A Pilot Study of Pembrolizumab Combined With Stereotactic Ablative Radiotherapy for Patients With Advanced or Metastatic Sarcoma.

OBJECTIVES: Immunotherapy with immune checkpoint inhibitors has shown only limited success in the management of metastatic soft tissue sarcoma. Overall response rates (ORR) with single agent pembrolizumab were 18% and median PFS was 18 weeks on the clinical trial SARC028. One strategy to improve the responses to immunotherapy is with stereotactic body radiation therapy (SBRT), which can enhance the antitumor CD8 T cell response through the release of tumor-specific antigens, potentially priming a more diverse class of T cell receptors. METHODS: This is a phase 0, pilot prospective study taking place at a single center with 2 arms. In Arm A, patients are treated with pembrolizumab 400 mg IV infusion on day 1 of a 42-day cycle. Stereotactic body radiation therapy (SBRT) is delivered in 1-5 fractions starting on C1D15-28 and given every other day. In Arm B, patients who have started an immune checkpoint inhibitor within 60 days are treated with SBRT in addition to the current therapy. RESULTS: In this study we outline testing the feasibility of adding SBRT to pembrolizumab. CONCLUSION: The ultimate goal of combination therapy is improved overall response, including tumors not treated with SBRT. This trial can be found registered online: NCT05488366.

The Correlation Between Lymphocyte Nadir and Radiation Therapy for Soft Tissue Sarcoma: Defining Key Dosimetric Parameters and Outlining Clinical Significance.

Purpose: The objectives of this study were to identify key dosimetric parameters associated with postradiation therapy lymphopenia and uncover any effect on clinical outcomes. Methods and Materials: This was a retrospective review of 69 patients (between April 2010 and January 2023) who underwent radiation therapy (RT) as a part of curative intent for soft tissue sarcoma (STS) at a single academic institution. All patients with treatment plans available to review and measurable absolute lymphocyte count (ALC) nadir within a year after completion of RT were included. Results: Median follow-up was 22 months after the start of RT. A decrease in lymphocyte count was noted as early as during treatment and persisted at least 3 months after the completion of RT. On multivariable linear regression, the strongest correlations with ALC nadir were mean body dose, body V10 Gy, mean bone dose, bone V10 Gy, and bone V20 Gy. Five-year overall survival was 60% and 5-year disease-free survival was 44%. Advanced T-stage, chemotherapy use, use of intensity-modulated RT, lower ALC nadir, and the development of grade ≥2 lymphopenia at nadir were associated with worse overall survival and disease-free survival. Conclusions: Post-RT lymphopenia was associated with worse outcomes in STS. There were associations between higher body V10 Gy and bone V10 Gy and lower post-RT ALC nadir, despite the varying sites of STS presentation, which aligns with the well-known radiosensitivity of lymphocyte cell lines. These findings support efforts to reduce treatment-related hematopoietic toxicity as a way to improve oncologic outcomes. Additionally, this study supports the idea that the effect of radiation on lymphocyte progenitors in the bone marrow is more significant than that on circulating lymphocytes in treatments with limited involvement of the heart and lung.

Severity of Financial Toxicity for Patients Receiving Palliative Radiation Therapy.

Introduction: Financial toxicity has negative implications for patient well-being and health outcomes. There is a gap in understanding financial toxicity for patients undergoing palliative radiotherapy (RT). Methods: A review of patients treated with palliative RT was conducted from January 2021 to December 2022. The FACIT-COST (COST) was measured (higher scores implying better financial well-being). Financial toxicity was graded according to previously suggested cutoffs: Grade 0 (score ≥26), Grade 1 (14-25), Grade 2 (1-13), and Grade 3 (0). FACIT-TS-G was used for treatment satisfaction, and EORTC QLQ-C30 was assessed for global health status and functional scales. Results: 53 patients were identified. Median COST was 25 (range 0-44), 49% had Grade 0 financial toxicity, 32% Grade 1, 15% Grade 2, and 4% Grade 3. Overall, cancer caused financial hardship among 45%. Higher COST was weakly associated with higher global health status/Quality of Life (QoL), physical functioning, role functioning, and cognitive functioning; moderately associated with higher social functioning; and strongly associated with improved emotional functioning. Higher income or Medicare or private coverage (rather than Medicaid) was associated with less financial toxicity, whereas an underrepresented minority background or a non-English language preference was associated with greater financial toxicity. A multivariate model found that higher area income (HR .80, P = .007) and higher cognitive functioning (HR .96, P = .01) were significantly associated with financial toxicity. Conclusions: Financial toxicity was seen in approximately half of patients receiving palliative RT. The highest risk groups were those with lower income and lower cognitive functioning. This study supports the measurement of financial toxicity by clinicians.

