Spon1+ inflammatory monocytes promote collagen remodeling and lung cancer metastasis through lipoprotein receptor 8 signaling.

Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) is the most common subset. We previously found that infiltration of tumor inflammatory monocytes (TIMs) into lung squamous carcinoma (LUSC) tumors is associated with increased metastases and poor survival. To further understand how TIMs promote metastases, we compared RNA-Seq profiles of TIMs from several LUSC metastatic models with inflammatory monocytes (IMs) of non-tumor-bearing controls. We identified Spon1 as upregulated in TIMs and found that Spon1 expression in LUSC tumors corresponded with poor survival and enrichment of collagen extracellular matrix signatures. We observed SPON1+ TIMs mediate their effects directly through LRP8 on NSCLC cells, which resulted in TGF-ß1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrated that SPON1+ TIMs were sufficient to promote NSCLC metastases. Additionally, we found that Spon1 loss in the host, or Lrp8 loss in cancer cells, resulted in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirmed the relevance of the SPON1/LRP8/TGF-ß1 axis with collagen production and survival in patients with NSCLC. Taken together, our study describes how SPON1+ TIMs promote collagen remodeling and NSCLC metastases through an LRP8/TGF-ß1 signaling axis.

[Management of bone metastasis in non-small cell lung cancer]. / Prise en charge des métastases osseuses du cancer pulmonaire non à petites cellules.

Lung cancer is notoriously known for its predisposition to metastasize to the bones. Diagnostic tools, including positron emission tomography coupled with computed tomography, offer increased sensitivity in detecting bone infiltration. Management strategies encompass a multidisciplinary approach, including pharmacological pain management, anti-resorptive therapy, radiotherapy, interventional techniques, and surgery. This article provides an in-depth analysis of the incidence and distribution of bone metastases, skeletal-related events (SRE), diagnostic imaging techniques, and contemporary therapeutic strategies to prevent SRE. Systemic anticancer therapy and pain management, although crucial for treating BM, are not discussed in this article.

Le cancer du poumon est notoirement connu pour sa prédisposition à métastaser dans les os. Les outils diagnostiques, notamment la tomographie par émission de positrons couplée à la tomodensitométrie, offrent une sensibilité accrue pour détecter l'infiltration osseuse. Les stratégies de prise en charge englobent une approche multidisciplinaire, comprenant le traitement médicamenteux de la douleur, la thérapie antirésorptive, la radiothérapie, les techniques interventionnelles ainsi que la chirurgie. Cet article propose une analyse approfondie de l'incidence et de la distribution des métastases osseuses (MO), des événements liés au squelette (SRE), des techniques d'imagerie diagnostique et des stratégies thérapeutiques contemporaines pour prévenir les SRE. Le traitement systémique anticancéreux et la gestion de la douleur, bien que cruciaux pour traiter les MO, ne sont pas discutés dans cet article.

Short-term predictors of stereotactic radiosurgery outcome for untreated single non-small cell lung cancer brain metastases: a restrospective cohort study.

Stereotactic radiosurgery (SRS) is an option for brain metastases (BM) not eligible for surgical resection, however, predictors of SRS outcomes are poorly known. The aim of this study is to investigate predictors of SRS outcome in patients with BM secondary to non-small cell lung cancer (NSCLC). The secondary objective is to analyze the value of volumetric criteria in identifying BM progression. This retrospective cohort study included patients >18 years of age with a single untreated BM secondary to NSCLC. Demographic, clinical, and radiological data were assessed. The primary outcome was treatment failure, defined as a BM volumetric increase 12 months after SRS. The unidimensional measurement of the BM at follow-up was also assessed. One hundred thirty-five patients were included, with a median BM volume at baseline of 1.1 cm3 (IQR 0.4-2.3). Fifty-two (38.5%) patients had SRS failure at follow-up. Only right BM laterality was associated with SRS failure (p=0.039). Using the volumetric definition of SRS failure, the unidimensional criteria demonstrated a sensibility of 60.78% (46.11%-74.16%), specificity of 89.02% (80.18%-94.86%), positive LR of 5.54 (2.88-10.66) and negative LR of 0.44 (0.31-0.63). SRS demonstrated a 61.5% local control rate 12 months after treatment. Among the potential predictors of treatment outcome analyzed, only the right BM laterality had a significant association with SRS failure. The volumetric criteria were able to identify more subtle signs of BM increase than the unidimensional criteria, which may allow earlier diagnosis of disease progression and use of appropriate therapies.

