Pulmonary Metastases Research Articles

Patient Survival and Disease Recurrence Following Percutaneous Ablation of Pulmonary Metastasis

Patient Survival and Disease Recurrence Following Percutaneous Ablation of Pulmonary Metastasis

Phase II study of multidisciplinary therapy combined with pembrolizumab for patients with synchronous oligometastatic non-small cell lung cancer TRAP-OLIGO study (WJOG11118L): Feasibility analysis of induction therapy and local ablative therapy.

8564 Background: Several clinical trials have shown that local ablative therapy (LAT) to all sites of the disease might provide survival benefit for patients with oligometastatic non-small cell lung cancer (NSCLC). Few studies have evaluated feasibility of multiciliary therapy combined immune-checkpoint inhibitor plus chemotherapy with LAT to all sites of disease. Methods: This multicenter, single-arm, phase II trial enrolled untreated patients with stage IV NSCLC who had 3 or fewer metastatic lesions. All patients had received 2–4 cycles of a systemic treatment including pembrolizumab and platinum-doublet chemotherapy as induction therapy. LAT was administered to all residual lesions after induction therapy, followed by maintenance therapy including pembrolizumab. The primary endpoint is the progression-free survival (PFS) rate of 24 months from the date of initiation of LAT. The secondary endpoints are safety, response rate of induction therapy, PFS, overall survival, and proportion of implementation. The present analysis showed feasibility of induction therapy and LAT. Results: Between October 30, 2020, and August 12, 2022, 30 patients were enrolled. The number of metastases at diagnosis was one in 7 patients (7/30, 23%), two in 14 patients (14/30, 47%), and three in 9 patients (9/30, 30%). All patients received induction therapy, and the objective response rate was 21/30, 70% (95% confidence interval, 50% to 85%). Adverse events of grade 3/4 occurred in 21/30, 70%, including neutropenia (5/30, 17%), anemia (2/30, 7%), and thrombocytopenia (2/30, 7%). Seven patients did not receive planned LAT for the following reasons: disease progression (N=3), adverse events (N=2; pneumonitis grade 2, and hepatitis grade 3), sudden death (N=1), and one patient had proven stage III after induction therapy. Twenty-three patients (23/30, 77%) received planned LAT to all sites of residual disease. As LAT, five patients received surgery only, 12 patients received radiotherapy only, and 6 patients received both surgery and radiotherapy. Eighteen patients completed planned radiotherapy for 32 lesions (primary sites 22%, lymph node 25%, bone 25%, pulmonary metastasis 19%, brain 6% and adrenal 3%). Eleven patients received surgery (primary sites and lymph node) as LAT. Grade 3/4 adverse events during LAT occurred in 3 patients (3/23, 13%): rash (n=1), hypoxia (n=1) and CPK increased (n=1). There were no treatment-related deaths. Conclusions: Results of the TRAP-OLIGO study showed that multimodality treatment with platinum-based chemotherapy plus pembrolizumab and LAT had favorable implementation, and planned LAT was feasible in this population. Clinical trial information: jRCTs041200046 .

Hepatoblastoma: Experience of the paediatric haematology and oncology department, Hassan II university hospital of Fez.

Introduction: Hepatoblastoma is the most common malignant hepatic tumour in children. However, it is a rare disease, representing approximately 2% of childhood tumours. The treatment combines chemotherapy with surgical excision. The objective of this study was to describe the epidemiological, clinical, therapeutic and progressive aspects of hepatoblastoma treated in the paediatric haematology and oncology department at the University Hospital Hassan II of Fès. Patients and Methods: This was a descriptive and retrospective study conducted over a 11-year period. All patients aged 0 to 15 years who were admitted and treated for hepatoblastoma were included. Results: 24 patients met the study criteria, including 9 boys and 15 girls. The average age at diagnosis was 11.52 months ± 4.9. The most common reason for consultation was abdominal distension. Hepatomegaly was observed in 50% of cases. The average tumour size was 116 mm. At the time of diagnosis, one-third of patients had pulmonary metastases, and all patients were classified as high risk. Therapeutically, 19 patients (79.17%) received chemotherapy and 16 (66.67%) underwent surgery. On the evolutionary level, we observed a recovery without events in 10 (41.67%) patients. Conclusion: hepatoblastoma is a rare tumour, but remains the most common hepatic tumour in children. Despite progress in diagnostic and therapeutic means, the mortality rate is significant.

