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Abstract Background An intense search is underway for tau PET tracers with enhanced capability to visualize tau aggregates. Research indicates that [18F] AV1451 and [18F]MK 6240 exhibit comparable binding properties in terms of spatial distribution and severity of tau aggregates, as observed both in‐vivo and in‐vitro. This study focused on head‐to‐head pathological comparison of both the tracers binding specificity to tangle maturity levels (pretangles, mature tangles and ghost tangles) of tau aggregates as seen on autoradiography as compared to CP‐13 (early tangle maturity marker) and PHF‐1(middling tangle maturity marker) immunohistochemical (IHC) stains in Alzheimer's disease (AD) and non‐AD tauopathies. Method Study participants included included those with AD and non‐AD tauopathies. Analyses were performed on serial 5um formalin fixed paraffin embedded postmortem human brain sections acquired from Mayo clinic brain bank. Visual assessment of colocalization with IHC as well as quantitative analyses were used. IHC sections were incubated with antibodies CP‐13 (recognizing early tangle maturity) and PHF‐1 (recognizing middling tangle maturity). Result A total of 38 participants were examined. The participants included a spectrum from normal to AD, including mild cognitive impairment (MCI) and atypical AD. Participants with N279K (4R), P301L (4R), and R406W MAPT mutations (3R+4R) were included as well. Both the tracers showed strong binding to AD tau aggregates and no or minimal binding to non‐AD tauopathies. Generally, early tangle maturity tau accumulation participants had more tau demonstrated with CP‐13 than PHF‐1 and both the tracers [18F]MK 6240 and [18F]AV 1451 binding are well correlated with the PHF‐1 staining suggesting the preference for middling tangle level and minimal to early tangles. Conclusion The emergence and validation of these new tau PET tracers have opened new opportunities for the development of more accurate diagnostic and management tools for AD. In our study on post‐mortem sections, [ 18 F]MK‐6240 and [ 18 F]Flortaucipir showed similar binding profiles with preference to middling tangle maturity levels.

Background/Objectives: Surveillance for anal squamous cell carcinoma (ASCC) recurrence relies on clinical examination and imaging. Post-treatment edema, fibrosis, and inflammation can result in clinically indeterminate findings (CIFs) that delay diagnosis and increase patient and system burden. Circulating tumor tissue-modified viral (TTMV)-HPV DNA offers a biologically specific, noninvasive biomarker that may clarify equivocal assessments. Methods: In this multi-center retrospective study, 233 patients with HPV-associated ASCC were evaluated, including 185 with ≥1 post-treatment TTMV-HPV DNA test. CIFs were defined as exams or imaging results not definitively positive or negative for disease, and were paired with subsequent TTMV-HPV DNA tests. Concordance was defined by prespecified follow-up windows comparing TTMV-HPV DNA results with subsequent clinical outcomes. Results: Ninety patients (39%) experienced 214 CIFs, arising from exams (46%, 98) or imaging (54%, 116). Indeterminate rates by assessment were 7% for exams, 17% for imaging, and 1.3% for TTMV-HPV DNA testing. Overall, 52 CIF/TTMV-HPV DNA pairs were eligible for analysis, and TTMV-HPV DNA resolved disease status accurately for 48/52 (92%, 95% CI: 81.5–97.9). Negative tests predicted cancer-free status for 37/41 CIFs (90%), while 100% of positive tests (11/11) were concordant with clinically confirmed recurrence. In 73% of positive cases (8/11), TTMV-HPV DNA was the first indication of recurrence (median lead-time 29 days; IQR 25–147). Conclusions: TTMV-HPV DNA testing reliably clarifies clinically indeterminate findings during ASCC surveillance, demonstrating high accuracy (92%) and earlier detection of recurrence. These data support integration into post-treatment management to reduce diagnostic uncertainty and guide timely care.

