Pulmonary Metastatic Lesions Research Articles

Gene expression profile comparison of primary and pulmonary metastatic lesions in a dog with appendicular osteosarcoma and hypertrophic osteopathy

Hypertrophic osteopathy (HO) is a paraneoplastic syndrome, and the most notable cause in dogs is pulmonary metastatic osteosarcoma (OSA). Although many molecular factors in canine OSA have been shown in metastasis, little is known about the gene expression profile of HO secondary to metastatic OSA. Therefore, the purpose of this study was to compare the gene expression profiles between primary and metastatic OSA lesions from the same dog and to look for gene expression changes that can elucidate the molecular mechanism of metastases and HO. Tumoral samples were obtained from a 2-year-old, intact male, Labrador retriever. At the first visit, the patient presented with an appendicular OSA as the primary lesion. About 10 months later, the dog developed HO due to a single pulmonary metastasis. Using these primary and metastatic samples from the same dog, as well as normal canine osteoblasts, we investigated the gene expression profiling using the NanoString nCounter® Canine IO panel. A total of 180 differentially expressed genes were identified between malignant OSA cells and non-malignant canine osteoblasts. Furthermore, 5 genes (CCL17, VEGFC, C3, C4BPA, and FOS) were differentially expressed in comparison between primary and metastatic OSA samples. CCL17 and VEGFC were upregulated in the primary lesion compared to the metastatic lesion, while C3, C4BPA, and FOS were downregulated in the primary lesion relative to the metastatic lesion. Given that the metastatic lesion was relevant to the development of HO, the different gene expression profiles may be relevant to understanding the pathophysiology of HO.

Nd-YAG laser-assisted pulmonary metastasectomy: initial experience from a tertiary care cancer center in India.

Pulmonary metastasectomy is recommended for metastatic lung lesions when R0 resection is possible, the primary site is in controlled status, surgery is of low risk, and extrathoracic metastases are absent. We present the initial experiences of laser-assisted surgery (LAS) for pulmonary metastatic lesions from a tertiary care cancer center in India. All patients undergoing non-anatomical pulmonary metastasectomy between September 2022 and January 2023 for synchronous and metachronous lesions, operated on by a single consultant thoracic oncosurgeon in a tertiary care center of India, were identified from a prospective database. Ten patients with 124 metastatic lesions were included in the study. A hybrid approach (video-assisted thoracoscopic surgery (VATS) with mini-thoracotomy) was performed. Measurements of total lesion volume and lung parenchyma resected were taken from the final histopathological analysis of the intraoperative sample. LAS was performed for 102 lesions and stapled wedge resection for 22 lesions. Evidence of malignancy was noted in 88/102 (86.3%) of the lesions excised. Patients with LAS had advantages of parenchyma preservation, less postoperative morbidities, and shorter hospital stays. LAS of pulmonary metastatic lesions addresses more lesions in a single sitting; the bilateral lung lesions can be operated and has parenchyma preserving and good sealant properties. The online version contains supplementary material available at 10.1007/s12055-024-01723-8.

A retrospective study of 68Ga-FAPI PET/CT in differentiating the nature of pulmonary lesions.

This study aimed to investigate the characteristics of various pulmonary lesions as revealed by 68Ga-FAPI PET/CT and to determine the utility of 68Ga-FAPI PET/CT in distinguishing the nature of these pulmonary lesions. A retrospective analysis was conducted on 99 patients with pulmonary lesions, who were categorized into three distinct groups: primary lung tumors (G1), metastatic lung tumors (G2), and benign lesions (G3). Each participant underwent a 68Ga-FAPI PET/CT scan. Among these groups, variables such as the Tumor/Background Ratio (TBR), Maximum Standardized Uptake Value (SUVmax), and the true positive rate of the lesions were compared. Furthermore, the FAPI uptake in nodular-like pulmonary lesions (d<3cm) and those with irregular borders was evaluated across the groups. A correlation analysis sought to understand the relationship between FAPI uptake in primary and pulmonary metastatic lesions. The study's participants were composed of 52 males and 47 females, with an average age of 56.8 ± 13.2 years. A higher uptake and detection rate for pulmonary lesions were exhibited by Group G1 compared to the other groups (SUVmax [G1 vs. G2 vs. G3: 9.1 ± 4.1 vs. 6.1 ± 4.1 vs. 5.3 ± 5.8], P<0.05; TBR [G1 vs. G2 vs. G3: 6.2 ± 2.4 vs. 4.1 ± 2.2 vs. 3.2 ± 2.7], P<0.01; true positive rate 95.1% vs. 88% vs. 75.6%]. In nodular-like lung lesions smaller than 3 cm, G1 showed a significantly higher FAPI uptake compared to G2 and G3 (SUVmax [G1 vs. G2 vs. G3: 8.8 ± 4.3 vs. 5.2 ± 3.2 vs. 4.9 ± 6.1], P<0.01; TBR [G1 vs. G2 vs. G3: 5.7 ± 2.7 vs. 3.7 ± 2.1 vs. 3.3 ± 4.4], P<0.05). Both G1 and G2 demonstrated significantly elevated FAPI agent activity in irregular-bordered pulmonary lesions when compared to G3 (SUVmax [G1 vs. G2 vs. G3: 10.9 ± 3.3 vs. 8.5 ± 2.7 vs. 4.6 ± 2.7], P<0.01; TBR [G1 vs. G2 vs. G3: 7.2 ± 2.1 vs. 6.4 ± 1.3 vs. 3.2 ± 2.4], P<0.01). A positive correlation was identified between the level of 68Ga-FAPI uptake in primary lesions and the uptake in pulmonary metastatic lesions within G2 (r=0.856, P<0.05). 68Ga-FAPI PET/CT imaging proves to be of significant value in the evaluation of pulmonary lesions, offering distinctive insights into their nature.

