Immunological responses to brain metastasis stereotactic radiosurgery in patient-matched longitudinal blood and tumour samples.

Background: Stereotactic radiosurgery (SRS) is highly effective as focal treatment for brain metastases (BrMs), but whether it can promote anti-tumour immune responses that synergise with immunotherapy remains unclear. We investigated this by examining blood samples from a clinical trial for HER2-amplified breast cancer (HER2-BC) BrMs, matched with longitudinal HER2-BC BrM samples resected from the same location in the same patient. Methods: Blood samples from 10 patients taken pre- and 7-14 days post-SRS were analysed by mass and flow cytometry. One patient received pre-operative SRS for a BrM that recurred 7 months after resection, followed by planned re-resection 8 days post-SRS. Pre- and post-SRS tumours from this patient were analysed by bulk RNAseq, multiplex immunohistochemistry (mIHC), and TCR sequencing. Results: Monocytes, central memory CD8+ T and regulatory T cells were enriched in blood post-SRS, together with increased MHC-II expression on monocytes, conventional DCs, and monocytic MDSCs. In tumour, SRS upregulated antigen presentation, T cell proliferation and T cell co-stimulation signatures, alongside an influx of tumour-associated macrophages (TAMs) and CD4+ T cells. Specifically, TAMs and CD4+ T cells, but not CD8+ T cells, demonstrated spatial co-localisation post-SRS. These TAMs were lowly PD-L1 expressing, but CD4+ T cells showed increased PD-1 expression. A sizeable proportion of T cell clonotypes were retained post-SRS, and four clones demonstrated significant, non-stochastic expansion. Conclusion: Systemic and local immunological changes in this homogenous patient cohort suggest that SRS may facilitate MHC-II-restricted T cell priming responses involving the monocyte-macrophage lineage and CD4+ T cells, which should be further explored.

Stereotactic Body Radiation Therapy for Primary Lung Cancer and Metastases: A Case Based Discussion on Challenging Cases.

PURPOSE: Data informing the safety, efficacy, treatment logistics, and dosimetry of stereotactic body radiation therapy (SBRT) for lung tumors has primarily been derived from patients with favorably located solitary tumors. SBRT is now considered a standard-of-care treatment for inoperable early-stage non-small cell lung cancer and lung metastases, and therefore extrapolation beyond this limited foundational patient population remains an active source of interest. MATERIALS AND METHODS: This case-based discussion provides a practical framework for delivering SBRT to challenging, yet frequently encountered, cases in radiation oncology. The cases highlighted herein include the use of SBRT for ultracentral tumors, multiple tumors, and re-irradiation. Patient characteristics, fractionation, prescription dose, treatment technique, and dose constraints were discussed. Relevant literature to these cases was summarized to provide a framework for the treatment of similar patients. RESULTS: Treatment of challenging cases with lung SBRT requires many considerations, including treatment intent, fractionation selection, tumor localization, and plan optimization. In such scenarios, patient selection is critical to understanding the risk-benefit profile of an SBRT approach despite significant advances in delivery techniques and safety. CONCLUSIONS: A case-based discussion was developed by the Radiosurgery Society to provide a practical guide to the common challenging scenarios noted above affecting patients with lung tumors. A multidisciplinary approach should guide the treatment of such cases to maximize the therapeutic window.

Biology-guided radiotherapy in metastatic prostate cancer: time to push the envelope?

The therapeutic landscape of metastatic prostate cancer has undergone a profound revolution in recent years. In addition to the introduction of novel molecules in the clinics, the field has witnessed a tremendous development of functional imaging modalities adding new biological insights which can ultimately inform tailored treatment strategies, including local therapies. The evolution and rise of Stereotactic Body Radiotherapy (SBRT) have been particularly notable in patients with oligometastatic disease, where it has been demonstrated to be a safe and effective treatment strategy yielding favorable results in terms of disease control and improved oncological outcomes. The possibility of debulking all sites of disease, matched with the ambition of potentially extending this treatment paradigm to polymetastatic patients in the not-too-distant future, makes Biology-guided Radiotherapy (BgRT) an attractive paradigm which can be used in conjunction with systemic therapy in the management of patients with metastatic prostate cancer.