CircPIAS1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis via the miR-455-3p/NUPR1/FTH1 axis

BackgroundThe role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC cases through bioinformatics analysis. This study aimed to investigate the oncogenic properties and mechanisms of circPIAS1 in HCC development.MethodsFunctional analyses were conducted to assess circPIAS1’s impact on HCC cell proliferation, migration, and ferroptosis. Xenograft mouse models were employed to evaluate circPIAS1’s effects on tumor growth and pulmonary metastasis in vivo. Bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays were utilized to elucidate the molecular pathways influenced by circPIAS1. Additional techniques, including RNA pulldown, fluorescence in situ hybridization (FISH), chromatin immunoprecipitation (ChIP), qPCR, and western blotting, were used to further explore the underlying mechanisms.ResultsCircPIAS1 expression was elevated in HCC tissues and cells. Silencing circPIAS1 suppressed HCC cell proliferation and migration both in vitro and in vivo. Mechanically, circPIAS1 overexpression inhibited ferroptosis by competitively binding to miR-455-3p, leading to upregulation of Nuclear Protein 1 (NUPR1). Furthermore, NUPR1 promoted FTH1 transcription, enhancing iron storage in HCC cells and conferring resistance to ferroptosis. Treatment with ZZW-115, an NUPR1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib.ConclusionThis study highlights the critical role of circPIAS1 in HCC progression through modulation of ferroptosis. Targeting the circPIAS1/miR-455-3p/NUPR1/FTH1 regulatory axis may represent a promising therapeutic strategy for HCC.

Surgical treatment for pulmonary metastasis from ovarian cancer: a retrospective case series

BackgroundDistant metastases of ovarian cancer are rarely detected alone. The effectiveness of surgical intervention for pulmonary metastases from ovarian cancer remains uncertain. This study aimed to investigate the clinicopathologic characteristics and outcomes of patients undergoing resection for pulmonary metastasis from ovarian cancer.Case presentationThe clinicopathologic characteristics and outcomes of radical surgery for pulmonary metastasis from ovarian cancer were investigated. Out of 537 patients who underwent pulmonary metastasis resection at two affiliated hospitals between 2010 and 2021, four (0.74%) patients who underwent radical surgery for pulmonary metastasis from ovarian cancer were included. The patients were aged 67, 47, 21, and 59 years; the intervals from primary surgery to detection of pulmonary metastasis from ovarian cancer were 94, 21, 36, and 50 months; and the overall survival times after pulmonary metastasectomy were 53, 50, 94, and 34 months, respectively. Three of the four patients experienced recurrence after pulmonary metastasectomy. Further, preoperative carbohydrate antigen (CA) 125 levels were normal in two surviving patients and elevated in the two deceased patients.ConclusionIn this study, three of the four patients experienced recurrence after pulmonary metastasectomy, but all patients survived for > 30 months after surgery. Patients with ovarian cancer and elevated CA125 levels may not be optimal candidates for pulmonary metastasectomy. To establish appropriate criteria for pulmonary metastasectomy in patients with ovarian cancer, further research on a larger patient cohort is warranted.

Development of a CT-Based comprehensive model combining clinical, radiomics with deep learning for differentiating pulmonary metastases from noncalcified pulmonary hamartomas: a retrospective cohort study.

Clinical differentiation between pulmonary metastases and noncalcified pulmonary hamartomas (NCPH) often presents challenges, leading to potential misdiagnosis. However, the efficacy of a comprehensive model that integrates clinical features, radiomics, and deep learning (CRDL) for differential diagnosis of these two diseases remains uncertain. This study evaluated the diagnostic efficacy of a CRDL model in differentiating pulmonary metastases from NCPH. The authors retrospectively analyzed the clinical and imaging data of 256 patients from the First Medical Centre of the General Hospital of the People's Liberation Army (PLA) and 85 patients from Shanghai Changhai Hospital, who were pathologically confirmed pulmonary hamartomas or pulmonary metastases after thoracic surgery. Employing Python 3.7 software suites, the authors extracted radiomic features and deep learning (DL) attributes from patient datasets. The cohort was divided into training set, internal validation set, and external validation set. The diagnostic performance of the constructed models was evaluated using receiver operating characteristic (ROC) curve analysis to determine their effectiveness in differentiating between pulmonary metastases and NCPH. Clinical features such as white blood cell count (WBC), platelet count (PLT), history of cancer, carcinoembryonic antigen (CEA) level, tumor marker status, lesion margin characteristics (smooth or blurred), and maximum diameter were found to have diagnostic value in differentiating between the two diseases. In the domains of radiomics and DL. Of the 1130 radiomics features and 512 DL features, 24 and 7, respectively, were selected for model development. The area under the ROC curve (AUC) values for the four groups were 0.980, 0.979, 0.999, and 0.985 in the training set, 0.947, 0.816, 0.934, and 0.952 in the internal validation set, and 0.890, 0.904, 0.923, and 0.938 in the external validation set. This demonstrated that the CRDL model showed the greatest efficacy. The comprehensive model incorporating clinical features, radiomics, and DL shows promise for aiding in the differentiation between pulmonary metastases and hamartomas.