Diagnostic yield of cone beam CT based navigation bronchoscopy in patients with metastatic lesions: A propensity score matched case-control study

BackgroundCone beam CT based Navigation Bronchoscopy (CBCT-NB) has predominantly been investigated as a diagnostic tool in (suspected) primary lung cancers. Small metastatic lesions are clinically considered more challenging to diagnose, but no study has explored the yield of navigation bronchoscopy in patients with pulmonary metastatic lesions (ML) compared to primary lung cancers (PL), correcting for known lesion characteristics affecting diagnostic yield. Materials and methodsThis is a single-center, retrospective, propensity score-matched case-control study. We matched a subset of patients who underwent CBCT-NB and received a final diagnosis of pulmonary metastases of solid tumors between December 2017 and 2021 against confirmed primary lung cancer lesions subjected to CBCT-NB in the same time period. The lesions were propensity score matched based on known characteristics affecting yield, including location (upper lobe, lower lobe), size, bronchus sign, and lesion solidity. ResultsFifty-six metastatic pulmonary lesions (mean size 14.7 mm) were individually case-matched to a selection of 297 available primary lung cancer lesions. Case-matching revealed non-significant differences in navigation success rate (PL: 89.3 % vs. ML: 82.1 %, 95%CI on differences: −21.8 to +7.5) and yield (PL: 60.7 % vs. ML: 55.4 %, 95%CI on differences: −25.4 to +14.7). The overall complication rate was comparable (5.4 % in PL vs. 5,4 % in ML). ConclusionAfter matching primary and metastatic lesions based on CT assessable lesions characteristics, CBCT-NB showed no clinically relevant or significantly different navigation success or yield in either group. We recommend a careful assessment of CT characteristics to determine procedural difficulty rather than selecting based on the suspicion of lesion origin.

Dynamic Fluctuations of Metastatic Pulmonary Lesions.

Dynamic Fluctuations of Metastatic Pulmonary Lesions.

Clinicopathological Features of Three Rare EWSR1::NFATC2 Sarcomas of Bone and Soft Tissues.

Certain undifferentiated round cell sarcomas displaying EWSR1::NFATC2 fusion have recently been reported, mostly in the bones. This report presents clinicopathological features of 3 additional EWSR1::NFATC2 fusion sarcomas of bone and soft tissues. We present 2 soft tissue and 1 bone tumors: A 62-year-old man with pain and a slowly growing, 8-cm-sized soft tissue mass in the anterolateral compartment of his right calf, along with multiple pulmonary metastatic lesions; a 63-year-old man with a 5-cm sized axillary mass of 4 months duration and a cystic renal mass; and a 53-year-old man with a complaint of leg pain was found to have a 2-cm diameter, intramedullary, lytic mass in the diaphysis of his left femur. Microscopic examination of the tumors in all patients revealed round to epithelioid cells arranged in cords and trabeculae in a myxohyaline stroma. Immunohistochemically, the tumor cells were positive for MIC2/CD99 (3/3), EMA (3/3), NKX3.1 (3/3), NKX2.2 (2/2), CD10 (2/2), and aggrecan (1/1), while negative for S100P and GFAP. Various keratins were also negative except focal AE1/AE3 positivity in the third tumor. By fluorescence in-situ hybridization, 2 tumors (#1 and #3) revealed EWSR1 gene rearrangement and amplification. Furthermore, 2 tumors (#1 and #2) displayed EWSR1ex8::NFATC2ex3 fusion with next-generation sequencing (NGS). The first patient was offered chemotherapy. However, he died of pulmonary metastasis. This report highlights the value of combining histopathological features and immunostains such as NXK3.1, NKX2.2, CD10, and aggrecan, along with EWSR1 testing for triaging these tumors for rare gene fusions by NGS that has prognostic implications.