Microwave ablation combined with percutaneous vertebroplasty for treating painful non-small cell lung cancer with spinal metastases under real-time temperature monitoring.

PURPOSE: To retrospectively study the therapeutic effect and safety performance of the combination strategies of the computed tomography (CT)-guided microwave ablation (MWA) and percutaneous vertebroplasty (PVP) as a treatment for painful non-small cell lung cancer (NSCLC) with spinal metastases. MATERIALS AND METHODS: A retrospective review included 71 patients with 109 vertebral metastases who underwent microwave ablation combined with percutaneous vertebroplasty by the image-guided and real-time temperature monitoring. Treatment efficacy was determined by comparing visual analog scale (VAS) scores, daily morphine equivalent opioid consumption, and Oswestry Disability Index (ODI) scores before treatment and during the follow-up period. RESULTS: Technical success was achieved in all patients. The mean pre-procedure VAS score and morphine doses were 6.6 ± 1.8 (4-10) and 137.2 ± 38.7 (40-200) mg, respectively. The mean VAS scores and daily morphine doses at 24 h and 1, 4, 12, and 24 weeks postoperatively were 3.3 ± 1.9 and 73.5 ± 39.4 mg; 2.2 ± 1.5 and 40.2 ± 29.8 mg; 1.7 ± 1.2 and 31.3 ± 23.6 mg; 1.4 ± 1.1 and 27.3 ± 21.4 mg; and 1.3 ± 1.1 and 24.8 ± 21.0 mg, respectively (all P < 0.001). ODI scores significantly decreased (P < 0.05). Minor cement leakage occurred in 51 cases (46.8%), with one patient having a grade 3 neural injury. No local tumor progression was observed by follow-up imaging. CONCLUSIONS: MWA combined with PVP can significantly relieve pain and improve patients' quality of life, which implied this is an effective treatment option for painful NSCLC with spinal metastases. Additionally, its efficacy should be further verified through the mid- and long-term studies.

Is it too early to recommend local treatment in oligometastatic non-small cell lung cancer: a plea for equipoise.

Oligometastatic non-small cell lung cancer (OMD NSCLC) has been proposed to bridge the spectrum between non-metastatic and widely metastatic states and is perceived as an opportunity for potential cure if removed. Twelve clinical trials on local treatment have been reported, yet none are conclusive. These trials informed the development of a joint clinical practice guideline by the American & European Societies for Radiation Oncology, which endorses local treatment for OMD NSCLC. However, the heterogeneity between prognostic factors within these trials likely influenced outcomes and can only support guidance at this time. Caution against an uncritical acceptance of the guideline is discussed, as strong recommendations are offered based on expert opinion and inconclusive evidence. The guideline is also examined by a patient's caregiver, who emphasizes that uncertain evidence impedes shared decision making.

Head-to-head comparison of 18F-FDG PET/CT and 18F-FDG PET/MRI for lymph node metastasis staging in non-small cell lung cancer: a meta-analysis.

PURPOSE: The current meta-analysis aimed to compare the diagnostic performance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) with 18F-FDG PET/magnetic resonance imaging (MRI) in non-small cell lung cancer (NSCLC) lymph node metastasis staging. METHODS: We searched the PubMed, Web of Science, and Embase databases for relevant articles between November 1992 and September 2022. Studies evaluating the head-to-head comparison of 18F-FDG PET/CT and 18F-FDG PET/MRI for lymph node metastasis in patients with NSCLC were included. The quality of each study was assessed using the Quality Assessment of Diagnostic Performance Studies-2 tool. RESULTS: The analysis includes six studies with a total of 434 patients. The pooled sensitivity of 18F-FDG PET/CT and 18F-FDG PET/MRI was 0.78 [95% confidence interval (CI): 0.59-0.90] and 0.84 (95% CI: 0.68-0.93), and the pooled specificity was 0.87 (95% CI: 0.72-0.94) and 0.87 (95% CI: 0.80-0.92), respectively. The accuracy of 18F-FDG PET/CT and 18F-FDG PET/MRI was 0.81 (95% CI: 0.71-0.90) and 0.84 (95% CI: 0.75-0.92), respectively. When the pre-test probability was set at 50%, the post-test probability for 18F-FDG PET/CT could increase to 85%, and the post-test probability for 18F-FDG PET/MRI could increase to 87%. CONCLUSION: 18F-FDG PET/CT and 18F-FDG PET/MRI have similar diagnostic performance in detecting lymph node metastasis in NSCLC. However, the results of this study were from a small sample study, and further studies with larger sample sizes are needed.

