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Various driver mutations and the corresponding molecular-targeted drugs have been detected and developed in non-small cell lung cancer. There were many cases in which surgical specimens had happened to find double primary cancers. However, to our knowledge, our case was the first report of synchronous double primary lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) L858R and mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations. A 75-year-old Japanese woman with chronic heart and renal failures was referred to our department because of a growing nodule in the right upper lung field on chest X-ray films. Chest computed tomography (CT) detected a nodule in the right S1 and another nodule in the left S1+2. Bronchoscopic biopsy diagnosed the right S1 nodule as moderately differentiated adenocarcinoma. Oncomine Dx Target Test Multi-CDx system of the right S1 adenocarcinoma detected EGFR L858R mutation. The 18F-fluorodeoxyglucose positron emission tomography/CT showed abnormal uptakes both in the right S1 and the left S1+2 nodules, and in the bilateral inferior paratracheal lymph nodes. We made a diagnosis of c-stage IIIA (cT1bN2M0) of adenocarcinoma in the right S1 and suspected another primary lung cancer in the left S1+2. Considering her general conditions, comorbidities and wishes, we started osimertinib. The right S1 cancer achieved partial response (PR), while the left S1+2 nodule and lymph nodes enlarged. Aspiration cytology from the left supraclavicular lymph node showed adenocarcinoma. The FoundationOne® Liquid CDx tumor profiling test detected not only EGFR L858R, but also MET exon 14 skipping mutation. We made a diagnosis of another primary adenocarcinoma from the left S1+2 nodule (cT1bN3M0, c-stage IIIB) with MET mutation, and changed osimertinib to capmatinib. Although the left S1+2 cancer achieved and maintained PR by capmatinib, the right S1 cancer increased, and several new metastases appeared. The subsequent switch from capmatinib to osimertinib could not control cancers. In this case, we tried to switch monotherapies from osimertinib to capmatinib for double primary adenocarcinomas harboring different two driver mutations, according to each cancer progression. The temporal and spatial heterogeneity reinforces the need for primary tissue biopsy if dual primaries are suspected. Temporally distinct liquid biopsies, not standard at present, may be considered.
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Multiple primary lung cancers (MPLCs), characterized by the presence of more than one distinct primary lung tumors, may develop either synchronously (simultaneously) or metachronously (after initial cancer treatment). This case describes a rare occurrence of three primary lung cancers in a chronic smoker. After a lobectomy for right middle lobe adenocarcinoma (ADC), the patient was diagnosed with synchronous small cell carcinoma (SCLC) in the right upper lobe and squamous cell carcinoma (SCC) in the right lower lobe. Notably, the ADC and subsequent lung cancers were metachronous. Due to her unsuitability for surgery, the patient pursued a treatment regimen involving radiation therapy, chemotherapy, and immunotherapy. This case underscores the need for vigilant identification and comprehensive management of MPLCs, particularly in high-risk patients, to improve outcomes and reduce the burden of this rare condition.