GMI, a Ganoderma microsporum protein, abolishes focal adhesion network to reduce cell migration and metastasis of lung cancer

BackgroundCancer metastasis is a major cause of cancer-related deaths, emphasizing the urgent need for effective therapies. Although it has been shown that GMI, a fungal protein from Ganoderma microsporum, could suppress primary tumor growth in a wide spectrum of cancer types, it is still unclear whether GMI exhibits anti-metastasis properties, particularly in lung cancers. Further investigation is needed. Aims and objectivesThe objective of this study is to investigate the potential inhibitory effects of GMI on lung cancer metastasis in vivo. Utilizing systematic and comprehensive approaches, our research aims to elucidate the underlying molecular mechanisms responsible for the anti-metastatic effects. Materials and methodsIn vitro migration and cell adhesion assays addressed the epithelial-to-mesenchymal transition (EMT)-related phenotype. Proteomic and bioinformatic analyses identified the GMI-regulated proteins and cellular responses. GMI-treated LLC1-bearing mice were analyzed using IVIS Spectrum to assess the anti-metastatic effect. Key findingsGMI inhibits EMT as well as cell migration. GMI disrupts cell adhesion and downregulates integrin, resulting in inhibition of phosphorylated FAK. GMI induces macropinocytosis and lysosome-mediated degradation of integrin αv, α5, α6 and β1. GMI downregulates Slug via inhibition of FAK activity, which in turn enhances expressions of epithelial-related markers and decreases cell mobility. Mechanistically, GMI-induced FAK inhibition engenders MDM2 expression and enhances MDM2/p21/Slug complex formation, leading to Slug degradation. GMI treatment reduces the metastatic pulmonary lesion and prolongs the survival of LLC1-bearing mice. SignificanceOur findings highlight GMI as a promising therapeutic candidate for metastatic lung cancers, offering potential avenues for further research and drug development.

Clinical Efficacy and Safety of Once-Weekly Fractionation in Stereotactic Body Radiotherapy for Pulmonary Oligometastatic Lesions

As the oligometastatic disease paradigm has become more widely accepted, further investigation is needed to risk-stratify patients within this spectrum of disease and define optimal treatment methods. Stereotactic Body Radiotherapy (SBRT) has emerged as an efficacious and safe modality to control individual lesions and improve clinical outcomes in the setting of oligometastatic disease. There is scant literature describing ideal SBRT inter-fraction time intervals or their impact on clinical outcomes, especially for treating pulmonary oligometastases. Most institutions appear to offer treatments on consecutive days or every other day. In this abstract, we sought to evaluate the efficacy and safety of delivering SBRT treatments in a once-weekly fractionation scheme. The study was undertaken via retrospective review at a single institution. We included patients with pulmonary metastatic lesions treated with SBRT at our institution between 2015 and 2019. Patients with oligometastatic disease were included, defined as patients with 5 or fewer total metastatic lesions. Treatments were delivered between 3 and 5 fractions and using at least 5 Gy per fraction. Per institutional protocol, all treatments were delivered 7 days apart. From a single institution, 204 lesions from 111 patients were included. Median follow-up was 16.5 months [IQR 7 - 36.3]. Median dose was 40 Gy [IQR 30 - 50], median BED was 80 Gy [IQR 60-100], median dose per fraction was 10 Gy [IQR 8-11]. Median internal target volume (ITV) was 18.5 cc [IQR 9.3 - 45.8]. The most common tumor histologies were lung adenocarcinoma (38.2%), colorectal adenocarcinoma (15.6%), lung squamous cell carcinoma (12.7%), renal cell carcinoma (5.9%), breast invasive ductal carcinoma (5.4%), small cell lung cancer (3.9%), and melanoma (2.9%). 2-year local control (LC) rate was 85.7% and 5-year LC rate was 84.3%. 2-year regional control (RC) rate was 53.9% and 5-year RC was 49%. Median overall survival (OS) was 20 months [IQR 9 - 37.3]. Cox regression analysis revealed biologically effective dose (BED) (HR 0.99 [0.98 - 0.99] p = 0.001) as well as dose per fraction (HR 0.92 [0.86 - 0.97] p = 0.003) were both associated with improved OS. Longest tumor dimension was associated with worse OS independent of BED and dose per fraction (HR 1.26 [1.1 - 1.4] p = 0.001). Total toxicity incidence was 7.3%, which consisted only of G1-G2 cough, dyspnea, and fatigue. Treatment of pulmonary oligometastatic lesions with SBRT delivered via once-weekly fractionation is associated with excellent local control and minimal toxicity. Larger studies are warranted to directly compare clinical outcomes of weekly SBRT fractionation to other conventional SBRT treatment schedules.