Reduced Mortality and Radiation Necrosis After Surgery With Postoperative Stereotactic Radiation in Patients With Multiple Brain Metastases.

BACKGROUND AND OBJECTIVES: Although stereotactic radiation has frequently supplanted whole-brain radiation therapy (WBRT) in treating patients with multiple brain metastases, the role of surgery for these patients remains unresolved. No randomized trials have compared surgical resection with postoperative stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) to SRS/SRT alone. Previous studies addressing surgery for patients with multiple brain metastases are often limited by small sample sizes, a lack of appropriate comparison groups, or a focus on patients treated before recent advances in targeted therapy and immunotherapy. We compared outcomes in patients with multiple brain metastases treated with surgical resection and postoperative SRS/SRT to those treated with SRS/SRT alone. METHODS: We studied 734 patients with multiple newly diagnosed brain metastases (surgery with SRS/SRT, n = 228; SRS/SRT alone, n = 506) from 2011 to 2022 in a retrospective, single-institution cohort. Patients who received upfront whole-brain radiotherapy were excluded. Cox proportional hazards models were constructed for overall survival and additional intracranial outcomes. RESULTS: After adjustment for potential confounders, surgery with postoperative SRS/SRT was associated with decreased all-cause mortality compared with SRS/SRT alone (hazard ratio [HR]: 0.67, 95% CI [0.50-0.89], P = 5.56 × 10 -3 ). The association between surgical resection and overall survival was replicated in a subset of the cohort after cardinality matching (HR: 0.64, 95% CI [0.46-0.88], P = 6.68 × 10 -3 ). Patients with melanoma benefited significantly less from surgical resection compared with patients with other tumor types, most notably non-small-cell lung cancer. Compared with definitive SRS/SRT, cavity SRS/SRT was associated with a significantly reduced risk of both symptomatic radiation necrosis (HR: 0.22, 95% CI [0.08-0.59], P = 2.70 × 10 -3 ) and radiographic radiation necrosis (HR: 0.23, 95% CI [0.09-0.57], P = 1.43 × 10 -3 ) in multivariable models. CONCLUSION: In patients with multiple brain metastases, surgical resection before SRS/SRT is associated with reduced mortality and radiation necrosis. Prospective studies may further delineate patient populations that benefit from aggressive local, brain-directed treatment even with significant intracranial disease burden.

Case report: Successful sequential therapy of crizotinb and entrectinib in ROS1-positive non-small-cell lung cancer with brain metastasis in later-settings.

RATIONALE: Crizotinib has been approved in many countries for the treatment of patients with advanced ROS1-rearranged non-small cell lung cancers (NSCLC). Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the central nervous system (CNS) and has been recommended as first-line therapy. Few reports have precisely described sequential crizotinb followed by entrectinib in patients with ROS1 fusion in later settings. PATIENT CONCERNS: A 56-year-old man with a history of occasional smoking visited our hospital with cough, sputum, and shortness of breath. DIAGNOSIS: He was diagnosed with right lung adenocarcinoma (T4N2M1a, stage IV) after image and histological examination, without EGFR or ALK fusion mutation. INTERVENTIONS: He received three prior lines of therapies, including chemotherapy, nivolumab monotherapy, and paclitaxel plus anlotinib, with progression-free survival (PFS) of 5, 2, and 11.5 months, respectively. Then the patient began to have headaches and dizziness, and brain magnetic resonance imaging showed multiple brain metastases. Next-generation sequencing (NGS) of the biopsy from neck lymph node identified EZR-ROS1 (1.25% abundance). After 2 months of crizotinib (250 mg daily) plus bevacizumab, all pulmonary and brain lesions decreased, but a small liver lesion was discovered. As treatment went on for another 4 months, the liver lesion continued to grow while other lesions kept decreased or stable state. NGS analysis on the peripheral blood found the disappearance of EZR-ROS1 fusion and a new NTRK2 mutation (c.5C>T, p.Ser2Leu, 0.34% abundance) without other targetable molecular alteration. He received entrectinib (600 mg daily) plus bevacizumab and achieved a partial response. After 7 months of therapy, examination revealed progression of brain lesions. OUTCOMES: The patient had a total PFS of 13 months from sequential crizotinib and entrectinib therapy. LESSONS: A ROS1-rearranged NSCLC with CNS metastases responded to sequential tyrosine kinase inhibitors treatment of crizotinb followed by entrectinib. This report has potential implications in guiding decisions for the treatment after crizotinib resistance.