Deformation behavior of thermally rejuvenated Zr-Cu-Al-(Ti) bulk metallic glass.

The deformation behavior of metallic glasses has been shown in prior studies to be often dependent on its structural state, namely higher energy "rejuvenated" state versus lower energy "relaxed" state. Here, the deformation behavior of thermally rejuvenated Zr-Cu-Al-(Ti) bulk metallic glasses (BMGs) was evaluated. Rejuvenation was achieved by cryogenic thermal cycling with increase of free volume measured in terms of enthalpy of relaxation. Hardness, stiffness, and yield strength of the BMGs were all found to decrease while plasticity increased after rejuvenation. More free volume in the rejuvenated BMG resulted in homogeneous plastic deformation as was evident from the high strain rate sensitivity and more pronounced shear band multiplication during uniaxial compression. Shear transformation zone (STZ) volume was calculated by cooperative shear model and correlated well with the change in structural state after rejuvenation. The enhanced plasticity with the addition of 1 at. % Ti as well as after cryogenic thermal cycling was explained by lower activation energy for shear flow initiation due to increased heterogeneity induced in the system. Molecular dynamics simulation demonstrated that the variation in plastic deformation behavior is correlated with local atomic structure changes.

Focal therapy for oligometastatic and oligoprogressive renal cell carcinoma: a narrative review.

Metastatic renal cell carcinoma (RCC) can present with oligometastatic disease and/or develop oligoprogression following systemic therapy. Cytoreductive and focal metastasis-directed therapy options include resection, stereotactic ablative radiation and thermal ablation. Aggressive focal therapy may allow delay in initiation of or modification to systemic therapy and improve clinical outcomes. In this narrative review we synthesize current practice guidelines and prospective data on focal therapy management options and highlight future research. Patient selection and the choice of focal treatment techniques are controversial due to limited and heterogeneous data and patients may benefit from multidisciplinary evaluation. Prospective comparative trials with clearly defined inclusion criteria and relevant end points are needed to clarify the risks and benefits of different approaches.

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Accelerated hypofractionated radiotherapy for locally-advanced non-small cell lung cancer: A systematic review from the International Association for the Study of Lung Cancer (IASLC) Advanced Radiation Technology (ART) Subcommittee.

INTRODUCTION: Accelerated hypofractionated radiotherapy has gained increasing interest for locally-advanced non-small cell lung cancer (NSCLC), as it can potentially increase radiobiologically effective (RBE) dose and reduce healthcare resource utilization. However, there is sparse prospective evidence supporting routine use of accelerated hypofractionation with or without concurrent chemotherapy. For this reason, the International Association for the Study of Lung Cancer (IASLC) Advanced Radiation Technology (ART) Subcommittee conducted a systematic review of prospective studies of accelerated hypofractionation for locally-advanced NSCLC. METHODS: A systematic search was conducted on Ovid MEDLINE, Ovid Embase, Wiley Cochrane Library, and ClinicalTrials.gov for English publications from 2010 to 2024 for prospective clinical trials and registries investigating accelerated hypofractionated radiotherapy defined as >2 Gy delivered over 10-25 fractions for non-metastatic locally-advanced (Stage III) NSCLC. RESULTS: There were 33 prospective studies identified that met criteria for inclusion. Of 14 prospective studies evaluating definitive accelerated hypofractionation (without concurrent chemotherapy), there were 6 prospective registries, 7 Phase 1-2 trials, and 1 Phase 3 randomized clinical trial (RCT), with a median dose of 60 Gy delivered in a median of 16 fractions, median progression free survival 6.4-25 months, median survival 6-34 months, and 0-8% severe grade ≥ 3 esophagitis. There were 19 studies evaluating accelerated hypofractionated chemoradiation with platinum doublet-based chemotherapy as the most common concurrent regimen. Of these accelerated hypofractionated chemoradiation studies, there were 18 Phase 1-2 trials and one prospective registry with a median radiation dose of 61.6 Gy delivered in a median of 23 fractions, median PFS 10-25 months, median survival 13-38 months, grade ≥ 3 esophagitis 0-23.5% and grade ≥ pneumonitis 0-11.8%. CONCLUSION: Despite the increasing use of accelerated hypofractionation for locally-advanced NSCLC, the supporting randomized evidence remains sparse. Only one RCT comparing 60 Gy in 15 fractions with 60 Gy in 30 fractions without concurrent chemotherapy did not demonstrate the superiority of accelerated hypofractionation. Therefore, the use of accelerated hypofractionated radiotherapy approached with caution, utilizing advanced radiation techniques, especially with concurrent chemotherapy or targeted agents. Accelerated hypofractionated radiotherapy should be carefully considered alongside other multidisciplinary options and be further investigated through prospective clinical trials.