PRG4 represses the genesis and metastasis of osteosarcoma by inhibiting PDL1 expression

BackgroundOsteosarcoma is originated from skeletal system. Recombinant human proteoglycan 4 (rhPRG4) can inhibit cell proliferation and migration in multiple cancers. This research is designed to dig out the role and mechanism of PRG4 in osteosarcoma. MethodsHuman osteosarcoma cell lines, MG63 and 143B, were transfected with programmed death 1 (PD-L1) overexpression vectors and/or treated with 20, 50, and 100 μg/mL rhPRG4, followed by the determination of cell viability, colony formation, sphere formation, invasion, migration, apoptosis, and the expressions of matrix metalloproteinases (MMPs), PD-L1 and apoptosis-related proteins. Tumor-bearing mouse models were constructed by injection of 143B cells and treatment of anti-PD-L1 antibody and/or adenovirus PRG4 (AdPRG4). Tumor volume was monitored, and immunohistochemical location of Ki67 was performed. Expressions of MMPs, transforming growth factor-β (TGF-β), PD-L1, and epithelial mesenchymal transition (EMT)-related proteins were measured in tumors. ResultsRhPRG4 (20, 50, and 100 μg/mL) inhibited the viability, colony formation, sphere formation, invasion, migration, and the expressions of MMP2, MMP9 and Bcl2 in osteosarcoma cells, while promoting cell apoptosis as well as Bax and c-caspase3 expressions, at a dose-dependent manner; by contrast, PD-L1 overexpression reversed the above effects of 100 μg/mL rhPRG4. AdPRG4 or anti-PD-L1 antibody decreased tumor volume, number of pulmonary metastasis nodule, Ki67 location, and expressions of TGF-β, PD-L1, MMP2, MMP9, Vimentin, and Snail, but increased E-cadherin expression in tumor cells. Moreover, anti-PD-L1 antibody and AdPRG4 together functioned more effectively than them alone in reducing tumor burden. ConclusionPRG4 represses the genesis and metastasis of osteosarcoma via inhibiting PD-L1 expression, and AdPRG4 enhances the effectiveness of anti-PD-L1 therapy.

Impact of age on tumor characteristics and treatment outcomes in pediatric Differentiated Thyroid Carcinoma.

There is a tendency to use data generated for adults in the management of pediatric Differentiated Thyroid Carcinoma, neglecting the clinical peculiarities of this condition in childhood. This study aimed to assess and compare the clinical-epidemiological characteristics and their significance in the evolution of thyroid carcinoma diagnosed in childhood across different age groups. Seventy-seven patients diagnosed with Differentiated Thyroid Carcinoma (DTC) up to 21 years old were selected and divided into different age groups: up to 10 years, 11 to 18 years, and 19 to 21 years old. Clinical-epidemiological data and their influence in the disease progression were analyzed and compared across age groups. Patients diagnosed below 10 years of age were associated with tumors showing extrathyroidal extension, metastasis in regional lymph nodes, higher levels of stimulated thyroglobulin in the diagnostic iodine-131 whole-body scan (WBS), and under TSH suppression in the last assessment. Additionally, pulmonary metastasis were associated in both diagnostic and post-radioiodine dose WBSs in these younger patients. Analysis of findings in the post-radioiodine therapy WBS revealed significant differences between all age groups (p = 0.0029). The time of diagnosis was identified as a factor associated with an excellent response in subgroups up to 18 years and up to 21 years. No factors associated with dynamic responses over the 1st, 3rd and 5th years of follow-up and the persistence/recurrence of the disease were identified in the subgroup up to 18 years. In the subgroup up to 21 years, having an incomplete structural response in the 3rd year of follow-up increased the chances of recurrent or persistent response by 5.5 times, and by 32.6 times if found in the 5th year of follow-up. Younger patients exhibited more aggressive tumor characteristics and underwent more rigorous treatment. However, treatment response and disease status in the last assessment, whether free or recurrent/persistence, were similar when comparing the age groups of 11 to 18 and 19 to 21 years. Nonetheless, responses obtained in the 3rd and 5th years post-treatment emerged as factors associated with the persistence/recurrence of the disease in the last assessment in the age group up to 21 years but not in patients diagnosed up to 18 years, a relevant distinction considering the tumor behavior in defining the pediatric age range in thyroid cancer.