Treatment Efficacy Outcomes Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Survival Analysis of a Phase IB trial

Aggressivelocal treatment to a limited number of metastatic sites in patients with oligometastatic NSCLC increases progression free survival (PFS) and overall survival (OS). Prior studies have shown the safety of combining high dose stereotactic body radiation therapy (SBRT) with single agent anti-PD1/PD-L1 therapy. Here, we report secondary survival endpoint outcomes from a phase Ib clinical trial investigating the safety of combining ablative, high dose radiation with dual checkpoint, anti-CTLA-4 and anti-PD-L1 immunotherapy for patients with oligometastatic NSCLC. Patients with up to 6 sites of extracranial metastatic disease were eligible for trial enrollment. All sites of disease were treated with stereotactic body radiation therapy to a dose of 30 - 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days following completion of radiation utilizing anti-CTLA-4 (Tremelimumab) and anti-PD-L1 (Durvalumab) immunotherapy for a total of four cycles followed by durvalumab alone until dose limiting toxicity or progression was observed. Primary toxicity outcomes were previously reported. Progression free and overall survival was analyzed using Kaplan Meier statistical methods. Fifteen patients were treated with SBRT and received at least one dose of dual agent immunotherapy per protocol. The median follow up was 43 months. The median number of extracranial metastatic sites was 2. Seven patients had 3 or more sites of extracranial disease. The most commonly treated sites were separate metastatic pulmonary lesions or osseous metastatic lesions. Median progression free survival (PFS) was 42 months and median overall survival (OS) was 48 months. Seven patients remain alive without evidence of progressive disease. Prior history of brain metastases was associated with significantly worse PFS (Median PFS 4 months vs 42 months, HR 6.1 (95% CI 1.6 - 37.0) p = 0.0248), but no difference in OS (Median OS 24 vs 42 months, HR 1.9 (95% CI 0.3 - 10.4). Ablative SBRT radiation to up to 6 sites of disease followed by dual checkpoint immunotherapy in oligometastatic NSCLC resulted in a favorable progression free survival (42 months) and overall survival (48 months) compared to historical controls. These findings suggest potential benefit to patient outcomes compared to immunotherapy or radiation alone in this patient population and warrant further investigation.

Differentiating primary from secondary lung cancer with FDG PET/CT and extra-pulmonary tumor grade

ObjectiveAssess feasibility of differentiating primary from secondary lung cancer in patients with a solid solitary malignant pulmonary lesion (SMPL) and a previously resected extrapulmonary tumor. MethodsPatients with pathology proven primary or secondary lung cancer from a solitary pulmonary lesion and known histopathology of extrapulmonary tumor were included. Patients with a small pulmonary lesion size, multiple malignant pulmonary nodules or an active infectious/inflammatory process were excluded. Extrapulmonary tumor grade was categorized as low, intermediate and high and was matched to FDG uptake intensity of SMPL, with FDG uptake range (SMPL/Liver SUVmax) of <0.9 for low, 0.91–1.99 for intermediate and >2.0 for high extrapulmonary tumor grade. ResultsOf 274 patients, 62 met the study criteria. 46 are primary and 16 are secondary lung cancer. There are 19 low, 27 intermediate and 16 high grade extrapulmonary tumors. Mean SMPL SUVmax is 8.2 ± 4.5 and SMPL/liver SUVmax is 2.4 ± 1.4. There are 37 cases (60%) with mismatched results (e.g., low FDG SMPL with intermediate or high grade extrapulmonary tumor or vice versa) and 25 matched cases (40%) that are inconclusive (e.g., low FDG with low tumor grade or high FDG with high tumor grade). Of the mismatched cases, we correctly predicted 30 cases (81%) as primary lung cancers. ConclusionA mismatch between the SMPL SUVmax and the extrapulmonary tumor grade could be used to differentiate a primary lung cancer from a metastasis with reasonable accuracy. Our preliminary results support the hypothesis that FDG uptake intensity of a metastatic pulmonary lesion mirrors the tumor aggressiveness of its extrapulmonary neoplasm of origin.