Immune checkpoint inhibition and single fraction stereotactic radiosurgery in brain metastases from non-small cell lung cancer: an international multicenter study of 395 patients.

PURPOSE: Approximately 80% of brain metastases originate from non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are frequently utilized in this setting. However, concerns remain regarding the risk of radiation necrosis (RN) when SRS and ICI are administered concurrently. METHODS: A retrospective study was conducted through the International Radiosurgery Research Foundation. Logistic regression models and competing risks analyses were utilized to identify predictors of any grade RN and symptomatic RN (SRN). RESULTS: The study included 395 patients with 2,540 brain metastases treated with single fraction SRS and ICI across 11 institutions in four countries with a median follow-up of 14.2 months. The median age was 67 years. The median margin SRS dose was 19 Gy; 36.5% of patients had a V12 Gy ≥ 10 cm3. On multivariable analysis, V12 Gy ≥ 10 cm3 was a significant predictor of developing any grade RN (OR: 2.18) and SRN (OR: 3.95). At 1-year, the cumulative incidence of any grade and SRN for all patients was 4.8% and 3.8%, respectively. For concurrent and non-concurrent groups, the cumulative incidence of any grade RN was 3.8% versus 5.3%, respectively (p = 0.35); and for SRN was 3.8% vs. 3.6%, respectively (p = 0.95). CONCLUSION: The risk of any grade RN and symptomatic RN following single fraction SRS and ICI for NSCLC brain metastases increases as V12 Gy exceeds 10 cm3. Concurrent ICI and SRS do not appear to increase this risk. Radiosurgical planning techniques should aim to minimize V12 Gy.

Comparison of preoperative versus postoperative treatment dosimetry plans of single-fraction stereotactic radiosurgery for surgically resected brain metastases.

OBJECTIVE: Stereotactic radiosurgery (SRS) for operative brain metastasis (BrM) is usually administered 1 to 6 weeks after resection. Preoperative versus postoperative timing of SRS delivery related to surgery remains a critical question, as a pattern of failure is the development of leptomeningeal disease (LMD) in as many as 35% of patients who undergo postoperative SRS or the occurrence of radiation necrosis. As they await level I clinical data from ongoing trials, the authors aimed to bridge the gap by comparing postoperative with simulated preoperative single-fraction SRS dosimetry plans for patients with surgically resected BrM. METHODS: The authors queried their institutional database to retrospectively identify patients who underwent postoperative Gamma Knife SRS (GKSRS) after resection of BrM between January 2014 and January 2021. Exclusion criteria were prior radiation delivered to the lesion, age < 18 years, and prior diagnosis of LMD. Once identified, a simulated preoperative SRS plan was designed to treat the unresected BrM and compared with the standard postoperative treatment delivered to the resection cavity per Radiation Therapy Oncology Group (RTOG) 90-05 guidelines. Numerous comparisons between preoperative and postoperative GKSRS treatment parameters were then made using paired statistical analyses. RESULTS: The authors' cohort included 45 patients with a median age of 59 years who were treated with GKSRS after resection of a BrM. Primary cancer origins included colorectal cancer (27%), non-small cell lung cancer (22%), breast cancer (11%), melanoma (11%), and others (29%). The mean tumor and cavity volumes were 15.06 cm3 and 12.61 cm3, respectively. In a paired comparison, there was no significant difference in the planned treatment volumes between the two groups. When the authors compared the volume of surrounding brain that received 12 Gy or more (V12Gy), an important predictor of radiation necrosis, 64% of patient plans in the postoperative SRS group (29/45, p = 0.008) recorded greater V12 volumes. Preoperative plans were more conformal (p < 0.001) and exhibited sharper dose drop-off at the lesion margins (p = 0.0018) when compared with postoperative plans. CONCLUSIONS: Comparison of simulated preoperative and delivered postoperative SRS plans administered to the BrM or resection cavity suggested that preoperative SRS allows for more highly conformal lesional coverage and sharper dose drop-off compared with postoperative plans. Furthermore, V12Gy was lower in the presurgical GKSRS plans, which may account for the decreased incidence of radiation necrosis seen in prior retrospective studies.

