Multiplexed analysis of macrophage polarisation in pulmonary metastases of microsatellite stable colorectal cancer.

Tumour-associated macrophages (TAMs) express a continuum of phenotypes ranging from an anti-tumoural M1-like phenotype to a pro-tumoural M2-like phenotype. During cancer progression, TAMs may shift to a more M2-like polarisation state, but the role of TAMs in CRC metastases is unclear. We conducted a comprehensive spatial and prognostic analysis of TAMs in CRC pulmonary metastases and corresponding primary tumours using multiplexed immunohistochemistry and machine learning-based image analysis. We obtained data from 106 resected pulmonary metastases and 74 corresponding primary tumours. TAMs in the resected pulmonary metastases were located closer to the cancer cells and presented a more M2-like polarised state in comparison to the primary tumours. Higher stromal M2-like macrophage densities in the invasive margin of pulmonary metastases were associated with worse 5-year overall survival (HR 3.19, 95% CI 1.35-7.55, p = 0.008). The results of this study highlight the value of multiplexed analysis of macrophage polarisation in cancer metastases and might have clinical implications in future cancer therapy.

Predictors of pulmonary metastases on chest computed tomography in children and adolescents with osteosarcoma-tips for qualifying patients for thoracotomy.

BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Lungs are the most frequent and often the only site of metastatic disease. The presence of pulmonary metastases is a significant unfavourable prognostic factor. Thoracotomy is strongly recommended in these patients, while computed tomography (CT) remains the gold imaging standard. The purpose of our study was to create tools for the CT-based qualification for thoracotomy in osteosarcoma patients in order to reduce the rate of useless thoracotomies. METHODS: Sixty-four osteosarcoma paediatric patients suspected of lung metastases on CT and their first-time thoracotomies (n = 100) were included in this retrospective analysis. All CT scans were analysed using a compartmental evaluation method based on the number and size of nodules. Calcification and location of lung lesions were also analysed. Inter-observer reliability between two experienced radiologists was assessed. The CT findings were then correlated with the histopathological results of thoracotomies. Various multivariate predictive models (logistic regression, classification tree and random forest) were built and predictors of lung metastases were identified. RESULTS: All applied models proved that calcified nodules on the preoperative CT scan best predict the presence of pulmonary metastases. The rating of the operated lung on the preoperative CT scan, dependent on the number and size of nodules, and the total number of nodules on this scan were also found to be important predictors. All three models achieved a relatively high sensitivity (72-92%), positive predictive value (81-90%) and accuracy (74-79%). The positive predictive value of each model was higher than of the qualification for thoracotomy performed at the time of treatment. Inter-observer reliability was at least substantial for qualitative variables and excellent for quantitative variables. CONCLUSIONS: The multivariate models built and tested in our study may be useful in the qualification of osteosarcoma patients for metastasectomy through thoracotomy and may contribute to reducing the rate of unnecessary invasive procedures in the future.

Prognostic Outcome of Pulmonary Resection for Pulmonary Metastases from Gastric Cancer.

PURPOSE: Regardless of the devastating outcomes of pulmonary resection for metastases from gastric cancer, a handful of patients survive long after pulmonary metastasectomy. This study aimed to identify a good candidate for pulmonary resection for metastases from gastric cancer. METHODS: Between 2005 and 2023, 564 patients underwent pulmonary metastasectomy in our department, of which 12 patients underwent pulmonary resection for metastases from gastric cancer. Variables evaluated were the number and size of metastatic lesions, surgical procedure, disease-free interval (DFI), and the serum carcinoembryonic antigen at pulmonary metastasectomy. RESULTS: The DFI following gastrectomy ≤12.5 months group had a significantly worse overall survival (OS) than the other group (p = 0.005). A comparison between DFI following gastrectomy ≤12.5 months group and DFI following gastrectomy >12.5 months group showed a significant difference in serum carcinoembryonic antigen (CEA) value at pulmonary metastasectomy (p = 0.048). The serum CEA value at pulmonary metastasectomy >5.8 ng/ml group had a significantly worse OS than the other group (p = 0.001). CONCLUSION: Pulmonary metastasectomy can be indicated in some patients with metastasis from gastric cancer who have longer DFI from gastrectomy and lower serum CEA at pulmonary metastasectomy.