Stereotactic Body Radiation Therapy for Pulmonary Metastasis from Colorectal Adenocarcinoma: Biologically Effective Dose 150 Gy is Preferred for Tumour Control

AimsTo compare the local control rate of pulmonary metastatic lesions in colorectal adenocarcinoma treated with stereotactic body radiation therapy (SBRT) using a biologically effective dose with an α/β ratio of 10 (BED10) of 150 Gy. Materials and methodsWe analysed 231 pulmonary metastatic lesions from colorectal adenocarcinoma treated with SBRT in 135 patients. The patients were referred for the control of oligometastatic or oligoprogressive disease in the lungs. A dose of 40–60 Gy in three to eight fractions was delivered. The local control per tumour (LCpT) by BED10 was evaluated. The local control per patient (LCpP), pulmonary progression-free survival (PPFS), any progression-free survival (APFS) and overall survival were also reported as clinical outcomes. ResultsA significant difference was observed in the LCpT between the BED10 groups (P < 0.001). The 1-, 2- and 3-year LCpT were 38.9%, 25.9% and 25.9% in BED10 < 100 group; 84.1%, 62.6% and 60.4% in 100 ≤ BED10 < 150 Gy group; and 97.3%, 94.9% and 85.2% in BED10 ≥ 150 Gy group, respectively. BED10 ≥ 150 Gy remained significant in the multivariate analysis of LCpT. The 3-year LCpP, PPFS, APFS and overall survival rates were 62.7%, 26.5%, 24.8% and 67.7%, respectively. Oligoprogression (versus oligometastasis), multiple pulmonary nodules and extrapulmonary metastasis were associated with a poor prognosis. ConclusionA BED10 ≥ 150 Gy may be required to achieve sufficient local control. The indications for SBRT and the extent of metastatic disease should be assessed for proper estimation of the clinical outcomes.

Bilateral staged anatomic lung resection for bronchiectasis and infected polycystic disease complicated by bleeding: viability with 3 hypertrophied segments maintained

Bilateral lung resections are performed for various pathologies: pulmonary emphysema, parasitic diseases, metastatic lesions, and bronchiectasis. In clinical practice, sequential or staged interventions are more common. Surgical treatment of bronchiectasis is currently carried out only in cases with complications of localized forms and, as a rule, consists of resection of the affected part of the lung. The percentage of such patients is not large and amounts to about 5%. Taking into account the chronic course of bronchiectasis and certain successes of the conservative treatment, indications for resection operations may arise at different periods of the patient’s life. Sometimes, up to several decades can pass between the surgeries. Aim. To demonstrate a rare clinical case of staged lung resection for bronchiectasis in a patient who had 4 lung lobes removed with an interval of 52 years. Results. History of the disease was described. Indications for staged surgical interventions were identified. The main characteristics of the health status after the surgeries were described. Conclusion. The presented case illustrates the place and role of surgical methods in the treatment of bronchiectasis, as well as the compensatory capabilities of the lung tissue in the case of staged resection interventions.

Stereotactic Body Radiation Therapy for Pulmonary Oligometastasis from Head and Neck Cancer: The Potential Survival Benefits from PD-1 Inhibitors

Objective: Stereotactic body radiotherapy is suitable for most pulmonary oligometastasis, but there is little data that reported the different values of SBRT combined with systemic therapy between NP and non-NP cancers. Method: This was a retrospective study on patients with pulmonary oligometastatic HNC treated with SBRT at Zhejiang Cancer Hospital. Main Results: A total of 43 patients with 65 pulmonary metastatic lesions were included in the study.24 cases originated from NP cancer, and 19 originated from non-NP cancer. The median follow-up time was 29.7 months. The 1-year local control rate was 95.4%, and 3-year PFS and OS2 were 68.7% and 46.0% in the whole group. Subgroup analysis showed local control rates were 95.1% and 95.8% in the NP group and non-NP group (p=1.000). Median PFS times were 47.0 months and 13.3months (p=0.006), and 3-year OS2 was 87.1% and 47.9% in the two groups (p=0.011). Primary tumor location, time to metastasis, number of pulmonary lesions, BED, and systemic therapy were found to be significant predictors for PFS and (or) OS2 in univariate analysis. Systemic therapy and the number of pulmonary lesions were maintained in Cox regression analysis. No SBRT-related toxicity above grade 3 was observed. Conclusion: SBRT is an effective and tolerable therapy for patients with pulmonary oligometastasis from HNC. On the basis of systemic treatment, radical curative-intent with SBRT could be achieved in selected HNC patients.