ROS-responsive core–shell nano-inhibitor impedes pyruvate metabolism for reinforced photodynamic therapy and interrupted pre-metastatic niche formation

The formation of pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor requires the communication between the tumor cells and the host environment. Pyruvate is a fundamental nutrient by which the tumor cells metabolically reshape the extracellular matrix in the lung to facilitate their own metastatic development. Here we report a combination regimen by integrating the photo-sensitizer and the mitochondrial pyruvate carrier (MPC) inhibitor in a dendritic polycarbonate core-hyaluronic acid shell nano-platform with multivalent reversible crosslinker embedded in it (DOH-NI+L) to reinforce photodynamic therapy (PDT) toward the primary tumor and interrupt PMN formation in the lung via impeding pyruvate uptake. We show that DOH-NI+L mediates tumor-specific MPC inhibitor liberation, inhibiting the aerobic respiration for facilitated PDT and restraining ATP generation for paralyzing cell invasion. Remarkably, DOH-NI+L is demonstrated to block the metabolic crosstalk of tumor cell-host environment by dampening pyruvate metabolism, provoking a series of metabolic responses and resulting in the pulmonary PMN interruption. Consequently, DOH-NI+L realizes a significant primary tumor inhibition and an efficient pulmonary metastasis prevention. Our research extends nano-based anti-metastatic strategies aiming at PMN intervention and such a dendritic core–shell nano-inhibitor provides an innovative paradigm to inhibit tumor growth and prevent metastasis efficiently. Statement of significanceIn the progression of cancer metastasis, the formation of a pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor is one of the rate-limiting stages. The current nano-based anti-metastatic modalities mainly focus on targeted killing of tumor cells and specific inhibition of tumor cell invasion, while nanomedicine-mediated interruption of PMN formation has been rarely reported. Here we report a combination regimen by integrating a photo-sensitizer and an inhibitor of mitochondrial pyruvate carrier in a dendritic core–shell nano-platform with a reversible crosslinker embedded in it to reinforce PDT toward the primary tumor and interrupt PMN formation via impeding the uptake of pyruvate that is a fundamental nutrient facilitating aerobic respiration and PMN formation. Our research proposed a nano-based anti-metastatic strategy aiming at PMN intervention.

Stimuli-sensitive biomimetic nanoparticles for the inhibition of breast cancer recurrence and pulmonary metastasis

Biomimetic nanoparticles represent a promising avenue for mitigating rapid clearance by the reticuloendothelial system (RES); however, current challenges include insufficient tumour targeting, suboptimal adhesion, and inadequate localized drug release within tumour regions. These shortcomings contribute to persistent contests, such as recurrence and pulmonary metastasis, even with advanced breast cancer therapies. Stimuli-sensitive drug release can furbish the membrane coated nanoparticles for their efficiency against the stated problems. To enhance the efficacy of biomimetic nanoparticles in addressing these issues, we proposed a versatile, stimuli-responsive drug delivery system by encapsulating doxorubicin (Dox) and perfluorohexane (PFH) within poly (lactic-co-glycolic acid) (PLGA) nanoparticles, subsequently coated with macrophage-derived cell membranes. Within this framework, PFH serves as the mediator for ultrasonic (US)-irradiation-triggered drug release specifically within tumour microenvironment, while the macrophage-derived cell membrane coating enhances cell adhesion, enables immune evasion, and natural tumour-homing ability. The characterization assays and in vitro evaluations yielded encouraging results, indicating enhanced targeting and release efficiencies. In vivo studies demonstrated marked inhibitory effects on both breast cancer recurrence and pulmonary metastasis. The resulting data indicate that these engineered nanoparticles have notable potential for targeted delivery and controlled release upon US irradiation, thereby offering significant therapeutic efficacy against primary breast cancer, pulmonary metastasis, and recurrent malignancies. Our findings lay the groundwork for a novel clinical approach, representing an intriguing direction for ongoing investigation by oncologists.