Radiosurgery Society Case-Based Guide to Stereotactic Body Radiation Therapy for Challenging Cases of Spinal Metastases.

PURPOSE: Spinal stereotactic body radiation therapy (SBRT) has become the standard of care in management of patients with limited sites of metastatic disease, radioresistant histologies, painful vertebral metastases with long life expectancy and cases of reirradiation. Our case-based guidelines aim to assist radiation oncologists in the appropriate utilization of SBRT for common, yet challenging, cases of spinal metastases. METHODS AND MATERIALS: Cases were selected to include scenarios of large volume sacral disease with nerve entrapment, medically inoperable disease abutting the thecal sac, and local failure after prior SBRT. Relevant literature was reviewed, and areas requiring further investigation were discussed to offer a framework for evidence-based clinical practice. RESULTS: Spinal SBRT can be effectively delivered in challenging cases following multidisciplinary discussion by using a methodical approach to patient selection, appropriate dose selection, and adherence to evidence-based dose constraints. CONCLUSIONS: The Radiosurgery Society's case-based practice review offers guidance to practicing physicians treating technically challenging SBRT candidate patients with spinal metastases.

Evolving Paradigms in Prostate Cancer: The Integral Role of Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography in Primary Staging and Therapeutic Decision-Making.

Prostate-specific membrane antigen (PSMA) positron emission tomography or computed tomography (PET/CT) has emerged as a superior imaging option to conventional imaging for prostate cancer. The majority of early evidence and prospective trials evaluated PSMA PET/CT in the biochemical recurrence or metastatic setting. However, there has been an increasing number of prospective trials in the primary setting. The purpose of this narrative review was to describe the role of PSMA PET/CT in localized primary prostate cancer. This narrative review focuses on the prospective evidence available in this setting. We detail the current practice and future potential for PSMA PET/CT to be used in multiple stages of localized primary prostate cancer. The most common practice currently for PSMA PET/CT is in the primary nodal and metastatic staging of high-risk prostate cancer. We describe other roles of PSMA PET/CT, including in intermediate-risk prostate cancer as well as local staging and the impact on radiation therapy and surgical management. We also discuss the potential future roles of PSMA PET/CT in prediagnosis such as risk stratification for biopsy, prognosis, and specific surgical roles. Potential pitfalls of PSMA PET/CT are also addressed. PSMA PET/CT has already had a significant influence on prostate cancer, and there will continue to be a greater role for this imaging modality in localized primary prostate cancer.

Salvage stereotactic ablative body radiotherapy after thermal ablation of primary kidney cancer.

OBJECTIVE: To evaluate the effectiveness and safety of salvage stereotactic ablative body radiotherapy (SABR) for recurrent renal cell carcinoma (RCC) after thermal ablation (TA). MATERIALS AND METHODS: This study was a multi-institutional retrospective analysis of patients with recurrent RCC following TA who received SABR between 2016 and 2020. The primary study outcome was freedom from local failure, evaluated radiographically based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Distant failure, cancer-specific survival (CSS), overall survival (OS), treatment-related toxicity and renal function changes following SABR were the secondary outcomes. The Kaplan-Meier method was used to estimate freedom from local and distant failure, CSS and OS. RESULTS: Seventeen patients with 18 biopsy-confirmed RCCs were included, with a median (interquartile range [IQR]) age at time of SABR of 75.2 (72.6-68.7) years, a median (IQR) tumour size of 3.5 (1.9-4.1) cm and follow-up (reverse Kaplan-Meier method) of 3.36 (95% confidence interval [CI] 1.6-4.1) years. Six of the 17 patients had a solitary kidney. Five patients had failed repeat TA prior to SABR. The median (IQR) time from TA procedure to SABR was 3.03 (1.5-5.1) years. No patient experienced local progression, with a local control rate of 100%. Four patients, two with baseline metastatic disease, experienced distant progression. The distant progression-free survival, CSS and OS at 3 years were 72.1% (95% CI 51.9%-100%), 92.3% (95% CI 78.9%-100%) and 82.1% (95% CI 62.1%-100%), respectively. The median (IQR) glomerular filtration rate before SABR was 58 (40-71) mL/min, and at last follow-up, it was 48 (33-57) mL/min. No patient experienced grade 3+ toxicity or went on to develop end-stage renal disease. CONCLUSION: The results showed that SABR appears to be an effective and safe salvage strategy in patients with recurrent RCC following TA.

