease. Although clinical trials have only recently begun and the evidence remains limited, panelists also agreed it may be appropriate to consider treatment with phosphoinositide 3-kinase/serine/threonine protein kinase inhibitors in severely affected patients with a confirmed PIK3CA variant or without a confirmed variant but with progressive disease. Conclusion: These recommendations represent the consensus of experts informed by published literature and experience. Future research should validate this guidance using clinical data. Once validated, we hope these recommendations will improve outcomes for patients with PROS.

Abstract Aims In this protocol-predefined substudy of the RHAPSODY trial, the primary aim was to assess whether pericardial late gadolinium enhancement (LGE) was associated with time to pericarditis recurrence. Methods and results RHAPSODY was a Phase 3 double-blind, placebo-controlled, randomized-withdrawal trial that demonstrated the efficacy of rilonacept in recurrent pericarditis (RP). Patients with a history of multiple RP and an active recurrence were enrolled and had the option to participate in a cardiac magnetic resonance (CMR) imaging substudy. CMRs were interpreted by a blinded independent core laboratory with prespecified criteria to define pericardial LGE. Compared to patients with trace or mild pericardial LGE (n = 9), patients with moderate or severe pericardial LGE (n = 16) generally had a higher number of recurrent episodes per year (5.3 vs. 3.9) and a higher mean CRP level (3.6 vs. 1.1 mg/dL). Overall, 10/14 (71.4%) who received a placebo had a recurrence compared to 0/11 (0%) who received rilonacept. In patients randomized to placebo who had moderate or severe pericardial LGE, the median time to recurrence was 4.2 weeks compared to 10.7 weeks in patients who had trace or mild pericardial LGE. At the conclusion of the event-driven randomized-withdrawal period, among patients receiving a placebo, 5/7 (71.4%) with trace or mild pericardial LGE and 5/7 (71.4%) with moderate or severe pericardial LGE had a recurrence. Conclusions Among patients with multiple RP, these preliminary findings support the concept of pericardial LGE as an imaging biomarker that may inform the duration of treatment and risk of recurrence with cessation of therapy and larger studies should be considered. ClinicalTrials.gov Identifier NCT03737110

Abstract Introduction Erectile dysfunction (ED) stems from a variety of etiologies and often requires a multidisciplinary approach to optimize patient care. Objective We sought to assess attitudes and confidence regarding the treatment of erectile dysfunction across different provider types. Methods Responses were obtained through an anonymous, email-based survey of our institution's providers in the disciplines of urology, internal medicine, and family medicine. We created a novel tool of 25 5-point Likert scale questions regarding ED treatment. Data were analyzed through descriptive statistics and Fisher’s exact test and sorted by respondent specialty. Ethical Committee approval was obtained before study. Results 138 health care providers returned surveys, including 58 internists (IM), 47 family physicians (FP), and 33 urologists (GU). FP and IM responses showed significant overlap with a few key statistically significant differences. In general, IM was much more positive in VED, penile implant as an option, penile implant satisfaction, and penile implant risk. 37% of IM agreed or strongly agreed inflatable penile prosthesis risk is low vs 6% FP (p = .0032). IM also more strongly supported team-based care and referral to specialists IM 71% vs. 51% FP (p = .0012). (Figures) When comparing GU versus FP + IM 24/25 questions revealed statistically significant differences revealing greater GU confidence and knowledge about ED with only the importance of a team-based approach not differing. Noteworthy points include 46% vs. 18% confidence for a detailed sexual history for GU vs. FP + IM (all other points % and same provider sequence). IIEF usage and familiarity were 61 vs. 3 and 88 vs. 18, respectively. 100 and 85 strongly/agreed that good options remained after pills failed. Regarding inflatable penile prosthesis, agreement or strong agreement for patient willingness to undergo surgery for ED 67 vs. 13; patient satisfaction 91 vs. 25, partner satisfaction 80 vs. 25; and would repeat surgery or recommend to a friend was 82 vs. 17. Finally, and perhaps most notably 83 vs. 11 of providers were aware that Medicare covered implants. (Figures). Conclusions Conclusions This survey reveals significant knowledge gaps for treatment options and outcomes for ED. Targeted provider education, particularly about penile prostheses, could optimize patient care. Disclosure No