Biologically Effective Dose as a Predictor of Radiosurgery Treatment Outcomes for Pulmonary Metastases

<h3>Purpose/Objective(s)</h3> As targeted therapy for oligometastatic disease becomes more widely accepted, continued investigation is needed to characterize predictors of treatment outcomes and better inform clinical management. In this abstract we describe how biologically effective dose (BED) impacts local control (LC), regional control (RC) distant control (DC), and overall survival (OS) in a cohort of patients receiving stereotactic body radiotherapy (SBRT) for metastatic and recurrent pulmonary lesions. <h3>Materials/Methods</h3> The study was undertaken via retrospective review at a single institution. Lung lesions in patients who underwent SBRT to pulmonary metastases from distant primaries or recurrent tumors from previously treated lung cancer were included. Only patients who were treated between 2016 and 2019 were included. Patients with newly diagnosed primary lung cancer manifesting as single pulmonary lesions were excluded. A two-proportion z-test was employed for statistical analysis. <h3>Results</h3> From a single institution, 246 treated metastatic lesions from 75 patients were included. A subset of 114 treated metastatic lesions from 41 patients received a BED < 80 Gy. A subset of 132 treated metastatic lesions from 66 patients received a BED of ≥ 80 Gy. SBRT was performed at a median BED of 57.6Gy (interquartile range [IQR], (38.4,60)]) for lesions receiving BED < 80Gy and at a median BED of 100Gy (IQR, 80-112.5) for lesions receiving BED ≥ 80Gy. Two-year LC was 82.5% (94/114) for lesions with BED <80Gy and 90.9% (120/132) for lesions with BED ≥ 80Gy (p=0.048). Two-year RC was 51.8% (59/114) for lesions with BED <80Gy and 56.8% (75/132) for lesions with BED ≥ 80Gy (p=0.424). Two-year DC was 48.2% (55/114) for lesions with BED <80Gy and 59.1% (78/132) for lesions with BED ≥ 80Gy (p=0.089). Two-year OS was 33.3% (38/114) for lesions with BED <80Gy and 60.6% (80/132) for lesions with BED ≥ 80Gy (p<0.0001). <h3>Conclusion</h3> When treating oligometastatic pulmonary lesions with SBRT, a BED of greater than or equal to 80Gy is associated with improved two-year LC and two-year OS to a statistically significant degree. However, no significant difference in two-year RC and DC is noted when using a BED greater than or equal to 80Gy. These results suggest that higher radiation doses are more effective when using SBRT to treat oligometastatic pulmonary lesions, and that a goal BED of 80 Gy or more should be pursued.

Metastatic human hepatoblastoma cells exhibit enhanced tumorigenicity, invasiveness and a stem cell-like phenotype

Background/PurposeMetastatic hepatoblastoma continues to pose a significant treatment challenge, primarily because the precise mechanisms involved in metastasis are not fully understood, making cell lines and preclinical models that depict the progression of disease and metastasis-related biology paramount. We aimed to generate and characterize a metastatic hepatoblastoma cell line to create a model for investigation of the molecular mechanisms associated with metastasis. Materials/MethodsUsing a murine model of serial tail vein injections of the human hepatoblastoma HuH6 cell line, non-invasive bioluminescence imaging, and dissociation of metastatic pulmonary lesions, we successfully established and characterized the metastatic human hepatoblastoma cell line, HLM_3. ResultsThe HLM_3 cells exhibited enhanced tumorigenicity and invasiveness, both in vitro and in vivo compared to the parent HuH6 cell line. Moreover, HLM_3 metastatic hepatoblastoma cells exhibited a stem cell-like phenotype and were more resistant to the standard chemotherapeutic cisplatin. ConclusionThis newly described metastatic hepatoblastoma cell line offers a novel tool to study mechanisms of tumor metastasis and evaluate new therapeutic strategies for metastatic hepatoblastoma.

Successful Surgical Resection and Chemotherapy for Unresectable Hepatoblastoma With Pulmonary Metastases and for Lung Recurrence After Liver Transplantation: A Case Report

Liver transplantation (LTx) is indicated for unresectable hepatoblastoma (HB) without distal metastasis. However, to our knowledge, there is no consensus on the management of unresectable HB with pulmonary metastases, or on the treatment of recurrent HB. We report a successful case of metastatic HB treated with repeated lung resection, chemotherapy, and LTx. This study strictly complied with the Helsinki Congress and the Istanbul Declaration regarding donor source. Our case was a 1-year-old boy who developed pre-treatment extent of disease (PRETEXT) Ⅲ HB with multiple pulmonary metastases. The liver tumor was unresectable because it involved all hepatic veins. After 3 cycles of chemotherapy (cisplatin/carboplatin plus doxorubicin), the remaining 2 pulmonary metastases were resected and living donor liver transplantation (LDLT) was performed. Five months after LDLT, a tumor recurrence was detected in the right lung. Repeat lung resection was performed followed by 1 cycle of chemotherapy (carboplatin plus doxorubicin). There has been no recurrence for 18 months since the last lung resection. Previous reports revealed that 14 patients, including the present case, underwent LTx after resection of metastatic HB pulmonary lesions. Of these patients, the 2-year survival rate after LTx was 91%. Recurrence was reported in 5 patients, 2 of whom were successfully treated with repeated resection of the metastatic lesions. LTx after resection of lung recurrence may be a potential treatment for unresectable HB with pulmonary metastases.