Long-term Renal Function Outcomes After Stereotactic Ablative Body Radiotherapy for Primary Renal Cell Carcinoma Including Patients with a Solitary Kidney: A Report from the International Radiosurgery Oncology Consortium of the Kidney.

BACKGROUND AND OBJECTIVE: Renal function preservation is particularly important following nonoperative treatment of localized renal cell carcinoma (RCC) since patients are often older with medical comorbidities. Our objective was to report long-term renal function outcomes after stereotactic ablative radiotherapy (SABR) including patients with a solitary kidney. METHODS: Patients with primary RCC treated with SABR with ≥2 yr of follow-up at 12 International Radiosurgery Consortium for Kidney institutions were included. Renal function was measured by estimated glomerular filtration rate (eGFR). KEY FINDINGS AND LIMITATIONS: In total, 190 patients (56 with a solitary kidney) underwent SABR and were followed for a median of 5.0 yr (interquartile range [IQR]: 3.4-6.8). In patients with a solitary kidney versus bilateral kidneys, pre-SABR eGFR (mean [standard deviation]) was 61.1 (23.2) versus 58.0 (22.3) ml/min (p = 0.32) and the median tumor size was 3.65 cm (IQR: 2.59-4.50 cm) versus 4.00 cm (IQR: 3.00-5.00 cm; p = 0.026). At 5 yr after SABR, eGFR decreased by -14.5 (7.6) and -13.3 (15.9) ml/min (p = 0.67), respectively, and there were similar rates of post-SABR dialysis (3.6% [n = 2/56] vs 3.7% [n = 5/134]). A multivariable analysis demonstrated that increasing tumor size (odds ratio [OR] per 1 cm: 1.57; 95% confidence interval [CI]: 1.14-2.16, p = 0.0055) and baseline eGFR (OR per 10 ml/min: 1.30; 95% CI: 1.02-1.66, p = 0.034) were associated with an eGFR decline of ≥15 ml/min at 1 yr. CONCLUSIONS AND CLINICAL IMPLICATIONS: With long-term follow-up after SABR, kidney function decline remains moderate, with no observed difference between patients with a solitary kidney and bilateral kidneys. Tumor size and baseline eGFR are dominant factors predictive of long-term renal function decline. PATIENT SUMMARY: With long-term follow-up, stereotactic ablative radiotherapy (SABR) yields moderate long-term renal function decline and low dialysis rates even in patients with a solitary kidney. SABR thus represents a promising noninvasive, nephron-sparing option for patients with localized renal cell carcinoma.

A multi-centre retrospective study of long-term outcomes of spinal re-irradiation with SABR.

INTRODUCTION: Stereotactic ablative body radiotherapy (SABR) is a highly conformal technique utilising a high dose per fraction commonly employed in the re-treatment of spinal metastases. This study sought to determine the safety and efficacy of re-irradiation with SABR to previously treated spinal metastases. METHODS: This was a retrospective analysis of patients at three Australian centres who have undergone spinal SABR after previous spinal radiotherapy to the same or immediately adjacent vertebral level. Efficacy was determined in terms of rates of local control, while safety was characterised by rates of serious complications. RESULTS: Thirty-three spinal segments were evaluated from 32 patients. Median follow-up for all patients was 2.6 years, and median overall survival was 4.3 years. Eleven of 33 (33.3%) treated spinal segments had local progression, with a local control rate at 12 months of 71.4% (95% C.I. 55.2%-92.4%). Four patients (16.7%) went on to develop cauda equina or spinal cord compression. Thirteen out of 32 patients (40.6%) experienced acute toxicity, of which 12 were grade 2 or less. Five out of 30 spinal (16.7%) segments with follow-up imaging had a radiation-induced vertebral compression fracture. There was one case of radiation myelitis which occurred in a patient who had mediastinal radiotherapy with a treatment field which overlapped their prior spinal radiation. CONCLUSION: The patients in this study experienced long median survival, durable tumour control and high rates of freedom from long-term sequelae of treatment. These results support the use of SABR in patients who progress in the spine despite previous radiotherapy.