Current uses and applications of stereotactic body radiation therapy.

Stereotactic body radiation therapy (SBRT) is a modality that delivers high doses of radiation to a well-defined tumor target in a single or a few fractions and with high precision, which significantly reduces the dose received by surrounding normal tissues. SBRT is indicated for inoperable, early stage (T1 and T2) primary non-small cell lung cancer, lung metastases with a controlled primary tumor, prostate tumors and oligometastatic disease. Despite the lack of long-term or phase III studies, efficacy results in local control are higher than 90%, with similar toxicity to that reported with conventional fractionated radiotherapy. This article describes SBRT technology and technique, along with clinical applications, indications and limitations of this therapeutic modality.

La radioterapia corporal estereotáctica es una modalidad que con alta precisión administra dosis alta de radiación a un objetivo tumoral bien definido, en una o en pocas fracciones, y reduce significativamente la dosis que reciben los tejidos sanos circundantes. Está indicada en cáncer primario de pulmón de células no pequeñas en estadios tempranos (T1 y T2) no operable, metástasis pulmonares con un tumor primario controlado, tumores prostáticos y enfermedad oligometastásica. A pesar de la falta de estudios a largo plazo o fase III, los resultados de su eficacia en el control local es superior a 90 %, con toxicidad similar a la reportada con fraccionamientos convencionales de radioterapia. Este artículo describe la tecnología y la técnica de radioterapia corporal estereotáctica, con las aplicaciones clínicas, indicaciones y limitaciones de esta modalidad terapéutica.

Accuracy of nodal staging by 18F-FDG-PET/CT in limited disease small-cell lung cancer.

BACKGROUND: Small-cell lung cancer (SCLC) is highly aggressive with a nearly incurable disease in most cases. The most important prognostic factor is the status of the mediastinal lymph nodes. Only a small proportion of patients can be diagnosed at early stages and directed to curative multimodal treatment. Therefore, accuracy of nodal staging by (18F)-Fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) computed tomography (18F-FDG-PET/CT) in (very) limited disease SCLC, although not well investigated, is highly important. METHODS: Treatment naive, non-bulky patients treated or diagnosed with SCLC between June 2012 and April 2020 with complete data including FDG-PET/CT and invasive mediastinal staging were retrospectively analyzed (n = 19). Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and accuracy of mediastinal lymph node staging of 18F-FDG-PET/CT was calculated. RESULTS: The FDG-PET/CT showed a sensitivity of 91%, and the specificity was calculated as 87.5%. In this cohort, the disease prevalence in lymph nodes was 58% (n = 11). Positive predictive value was 91%, NPV 88% and accuracy calculated at 89%. One patient was upstaged from single-level N2 to multilevel N2. In one patient, upstaging in invasive staging was performed from N2 to N3, and one patient was downstaged from N1 to N0. CONCLUSIONS: FDG-PET/CT is a valuable tool for the detection of distant metastases, but in mediastinal staging of SCLC some limitations might remain. Invasive methods remain the gold standard. Therefore, the mediastinal lymph nodal status of patients with SCLC screened for multimodal treatment should be further evaluated by additional invasive techniques to verify the exact N-staging and to optimize treatment stratification.

The efficacy and outcomes of stereotactic body radiotherapy in adrenal gland metastases.

