Elsabbagh, Zaid

Background: Achilles tendon ruptures are among the most debilitating injuries in professional basketball, often leading to prolonged absence and long-term performance decline. While calf strains are common among National Basketball Association (NBA) athletes, their role as a precursor to Achilles rupture remains poorly understood. Hypothesis: A previous calf strain would be associated with increased odds of Achilles tendon rupture in NBA players and that affected players would experience significant post-injury performance declines. Study Design: Case-cohort study; Level of evidence, 3. Methods: Publicly available data on NBA players from 1958 to 2024 were analyzed, with the data search conducted in June 2025. Players with Achilles ruptures (n = 60) were compared with players with calf strains who did not sustain a rupture (n = 258). Logistic regression adjusted for age, body mass index, position, starter status, and workload. Pre- and postinjury performance was evaluated over 2 seasons using paired t tests. Descriptive analyses characterized injury laterality, game context, quarter, shoe type, and draft position. Video review assessed injury mechanisms. Results: Previous calf strain was associated with increased odds of Achilles rupture (odds ratio, 2.49; 95% CI, 1.16-5.22; P = .02). Among those with both injuries, 85.7% occurred on the same side, with a mean interval of 1.9 years. Of all players, a total of 75% returned to play. Postinjury declines were observed in player efficiency rating (−2.46), win shares (−3.23), games played (−260.3), and minutes per game (−5.19) (all P < .001). Return was more likely in younger players and those on multiyear contracts. Video analysis revealed a consistent “false step” mechanism in 95% of cases with footage. Most Achilles tendon ruptures occurred during in-game activity, while shoe type was evaluated descriptively and was not associated with player position or preinjury workload. Conclusion: Our study showed that previous calf strain is associated with an increased risk of Achilles tendon rupture in NBA players and may serve as a clinically identifiable risk marker. Rupture leads to substantial and sustained performance decline, even among those who return. Targeted rehabilitation and movement retraining may help mitigate progression to rupture in high-risk athletes.

Purpose: Neuroendocrine neoplasms (NENs) are increasingly recognized to have a hereditary predilection, yet the prevalence and clinical relevance of pathogenic germline variants (PGVs) in unselected patients with NEN remain poorly defined. This prospective, multicenter study aimed to evaluate the prevalence and clinical utility of PGVs through universal multigene panel testing in a diverse cohort of patients with NENs. Patients and Methods: Between 2018 and 2024, we enrolled unselected patients with NENs from 3 Mayo Clinic Cancer Centers. Germline genetic testing was performed using a next-generation sequencing panel of up to 84 cancer predisposition genes. Patients were not selected based on age, disease stage, ethnicity, or family history. Variants were classified as PGVs, variants of uncertain significance (VUS), or negative. Clinical and demographic data were analyzed descriptively. Results: Among 88 patients, PGVs were identified in 15.9% (n=14), most frequently in high- or moderate-penetrance genes including MEN1 , CHEK2 , MITF , and MUTYH . PGVs were most commonly found in pancreatic NENs [n=12/55 (21.8%)], followed by small bowel NENs [n=2/20 (10%)], with no PGVs detected in lung NENs. Mismatch repair (MMR) gene alterations were identified in 5.7% of patients, including 1 MLH1 PGV and 4 MSH2/MSH6 VUS, 2 of which demonstrated MMR deficiency by protein testing. VUS were reported in 34.1% of patients. Notably, 35.7% of PGV-positive patients did not meet current NCCN or ACMG testing criteria, and 53.9% had PGVs in genes outside of cancer-specific guideline recommendations. Conclusions: Universal germline testing in unselected patients with NEN identified clinically relevant PGVs in over 15% of cases. These findings support broader genetic testing approaches to guide treatment, enhance familial risk assessment, and inform cascade testing—regardless of traditional clinical selection criteria.