Living with low muscle mass and its impact throughout curative treatment for lung cancer: A qualitative study.

OBJECTIVES: To 1) explore the experience of patients with lung cancer with low muscle mass or muscle loss during treatment and the ability to cope with treatment, complete self-care, and 2) their receptiveness and preferences for nutrition and exercise interventions to halt or treat low muscle mass/muscle loss. METHODS: This was a qualitative study using individual semi-structured interviews conducted using purposive sampling in adults with a diagnosis of non-small cell lung cancer (NSCLC) or small-cell lung cancer (SCLC), treated with curative intent chemo-radiotherapy or radiotherapy. Patients who presented with computed tomography-assessed low muscle mass at treatment commencement or experienced loss of muscle mass throughout treatment were included. Data were analysed using thematic analysis. RESULTS: Eighteen adults (mean age 73 ± SD years, 61% male) with NSCLC (76%) treated with chemo-radiotherapy (76%) were included. Three themes were identified: 1) the effect of cancer and its treatment; 2) engaging in self-management; and 3) impact and influence of extrinsic factors. Although experiences varied, substantial impact on day-to-day functioning, eating, and ability to be physically active was reported. Patients were aware of the overall importance of nutrition and exercise and engaged in self-initiated or health professional supported self-management strategies. Early provision of nutrition and exercise advice, guidance from health professionals, and support from family and friends were valued, albeit with a need for consideration of individual circumstances. CONCLUSION: Adults with NSCLC with or experiencing muscle loss described a diverse range of experiences regarding treatment. The types of support required were highly individual, highlighting the crucial role of personalised assessment of needs and subsequent intervention.

Stereotactic Body Radiation Therapy for Primary Renal Cell Carcinoma: A Case-Based Radiosurgery Society Practice Guide.

Traditionally, renal cell carcinoma (RCC) was considered a radioresistant tumor, thereby limiting definitive radiation therapy management options. However, several recent studies have demonstrated that stereotactic body radiation therapy (SBRT) can achieve high rates of local control for the treatment of primary RCC. In the setting of expanding use of SBRT for primary RCC, it is crucial to provide guidance on practical considerations such as patient selection, fractionation, target delineation, and response assessment. This is particularly important in challenging scenarios where a paucity of evidence exists, such as in patients with a solitary kidney, bulky tumors, or tumor thrombus. The Radiosurgery Society endorses this case-based guide to provide a practical framework for delivering SBRT to primary RCC, exemplified by 3 cases. This article explores topics of tumor size and dose fractionation, impact on renal function and treatment in the setting of a solitary kidney, and radiation's role in the management of inferior vena cava tumor thrombus. Additionally, we review existing evidence and expert opinion on target delineation, advanced techniques such as magnetic resonance imaging guided SBRT, and SBRT response assessment.

Artificial intelligence-assisted quantitative CT analysis of airway changes following SABR for central lung tumors.