Abstract Introduction Sexual therapy for male sexual dysfunction has been used to help patients address a variety of sexual dysfunction-related conditions. While this intervention is frequently recommended for patients by male sexual health experts, the rate of adherence to the recommended therapy and associated factors is unknown. Objective To understand factors leading to completion of sex therapy consultations and barriers that prevent it. Methods A survey was developed by experts in the management of male sexual dysfunction and sex therapy at our institution. The survey included questions focusing on the decision to pursue sex therapy (or not), barriers or facilitating factors, patient perceptions regarding the referral, and treatment success. A retrospective chart review was performed to identify those patients who were referred for sexual therapy after undergoing evaluation for male sexual dysfunction at an academic Men’s Health urology clinic from 2017 - present. The survey was mailed out to these patients, and respondent survey data was compiled to evaluate survey responses. Results To date, 23 patients completed the survey (20% response rate). Sixty-five percent of survey respondents were ≥ 50 years of age, 87% were straight, and 71% were married. Reasons for sex therapy referral were frequently multi-factorial and included erectile dysfunction (65%, n=15), low libido (43%, n=10), ejaculatory dysfunction (39%, n=9), performance anxiety (30%, n=7), relationship problems (30%, n-7), and genital pain (14%, n=3). Seventy-eight percent of patients (n=18) felt that sex therapy consultation was a reasonable part of their treatment plans. Six (26%) patients did not attend their recommended sex therapy consultations. Reported barriers included sense of shame (n=2), embarrassment (n=2), scheduling conflicts (n=1), lack of anticipated benefits (n=1), and feeling dismissed by the referring provider (n=2). Those who attended sex therapy frequently reported the perception that referral made sense based on their symptoms (n=10, 59%) and/or a feeling of desperation to “do anything do get better” (n=11, 65%). Seventy-eight percent of patients who attended sex therapy found it helpful and would recommend it to a friend with a similar concern. Conclusions The majority of male patients who are referred to sexual therapy feel it is beneficial. However, one in four men choose not to pursue this line of treatment despite recommendations from their treating physicians. Future work is needed to address barriers to pursuing sex therapy. Disclosure No

AbstractBackgroundPatients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.MethodsThis was a multicenter, open‐label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two‐stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1–10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1–5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.ResultsThe composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%–26.8%) and 30.8% (95% confidence interval, 9.1%–61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.ConclusionsThe combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

Abstract Purpose: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6–43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2–8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.

Abstract Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines. Patients and Methods: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. Results: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. Conclusions: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued.

Abstract Purpose: Young women’s breast cancers (YBCs), defined herein as breast cancer (BC) diagnosed at age ≤ 40 years, are etiologically and biologically distinct from postmenopausal BCs, demonstrating a higher proportion of estrogen receptor (ER) negative subtypes and a worse prognosis. Studies have not assessed whether risk factors such as recent parity and body mass index (BMI) are linked to protein expression profiles in YBCs. Accordingly, we examined protein expression assessed with GeoMx® Digital Spatial Profiling (DSP) in 640 YBCs prepared as tissue microarrays (TMAs) in the Young Women’s BC Study (YWBCS). Methods: The YWBCS is a multi-institutional cohort of 1,297 women with incident BC diagnosed at age &lt;40 years identified through medical record review, with risk factor data collected via questionnaires. TMAs including 1,505 cores of 640 YBCs that were collected prior to therapy and were suitable for molecular analysis were evaluated for 72 markers with NanoString GeoMx DSP. Associations of log-transformed biomarker expression with BMI and time from last live birth to BC diagnosis were carried out using linear mixed modeling approaches, accounting for multiple tumor tissue cores per individual. Results: Mean age at BC was 35.5 years (range 17-40). Tumor subtypes based on clinical immunostaining were the following: luminal B 46%; luminal A 36%; triple negative 12% and HER2+ 6%. Of 72 biomarkers tested, 53 (74%) were evaluable after QC and normalization. GeoMx ER and PR protein levels were higher in luminal A and luminal B YBCs than in HER2+ and TNBC (p=2x10-94 and 2x10-52, respectively), supporting the accuracy of the GeoMx assay. Compared to nulliparas or those with most recent birth &gt; 3 years before BC, those who gave birth ≤ 3 years prior to BC had tumors with higher expression of PR (8x10-6) and ER (p=0.006), and lower expression of BCL-2 (p=0.006). In contrast, women with last birth ≥ 6 years prior to BC had higher expression of CD8 (p=0.006) and PD-1 (p=0.001) than nulliparas and those with more recent births. Compared to women with BMI between 18.5 and 29.9, those with higher or lower BMIs had higher expression of CD34 (p=0.0003), CD4 (p=0.0009) and CD14 (p=0.001). BCL-2 expression was higher among women with BMI &lt; 18.5 compared to those with higher values (p=0.005). Women with BMI of 30+ had higher β2-microglobulin levels than those with lower BMIs (p=0.003). Inverse dose-response associations (with higher BMI related to lower levels) were observed for expression of ER (p=0.01), pan cytokeratin (p=0.004) and four proteins in the p13K/AKT signaling pathway (p ≤ 0.01 for each). Conclusions: Preliminarily, we identify differences in hormonal and immune markers in YBCs in relation to timing of births and BMI, suggesting that these factors may contribute to etiologic heterogeneity. Multivariate modeling is ongoing to incorporate molecular subtype and other risk factors. Citation Format: Robert A. Vierkant, Laura M. Pacheco-Spann, Stacey J. Winham, Jennifer M. Kachergus, Ji Shi, Craig Snow, Fergus J. Couch, Janet E. Olson, Chen Wang, Derek C. Radisky, Amy C. Degnim, E. Aubrey Thompson, Laura C. Collins, Kathryn J. Ruddy, Ann H. Partridge, Mark E. Sherman. Associations of parity and body mass index with NanoString digital spatial protein profiling in early onset breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1000.