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Background: Due to the widespread use of computed tomography (CT) screening and advances in diagnostic techniques, an increasing number of patients with multiple pulmonary nodules are being detected and pathologically diagnosed as synchronous multiple primary lung cancers (sMPLC). It has become a new challenge to treat multiple pulmonary nodules and obtain a favorable prognosis while minimizing the perioperative risk for patients. The purpose of this study was to summarize the preliminary experience with a hybrid surgery combining pulmonary resection and ablation for the treatment of sMPLC and to discuss the feasibility of this novel procedure with a literature review. Methods: This is a retrospective non-randomized controlled study. From January 1, 2022 to July 1, 2023, four patients underwent hybrid surgery combining thoracoscopic pulmonary resection and percutaneous pulmonary ablation for multiple pulmonary nodules. Patients were followed up at 3, 6 and 12 months postoperatively and the last follow-up was on November 30, 2023. Clinical characteristics, perioperative outcomes, pulmonary function recovery and oncologic prognosis were recorded. Meanwhile we did a literature review of studies on hybridized pulmonary surgery for the treatment of multiple pulmonary nodules. Results: All the four patients were female, aged 52 to 70 years, and had no severe cardiopulmonary dysfunction on preoperative examination. Hybrid surgery of simultaneous pulmonary resection and ablation were performed in these patients to treat 2 to 4 pulmonary nodules, assisted by intraoperative real-time guide of C-arm X-ray machine. The operation time was from 155 to 240 minutes, and intraoperative blood loss was from 50 to 200 mL. Postoperative hospital stay was 2 to 7 days, thoracic drainage duration was 2 to 6 days, and pleural drainage volume was 300-1,770 mL. One patient presented with a bronchopleural fistula due to pulmonary ablation; the fistula was identified and sutured during thoracoscopic surgery and the patient recovered well. No postoperative 90-day complications occurred. After 3 months postoperatively, performance status scores for these patients recovered to 80 to 100. No tumor recurrence or metastasis was detected during the follow-up period. Conclusions: Hybrid procedures combining minimally invasive pulmonary resection with ablation are particularly suitable for the simultaneous treatment of sMPLC. Patients had less loss of pulmonary function, fewer perioperative complications, and favorable oncologic prognosis. Hybrid surgery is expected to be a better treatment option for patients with sMPLC.
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To compare the dosimetric differences in volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) in stereotactic body radiation therapy (SBRT) of multiple lung lesions and determine a normal tissue complication probability (NTCP) model-based decision strategy that determines which treatment modality the patient will use. A total of 41 patients were retrospectively selected for this study. The number of patients with 1-6 lesions was 5, 16, 7, 6, 3, and 4, respectively. A prescription dose of 70 GyRBE in 10 fractions was given to each lesion. SBRT plans were generated using VMAT and IMPT. All the IMPT plans used robustness optimization with ± 3.5% range uncertainties and 5 mm setup uncertainties. Dosimetric metrics and the predicted NTCP value of radiation pneumonitis (RP), esophagitis, and pericarditis were analyzed to evaluate the potential clinical benefits between different planning groups. In addition, a threshold for the ratio of PTV to lungs (%) to determine whether a patient would benefit highly from IMPT was determined using receiver operating characteristic curves. All plans reached target coverage (V70GyRBE ≥ 95%). Compared with VMAT, IMPT resulted in a significantly lower dose of most thoracic normal tissues. For the 1-2, 3-4 and 5-6 lesion groups, the lung V5 was 29.90 ± 9.44%, 58.33 ± 13.35%, and 81.02 ± 5.91% for VMAT and 11.34 ± 3.11% (p < 0.001), 21.45 ± 3.80% (p < 0.001), and 32.48 ± 4.90% (p < 0.001) for IMPT, respectively. The lung V20 was 12.07 ± 4.94%, 25.57 ± 6.54%, and 43.99 ± 11.83% for VMAT and 6.76 ± 1.80% (p < 0.001), 13.14 ± 2.27% (p < 0.01), and 19.62 ± 3.48% (p < 0.01) for IMPT. The Dmean of the total lung was 7.65 ± 2.47 GyRBE, 14.78 ± 2.75 GyRBE, and 21.64 ± 4.07 GyRBE for VMAT and 3.69 ± 1.04 GyRBE (p < 0.001), 7.13 ± 1.41 GyRBE (p < 0.001), and 10.69 ± 1.81 GyRBE (p < 0.001) for IMPT. Additionally, in the VMAT group, the maximum NTCP value of radiation pneumonitis was 73.91%, whereas it was significantly lower in the IMPT group at 10.73%. The accuracy of our NTCP model-based decision model, which combines the number of lesions and PTV/Lungs (%), was 97.6%. The study demonstrated that the IMPT SBRT for multiple lung lesions had satisfactory dosimetry results, even when the number of lesions reached 6. The NTCP model-based decision strategy presented in our study could serve as an effective tool in clinical practice, aiding in the selection of the optimal treatment modality between VMAT and IMPT.