The Remarkable Anti-Breast Cancer Efficacy and Anti-Metastasis by Multifunctional Nanoparticles Co-Loading Squamocin, R848 and IR 780.

Breast cancer is a heterogeneous disease globally accounting for approximately 1 million new cases annually. Chemotherapy remains the main therapeutic option, but the antitumor efficacy needs to be improved. Two multifunctional nanoparticles were developed in this paper using oleic acid and mPEG2k-PCL2k as the drug carriers. Squamocin (Squ) was employed as a chemotherapeutic agent. Resiquimod (R848) or ginsenoside Rh2 was co-encapsulated in the nanoparticles to remold the immunosuppressive tumor microenvironment, and IR780 was coloaded as a photosensitizer to realize photothermal therapy. The obtained Squ-R848-IR780 nanoparticles and Squ-Rh2-IR780 nanoparticles were uniformly spherical and approximately (162.200 ± 2.800) nm and (157.300 ± 1.1590) nm, respectively, in average diameter, with good encapsulation efficiency (above 85% for each drug), excellent stability in various physiological media and high photothermal conversion efficiency (24.10% and 22.58%, respectively). After intravenous administration, both nanoparticles quickly accumulated in the tumor and effectively enhanced the local temperature of the tumor to over 45 °C when irradiated by an 808 nm laser. At a low dose of 0.1 mg/kg, Squ nanoparticles treatment alone displayed a tumor inhibition rate of 55.28%, pulmonary metastasis inhibition rate of 59.47% and a mean survival time of 38 days, which were all higher than those of PTX injection (8 mg/kg) (43.64%, 25 days and 37.25%), indicating that Squ was a potent and effective antitumor agent. Both multifunctional nanoparticles, Squ-Rh2-IR780 nanoparticles and Squ-R848-IR780 nanoparticles, demonstrated even better therapeutic efficacy, with tumor inhibition rates of 90.02% and 97.28%, pulmonary metastasis inhibition rates of 95.42% and 98.09, and mean survival times of 46 days and 52 days, respectively. The multifunctional nanoparticles coloaded with squamocin, R848 and IR 780 achieved extraordinary therapeutic efficacy and excellent antimetastasis activity and are thus promising in the future treatment of breast tumors and probably other tumors.

Pembrolizumab-Induced Pancytopenia: A Case Report

Introduction: Immunotherapy is increasingly acknowledged as an effective treatment for metastatic melanoma. Hematological immune-mediated adverse events are rarely reported. In this article, we report a case of a patient who developed pancytopenia following administration of pembrolizumab. Case Report: A 63 -year-old woman, followed for a scalp melanoma with pulmonary metastasis developed severe pancytopenia after receiving 4 cycles of pembrolizumab. Outcome and Management: Following the appearance of the adverse effect, Pembrolizumab was stopped. A series of blood tests were performed in order to get the reasons of this event. The patient received high-dose of corticosteroids with tapering the dose over 6 weeks, and blood transfusion was required. Discussion: Checkpoint inhibitors (ICI) stimulate both humoral and cellular immune responses against tumor antigens, potentially resulting in immune-related adverse effects, including hematological issues like pancytopenia. Due to the substantial morbidity and mortality linked to ICI-induced pancytopenia, further data is essential to formulate evidence-based management guidelines.

Prognostic factors in pulmonary metastases resection from colorectal cancer: impact of right-sided colon cancer and early recurrence.