Aim: This retrospective study presents our single-institutional experience with stereotactic body radiotherapy for adrenal gland metastases. Materials and Methods: We evaluated patients with adrenal metastases treated by stereotactic body radiotherapy (SBRT) from 2014 to 2020. We performed an analysis of 35 patients. The median age of the patients was 62.2. Dosimetric parameters and treatment outcomes were evaluated. Results: The primary diagnosis of the majority of patients was non-small cell lung cancer (94.3%). Treatment was performed in a median of 3 fractions, and the median prescribed dose was 24 Gy (range 22,5-27). The median follow-up was 17 months. Treatment response according to Response Evaluation Criteria in Solid Tumours was categorized as complete response in 11 patients, partial response in nine patients, stable disease in 7, and progressive disease in eight patients. Twenty seven patients had oligometastatic disease and treatment response. Patients with oligometastatic disease had a significantly higher rate of complete response and partial response to treatment than patients with common disease (P = 0,011). The 6-month and 1-year local control rates were 68.4% and 43%, respectively. In general, SBRT was well tolerated and no acute toxicities were observed. Conclusion: Our retrospective study shows that SBRT can be applied safely in adrenal metastases with good results especially in patients with oligometastatic disease.

Efficacy of neoadjuvant stereotactic radiotherapy in brain metastases from solid cancer: a systematic review of literature and meta-analysis.

Neoadjuvant stereotactic radiotherapy (NaSRT) is a novel strategy for brain metastasis (BM) treatment, promising to achieve good local control, improved survival, and low toxicity. This is a systematic review of available literature and meta-analysis of 8 articles eligible for inclusion after searching MEDLINE via PubMed, Web-of-science, Cochrane Wiley, and Embase databases up to March 2023. A total of 484 patients undergoing NaSRT to treat 507 lesions were included. The median age was 60.9 (IQR 57-63) years, with a median tumor volume of 12.1 (IQR 9-14) cm3. The most frequent histology was non-small-cell lung cancer (41.3%), followed by breast (18.8%), and melanoma (14.3%). Lesions had a preferred supratentorial location (77.4%). Most of the studies used a single fraction schedule (91% of patients, n = 440). Treatment parameters were homogeneous and showed a median dose of 18 (IQR 15.5-20.5) Gy at a median of 80% isodose. Surgery was performed after a median of 1.5 (IQR 1-2.4) days and achieved gross-total extent in 94% of cases. Median follow-up was 12.9 (IQR 10-15.7) months. NaSRT showed an overall mortality rate of 58% (95% CI 43-73) at the last follow-up. Actuarial outcomes rates were 60% (95% CI 55-64) for 1-year overall survival (1y-OS), 38% (95% CI 33-43) for 2y-OS, 29% (95% CI 24-34) for 3y-OS; overall 15% (95% CI 11-19) for local failure, 46% (95% CI 37-55) for distant brain failure, 6% (95% CI 3-8) for radionecrosis, and 5% (95% CI 3-8) for leptomeningeal dissemination. The median local progression-free survival time was 10.4 (IQR 9.5-11.4) months, while the median survival without distant failure was 7.4 (IQR 6.9-8) months. The median OS time for the entire cohort was 17 (IQR 14.9-17.9) months. Existing data suggest that NaSRT is effective and safe in the treatment of BMs, achieving good local control on BMs with and low incidence of radionecrosis and leptomeningeal dissemination. Distant control appears limited compared to other radiation regimens.

Single-Session Gamma Knife Radiosurgery for Patients With 20 or More Brain Metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) is a widely accepted treatment modality for brain metastases. The role of SRS in patients with higher numbers of metastases remains controversial. OBJECTIVES: To define outcomes in patients with ≥20 brain metastases managed using single-session SRS. METHODS: This single-institution retrospective cohort study studied 75 patients (26 non-small-cell lung cancer, 21 small-cell lung cancer, 14 breast cancer, and 14 melanoma) undergoing single-session SRS. The median number of tumors per patient was 24, and the median cumulative tumor volume was 3.70 cc. The median margin dose prescribed to each individual tumor was 16 Gy. The median integral cranial dose was 5492 mJ. The median beam on time was 160 minutes. Univariate and multivariate analyses were performed with significance set at P < .05. RESULTS: The median overall survival after SRS was 8.8 months (patients with non-small-cell lung cancer), 4.6 months (patients with small-cell lung cancer), 11.3 months (patients with breast cancer), and 4.1 months (patients with melanoma). Primary cancer type, number of brain metastases, and concurrent immunotherapy were significant factors in predicting survival. Local tumor control rate per patient was 97.3% and 94.6% at 6 and 12 months after SRS, respectively. Thirty-six patients underwent additional SRS for new tumor development with a median time after SRS of 5 months. Three patients experienced adverse radiation events. CONCLUSION: Single-session SRS is a well-tolerated palliative treatment option even in patients with ≥20 brain metastases, achieving local control rate >90% with low risks of neurotoxicity while continuing concurrent systemic oncological care.