Radiographic assessment of pulmonary metastatic lesions in superficial cutaneous and mammary neoplasms in dogs.

The present study was carried out to assess the pulmonary metastatic lesions in cases of canine superficial and mammary neoplasms presented to the University Veterinary Hospitals, Mannuthy and Kokkalai, Kerala Veterinary and Animal Sciences University during a twelve month period from February 2019 to February 2020. Twenty-four cases of neoplasms in dogs consisting of 12 cases of superficial neoplasms and 12 cases of mammary neoplasms were subjected to fine needle aspiration cytology (FNAC) for the confirmation of malignancy of neoplasm and three view thoracic radiographs were taken to assess the pulmonary metastatic pattern. The results were correlated with the malignancy detected in histopathological analysis after excisional biopsy. The most commonly observed pulmonary metastatic lesions were pulmonary nodules followed by pulmonary micronodules, miliary nodules, and pulmonary mass. These lesions were more evident in malignant mammary neoplasms especially in tubulopapillary carcinoma, ductal carcinoma, and medullary mammary carcinoma with spatial arrangements more in the perihilar region followed by caudodorsal, midventral, and cranioventral area of lung parenchyma. In case of superficial neoplasms miliary patterns and pulmonary microndules were mostly detected as pulmonary metastatic pattern in soft tissue sarcoma, round cell tumour, and malignant fibrohistiocytoma.

KLF2 inhibits cancer cell migration and invasion by regulating ferroptosis through GPX4 in clear cell renal cell carcinoma

The metastatic dissemination and underlying mechanisms of clear cell renal cell carcinoma (ccRCC) remain insufficiently understood. In this study, we identified the essential role of KLF2 in suppressing the metastasis of ccRCC. Downregulation of KLF2 detected by immunohistochemistry in primary metastatic ccRCC was remarkably related to poor clinical outcomes. Overexpression of KLF2 in vitro inhibited growth, migration and invasion of RCC cells. Analysis of clinical specimens revealed that there is a close correlation between KLF2 and GPX4 in ccRCC. Mechanistically, KLF2 deficiency is sufficient to inhibit ferroptosis on account of the impairment of transcriptional repression of GPX4 and thus promotes the migration and invasion of RCC cells. Reverting KLF2 expression in vivo decreased pulmonary metastatic lesions and prolonged life span of mice, whereas GPX4 overexpression reversed these properties. Overall, our results established a novel critical pathway that drives human ccRCC invasion and metastasis, which could be a promising target regarding to the therapies of advanced ccRCC in the clinic.

Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models.

Osteosarcoma is the most common primary bone cancer in children and adolescents, with lungs as the most common metastatic site. The five-year survival rate of osteosarcoma patients with pulmonary metastasis is less than 30%.Therefore, the utilization of mouse models mimicking the osteosarcoma development in humans is of great significance for understanding the fundamental mechanism of osteosarcoma carcinogenesis and pulmonary metastasis to develop novel therapeutics. Here, detailed procedures are reported to generate the primary osteosarcoma and pulmonary metastasis mouse models viaintratibia injection of osteosarcoma cells. Combined with the bioluminescence or X-ray live imaging system, these living mouse models are utilized to monitor and quantify osteosarcoma growth and metastasis. To establish this model, a basement membrane matrix containing osteosarcoma cells was loaded in a micro-volume syringe and injected into one tibia of each athymic mouse after being anesthetized. The mice were sacrificed when the primary osteosarcoma reached the size limitation in the IACUC-approved protocol. The legs bearing osteosarcoma and the lungs with metastasis lesions were separated. These models are characterized by a short incubation period, rapid growth, severe lesions, and sensitivity in monitoring the development of primary and pulmonary metastatic lesions. Therefore, these are ideal models for exploring the functions and mechanisms of specific factors in osteosarcoma carcinogenesis and pulmonary metastasis, the tumor microenvironment, and evaluating the therapeutic efficacy in vivo.