Abstract Introduction Labral reconstruction has seen an increase in utilization over the last decade. As a result of the increasing number of labral reconstructions being performed, there has been a subsequent increase in the number of failed labral reconstructions requiring revision. The purpose of the present study was to report the short-term survivorship and outcomes of patients who underwent segmental acetabular labral reconstruction in the setting of a failed prior labral reconstruction. Methods A retrospective review of all labral reconstructions performed by the senior author between 01/01/2010-04/01/2022 was conducted. Patients who underwent a labral reconstruction and were over 18 at the time of surgery were included. Patients with a history of avascular necrosis, Legg-Calvé-Perthes, or with a lateral center edge angle < 18° were excluded. Demographics, radiographic parameters, and patient reported outcomes (PROs) were collected. Patients who underwent a labral reconstruction in the setting of a prior failed labral reconstruction (Group B) were matched in a 1:1 fashion to patients in a control group who underwent only one labral reconstruction (Group A) by age, sex, LCEA, minimum joint space, and the presence of an Outerbridge Grade 3 or 4 defect. Results A total of 24 hips (23 patients) were included in Group B. Mean age at the time of surgery was 36 ± 13 years, and most hips were female (n=14, 58%). Twenty-two (92%) of the hips met a study endpoint, with 3 (14%) converting to total hip arthroplasty (THA) and 3 (14%) undergoing a subsequent hip-preserving surgery. The remaining 16 hips reported 2-year minimum PROs and had a median patient satisfaction of 9.5 (Range: 6-10). Additionally, they demonstrated significant improvement from baseline in SF-12 PCS (p=0.004), WOMAC Total (p<0.001), mHHS (p=0.004), HOS-ADL (p=0.002), and HOS-Sport (p=0.002). Notably, patients in Group B demonstrated similar improvement in PROs from baseline compared to the matched-control group (Group A). Conclusion Patients who undergo revision labral reconstruction in the setting of a failed prior labral reconstruction demonstrate significant improvement in PROs post-operatively compared to baseline at a rate similar to patients who underwent only one labral reconstruction.

Background: Among the 1.5 million cases of cutaneous squamous cell carcinoma (cSCC) diagnosed annually in the United States, a subset of aggressive tumors recur or metastasize. Treatment options include total margin-controlled surgery, such as Mohs micrographic surgery or other forms of peripheral and deep en face margin assessment (MMS/PDEMA), and standard excision with postoperative vertical section margin assessment (SEVMA). NCCN Guidelines recommend MMS/PDEMA for the management of cSCC classified as very high risk based on NCCN risk stratification criteria. This study aims to validate the recommendation of MMS/PDEMA as the preferred surgical approach for NCCN very high-risk cSCCs, using data from a multicenter, multinational cohort. Methods: A multicenter cohort study was conducted across 12 sites, including 10 in the United States, 1 in Spain, and 1 in Brazil, comprising 2,752 primary NCCN very high-risk cSCCs treated with MMS/PDEMA or SEVMA. Propensity score–weighted analysis was used to balance baseline characteristics. Outcomes included local recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD). Results: After balancing baseline characteristics, SEVMA was associated with a 2-fold higher rate of poor outcomes, including recurrence, metastasis, and DSD, compared with MMS/PDEMA. The 3-year cumulative incidence of poor outcomes was higher for SEVMA: LR (12.5% vs 5.9%), NM (11.6% vs 6.0%), DM (4.3% vs 1.9%), and DSD (6.2% vs 3.3%). Conclusions: This study supports the NCCN recommendation of MMS/PDEMA for NCCN very high-risk cSCC, showing reduced recurrence, metastasis, and cSCC-specific mortality compared with SEVMA.