Background: Tendinopathies are common in middle-aged women. While estrogen regulates tendon remodeling, the influence of systemic hormone replacement therapy (HRT) on the risk of tendon degeneration remains unclear. Hypothesis/Purpose: The purpose of this study was to investigate the association between systemic HRT use and tendon injuries/repair in perimenopausal women. It was hypothesized that systemic HRT would be associated with an increased incidence of tendon injuries and repair. Study Design: Cohort study; Level of evidence, 4. Methods: Using the TriNetX Research Network, we identified female patients aged ≥45 years diagnosed with major tendon abnormalities, including rotator cuff tears, bicipital tendinitis, lateral or medial epicondylitis, Achilles tendinopathy, patellar tendinitis, or quadriceps strain, from January 2004 to July 2025. HRT exposure was defined as systemic estrogen and/or progestin use within 1 year before a diagnosis. Patients with contraindications to HRT were excluded. After 1:1 propensity score matching, 2 groups of 63,836 patients each were generated. Primary outcomes included diagnosis rates of specific tendon conditions; secondary outcomes were lifetime rates of corresponding tendon repair procedures. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The independent t test and chi-square test were used for analysis. Results: HRT users had significantly higher rates of several tendon abnormalities compared to matched controls, including rotator cuff tears (39.2% vs 37.9%, respectively; P < .001), bicipital tendinitis (13.3% vs 11.0%, respectively; P < .001), lateral epicondylitis (27.8% vs 22.7%, respectively; P < .001), and medial epicondylitis (6.8% vs 5.3%, respectively; P < .001). Achilles tendinopathy had similar rates between the 2 groups (14.6% vs 14.5%, respectively; P = .387). Surgical repair was more common in the HRT group, including biceps tendon repair/tenodesis (3.9% vs 3.3%, respectively; OR, 1.16 [95% CI, 1.10-1.23]; P < .001), rotator cuff repair (6.6% vs 6.2%, respectively; OR, 1.06 [95% CI, 1.01-1.11]; P = .013), and Achilles tendon repair (0.7% vs 0.6%, respectively; OR, 1.23 [95% CI, 1.06-1.41]; P = .005). Conclusion: Our study showed that systemic HRT use in women aged ≥45 years was associated with an increased risk of tendon injuries and a greater likelihood of surgical repair, although the absolute risk differences were modest. These findings underscore the need for awareness of the possible musculoskeletal effects of hormone therapy and highlight an underexplored area in women's orthopaedic health.

Case: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic ossification. Scoliosis may develop and progress rapidly, especially during adolescence. We report 4 patients with FOP and scoliosis during early adolescence: A 12-year-old girl underwent T4-S2 posterior spinal fusion (PSF); another 12-year-old girl underwent T4-S2 PSF; a 13-year-old boy underwent T3-L4 PSF; and a 14-year-old girl was managed nonoperatively because the complex deformity and ankylosed shoulders could not be adequately balanced with surgery. Conclusion: In patients with FOP, surgical intervention can reduce thoracic deformity and improve pulmonary function but carries substantial risks, including heterotopic ossification.

PURPOSE Pancreatic acinar cell carcinoma (PACC) is a rare and aggressive form of pancreatic cancer that originates in the acinar cells of the exocrine pancreas. In this study, we aimed to investigate the clinical and molecular characteristics of patients with PACC at our institution. METHODS This was a retrospective study of patients with PACC seen at Mayo Clinic between 2002 and 2023. Baseline patient characteristics, tumor pathology, treatment strategies used, and survival outcomes were analyzed. Kaplan-Meier curves were estimated using newsurv macros in SAS. RESULTS The study included a total of 65 patients with PACC. The median age at diagnosis was 66 years. Almost half of the patients (48%) presented with resectable/borderline-resectable disease (n = 28). Five-year overall survival (OS) for resectable/borderline-resectable, locally advanced/unresectable, and metastatic disease were 72.0%, 21.6%, and 20.9%, respectively. Somatic and germline next-generation sequencing identified numerous potentially actionable targets including homologous recombination (43% somatic, 33% germline), RAF alterations (29% somatic), and mismatch repair (14% somatic). CONCLUSION Our findings underscore the heterogeneity and aggressive nature of PACC. Despite the improved prognosis for patients with resectable/borderline-resectable disease, OS remains poor, particularly for those with locally advanced or metastatic disease. The identification of actionable molecular targets in a significant proportion of patients highlights the potential for personalized therapeutic approaches. Future research should focus on tailored treatment strategies to exploit these molecular vulnerabilities, which may offer new options for improving outcomes in this rare malignancy.

PURPOSE Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. MATERIALS AND METHODS Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. RESULTS Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes ( DNMT3A, TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CONCLUSION CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT.