Controversies in Lung Cancer: Heterogeneity in Treatment Recommendations for Stage III NSCLC According to Disease Burden and Oncogenic Driver Alterations.

INTRODUCTION: Therapeutic options for stage III non-small-cell lung cancer (NSCLC) consist of definitive chemoradiation, surgery combined with neoadjuvant/adjuvant chemotherapy, and trimodality therapy. More recently, biologically driven systemic therapy options, including immunotherapy and targeted therapy, have become increasingly available. METHODS: A customized, case-based survey was designed and distributed to members of the International Association for the Study of Lung Cancer (IASLC) to determine practice habits and preferences for NSCLC patients with stage III disease and N2 to N3 nodal involvement. RESULTS: Data were compiled from 87 respondents from 31 countries, including medical oncologists (49%), surgical oncologists (24%), and radiation oncologists (21%). Definitive chemoradiation was more likely to be recommended for stage IIIC (98.2%) or stage IIIB (75.8%) scenarios compared with stage IIIA (59.6%) without actionable driver alterations (P < .0001 and .0003, respectively); and chemoradiation was more likely for stage IIIB (57.7%) compared to stage IIIA (39.9%) with actionable EGFR/ALK alterations (P = .008). Surgery was more likely to be recommended in the presence of an actionable alteration (38.7% vs. 19%, P < .0001). Surgeons were more likely than medical oncologists to recommend surgical approaches in scenarios without actionable alterations (25.6% vs. 11.2%, P < .0001) or with actionable alterations (57.5% vs. 31.1%, P = .0001). DISCUSSION: The dominant recommended strategy for stage III NSCLC was chemoradiation, although respondents were more likely to recommend surgical approaches in the presence of actionable alterations. Despite the lack of reported clinical trial data, many IASLC lung cancer experts favored targeted therapy when actionable driver alterations were present.

Evaluating radiocarpal cartilage matrix changes 3-months after anti-TNF treatment for rheumatoid arthritis using MR T1ρ imaging.

PURPOSE: To evaluate the feasibility of MR T1ρ in assessing radiocarpal cartilage matrix changes following rheumatoid arthritis (RA) treatment. MATERIALS AND METHODS: Five healthy controls and nine RA patients were studied: three RA patients with low disease activity that were treated with methotrexate (MTX) alone and six with active disease despite MTX treatment who were additionally treated with certolizumab pegol, an anti-tumor necrosis factor biologic. Wrist 3 Tesla MRI were acquired at baseline and 3-month follow-up. T1ρ were quantified for lunar, radius, and scaphoid cartilage. Reproducibility was evaluated using coefficients of variation (CV). Longitudinal changes were evaluated with t-test and relationships between T1ρ with clinical, MRI, and patient-reported outcomes were evaluated with Spearman's rho. RESULTS: Scan/re-scan CVs of T1ρ values were all <5%, and intra- and inter-reader CVs were all < 2.0%. Baseline scaphoid T1ρ values were significantly higher in RA patients compared with healthy controls (P = 0.032). Changes in T1ρ (baseline, 3-month) were correlated with EULAR treatment response criteria: -2.26 ± 0.75 ms, 1.08 ± 0.52 ms, and 2.18 ± 0.45 ms for good, moderate, and nonresponders, respectively. Significant correlations were found between changes in global T1ρ values and changes in DAS28-CRP (rs = 0.683; P = 0.042), MHQ (rs = -0.783; P = 0.013), and HAQ (rs = 0.833; P = 0.010). CONCLUSION: Despite the limited sample size and follow-up time points, there were significant correlations between changes in radiocarpal T1ρ and changes in disease activity as assessed by clinical and patient-reported outcomes. Our findings encourage further research into MR T1ρ assessment of RA disease activity and treatment response. LEVEL OF EVIDENCE: 1 J. MAGN. RESON. IMAGING 2017;45:1514-1522.