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

OBJECTIVE: This retrospective cohort study aimed to explore the surgical outcomes and prognostic factors of resection of pulmonary metastases (PM) from colorectal cancer (CRC). METHODS: 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. RESULTS: 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 1 year and 9 after 1 year). 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) (> 5.0 mg/dL) before PM resection was a risk factor for early recurrence (HR 3.275, 95% CI 1.092-9.821; p = 0.034). CONCLUSION: 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.

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

BACKGROUND: The 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. METHODS: This 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. RESULTS: The 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. CONCLUSION: METTL3 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.

Mapping the metabolic responses to oxaliplatin-based chemotherapy with in vivo spatiotemporal metabolomics.

Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors related to patient and tumor characteristics is necessary for managing chemotherapy treatment in metastatic CRC patients with lung disease, as such factors dictate the timing and drug regimen, which may affect treatment response and prognosis. In this study, we explore the potential of spatial metabolomics for evaluating metabolic phenotypes and therapy outcomes during the local delivery of the anticancer drug, oxaliplatin, to the lung. 12 male Yorkshire pigs underwent a 3 h left lung in vivo lung perfusion (IVLP) with various doses of oxaliplatin (7.5, 10, 20, 40, and 80 mg/L), which were administered to the perfusion circuit reservoir as a bolus. Biocompatible solid-phase microextraction (SPME) microprobes were combined with global metabolite profiling to obtain spatiotemporal information about the activity of the drug, determine toxic doses that exceed therapeutic efficacy, and conduct a mechanistic exploration of associated lung injury. Mild and subclinical lung injury was observed at 40 mg/L of oxaliplatin, and significant compromise of the hemodynamic lung function was found at 80 mg/L. This result was associated with massive alterations in metabolic patterns of lung tissue and perfusate, resulting in a total of 139 discriminant compounds. Uncontrolled inflammatory response, abnormalities in energy metabolism, and mitochondrial dysfunction next to accelerated kynurenine and aldosterone production were recognized as distinct features of dysregulated metabolipidome. Spatial pharmacometabolomics may be a promising tool for identifying pathological responses to chemotherapy.

CT-Based Screening for Pulmonary Metastases in Head and Neck Squamous Cell Cancers: Diagnostic Accuracy and Cost Comparison with PET-CECT.

This study's objective was to compare detection rates of radiograph, computed tomography (CT), and positron emission tomography-contrast-enhanced computed tomography (PET-CECT) for pulmonary metastasis/synchronous primary lung tumors in head and neck squamous cell cancer (HNSCC) and its association with clinico-radio-pathological factors. Our retrospective study included 837 HNSCC patients from January 2012 to December 2017. Lung nodules were characterized on CT as benign, indeterminate, and metastatic. The true detection rate and statistical significance of associated risk factors were calculated. Risk factors for metastasis were determined using univariate and multivariate logistic regression models. Seventy-five (8.9%) patients had pulmonary metastasis and 3 (0.3%) had second lung primary. Detection rate of pulmonary metastasis by CT was higher (sensitivity-97.3%, specificity-97.2%) as compared to radiograph (sensitivity 49% and specificity 89%). Correlation was found between pulmonary and extra-pulmonary metastasis and N classification (P = 0.01, P = 0.02) and positive low jugular node (P = 0.001, P = 0.001). Using PET-CECT in place of CT costed an extra outlay of 7,033,805 INR (95,551.85 USD) while detecting distant metastasis in only 4 (0.47%) extra cases. Chest CT is a useful pulmonary metastases screening tool in advanced HNSCC patients with reasonable imaging cost as compared to PET-CT.

Case Report: Acute arterial occlusion of the right lower extremity due to left atrial invasion from pulmonary metastases of thyroid cancer.

Cardiac metastases of thyroid cancer are rare. The most common metastatic route is through lymphatic or hematogenous spread to the right side of the heart. Direct invasion of metastases from other adjacent organs to the left side of the heart is even rarer. In many cases, the disease progresses asymptomatically, and symptoms appear only when it is already fatal. A 68-year-old woman underwent total thyroidectomy and right-side lymph node dissection for papillary thyroid cancer and multiple lung metastases 7 years previously. The patient was referred to our hospital due to sudden pain in the right lower extremity and motor disturbance. Computed tomography revealed acute arterial occlusion of the right lower extremity due to tumor dispersal from a left atrial invasion caused by multiple pulmonary metastases of thyroid cancer, and only emergency thrombectomy was performed. Although blood flow was restored, the patient died of respiratory failure 2 months after the procedure. Radical resection is considered difficult in cases of direct invasion of metastases from other adjacent organs because multiple metastases have often already occurred. Therefore, in the terminal stage, it might be too invasive to resect a tumor only to prevent embolism recurrence. The treatment strategy should depend on the patient's prognosis and choice.