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BACKGROUND: The treatment for bilateral synchronous multiple primary lung cancers (MPLC) remains challenging. Simultaneous bilateral video-assisted thoracic surgery (VATS) may be an optimal treatment with curative intent, but its safety and feasibility are controversial. METHODS: One hundred and fifty-eight patients who underwent simultaneous bilateral VATS (simultaneous group) and 79 who underwent two-staged bilateral VATS (two-staged group) were included in this study. Their medical records were retrospectively reviewed and analyzed. RESULTS: The majority of patients were female and non-smokers. The most common surgical plan was lobectomy and contralateral wedge resection in both groups. There was no significant difference in the postoperative complication rate between the simultaneous groups and two-staged group (13.3% vs. 11.4%, p = 0.73). Patients who underwent simultaneous bilateral resection had shorter hospital stays, shorter anesthesia time and less chest drainage compared with those who underwent two-staged resection. Advanced TNM stage, complicated surgical plan and aggressive lymph node resection were risk factors for postoperative complications in simultaneous bilateral VATS. Patients in two groups had similar overall survival and disease free survival (p = 0.2). CONCLUSIONS: Simultaneous bilateral VATS for bilateral lung nodule resection is as safe and feasible as two-staged bilateral VATS. Patients who underwent simultaneous bilateral resection had similar or even better outcomes compared to that of the two-staged group. Simultaneous bilateral VATS is potentially an optimal treatment option for patients with erarly cTNM stage and good physical condition.
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Estudios de Factibilidad , Neoplasias Pulmonares , Neumonectomía , Cirugía Torácica Asistida por Video , Humanos , Cirugía Torácica Asistida por Video/métodos , Femenino , Masculino , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Neumonectomía/métodos , Neoplasias Primarias Múltiples/cirugía , Complicaciones Posoperatorias/epidemiología , Resultado del TratamientoRESUMEN
BACKGROUND: Surgery is the standard care for patients with early-stage lung cancer, and stereotactic body radiation therapy is an option for those who are medically inoperable or refuse surgery. Medical developments in diagnostic and therapeutic strategies would prolong prognosis of patients with cancer. The number of patients with multiple cancers has also increased. Duplex primary malignant neoplasms are the most common, and triple or more primary malignant neoplasms were extremely rare. This is the first case of sextuple primary malignant neoplasms with lung cancer. CASE PRESENTATION: We report a case of two courses of stereotactic body radiation therapy for an 88-year-old Japanese male patient with six primary cancers in five organs. Cancers were detected in the thyroid, prostate, esophagus, bladder, and lungs. He also had a history of angina pectoris and had undergone percutaneous coronary intervention. Although he was capable of undergoing surgery for lung cancers, he refused it because he had experienced many invasive treatments, such as surgeries and percutaneous coronary intervention. In January 2020, the first stereotactic body radiation therapy was performed for the adenocarcinoma in the right lung. In March 2022, the second stereotactic body radiation therapy was performed for the nodule of the left lung. Although he complained of mild dyspnea after the first stereotactic body radiation therapy, we did not use steroids because his peripheral oxygen saturation was within the normal range. He had pleural effusion, cardiac dilatation, and pericardial effusion 2 months after the second stereotactic body radiation therapy, which improved with the use of compression stockings. CONCLUSION: A total of 43 and 17 months have passed since the first and second stereotactic body radiation therapy, respectively, there is no local recurrence and the patient can walk independently. We safely performed stereotactic body radiation therapy twice for our older patient with metachronous early-stage lung cancers. If another new tumor is detected, stereotactic body radiation therapy would be a good treatment option for the functional preservation of organs.