Analysis of Serious Weight Gain in Patients Using Alectinib for ALK-Positive Lung Cancer.

INTRODUCTION: Alectinib is a standard-of-care treatment for metastatic ALK+ NSCLC. Weight gain is an unexplored side effect reported in approximately 10%. To prevent or intervene alectinib-induced weight gain, more insight in its extent and etiology is needed. METHODS: Change in body composition was analyzed in a prospective series of 46 patients with ALK+ NSCLC, treated with alectinib. Waist circumference, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and skeletal muscle were quantified using sliceOmatic software on computed tomography images at baseline, 3 months (3M), and 1 year (1Y). To investigate an exposure-toxicity relationship, alectinib plasma concentrations were quantified. Four patients with more than 10 kg weight gain were referred to Erasmus MC Obesity Center CGG for in-depth analysis (e.g., assessments of appetite, dietary habits, other lifestyle, medical and psychosocial factors, and extensive metabolic and endocrine assessments, including resting energy expenditure). RESULTS: Mean increase in waist circumference was 9 cm (9.7%, p < 0.001) in 1Y with a 40% increase in abdominal obesity (p = 0.014). VAT increased to 10.8 cm2 (15.0%, p = 0.003) in 3M and 35.7 cm2 (39.0%, p < 0.001) in 1Y. SAT increased to 18.8 cm2 (12.4%, p < 0.001) in 3M and 45.4 cm2 (33.3%, p < 0.001) in 1Y. The incidence of sarcopenic obesity increased from 23.7% to 47.4% during 1Y of treatment. Baseline waist circumference was a positive predictor of increase in VAT (p = 0.037). No exposure-toxicity relationship was found. In-depth analysis (n = 4) revealed increased appetite in two patients and metabolic syndrome in all four patients. CONCLUSIONS: Alectinib may cause relevant increased sarcopenic abdominal obesity, with increases of both VAT and SAT, quickly after initiation. This may lead to many serious metabolic, physical, and mental disturbances in long-surviving patients.

CNS Downstaging: An Emerging Treatment Paradigm for Extensive Brain Metastases in Oncogene-Addicted Lung Cancer.

INTRODUCTION: For extensive brain metastases (BrM) presentations arising from oncogene-addicted lung cancer, tyrosine kinase inhibitors (TKIs) with high response rates in the central nervous system (CNS) could potentially downstage the CNS disease burden, allowing for the avoidance of upfront whole-brain radiotherapy (WBRT) and the conversion of some patients into candidates for focal stereotactic radiosurgery (SRS). METHODS: We describe the outcomes of patients with ALK, EGFR, and ROS1-driven NSCLC with extensive BrM presentations (defined as > 10 BrMs or leptomeningeal disease) treated with upfront newer generation CNS-active TKIs alone, including osimertinib, alectinib, brigatinib, lorlatinib, and entrectinib, from 2012 to 2021 at our institution. All BrMs were contoured at study entry, best CNS response (nadir), and first CNS progression. RESULTS: Twelve patients met criteria including 6 with ALK, 3 with EGFR, and 3 with ROS1-driven NSCLC. The median number and volume of BrMs at presentation were 49 and 19.6 cm3, respectively. Eleven patients (91.7 %) achieved a CNS response by modified-RECIST criteria to upfront TKI (10 partial responses, 1 complete response, 1 stable disease) with nadir observed at a median of 5.1 months. At nadir, the median number and volume of BrMs were 5 (median 91.7 % reduction per-patient) and 0.3 cm3(median 96.5 % reduction per-patient), respectively. Eleven patients (91.6 %) developed subsequent CNS progression (7 local failures, 3 local + distant, 1 distant) at a median of 17.9 months. At CNS progression, the median number and volume of BrMs were 7 and 0.7 cm3, respectively. Seven patients (58.3 %) received salvage SRS and no patients received salvage WBRT. The median overall survival from initiation of TKI for the extensive BrM presentation was 43.2 months. CONCLUSION: In this initial case series, we describe CNS downstaging as a promising multidisciplinary treatment paradigm involving the upfront administration CNS-active systemic therapy and close MRI surveillance for extensive BrMs as a strategy to avoid upfront WBRT and to convert some patients into SRS candidates.

FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites.

Rationale: Metastasis is a complex process with a molecular underpinning that remains unclear. We hypothesize that cargo proteins conducted by extracellular vesicles (EVs) released from tumors may confer growth and metastasis potential on recipient cells. Here, we report that a cytokine-like secreted protein, FAM3C, contributes to late-stage lung tumor progression. Methods: EV protein profiling was conducted with an unbiased proteomic mass spectrometry analysis on non-small cell lung cancer (NSCLC) and normal lung fibroblast cell lines. Expression of FAM3C was confirmed in a panel of NSCLC cell lines, and correlated to the invasive and metastatic potentials. Functional phenotype of endogenous FAM3C and tumor-derived EVs (TDEs) were further investigated using various biological approaches in RNA and protein levels. Metastasis potential of TDEs secreted by FAM3C-overexpressing carcinoma cells was validated in mouse models. Results: Transcriptomic meta-analysis of pan-cancer datasets confirmed the overexpression of FAM3C - a gene encoding for interleukin-like EMT inducer (ILEI) - in NSCLC tumors, with strong association with poor patient prognosis and cancer metastasis. Aberrant expression of FAM3C in lung carcinoma cells enhances cellular transformation and promotes distant lung tumor colonization. In addition, higher FAM3C concentrations were detected in EVs extracted from plasma samples of NSCLC patients compared to those of healthy subjects. More importantly, we defined a hitherto-unknown mode of microenvironmental crosstalk involving FAM3C in EVs, whereby the delivery and uptake of FAM3C via TDEs enhances oncogenic signaling - in recipient cells that phenocopies the cell-endogenous overexpression of FAM3C. The oncogenicity transduced by FAM3C is executed via a novel interaction with the Ras-related protein RalA, triggering the downstream activation of the Src/Stat3 signaling cascade. Conclusions: Our study describes a novel mechanism for FAM3C-driven carcinogenesis and shed light on EV FAM3C as a driver for metastatic lung tumors that could be exploited for cancer therapeutics.

Deep Learning Based on Enhanced MRI T1 Imaging to Differentiate Small-cell and Non-small-cell Primary Lung Cancers in Patients with Brain Metastases.

OBJECTIVES: To differentiate the primary small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) for patients with brain metastases (BMs) based on a deep learning (DL) model using contrast-enhanced magnetic resonance imaging (MRI) T1 weighted (T1CE) images. METHODS: Out of 711 patients with BMs of lung cancer origin (SCLC 232, NSCLC 479), the MRI datasets of 192 patients (lesions' widths and heights > 30 pixels) with BMs from lung cancer (73 SCLC and 119 NSCLC) confirmed pathologically were enrolled, retrospectively. A typical convolutional neural network ResNet18 was applied for the automatic classification of BMs lesions from lung cancer based on T1CE images, with training and testing groups randomized per patient to eliminate learning bias. A 5-fold cross-validation was performed to evaluate the classification of the model. The receiver operating characteristic (ROC) curve, accuracy, precision, recall and f1 score were calculated. RESULTS: For a 5-fold cross-validation test, the DL model achieved AUCs of 0.8019 and 0.8024 for SCLC and NSCLC patients with BMs, respectively, and a mean overall accuracy of 0.7515±0.04. The DL model performed well in differentiating the primary SCLC and NSCLC with BMs. CONCLUSION: The proposed DL model is feasible and effective in differentiating the pathological subtypes of SCLC and NSCLC causing BMs, which may be used as a new tool for oncologists to diagnose noninvasively BMs and guide therapy based on the imaging structure of tumors.