ABSTRACT Pulmonary arterial hypertension (PAH) is a progressive disease with significant morbidity and mortality. Due to nonspecific symptoms, diagnosis can be challenging and subject to substantial delays. Using data from Mayo Clinic′s electronic health records, we looked at causes of delayed diagnosis and whether earlier diagnosis means better outcomes. This retrospective cohort study included adults with PAH confirmed by right heart catheterization (RHC) between 2015 and 2019. Univariate and multivariate analyses evaluated the association of 229 clinical and laboratory features with time to PAH diagnosis and survival outcomes. Early diagnosis was defined as < 6 months and a delayed diagnosis as ≥ 22.2 months from an eligible event. Survival probability was determined using Kaplan‐Meier analysis . The study enrolled 160 patients. The most common initial PAH symptoms were dyspnea (42.5%) and fatigue (16.9%). It took a median of 7, 13, 26, and 123 days from eligible event to the first X‐ray, electrocardiogram, echocardiogram, and RHC, respectively. Factors most closely associated with delayed diagnosis were chronic obstructive pulmonary disease, normal creatinine, high systolic blood pressure, acute respiratory infection, normal iron, normal diastolic blood pressure, and being male aged 18.5 to < 25 years. Compared with delayed diagnosis patients (22.6%), more early diagnosis patients saw a pulmonologist (35.3%) before another provider. After 5 years, 73% of patients in the early diagnosis and 31% in the delayed diagnosis group were still alive. This study identified factors associated with a delayed diagnosis of PAH and found that earlier diagnosis and treatment initiation were associated with significantly improved survival.

Carotid blowout is the rupture of a carotid artery or branch vessel, a dangerous complication in post-treatment head and neck cancer patients. The purpose of this retrospective case review is to identify imaging features suggestive of eminent carotid blowout on routine surveillance post-treatment neck imaging, so that a prompt neuroendovascular consult is obtained and the patient is preemptively treated, thus improving patient outcomes. It is important to carefully interrogate the carotid vessels with appropriate window/leveling for irregularity, adjacent tissue ulceration, exposed vessel to either air or fluid, surrounding tumor, and pseudoaneurysm.

Abstract Context Recent studies suggest glucagon-like peptide receptor-1 agonists (GLP-1RA) and glucose-dependent insulinotropic polypeptide (GIP) may contribute to altered calcium metabolism. Objective This study examines the association between GLP-1RA/GIP-RA use and risk of post-thyroidectomy hypocalcemia. Methods This propensity-matched cohort study utilized the TriNetX Platform to analyze adult patients who underwent total thyroidectomy (2010 to 2024). The intervention cohort included patients with a GLP-1RA or GIP-RA prescription 1 year before thyroidectomy; the control group had no GLP-1RA/GIP-RA history. Propensity score matching controlled for demographics and relevant clinical covariates. Primary outcomes included risk of hypocalcemia at 0-1 month, 1-6 months, and 6-12 months after surgery. Using Poisson regression, odds ratios were reported (alpha = 0.05). Results Among 70 665 patients, 1759 (2.59%) received a GLP-1RA or GIP-RA. Each matched cohort contained 1732 patients with similar preoperative parathyroid hormone or calcium levels. The GLP-1RA/GIP-RA cohort had a 12% lower risk of hypocalcemia from 0 to 1 month after surgery (relative risk [RR] 0.88; 95% CI: 0.81-0.97). In the sensitivity analysis considering postoperative calcitriol supplementation, recipients with GLP-1RA/GIP-RAs use were less likely to develop hypocalcemia in the month after surgery (RR 0.84; 0.74-0.96), as were those with GLP-1RA/GIP-RAs who never received calcitriol in the month after surgery (RR 0.81; 0.72-0.90). Under subgroup analysis, semaglutide was the sole agent associated with a reduced risk of hypocalcemia. Conclusion Patients with a history of GLP-1RA/GIP-RA use may experience a lower risk of short-term hypocalcemia after thyroidectomy, suggesting personalized supplementation strategies may be required for this population.