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Neoplasias Pulmonares , Radiocirugia , Humanos , Masculino , Radiocirugia/métodos , Neoplasias Pulmonares/radioterapia , Anciano de 80 o más Años , Neoplasias Primarias Múltiples/radioterapia , Neoplasias Primarias Múltiples/cirugía , Neoplasias Primarias Múltiples/patología , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/cirugía , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/cirugía , Neoplasias Esofágicas/radioterapia , Neoplasias de la Vejiga Urinaria/radioterapia , Neoplasias de la Vejiga Urinaria/cirugía , Adenocarcinoma/radioterapia , Adenocarcinoma/cirugíaRESUMEN
Nineteen flavonoids were isolated from the fruits of Psoralea corylifolia L., including a novel flavanol (3) and three novel isoflavones (12-14). Their chemical structures were unequivocally determined through comprehensive spectral data analysis. The anti-proliferative effect of the isolated flavonoids was assessed in vitro using the MTT assay. Molecular docking and ELISA were employed to determine the inhibitory effects of the active compounds on ALK5. Isobavachalcone was found to inhibit TGF-ß1 induced EMT in A549 cells by Wound healing assay and Transwell chamber assay. Immunofluorescence assay and Western blot assay showed that IBC could inhibit cytoskeleton rearrangement, reduce the phosphorylation of ALK5, ERK, and Smad, down-regulate Snail expression, and up-regulate E-cadherin expression in TGF-ß1 induced A549 cells, thereby exerting the potential inhibitory effects on epithelial-mesenchymal transition (EMT) process in A549 cells. The findings presented herein establish a fundamental basis for investigating the anti-proliferative and anti-metastatic properties of psoralen flavonoids in human non-small cell lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Transición Epitelial-Mesenquimal , Flavonoides , Frutas , Neoplasias Pulmonares , Simulación del Acoplamiento Molecular , Psoralea , Humanos , Células A549 , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Transición Epitelial-Mesenquimal/efectos de los fármacos , Flavonoides/farmacología , Flavonoides/química , Flavonoides/aislamiento & purificación , Frutas/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Estructura Molecular , Psoralea/química , Receptor Tipo I de Factor de Crecimiento Transformador beta , Relación Estructura-Actividad , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Isoflavonas/química , Isoflavonas/aislamiento & purificación , Isoflavonas/farmacologíaRESUMEN
In a periodical medical checkup, a 39-year-old Mongolian underground miner was diagnosed with silicosis based on chest radiography, computed tomography (CT), and work history. Chest radiography showed diffuse bilateral rounded nodules in both lung fields, with upper lobe dominance and large opacities in the right upper zone. Chest CT presented conglomerated massive changes in the right upper lobe and the coalescence of small nodules in the left upper lung. In the blood test, serum levels of the lung cancer marker neuron-specific enolase (NSE) were elevated (24.58 ng/mL). Carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) levels were within the reference range. Subsequent to the suspicion of a tumour in the right upper lobe, a right upper lobectomy was performed. The histopathological examination of the lung specimen revealed the coalescence of numerous silica nodules, accompanied by indications of associated sarcoidosis. The histological features suggested the presence of two concurrent pathological processes: silicosis and sarcoidosis. This case demonstrated the combination of three clinical conditions diagnosed in one patient, including complicated silicosis associated with sarcoidosis and elevated serum NSE levels. This case report may serve as a foundation for future investigations exploring the potential of NSE as a marker for silicosis.
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BACKGROUND: The COVID-19 pandemic has significantly impacted global health and prompted studies on its effects across various diseases. Recent data suggest a potential correlation between COVID-19 and a decrease in lung cancer incidence. This study examines the association between COVID-19 infection and changes in lung cancer cases. MATERIAL AND METHODS: We conducted a retrospective analysis of medical records from Clinic Lüdenscheid, Germany, from January 1, 2018, to December 31, 2021, comparing lung cancer cases before and during the pandemic. Demographic characteristics and cancer stages were also assessed. RESULTS: We evaluated 523 patients; 269 pre-COVID and 254 during COVID. While the overall number of cases declined, a significant increase in advanced stage cancers was noted during COVID (P = 0.04). The adjusted incidence rates showed a nuanced decrease from approximately 33 cases per 100,000 pre-COVID to 31 during COVID. CONCLUSION: This retrospective study suggests a modest decline in lung cancer incidence and an increase in advanced stages during COVID. Further comparisons with national data indicate a similar trend across Germany, with a decrease of about 3 % in lung cancer diagnoses post-2020, highlighting potential pandemic impacts on cancer detection.