INTRODUCTION: Use of stereotactic ablative radiotherapy (SABR) for central lung tumors can result in up to a 35% incidence of late pulmonary toxicity. We evaluated an automated scoring method to quantify post-SABR bronchial changes by using artificial intelligence (AI)-based airway segmentation. MATERIALS AND METHODS: Central lung SABR patients treated at Amsterdam UMC (AUMC, internal reference dataset) and Peter MacCallum Cancer Centre (PMCC, external validation dataset) were identified. Patients were eligible if they had pre- and post-SABR CT scans with ≤ 1 mm resolution. The first step of the automated scoring method involved AI-based airway auto-segmentation using MEDPSeg, an end-to-end deep learning-based model. The Vascular Modeling Toolkit in 3D Slicer was then used to extract a centerline curve through the auto-segmented airway lumen, and cross-sectional measurements were computed along each bronchus for all CT scans. For AUMC patients, airway stenosis/occlusion was evaluated by both visual assessment and automated scoring. Only the automated method was applied to the PMCC dataset. RESULTS: Study patients comprised 26 from AUMC, and 33 from PMCC. Visual scoring identified stenosis/occlusion in 8 AUMC patients (31 %), most frequently in the segmental bronchi. After airway auto-segmentation, minor manual edits were needed in 9 % of patients. Segmentation for a single scan averaged 83sec (range 73-136). Automated scoring nearly doubled detected airway stenosis/occlusion (n = 15, 58 %), and allowed for earlier detection in 5/8 patients who had also visually scored changes. Estimated rates were 48 % and 66 % at 1- and 2-years, respectively, for the internal dataset. The automated detection rate was 52 % in the external dataset, with 1- and 2-year risks of 56 % and 61 %, respectively. CONCLUSION: An AI-based automated scoring method allows for detection of more bronchial stenosis/occlusion after lung SABR, and at an earlier time-point. This tool can facilitate studies to determine early airway changes and establish more reliable airway tolerance doses.

Emerging Novel Functional Imaging and Immunotherapy in Renal Cell Carcinoma and Current Treatment Sequencing Strategies After Immunotherapy.

The management of renal cell carcinoma (RCC) has advanced significantly in the past two decades. Many promising functional imaging modalities such as radiolabeled tracer targeting carbonic anhydrase IX and prostate-specific membrane antigen are under development to detect primary kidney tumors, stage systemic disease, and assess treatment response in RCC. Immune checkpoint inhibitors targeting PD-1 and cytotoxic T-cell lymphocyte-4 have changed the treatment paradigm in advanced RCC. Trials investigating novel mechanisms such as LAG-3 immune checkpoint inhibition, chimeric antigen receptor T-cell therapies, and T-cell engagers targeting RCC-associated antigens are currently ongoing. With the rapidly changing treatment landscape of RCC, the treatment sequence strategies will continue to evolve. Familiarity with the toxicities associated with the therapeutic agents and how to manage them are essential to achieve optimal patient outcomes. This review summarizes the recent developments of functional imaging and immunotherapy strategies in RCC, and the evidence supports treatment sequencing.

Optimal management of radiation pneumonitis: Findings of an international Delphi consensus study.

PURPOSE: Radiation pneumonitis (RP) is a dose-limiting toxicity for patients undergoing radiotherapy (RT) for lung cancer, however, the optimal practice for diagnosis, management, and follow-up for RP remains unclear. We thus sought to establish expert consensus recommendations through a Delphi Consensus study. METHODS: In Round 1, open questions were distributed to 31 expert clinicians treating thoracic malignancies. In Round 2, participants rated agreement/disagreement with statements derived from Round 1 answers using a 5-point Likert scale. Consensus was defined as ≥ 75 % agreement. Statements that did not achieve consensus were modified and re-tested in Round 3. RESULTS: Response rate was 74 % in Round 1 (n = 23/31; 17 oncologists, 6 pulmonologists); 82 % in Round 2 (n = 19/23; 15 oncologists, 4 pulmonologists); and 100 % in Round 3 (n = 19/19). Thirty-nine of 65 Round 2 statements achieved consensus; a further 10 of 26 statements achieved consensus in Round 3. In Round 2, there was agreement that risk stratification/mitigation includes patient factors; optimal treatment planning; the basis for diagnosis of RP; and that oncologists and pulmonologists should be involved in treatment. For uncomplicated radiation pneumonitis, an equivalent to 60 mg oral prednisone per day, with consideration of gastroprotection, is a typical initial regimen. However, in this study, no consensus was achieved for dosing recommendation. Initial steroid dose should be administered for a duration of 2 weeks, followed by a gradual, weekly taper (equivalent to 10 mg prednisone decrease per week). For severe pneumonitis, IV methylprednisolone is recommended for 3 days prior to initiating oral corticosteroids. Final consensus statements included that the treatment of RP should be multidisciplinary, the uncertainty of whether pneumonitis is drug versus radiation-induced, and the importance risk stratification, especially in the scenario of interstitial lung disease. CONCLUSIONS: This Delphi study achieved consensus recommendations and provides practical guidance on diagnosis and management of RP.