Abstract Background The advent of T-cell redirecting bispecific antibodies (BsAb) therapies has led to deeper and durable responses in patients with RRMM. We sought to identify adverse prognostic factors for patients treated with BsAbs. We also explored whether the extent of the non-involved free light chain (niFLC) suppression could serve as a potential marker of T-cell engager activity, given the binding of BsAbs to both clonal and non-clonal plasma cells and the short half-life of serum FLCs. Methods We conducted a retrospective analysis of RRMM patients treated with BsAbs between 2022 and 2025 at Mayo Clinic. Baseline lymphocyte counts and ferritin levels were collected and analyzed both as continuous and dichotomized variables. niFLC was considered undetectable if it was below the quantification limit, while the magnitude of niFLC suppression was defined as the absolute difference between niFLC levels and the lower normal range threshold at the time of best response. In addition to standard statistical methods, interaction models were used to explore the potential effect modification of niFLC dynamics. Results A total of 158 patients were included (teclistamab, 73%; talquetamab, 15%; elranatamab, 12%). The median follow-up is 12 months (range 0 to 28 months). Median age is 71(range 65 to 77); 52% (n=85) were triple-class refractory (refractory to an IMiD, a PI, and CD38-antibody) and 37% (n=60) were penta-refractory. CAR-T therapy was previously administered in 28% (n = 46) patients, and 70% had undergone an autologous stem cell transplant. One or more high risk cytogenetic features including del(17p), gain(1q), amp(1q), del(1p), t(4;14), and t(14;16) were present in 57% (n = 90) of patients. Extramedullary disease was noted at the time of BsAb therapy in 44% of patients. Utilizing IMWG response criteria, 68% (n=107) achieved ≥partial response, and 64% (n=101) had ≥ very good partial response (VGPR) as best response following BsAb treatment. The median time to best response was 1.6 months (range 0.7 to 4.4). On multivariable analyses, baseline immunoparesis (HR 1.96; 95% CI, 1.08–3.58; p = 0.0274) and elevated ferritin levels (≥ 337 ng/mL) (HR 1.96; 95% CI, 1.24–3.09; p = 0.0041) were independent predictors of inferior progression-free survival (PFS). Lower baseline absolute lymphocyte count, analyzed as a continuous variable, was significantly associated with shorter PFS in the univariable analysis (HR 0.66; 95% CI, 0.44–0.98; p = 0.04), but not in the multivariable model (HR 0.75; 95% CI, 0.5–1.13; p = 0.166). Detectable niFLC at the time of best response was also significantly associated with inferior PFS (HR 1.80; 95% CI, 1.14–2.84; p = 0.0114). However, the magnitude of niFLC suppression did not show a statistically significant impact on PFS. The median PFS was 5 months in patients with high ferritin levels (≥ 337 ng/mL) and 21 months in those with lower ferritin (p = &lt; 0.005). Similarly, PFS was 8 months in those with immunoparesis and not reached in those without baseline immunoparesis (p = 0.008). At the time of best response, detectable niFLC was associated with a trend toward shorter PFS (5 vs. 13 months), although the difference was not significant (p = 0.06). Logistic regression analysis supported these findings, with higher ferritin levels (OR 2.28; 95% CI: 1.09–4.96; p = 0.032) and the presence of baseline immunoparesis (OR 2.60; 95% CI: 1.18–6; p = 0.02) being significantly associated with higher likelihood of progression or death. Patients with deep reduction in niFLC achieved a VGPR or better. In contrast, those with detectable or higher-than-normal niFLC levels did worse in terms of response. Notably, niFLC became undetectable in 72% of patients with ≥VGPR (73/101), compared to 52% of those who did not achieve this level of response (30/57). Conclusion Among RRMM patients treated with BsAbs, baseline immunoparesis and elevated ferritin levels emerged as independent predictors of worse PFS. While failure to induce a deep reduction in niFLC at the time of best response suggests a tumor extrinsic mechanism of resistance, and it is also linked to inferior outcomes.

