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Introduction Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase involved in immune signaling and has been implicated in tumor-intrinsic resistance to DNA-damaging therapies. Although SYK activity has been associated with poor outcomes in triple-negative breast cancer (TNBC), its role in resistance to combined radiotherapy and immune checkpoint blockade remains unclear. Methods SYK expression and clinical relevance were assessed across multiple breast cancer cohorts, including radiotherapy-treated datasets. Integrated transcriptomic analyses were used to characterize SYK-associated immune states. The functional effects of pharmacologic SYK inhibition were evaluated using in vitro assays and an immunocompetent bilateral 4T1 tumor model in female BALB/c mice treated with radiotherapy and PD-1 blockade. Treatment-associated immune remodeling was assessed by flow cytometry and transcriptomic profiling. Results Across multiple cohorts, elevated SYK expression, particularly in TNBC, was associated with inferior clinical outcomes and immune dysregulation. Pharmacologic SYK inhibition enhanced tumor responses to radiotherapy and PD-1 blockade at both irradiated and distant tumor sites. These effects were accompanied by coordinated remodeling of the tumor immune microenvironment, including suppression of neutrophil-associated signatures and reductions in immunosuppressive myeloid populations, including M2-like macrophages and myeloid-derived suppressor cells. Discussion Pharmacologic SYK inhibition enhances responses to radiotherapy and PD-1 blockade in preclinical TNBC models and is accompanied by remodeling of the immunosuppressive myeloid compartment. These findings support further investigation of SYK-targeted strategies to improve responses to combined radiotherapy and immune checkpoint blockade.

Introduction Antibody–drug conjugates (ADCs) are now widely used in breast cancer across multiple disease subtypes. With increasing clinical use, treatment-related toxicities have become an important factor in therapeutic decision-making. However, comparative safety data among ADCs are limited because direct head-to-head trials are lacking. Methods We conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials evaluating ADCs in breast cancer, with the literature search updated through March 31, 2025. Treatment-related adverse events (TRAEs) and serious adverse events (SAEs) were classified according to the Common Terminology Criteria for Adverse Events. A Bayesian random-effects network meta-analysis was used to compare toxicity risks across regimens. Odds ratios (ORs) with 95% credible intervals (CrIs) were estimated, and surface under the cumulative ranking curve (SUCRA) values were used as descriptive ranking summaries interpreted alongside the corresponding comparative estimates. The protocol was registered in PROSPERO (CRD42024606194). Results Seventeen randomized trials including 8,946 patients and five ADCs—trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), and ARX788—were analyzed. SG and T-DXd showed the least favorable hematologic safety profiles, with SUCRA values for anemia/neutropenia of 22.6%/17.4% and 12.0%/27.0%, respectively. T-DM1-based regimens had the highest risk of thrombocytopenia. For gastrointestinal toxicities, SG ranked worst for diarrhea (SUCRA 6.0%), whereas T-DXd was associated with higher risks of nausea (2.2%), vomiting (7.9%), and decreased appetite (8.6%). In analyses of SAEs, SG had the highest rates of anemia (11.7%) and neutropenia (8.5%), while gastrointestinal SAEs occurred more frequently with T-DXd. Conclusions This network meta-analysis highlights clinically meaningful differences in ADC safety profiles and may help guide individualized toxicity management in breast cancer.

ABSTRACT Purpose We studied histologic Ewing sarcoma (ES) tumor response at local control surgery to explore associations between histologic response and chemotherapy practice changes over time and confirm its prognostic significance in the modern era. Methods We reviewed clinical data for 126 patients with ES treated at Mayo Clinic from 1977 to 2022, analyzing the percentage necrosis as a prognostic factor across chemotherapy regimens (including modern interval‐compressed VDC‐IE). Results In the historical cohort, 5‐year event‐free survival (EFS) and overall survival (OS) for patients with ≤5% versus greater than 5% viable tumor were 76% versus 59% ( p = 0.01) and 83% versus 62% ( p = 0.01). Review of 104 specimens by two pathologists identified the percentage remaining viable tumor as more reproducible than the percentage necrosis and/or fibrosis. On multivariable analysis of patients with localized disease ( n = 87), pelvic tumors and greater than 5% viable tumor remained independent risk factors for poor survival (EFS: hazard ratio [HR] 3.1, p < 0.01; OS: HR 2.1, p = 0.048). The modern cohort consisted of 22 patients. No patients with tumor size less than 8 cm at diagnosis and 100% necrosis after surgery had events; four of seven with tumors greater than 8 cm had events despite 100% necrosis. Conclusions Our results validate the historical threshold of greater than 5% viable tumor with older chemotherapy regimens but not with modern interval‐compressed VDC‐IE. In addition, inter‐rater reliability for the percentage viable is more reproducible than the percentage necrosis. Although numbers are small, tumors less than 8 cm with no viable tumor appear to be a favorable subgroup and suggest risk stratification using a combination of tumor size and any viable tumor should be evaluated in ES.