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COVID-19 , Neoplasias Pulmonares , Humanos , COVID-19/epidemiología , Estudios Retrospectivos , Incidencia , Masculino , Femenino , Neoplasias Pulmonares/epidemiología , Alemania/epidemiología , Persona de Mediana Edad , Anciano , SARS-CoV-2 , Anciano de 80 o más Años , AdultoRESUMEN
BACKGROUND: Photodynamic therapy (PDT) is used for the treatment of centrally-located early lung cancers (CLELCs) and is recommended for tumors ≤ 1.0 cm in diameter. We previously reported that PDT using talaporfin sodium, second-generation photosensitizer, for tumors > 1.0 cm but ≤ 2.0 cm in diameter was able to achieve a therapeutic outcome comparable to that of tumors with a diameter of ≤ 1.0 cm. However, the effectiveness of PDT using talaporfin sodium for tumors > 2.0 cm in diameter remains unclear. We conducted a retrospective analysis of cases in which PDT was performed for flat-type CLELCs with tumor diameters of > 2.0 cm. METHODS: We retrospectively analyzed seven cases (eight lesions) with tumor diameters > 2.0 cm and no evidence of extracartilaginous invasion or lymph node metastasis. RESULTS: All the patients underwent multiple PDT sessions. The PDT treatment results over the study period were partial response in one case (14.3 %), stable disease (SD) in three cases (42.9 %), and progressive disease (PD) in three cases (42.9 %). At the time of writing this report, five of seven cases (71.4 %) are still undergoing treatment. The duration of SD-the time from the start of treatment until the criteria for PD were met (SD or better maintained)-ranged from 7 to 52 months (mean, 25.3 months). CONCLUSIONS: "Maintenance PDT" for CLELCs > 2.0 cm in diameter has the potential to inhibit tumor progression in the long term while maintaining quality of life, rather than simply aiming only for a quick radical cure.
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Neoplasias Pulmonares , Fotoquimioterapia , Fármacos Fotosensibilizantes , Porfirinas , Humanos , Fotoquimioterapia/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Fármacos Fotosensibilizantes/uso terapéutico , Masculino , Anciano , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Porfirinas/uso terapéutico , Anciano de 80 o más Años , Resultado del TratamientoRESUMEN
Intercellular communication often relies on exosomes as messengers and is critical for cancer metastasis in hypoxic tumor microenvironment. Some circular RNAs (circRNAs) are enriched in cancer cell-derived exosomes, but little is known about their ability to regulate intercellular communication and cancer metastasis. Here, by systematically analyzing exosomes secreted by non-small cell lung cancer (NSCLC) cells, a hypoxia-induced exosomal circPLEKHM1 is identified that drives NSCLC metastasis through polarizing macrophages toward to M2 type. Mechanistically, exosomal circPLEKHM1 promoted PABPC1-eIF4G interaction to facilitate the translation of the oncostatin M receptor (OSMR), thereby promoting macrophage polarization for cancer metastasis. Importantly, circPLEKHM1-targeted therapy significantly reduces NSCLC metastasis in vivo. circPLEKHM1 serves as a prognostic biomarker for metastasis and poor survival in NSCLC patients. This study unveils a new circRNA-mediated mechanism underlying how cancer cells crosstalk with macrophages within the hypoxic tumor microenvironment to promote metastasis, highlighting the importance of exosomal circPLEKHM1 as a prognostic biomarker and therapeutic target for lung cancer metastasis.