688 Background: PACC is a rare malignancy originating from the exocrine pancreas, accounting for less than 1% of all pancreatic cancers. Due to the rarity of the disease entity, there is a paucity of data to guide treatment decisions. This retrospective study aims to provide additional clinical characteristics and outcomes to aid in future treatment decisions. Methods: Pathology records from Mayo Clinic (AZ, FL, MN) patients (pts) denoting acinar or mixed-acinar cell carcinoma were searched between 2002 to 2023 and selected for retrospective review. Pt demographics, treatment courses, and next generation sequencing (NGS) were collected. Results: A total of 62 pts (74% male, n = 46) were identified with median age 64 years old. Histologic subtypes were 67% pure acinar cell carcinoma (42/62), 24% mixed acinar-neuroendocrine (15/62), and 8% mixed acinar-adenocarcinoma (5/62). AJCC stages at diagnosis were 34% stage I/II (21/62), 16% stage III (10/62), and 50% stage IV (31/62). Early-stage disease was treated with upfront surgical resection (81%, 17/21). Locally advanced disease received neoadjuvant therapy (NAT) followed by surgical resection (80%, 8/10). FOLFIRINOX was most often chosen as NAT (65%, 11/17), while others received gemcitabine-based NAT. The R0 resection rate was 86%. The 3 and 5-year survival estimates for stage III were 90.9% (95% CI: 75.4 – 100%) and 67.3% (95% CI: 42.3 – 100%), respectively. The 3 and 5-year survival estimates for stage IV were 36.6% (95% CI: 18.6 – 71.9%) and 29.3% (95% CI: 13.1 – 65.5%), respectively. Median survival time for stage IV was 3 years. Somatic NGS testing was done in 24 pts with alterations found in: homologous recombination (HR) in 42% (10/24); RAF alterations in 25% (6/24); mismatch repair (MMR) in 13% (3/24; none of them with MMR germline mutations), 1 ETV6-NTRK3 fusion, and 1 FGFR mutation. Germline NGS testing was done in 21 pts and alterations in HR were seen in 33% (7/21) of pts. This led to additional therapeutic options in 46% (11/24) of pts. Conclusions: Unlike PDAC, PACC is a genomically diverse disease, with potentially targetable alterations in RAF, HRD, and MMR genes, offering additional therapeutic options for significant number of pts. In addition, more than one-third of the pts harbored germline mutations in HR genes. Therefore, somatic and germline testing should be considered for any pt diagnosed with PACC.

Abstract Introduction: Clonal hematopoiesis (CH) is defined by acquisition of somatic mutations in hematopoietic stem cells with potential for expansion over time. CH is influenced by exposures to chemotherapy/radiation & has been associated with therapy related myeloid neoplasms (tMN). Peptide receptor radionuclide therapy (PRRT) is a radionuclide therapy and is FDA approved for neuroendocrine tumors (NET). PRRT has been associated with a 2-10% risk of tMN, especially with prior exposure to alkylating agents. A prior study of 13 NET patients found CH prevalence of 64%. We carried out a prospective assessment of CH in NET patients prior to PRRT. Methods: We evaluated pre-PRRT blood samples in 37 NET patients. Genomic DNA from mononuclear cells was analyzed for CH using a custom panel targeting 229 genes to a targeted depth of &gt;1000X. Results: After approval by Mayo Clinic IRB, 45 patients with Stage IV NET were enrolled & CH data was available for 37. Fifty-one percent of patients were female, with a median age of 68yrs (range, 34-84yrs). Types of NET included small bowel (51%), pancreatic (29%), carcinoid (8%), paraganglioma (5%), & other (5%). The median number of therapies prior to PRRT was 1 (range, 0-4) & included somatostatin analogues (SSA)-81%, alkylating agents-30%, & prior radiation-13%. Thirty-six of 37 patients had variants identified, 5 of which were presumed germline (DDX41, CDKN2B, CHEK2, POT1, ERBB2), & 17 (45.9%) had pathogenic variants meeting the operational definition of CH (DNMT3A, TET2, PPM1D, TP53, SF3B1, ASXL1). The median number of pathogenic variants per patient was 1 (range, 0-2), & 6 patients had &gt;1. In patients &gt;60yrs old, 46% had pathogenic variants & 3 patients with pathogenic variants (TET2, TP53, DNMT3A) were &lt;60 years old. The most common pathogenic variants were in epigenetic regulators, DNMT3A (37.5%) & TET2 (16.7%) with a median VAF of 2.8% (range, 0.70-50%). Eight patients (47%) with pathogenic CH had grade 1 cytopenias at baseline, compared to 10 patients (50%) without pathogenic CH. One patient had grade 3/4 cytopenia at baseline & had a missense variant in TP53 (VAF 50%) & history of exposure to anthracyclines, alkylating agents, platinum & radiation. The patient developed MDS before receiving PRRT. Pathogenic CH variants were more common in patients with previous exposure to radiation (p=0.008) or SSA (p=0.005). Two patients had PPM1D variants, both with a history of prior radiation, one with a history of prior alkylating treatment. Conclusion: To our knowledge this is the largest prospective evaluation of CH in NET. We identified CH to be present in 46% of patients & DNMT3A mutations were most common. This establishes the clonal landscape with mutations involving epigenetic regulators, DNA damage repair, transcription & splicing factors. Prospective longitudinal evaluation will evaluate the association between CH, cytopenias and tMN. Citation Format: Yael Kusne, Terra Lasho, Zaid Elsabbagh, Abhishek Mangaonkar, Rachel Eiring, Timothy Hobday, Jason Starr, Tanios Bekaii-Saab, Thorvardur Halfdanarson, Mrinal Patnaik, Mohamad Sonbol. Prevalence of clonal hematopoiesis in neuroendocrine tumor patients prior to lutetium 177 dotatate therapy (Lu177): A prospective trial of 36 patients [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 5928.