HEAD ABOVE WATER: A RARE CASE OF SCALP ANGIOSARCOMA YIELDING SPONTANEOUS HYDROPNEUMOTHORAX

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Angiosarcomas are rare, highly aggressive neoplasms originating from vascular or lymphatic endothelium [1]. Cutaneous angiosarcoma of the scalp has a predilection to involve pleural/subpleural surfaces [2,3]. Able to induce pneumothorax, hemothorax, and pleural effusion, few reports link angiosarcoma of the scalp to cystic lung disease [3]. Herein, we present a case of cutaneous angiosarcoma of the scalp associated with cystic lung disease and hydropneumothorax. CASE PRESENTATION: An 80-year-old Asian man with a pertinent medical history of smoking, atrial fibrillation, hypertension, and coronary artery disease presented with 2 weeks of dyspnea and cough. Additionally, he endorsed the worsening of a large fungating scalp lesion for the past 3 months. Biopsy of the lesion was diagnostic of well-differentiated and atypical cell angiosarcoma of the scalp. This admission, CXR showed left-sided, moderate hydropneumothorax. CT thorax revealed new cystic/cavitary disease bilaterally, not present on prior imaging. The patient was administered 100% FiO2 via NRB with no resolution of pneumothorax. Subsequent thoracocentesis produced exudate. Upon worsening of symptoms, bronchoscopy with biopsy was performed, and chest tube placement drained voluminous serosanguinous fluid. BAL, quantiferon gold, AFBx2, fungal culture, and ova/parasite all returned negative. No evidence of metastatic disease resulted from biopsy. Upon patient stabilization and without significant reaccumulation of fluid/hydropneumothorax, he was discharged. Follow-up with pulmonology/CVT was recommended for small-bore catheter placement and possible pleurodesis. Eventually, pleural fluid analysis identified the presence of nontuberculous mycobacteria. DISCUSSION: Constituting only 2% of all soft tissue sarcomas, angiosarcoma has a propensity to metastasize to the lung [2]. Our patient presented with cystic lung disease and spontaneous hydropneumothorax with no evidence of metastases from the primary site. A series of Japanese autopsy data compared scalp vs. non-scalp angiosarcoma, in which pneumothorax was solely observed in patients with the scalp subtype [4]. Only 24 cases of angiosarcoma with spontaneous pneumothorax have been reported from 1978-2014, with fewer cases documented since [5]. Limited reports have linked angiosarcoma to spontaneous hydropneumothorax, as seen in our case. CONCLUSIONS: Angiosarcoma of the scalp has a predilection to yield pulmonary sequelae. Considering the scarcity of documented cases, such diagnosis should be considered in patients presenting with cystic lung disease or hydropneumothorax. The eventual identification of concurrent nontuberculous mycobacterium infection within our patient is remarkable. Mycobacteria actuating cystic lung disease is unorthodox [6]. However, the distinct etiology of our patient's presentation may have been multifactorial in nature, compounding the originality of this case. REFERENCE #1: Somasekharan Nair KK, Zabell AS, Vo KL, Shaikh MA. Pneumothorax: a classical presentation of metastatic scalp angiosarcoma. Ann Thorac Surg. 2012 Sep;94(3):e77-8. doi: 10.1016/j.athoracsur.2012.02.030. PMID: 22916786.2. Andersen KF, Albrecht-Beste E, Berthelsen AK, Loft A. Angiosarcoma of the Scalp: Metastatic Pulmonary Cystic Lesions Initially Misinterpreted as Benign Findings on 18F-FDG PET/CT. Diagnostics (Basel). 2015 Dec 22;6(1):1. doi: 10.3390/diagnostics6010001. PMID: 26838798; PMCID: PMC4808816. REFERENCE #2: Olsen D, Molloy C, Sriram PS. Rapidly progressive lung cysts and pleural effusion: a case report. Case Rep Pulmonol. 2011;2011:790274. doi: 10.1155/2011/790274. Epub 2011 Sep 8. PMID: 22937430; PMCID: PMC3420654.4. Kitagawa M, Tanaka I, Takemura T, Matsubara O, Kasuga T. Angiosarcoma of the scalp: report of two cases with fatal pulmonary complications and a review of Japanese autopsy registry data. Virchows Arch A Pathol Anat Histopathol. 1987;412(1):83-7. doi: 10.1007/BF00750735. PMID: 3120405. REFERENCE #3: Chang JH, Kim JH, Hong SH, Song ME, Ryu YJ, Lee JH, Shim SS, Cho MS, Sim YS. Angiosarcoma presenting with spontaneous hydropneumothorax: report of a case and review of the literature. Open Respir Med J. 2014 Dec 26;8:48-54. doi: 10.2174/1874306401408010048. PMID: 25614772; PMCID: PMC4296473.6. Baldi BG, Carvalho CRR, Dias OM, Marchiori E, Hochhegger B. Diffuse cystic lung diseases: differential diagnosis. J Bras Pneumol. 2017 Mar-Apr;43(2):140-149. doi: 10.1590/S1806-37562016000000341. PMID: 28538782; PMCID: PMC5474378. DISCLOSURES: No relevant relationships by Nicholas Barreras, source=Web Response No relevant relationships by Azim Hemani, source=Web Response No relevant relationships by Michael Markos, source=Web Response No relevant relationships by Travis Yamanaka, source=Web Response