Background: Myxofibrosarcomas are notoriously highly infiltrative soft-tissue sarcomas, making negative surgical margins difficult to obtain. Recently, vacuum-assisted closure (VAC) is used to delay wound closure until a negative margin has been achieved; however, this can delay care and increase costs. Our institution has historically performed single-stage resections with intraoperative frozen margin analysis and reconstruction in these patients. The purpose of this study is to report the outcomes of this technique. Methods: We reviewed 112 patients (62 males, mean age 70 ± 14 years) with superficial myxofibrosarcoma. Eighty-eight patients received preoperative radiation. All patients underwent surgical resection with intraoperative frozen margin analysis, and the planned reconstruction was performed in a single anesthetic. Results: The 10-year local recurrence-free survival was 90%; positive intraoperative frozen section (HR 7.44, p = 0.004) and final permanent margins (HR 8.53, p = 0.007) were associated with local recurrence. Intraoperative margins were negative in 103 (92%) of patients, 1 of which was positive on final permanent section. There were nine cases of microscopically positive margins, of which seven underwent immediate re-excision to a negative margin. The accuracy of frozen margin assessment for myxofibrosarcoma was between 92.92 and 98.23%. All patients underwent reconstruction at the time of resection, with 19% needing an additional procedure, most commonly due to a wound complication (12%). Conclusions: Multidisciplinary single-stage excision with intraoperative frozen margin assessment and soft-tissue reconstruction yields low rates of local recurrence in patients with superficial myxofibrosarcoma.

Objectives: To evaluate the clinical heterogeneity of sarcomas by examining associations between histological subtypes, metastatic patterns, treatment modalities, and survival outcomes. Methods: We analyzed data from 97,062 adult patients diagnosed with sarcoma between 2000 and 2020, using the Surveillance, Epidemiology, and End Results (SEER) database. Fourteen histological subtypes were included. Propensity score matching (PSM) was employed to adjust for baseline differences, and Cox proportional hazards models were used to identify prognostic variables. Results: The most prevalent subtypes were sarcoma not otherwise specified (31.9%), leiomyosarcoma (17.1%), and liposarcoma (13.9%). Metastatic patterns differed significantly by subtype; liver metastases were most common in sarcomas with small blue round cell (SBRC) features (8.9%) and stromal sarcoma (6.1%), while lung metastases were frequently observed in Ewing sarcoma (10.0%) and rhabdomyosarcoma (9.7%). Median overall survival (mOS) varied widely, ranging from 234 months in chondrosarcoma to 16–20 months in rhabdomyosarcoma and SBRC sarcoma. Overall, patients with primary sarcoma had significantly better survival than those with treatment-related disease (119.0 vs. 45.0 months, p < 0.0001), with this trend consistent across most subtypes. Treatment responses were subtype- and size-dependent. For instance, surgery plus radiotherapy improved outcomes in giant cell sarcoma regardless of tumor size, whereas chemotherapy provided benefit only in tumors larger than 5 cm. Combined surgery and radiotherapy offered additional survival benefit in select subtypes, including chordoma, leiomyosarcoma (>5 cm), and synovial sarcoma (<5 cm). Conclusions: Sarcomas exhibit substantial clinical and prognostic heterogeneity across histological subtypes. These findings underscore the importance of subtype-specific, individualized treatment strategies in optimizing patient outcomes.