High-temporospatial-resolution dynamic contrast-enhanced (DCE) wrist MRI with variable-density pseudo-random circular Cartesian undersampling (CIRCUS) acquisition: evaluation of perfusion in rheumatoid arthritis patients.

This study is to evaluate highly accelerated three-dimensional (3D) dynamic contrast-enhanced (DCE) wrist MRI for assessment of perfusion in rheumatoid arthritis (RA) patients. A pseudo-random variable-density undersampling strategy, circular Cartesian undersampling (CIRCUS), was combined with k-t SPARSE-SENSE reconstruction to achieve a highly accelerated 3D DCE wrist MRI. Two healthy volunteers and 10 RA patients were studied. Two patients were on methotrexate (MTX) only (Group I) and the other eight were treated with a combination therapy of MTX and anti-tumor necrosis factor (TNF) therapy (Group II). Patients were scanned at baseline and 3 month follow-up. DCE MR images were used to evaluate perfusion in synovitis and bone marrow edema pattern in the RA wrist joints. A series of perfusion parameters was derived and compared with clinical disease activity scores of 28 joints (DAS28). 3D DCE wrist MR images were obtained with a spatial resolution of 0.3 × 0.3 × 1.5 mm(3) and temporal resolution of 5 s (with an acceleration factor of 20). The derived perfusion parameters, most notably transition time (dT) of synovitis, showed significant negative correlations with DAS28-ESR (r = -0.80, p < 0.05) and DAS28-CRP (r = -0.87, p < 0.05) at baseline and also correlated significantly with treatment responses evaluated by clinical score changes between baseline and 3 month follow-up (with DAS28-ESR r = -0.79, p < 0.05, and DAS28-CRP r = -0.82, p < 0.05). Highly accelerated 3D DCE wrist MRI with improved temporospatial resolution has been achieved in RA patients and provides accurate assessment of neovascularization and perfusion in RA joints, showing promise as a potential tool for evaluating treatment responses.

Assessment of epigenetic contributions to sexually-dimorphic Kiss1 expression in the anteroventral periventricular nucleus of mice.

The Kiss1 gene, which encodes kisspeptin and is critical for reproduction, is sexually differentiated in the hypothalamic anteroventral periventricular (AVPV)/rostral periventricular (PeN) nuclei. Specifically, female rodents have higher AVPV/PeN Kiss1 expression than males, but how this Kiss1 sex difference is induced in early development is poorly understood. Here, we explored the contribution of epigenetic mechanisms to the establishment of the AVPV/PeN Kiss1 sex difference, focusing on histone deacetylation and DNA methylation. First, we utilized postnatal pharmacological blockade of histone deacetylation and analyzed Kiss1 expression in the AVPV/PeN. Postnatal disruption of histone deacetylase modestly increased AVPV Kiss1 cell number in both sexes but did not alter the Kiss1 sex difference. Next, we assessed whether the level of CpG methylation, which can influence transcription factor binding and gene expression, in the murine Kiss1 gene differs between males and females. We found significant sex differences in methylation at several CpG sites in the putative promoter and first intron of the Kiss1 gene in the AVPV/PeN, but not in the arcuate (which lacks adult Kiss1 sex differences), suggesting that differential methylation of the Kiss1 gene may influence sexually-dimorphic Kiss1 expression in the AVPV/PeN. Transgenic impairment of methyl CpG-binding protein-2 function did not eliminate the Kiss1 sex difference, indicating that other methylation factors are involved. Interestingly, CpG methylation in the AVPV/PeN was lower in males than females, suggesting that transcriptional repressors may contribute to the AVPV/PeN Kiss1 sex difference, a possibility supported by in silico identification of putative repressor binding sites near some of the sexually-dimorphic CpG.