This retrospective cohort study aimed to explore the surgical outcomes and prognostic factors of resection of pulmonary metastases (PM) from colorectal cancer (CRC). Overall, 60 patients who underwent resection of PM from CRC between 2015 and 2021 at two institutions were reviewed. The primary outcome were overall survival (OS) and early recurrence after PM resection. The association between OS and right-sided colon cancer (RCC) was investigated. Early recurrence after PM resection was defined as recurrence within one year. The 5-year OS after CRC resection was 83.8% (95% confidence interval [CI] 67.5-92.4) and after PM resection was 69.4% (95% CI 47.5-83.6). In total, 25 patients had recurrence after PM resection (16 within 1year and 9 after 1year). In multivariable analysis for OS, RCC (hazard ratio [HR] 4.370, 95% CI 1.020-18.73; p = 0.047) and early recurrence after resection of PM (HR 17.23, 95% CI 2.685-110.6; p = 0.003) were risk factors for poor OS. In multivariable analysis for early recurrence after PM resection, higher value of carcinoembryonic antigen (CEA) (> 5.0mg/dL) before PM resection was a risk factor for early recurrence (HR 3.275, 95% CI 1.092-9.821; p = 0.034). The RCC and early recurrence after PM resection were poor prognosis factors of OS. Higher value of CEA before PM resection was an independent risk factor for early recurrence after resection of PM. Comparitive study between surgery and nonsurgery is necessary in patients with higher CEA values.

Short-Term Biological Toxicity Prediction of [177Lu]Lutetium-Oxodotreotide: An Original Retrospective Analysis.

Introduction: [177Lu]Lutetium (Lu)-oxodotreotide is a radiopharmaceutical drug used as peptide receptor radionuclide therapy (PRRT) for somatostatin receptor-expressing neuroendocrine neoplasms. It provides an additional effective alternative treatment for these rare cancers. Although well tolerated, its safety profile must continue to be characterized to support its use as a first-line treatment or for additional cycles. This study evaluated factors associated with the occurrence of [177Lu]Lu-oxodotreotide induced short-term toxicity. Materials and Methods: A retrospective observational monocentric study was carried out from July 2013 to October 2021. Inclusion criteria were defined as follows: patients who received at least four cycles of [177Lu]Lu-oxodotreotide and were followed up for 6 months after the last injection. Graduated toxicity was defined using the National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Cox regression was used in the analysis. Results: Forty patients were included. The most frequent toxicities occurred during the first cycle and were graded as G1 or G2. As expected, toxicities were predominantly hematological and hepatic, with incomplete reversibility after each cycle. The following factors were significantly related to the occurrence of hematological or hepatic toxicity during PRRT: gastrointestinal primary tumor diagnosis, bone metastases, peritoneal metastases, pancreatic metastases or pulmonary metastases, and high tumor grade. Conclusion: Knowledge and consideration of these factors in adjusting [177Lu]Lu-oxodotreotide treatment regimen could help prevent or reduce the severity of these toxicities. Further studies are still warranted to refine these results and improve treatment management.

Pulmonary "cannonball" metastasis from endometrial cancer: a rare case report

Endometrial cancer is the most common gynecological neoplasm in Italy and developed countries. Pulmonary metastases, though uncommon, signify advanced disease, with "cannonball" metastases being a distinctive pathological finding requiring careful management. Despite advancements in bronchoscopy technology, fundamental diagnostic procedures like Bronchoalveolar Lavage (BAL), Transbronchial Lung Biopsy (TBLB), and Transbronchial Needle Aspiration (TBNA) remain essential for evaluating bronchopulmonary diseases. These techniques enhance the diagnosis and staging of oncological diseases of the genitourinary system with pulmonary involvement. Traditional bronchoscopic procedures continue to play a vital role in managing lung disorders effectively.

Stereotactic Body Radiation Therapy and Concurrent Targeted Therapy for Lung Metastases in Pediatric Sarcoma

PurposeThe purpose of this investigation was to evaluate the efficacy and safety of stereotactic body radiotherapy (SBRT) for pulmonary metastases from pediatric sarcomas. MethodsThis study was a single institutional retrospective chart review including patients younger than 21 years of age at diagnosis who had received SBRT for pulmonary metastasis from metastatic sarcoma. Our current electronic record system was queried for all eligible patients. Primary endpoint was tumor response as defined by RECIST 1.1 criteria. Secondarily, we analyzed factors that affected tumor response as well as toxicity of treatment. Median dose was 50 Gy ranging from 45-60 Gy in 5 fractions to the planning tumor volume (PTV). ResultsThere were 7 patients, ranging from ages 6 to 21 years with a total of 14 pulmonary lesions treated with SBRT. Median and mean follow up times for the 7 patients were 10.6 months and 15.9 months respectively. The complete response rate was 50%, partial response 21%, stable disease 21%, and progressive disease 7%. Four of the seven patients were treated with concurrent systemic therapy, three of which were targeted oral therapies. Additionally, we observed that patients who were on targeted therapy such as regorafenib or pazopanib seemed to have better local control as compared to patients without. ConclusionsWith an overall response rate of 92%, SBRT provided a non-invasive effective palliative treatment option with few side effects in this small retrospective study of 7 patients. A larger prospective clinical trial is warranted to evaluate the role of SBRT in the treatment of unresectable metastatic pediatric sarcomas.