Background: Myxoid liposarcoma predominantly affects young and middle-aged individuals, and little is known regarding treatment tolerability and outcomes in older patients. This study aims to better understand this older patient population. Methods: This single institution retrospective study included patients aged 70 years and older with localized (non-metastatic) myxoid liposarcoma. Results: Sixteen patients were included. The median age was 75 years, and 9 (56%) were female. Fourteen (88%) were extremity tumors and two (12%) were trunk. The median tumor size was 10.4 cm (range, 3.6 to 28 cm). Five (31%) tumors had a round cell component. All patients had surgery. Fourteen (88%) had perioperative radiation, and three (19%) had perioperative chemotherapy. One patient had postoperative infection, and one patient had neutropenic fever from preoperative chemotherapy. The median follow up from surgery was 6.3 years. Eight (50%) patients died from MLPS. The median relapse-free survival and overall survival were 34 months and 75 months, respectively. Conclusions: Most older patients with localized MLPS received perioperative radiation therapy with surgery, and few serious toxicities were reported. Even with treatment, half of the patients relapsed.

Background: Synovial sarcoma is rare and may present as a small, slow-growing mass. These tumors are often mistaken as benign and are therefore prone to unplanned and/or non-oncologic excision. We sought to identify the rate of unplanned excision of synovial sarcoma and risk factors for recurrence and survival among this cohort. Methods: The medical records of 246 patients evaluated at a single institution for synovial sarcoma between 1997 and 2022 were retrospectively reviewed. Of these, 87 (35%) underwent unplanned, non-oncologic excision. The mean age of the cohort was 49 years. Primary tumors were located in the extremity (n = 63), abdomen (n = 6), thorax (n = 7), head/neck (n = 8), and paraspinal region (n = 3). The median maximum pre-treatment dimension of the primary tumor was 4.8 cm (IQR 7–2.4). Seventy-seven (86%) patients underwent re-excision of the tumor bed, 39 (45%) received chemotherapy, and 63 (72%) received radiation therapy. Results: Among patients who underwent unplanned excision, local recurrence-free survival (LRFS) was 98% at 1 year and 82% at 5 years. Metastasis-free survival (MFS) was 91% at 1 year and 72% at 5 years. Disease-specific survival (DSS) was 98% at 1 year and 72% at 5 years. When adjusting for tumor size, tumors which underwent unplanned excision did not have worse recurrence or survival compared to those which had planned excision (p > 0.10). Size > 5 cm, monophasic subtype, and axial location were associated with increased risk of disease recurrence. Forty-six patients had residual tumor following re-excision, which was associated with worse MFS (HR 8.17, 95% CI [1.89, 35.2], p < 0.01) and DSS (HR 7.66, 95% CI [1.76, 33.4], p < 0.01). Patients who received radiotherapy had improved MFS (HR 6.4, 95% CI [1.42, 29.0], p = 0.02) and DSS (HR 5.86, 95% CI [1.27, 26.9], p = 0.02). Conclusions: One-third of patients presenting with synovial sarcoma were diagnosed after unplanned, non-oncologic excision. Patients with large, axial tumors had worse survival. Approximately half of patients who underwent unplanned excision had no residual tumor after pre-operative radiation. The use of radiation was associated with decreased rates of recurrence and improved disease-specific survival. Our results suggest that margin-negative re-resection and radiotherapy should be considered when feasible following unplanned excision of synovial sarcoma.

Abstract Background Radiation‐associated soft tissue sarcomas (RA‐STS) are rare complications of patients receiving radiation therapy (RT) and are generally associated with a poor prognosis. Most of the literature surrounding RA‐STS of the chest is centered on angiosarcoma. Therefore, we aim to document the management and outcome of patients with non‐angiosarcoma RA‐STS of the chest. Methods We reviewed 17 patients (all female, median age 65 years) diagnosed with RA‐STS. The most common primary malignancy was breast carcinoma ( n = 15), with a median RT dose of 57.9 Gy. All patients underwent surgical resection; five patients (29%) received radiotherapy; and five patients (29%) received peri‐operative chemotherapy. Results The 5‐year local recurrence and metastatic‐free survival were 61% and 60%, while the 5‐year disease‐specific survival was 53%. Local recurrence was associated with death due to disease (HR 9.06, p = 0.01). Complications occurred in nine of patients, most commonly due to a wound complication ( n = 7). At the most recent follow‐up, the median Musculoskeletal Tumor Society Score was 63%. Conclusion RA‐STS involving the chest wall are aggressive tumors with a high risk of local relapse and death due to disease. Local recurrence was associated with death due to disease; as such, we recommend aggressive surgical management with evaluation for adjuvant therapies.

Background: Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. Methods: We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. Results: A total of 471 patients with lung cancer were included, of which 402 had non–small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69–16.92; P<.001; and HR, 2.81; 95% CI, 1.50–5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17–18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3–5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. Conclusions: Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.