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Carcinoma de Pulmón de Células no Pequeñas , Exosomas , Neoplasias Pulmonares , Macrófagos , ARN Circular , Microambiente Tumoral , Animales , Humanos , Ratones , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Exosomas/metabolismo , Exosomas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Macrófagos/metabolismo , Metástasis de la Neoplasia/genética , ARN Circular/genética , ARN Circular/metabolismo , Microambiente Tumoral/genética , Ratones DesnudosRESUMEN
PURPOSE: We investigated interplay effects and treatment time (TT) in scanned proton therapy for lung cancer patients. We compared free-breathing (FB) approaches with multiple rescanning strategies and respiratory-gating (RG) methods with various gating widths to identify the superior irradiation technique. METHODS: Plans were created with 4/1, 2/2, and 1/4 layered/volume rescans of FB (L4V1, L2V2, and L1V4), and 50%, 30%, and 10% gating widths of the total respiratory curves (G50, G30, and G10) of the RG plans with L4V1. We calculated 4-dimensional dynamic doses assuming a constant sinusoidal curve for six irradiation methods. The reconstructed doses per fraction were compared with planned doses in terms of dose differences in 99% clinical-target-volume (CTV) (ΔD99%), near-maximum dose differences (ΔD2%) at organs-at-risk (OARs), and TT. RESULTS: The mean/minimum CTV ΔD99% values for FB were -1.0%/-4.9%, -0.8%/-4.3%, and -0.1%/-1.0% for L4V1, L2V2, and L1V4, respectively. Those for RG were -0.3%/-1.7%, -0.1%/-1.0%, and 0.0%/-0.5% for G50, G30, and G10, respectively. The CTV ΔD99% of the RGs with less than 50% gate width and the FBs of L1V4 were within the desired tolerance (±3.0%), and the OARs ΔD2% for RG were lower than those for FB. The mean TTs were 90, 326, 824, 158, 203, and 422 s for L4V1, L2V2, L1V4, G50, G30, and G10, respectively. CONCLUSIONS: FB (L4V1) is the most efficient treatment, but not necessarily the optimal choice due to interplay effects. To satisfy both TT extensions and interplay, RG with a gate width as large as possible within safety limits is desirable.
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Neoplasias Pulmonares , Terapia de Protones , Humanos , Terapia de Protones/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Respiración , Dosificación Radioterapéutica , Tomografía Computarizada Cuatridimensional/métodosRESUMEN
Precision medicine has helped identify several tumor molecular aberrations to be treated with targeted therapies. These therapies showed substantial improvement in efficacy without excessive toxicity in patients with specific oncogenic drivers with advanced cancers. In metastatic lung cancers, the implementation of broad platforms for molecular tumor sequencing has helped oncology providers identify oncogenic drivers linked with better outcomes when treated upfront with targeted therapies. Mesenchymal-epithelial transition factor (MET) alterations are present in up to 60% of non-small cell lung cancer and are associated with a poor prognosis. Capmatinib and tepotinib are currently the only two approved targeted therapies by the U.S. Food and Drug Administration (FDA) for patients with MET exon 14 skipping mutation. Several agents are being developed to tackle an unmet need in patients with MET alterations. Some of these agents are being used in combination with EGFR targeted therapy to mitigate resistance to EGFR inhibitor. These agents are poised to provide new hope for these patients.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas c-met , Humanos , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Terapia Molecular Dirigida/métodos , Medicina de Precisión/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidoresRESUMEN
INTRODUCTION: It is clinically challenging to infer the phylogenetic relationship between different tumor lesions of patients with multiple synchronous lung cancers (MSLC), whether these lesions are the result of independently evolved tumor or intrapulmonary metastases. METHODS: We used the Illumina X10 platform to sequence 128 stage I lung cancer samples collected from 64 patients with MSLC. All samples were analyzed for mutation spectra and phylogenetic inference. RESULTS: We detected genetic aberrations within genes previously reported to be recurrently altered in lung adenocarcinoma including, EGFR, ERBB2, TP53, BRAF, and KRAS. Other putative driver mutations identified were enriched in RTK-RAS signaling, TP53 signaling, and cell cycle. Also, we