Metástasis pulmonar miliar como primera manifestación de carcinoma de tiroides bien diferenciado en niños

Objetivo: Presentar el caso de una adolescente con manifestaciones de afectación pulmonar como motivo de consulta, debido a una metástasis pulmonar miliar de carcinoma (Ca) papilar de tiroides. Caso Clínico: Se trata de una adolescente femenina de 13 años de edad quien presenta tos seca, disnea de esfuerzo, palpitaciones, dolor precordial, y pérdida de peso de 15 días de evolución. Al examen clínico se evidencia aumento de volumen de la región anterior del cuello a predominio izquierdo, con adenopatía cervical palpable, acrocianosis y cianosis peribucal. Hematología completa, función tiroidea y electrocardiograma normales. La gasometría arterial demuestra una hipoxemia severa. En Rx. de tórax se observa infiltrado miliar micro y macronodular bilateral. En ultrasonido impresionan adenopatías de ubicación pretraqueal y paracarotideas. Tomografía de cuello revela imagen altamente sugestiva de malignidad en lóbulo tiroideo izquierdo y tomografía toraco-abdominal muestra infiltrado pulmonar bilateral micronodular sugestivo de lesiones metastásicas. Estudio histopatológico de ganglio latero cervical izquierdo reporta metástasis de Ca papilar tiroideo a predominio de estructuras foliculares. Se hace diagnóstico de carcinoma papilar bien diferenciado de tiroides con metástasis a región pulmonar, se realiza tiroidectomía total y control de T4L y TSH a los 30 y 60 días post cirugía, con valores normales de T4L y ligeramente aumentados de TSH (7 uU/ml), planteándose metástasis pulmonares funcionantes. Se indica terapia ablativa con I131 presentando evolución clínica estable, pero con cifras de 300 mg/dL de tiroglobulina a los seis meses, por lo que se planifica otra sesión con radioyodo. A propósito de este caso, el segundo en cinco años en la Unidad de Endocrinología del IAHULA, se lleva a cabo una revisión de la literatura sobre esta entidad nosológica. Conclusiones: En niños, el Ca papilar de tiroides puede ponerse en evidencia por las manifestaciones clínicas debidas a la afectación pulmonar, con un pronóstico reservado, sobre todo si se trata de metástasis pulmonares de tipo miliar.

Objective: To present the case of a female adolescent admitted with findings of pulmonary illness due to miliar pulmonary metastases of thyroid cancer. Clinical Case: A girl of 13 years old with non productive cough, dyspnea, palpitations, precordial pain and decrease of weigh, since fifteen days before she consulted at the pediatric emergency. She presented with a goiter, predominantly growing of the left lobe, with a cervical adenopathy, acrocyanosis and cyanosis of her lips. Complete haematology, thyroid function and electrocardiogram were normal. The arterial gasometry showed severe hypoxia. Chest radiography showed diffuse micro and macronodular lesions. Neck ecography showed definitive regional adenopaties. Neck tomography demonstrated an image suggestive of malignancy in left thyroid lobe and the thoracic tomography showed micronodular bilateral lesions, suggestive of me- tastases. Biopsy of the cervical left adenopathy concluded in metastases of papillary thyroid cancer with follicular structures. Total thyroidectomy was performed. Levels of TSH 60 days after surgery, were slightly increased (7 uU/ml), suggesting functioning pulmonary metastases. Ablative therapy with 131I was administrated, but 6 months after it, thyroglobulin levels were elevated (300 mg/dl) and the patient is waiting for another 131I therapy session. This is the second case studied in the Endocrinology Unit at the IAHULA. Conclusions: The clinical findings of pulmonary affectation could be the first manifestations of papillary thyroid cancer in children, specially if miliar pulmonary metastases are present, worsening the prognosis.