METTL3 recruiting M2-type immunosuppressed macrophages by targeting m6A-SNAIL-CXCL2 axis to promote colorectal cancer pulmonary metastasis

BackgroundThe regulatory role of N6-methyladenosine (m6A) modification in the onset and progression of cancer has garnered increasing attention in recent years. However, the specific role of m6A modification in pulmonary metastasis of colorectal cancer remains unclear.MethodsThis study identified differential m6A gene expression between primary colorectal cancer and its pulmonary metastases using transcriptome sequencing and immunohistochemistry. We investigated the biological function of METTL3 gene both in vitro and in vivo using assays such as CCK-8, colony formation, wound healing, EDU, transwell, and apoptosis, along with a BALB/c nude mouse model. The regulatory mechanisms of METTL3 in colorectal cancer pulmonary metastasis were studied using methods like methylated RNA immunoprecipitation quantitative reverse transcription PCR, RNA stability analysis, luciferase reporter gene assay, Enzyme-Linked Immunosorbent Assay, and quantitative reverse transcription PCR.ResultsThe study revealed high expression of METTL3 and YTHDF1 in the tumors of patients with pulmonary metastasis of colorectal cancer. METTL3 promotes epithelial-mesenchymal transition in colorectal cancer by m6A modification of SNAIL mRNA, where SNAIL enhances the secretion of CXCL2 through the NF-κB pathway. Additionally, colorectal cancer cells expressing METTL3 recruit M2-type macrophages by secreting CXCL2.ConclusionMETTL3 facilitates pulmonary metastasis of colorectal cancer by targeting the m6A-Snail-CXCL2 axis to recruit M2-type immunosuppressive macrophages. This finding offers new research directions and potential therapeutic targets for colorectal cancer treatment.

Phase I dose escalation study for In Vivo Lung Perfusion (IVLP) as an adjuvant treatment for patients with resectable pulmonary metastasis of bone or soft tissue sarcomas

BackgroundMetastatic sarcoma is an aggressive disease with few effective treatment options. Standard of care for limited pulmonary metastasis is surgical resection, however micrometastasis are often present and go undetected. Here, we determine the maximal tolerated dose and safety of doxorubicin delivered via In Vivo Lung Perfusion (IVLP) for patients with resectable sarcoma pulmonary metastases. MethodsThis is a phase I dose escalation study using doxorubicin during IVLP in sarcoma patients with surgically resectable bilateral pulmonary metastases from 2017 to 2022. While the bilateral disease was surgically resected, only a single side underwent IVLP with doxorubicin at different dose levels (DL 1–3). Intraoperative serum, perfusate and lung tissue were collected and evaluated for doxorubicin levels. Patients were closely monitored intra- and post-operatively for adverse events. Results8 patients consented and six patients met the inclusion criteria, while 2 patients had progressive disease before surgery and were excluded. Initial dose of 5ucg/ml perfusate of doxorubicin (DL1) was used in 1 patient, 3 patients had a dose escalation to 7ucg/ml (DL2), 2 patients with the final dose escalation of doxorubicin to 9ucg/ml (DL3). With DL3, lung infiltrates were observed, therefore it was declared as the maximal administered dose and DL2 was deemed to be the recommended phase 2 dose (RP2D). There were no safety concerns during the IVLP procedure and no deaths within the first 90 days. ConclusionsHere, we demonstrate the safety and feasibility of doxorubicin as a treatment during IVLP for resectable limited pulmonary metastases for sarcomas.