Abstract Background: Parenteral DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC), including an attenuated 3-day regimen, are recommended in the NCCN Guidelines for patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) with clinically significant cytopenias. However, parenteral administration requires frequent clinic visits, which imposes a substantial burden on pts, particularly those requiring long-term therapy. Oral DMTIs offer more flexible dosing and maintenance of pts' autonomy. Oral DEC-cedazuridine (DEC-C) is a fixed-dose combination tablet containing DEC (35 mg) and cedazuridine (100 mg). ASTX727-03 (NCT03502668) is a randomized, open-label, multicenter, phase 1/2 clinical trial evaluating safety, efficacy, and pharmacokinetics (PK) of various DEC-C doses and regimens in pts with LR-MDS. Phase 1 identified a 5-day regimen of DEC 10 mg/cedazuridine 100 mg as the optimized low-dose (LD) regimen. Phase 2 compares this LD regimen with the attenuated standard-dose (SD) regimen. Here, we report phase 2 results on efficacy, safety, PK, and pharmacodynamic (PD) data. Methods: Adults (aged ≥18 years) with International Prognostic Scoring System (IPSS) low-risk or Intermediate-1 MDS, ECOG PS 0−2, and ≥1 cytopenia or red blood cell (RBC) transfusion dependence were randomized 1:1 to receive oral DEC-C LD (10 mg x 5 days) or SD (35 mg x 3 days). The primary endpoint was hematologic response. Secondary endpoints included PK, PD (by LINE-1 demethylation), time to bone marrow blasts &gt;5%, leukemia-free survival (LFS), overall survival (OS), and safety. Results: As of October 31, 2024, 81 pts were treated (LD arm: n=40; SD arm: n=41) and completed a median of 8.8 months on treatment. At cutoff, 17 (42.5%) and 12 (28.6%) LD and SD pts, respectively, were still continuing the study; 9 (22.5%) and 6 (14.6%) pts respectively, had discontinued treatment due to hematopoietic stem cell transplant. Median age was 70 (LD) and 75 (SD) years; 75.0% (LD) and 68.3% (SD) had IPSS Int-1 risk MDS and 60.0% vs 41.5% had IPSS-Molecular Lower-Risk MDS (very low, low, or moderate-low). Low-risk prognostic scoring system risk distribution was similar: Category 1 (2.5% vs 4.9%), Category 2 (47.5% vs 46.3%), and Category 3 (50.0% vs 48.8%). After a median follow-up of 29.3 months, median OS was 23.9 months (95% confidence interval [CI]: 13.0, not estimable [NE]) in the LD arm vs 26.0 months (95% CI: 19.4, 28.5) in the SD arm. Median LFS was 23.8 months (95% CI: 13.0, NE) and 25.7 months (95% CI: 17.8, 26.5), respectively. Hematologic improvement per International Working Group 2006 criteria was achieved in 27.5% (LD) and 26.8% (SD) of pts. Among RBC transfusion–dependent pts, 52.4% (LD) and 37.5% (SD) achieved ≥56-day independence and 47.6% (LD) and 20.8% (SD) achieved ≥112-day independence. Pts received a median of 10 (LD) and 9 (SD) cycles. Delayed cycles occurred in 72.5% (LD) vs 82.9% (SD) of pts; dose reductions occurred in 40.0% (LD) and 46.3% (SD) of pts. Both treatment regimens caused a decrease in blood counts, reaching a nadir before recovering in each cycle. Neutropenia was more pronounced during early cycles and was more severe in the SD arm. Blood counts across all lineages remained stable or improved through ≥12 cycles with the LD arm, suggesting a more favorable safety and tolerability profile. Grade ≥3 adverse events (AEs) occurred in 85.0% and 90.2% of pts in the LD and SD arms, respectively; treatment discontinuation due to AEs occurred in 2.5% and 17.1% of pts, respectively. Most commonly reported treatment-emergent AEs were anemia (42.5% LD, 39.0% SD), fatigue (32.5% LD, 43.9% SD), and thrombocytopenia (37.5% LD, 39.0% SD). Three deaths occurred in the trial: 2 in the LD arm, which were both unrelated to study treatment, and 1 in the SD arm (Pseudomonal bacteremia in Cycle 1), which was treatment related. Total AUC0–24 was 199 ng*h/mL in the LD arm and 465 ng*h/mL in the SD arm; AUC for all cycles of the LD arm was approximately half of the SD arm. Maximal % LINE-1 demethylation rate was lower with LD than SD, but narrowed by Cycle 3. Conclusion: LD oral DEC-C demonstrated comparable clinical benefit to SD oral DEC-C, with improved safety and tolerability, including fewer dose modifications and less severe myelosuppression. These findings support LD DEC-C as a potential optimal regimen for pts with LR-MDS. Clinical trial registration: NCT03502668