Lung-derived soluble factors support stemness/plasticity and metastatic behaviour of breast cancer cells via the FGF2-DACH1 axis

Patients with triple-negative breast cancer (TNBC) have an increased propensity to develop lung metastasis. Our previous studies demonstrated that stem-like ALDHhiCD44+ breast cancer cells interact with lung-derived soluble factors, resulting in enhanced migration and lung metastasis particularly in TNBC models. We have also observed that the presence of a primary TNBC tumor can ‘prime’ the lung microenvironment in preparation for metastasis. In this study, we hypothesized that soluble lung-derived factors secreted in the presence of a primary TNBC tumor can influence stemness/plasticity of breast cancer cells. Using an ex vivo pulmonary metastasis assay (PuMA), we observed that the lung microenvironment supports colonization and growth of ALDHhiCD44+ TNBC cells, potentially via interactions with lung-derived FGF2. Exposure of TNBC cells to lung-conditioned media (LCM) generated from mice bearing TNBC primary tumors (tbLCM) significantly enhanced the proportion of ALDHhiCD44+ cells compared to control or LCM from tumor-naïve mice (tnLCM). Further analysis using a human cancer stem cell qPCR array revealed that, relative to tnLCM or control, exposure of TNBC cells to tbLCM leads to downregulation of the transcription factor and putative tumor suppressor Dachshund homolog 1 (DACH1), a downstream regulator of FGF2. In addition, inhibition of DACH1 using siRNA or treatment with recombinant FGF2 enhanced the ALDHhiCD44+ phenotype. Taken together, our findings suggest that the FGF2-DACH1 signaling axis supports stemness/plasticity of TNBC cells in the lung microenvironment and lays the foundation for future evaluation of FGF2 as a potential novel therapeutic target for treatment or prevention of breast cancer metastasis to the lung.

Abstract LB273: Pharmacological synthetic lethality by co-inhibition of PARP and HDAC enzymes

Abstract Introduction: Inhibition of poly(ADP-ribose) polymerase (PARP) induces synthetic lethality in cells exhibiting defects in homologous repair (HR) pathways, such as BRCA1 and BRCA2-mutated breast or ovarian cancers, and 4 different PARP inhibitors (PARPi) are currently approved by the FDA. While HR-deficient cancers usually respond well to single agent PARPi, HR-proficient cancers are generally less sensitive to the treatment. Acquired resistance to PARPi due to activating mutations in BRCA genes are also not uncommon. In this work, we have examined strategies for enhancing PARPi activity in a HR-proficient context and identified histone deacetylases (HDACs) as targets for pharmacological synthetic lethality in the context of PARPi. Materials and methods: PARP1 and PARP2 activity were measured using Trevigen Universal Colorimetric PARP Assay Kit, BPS Bioscience PARP2 Colorimetric PARP2 Assay Kit, and PARylation assay. HDAC activity was measured using HeLa cell nuclear extracts and a fluorogenic peptide-based biochemical assay. Cell survival EC50 were determined using CellTiter Glo viability assay. Cell cycle analysis was performed by flow cytometry with propidium iodide staining. DNA damage was investigated by immunoblotting and immunofluorescence using gamma-H2AX antibodies, and comet assays for confirmation of double-strand breaks. Spheroid assays were performed using the Incucyte® S3 spheroid analysis module. In vivo metastasis formations were examined using the pulmonary metastasis assay (PuMA). Results and discussion: Combinations of PARP and HDAC inhibitors in HR-proficient tumor cells demonstrated that HDACi could enhance the efficacy of PARPi in vitro. This was associated with increased acute and sustained DNA-damage distinct cell cycle profiles showing activity in both S- and G2/M-phases. Importantly, dual single-molecule PARP-HDAC inhibitors showed potent inhibition of PARP1 and PARP2 activity and PAR synthesis, comparable to olaparib, as well as inhibition of HDAC with IC50 values in the low µM range. Dual PARP-HDAC inhibition decreased survival of HR-proficient cells in both 2D cultures and 3D spheroid assays with lower EC50 values than olaparib or vorinostat alone. Importantly, lung metastasis formation was significantly impaired by dual PARP-HDAC inhibition. Conclusion: Combination of PARP inhibition and HDAC inhibition showed increased efficacy compared to single agent PARP inhibition in HR-proficient cells. Development of bifunctional inhibitors may provide a novel therapeutic opportunity for tumors with limited response rates to single agent PARPi. Citation Format: Sarah Truong, Louise Ramos, Beibei Zhai, Fariba Ghaidi, Mona Marzban, Hans Adomat, Xiaoqi Chen, John Langlands, Dennis Brown, Jeffrey Bacha, Colin Collins, Poul H. Sorensen, Wang Shen, Mads Daugaard. Pharmacological synthetic lethality by co-inhibition of PARP and HDAC enzymes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB273.