found some interesting cases, two cases that carried EGFR L858R and T790M co-mutation in one tumor and another tumor with only EGFR 19del, and 1 case with two KRAS hotspots in the same tumor. Due to the short follow-up time and early stage, further investigation is needed to determine whether this unique mutation profile will affect their progression-free survival (PFS) and overall survival (OS). Regarding genetic evolution analysis among 64 tumor samples, 50 of them display distinct mutational profiles, suggesting these are independently evolved tumors, which is consistent with histopathological assessment. On the other hand, six patients were identified to be intrapulmonary metastasis as the mutations harbored in different lesions are clonally related. CONCLUSION: In summary, unlike intrapulmonary metastases, patients with MSLC harbor distinct genomic profiles in different tumor lesions, and we could distinguish MSLC from intrapulmonary metastases via clonality estimation.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Filogenia , Proteínas Proto-Oncogénicas p21(ras)/genética , Inhibidores de Proteínas Quinasas , Mutación , Genómica , China/epidemiologíaRESUMEN
Background: Immune checkpoint inhibitors (ICIs) have revolutionized non-small cell lung cancers (NSCLCs) treatment, but only 20-30% of patients benefit from these treatments. Currently, PD-L1 expression in tumor cells is the only clinically approved predictor of ICI response in lung cancer, but concerns arise due to its low negative and positive predictive value. Recent studies suggest that CXCL13+ T cells in the tumor microenvironment (TME) may be a good predictor of response. We aimed to assess if CXCL13+ cell localization within the TME can predict ICI response in advanced NSCLC patients. Methods: This retrospective study included 65 advanced NSCLC patients treated with Nivolumab/Pembrolizumab at IUCPQ or CHUM and for whom a pretreatment surgical specimen was available. Good responders were defined as having a complete radiologic response at 1 year, and bad responders were defined as showing cancer progression at 1 year. IHC staining for CXCL13 was carried out on a representative slide from a resection specimen, and CXCL13+ cell density was evaluated in tumor (T), invasive margin (IM), non-tumor (NT), and tertiary lymphoid structure (TLS) compartments. Cox models were used to analyze progression-free survival (PFS) and overall survival (OS) probability, while the Mann-Whitney test was used to compare CXCL13+ cell density between responders and non-responders. Results: We showed that CXCL13+ cell density localization within the TME is associated with ICI efficacy. An increased density of CXCL13+ cells across all compartments was associated with a poorer prognostic (OS; HR = 1.22; 95%CI = 1.04-1.42; p = 0.01, PFS; HR = 1.16; p = 0.02), or a better prognostic when colocalized within TLSs (PFS; HR = 0.84, p = 0.03). Conclusion: Our results support the role of CXCL13+ cells in advanced NSCLC patients, with favorable prognosis when localized within TLSs and unfavorable prognosis when present elsewhere. The concomitant proximity of CXCL13+ and CD20+ cells within TLSs may favor antigen presentation to T cells, thus enhancing the effect of PD-1/PD-L1 axis inhibition. Further validation is warranted to confirm the potential relevance of this biomarker in a clinical setting.
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Recent results show that polymorphisms of programmed death ligand 1 (PD-L1, also known as CD274 or B7-H1) might be used as a possible marker for effectiveness of chemotherapy and cancer risk. However, the effect of PD-L1 gene variations on PD-L1 expression remain unclear. Given the post-transcriptional machinery in tumor PD-L1 expression, we investigated single nucleotide polymorphisms (SNPs) in the 3'-untranslated region (3'-UTR) of the PD-L1 gene, rs4143815 and rs4742098, using formalin-fixed paraffin-embedded sections of 154 patients with non-small cell lung cancers (NSCLCs). In rs4143815, the GG genotype showed significant association with PD-L1 expression (P = 0.032). In rs4742098, the AA genotype was significantly associated with histology and PD-L1 expression (P = 0.022 and P = 0.008, respectively). In multivariate logistic regression analysis, the AA genotype in rs4742098 was correlated with PD-L1 expression (odds ratio 0.408, P = 0.048). Interestingly, approximately 10% of the NSCLC cases showed somatic mutation when we compared genotypes of these SNPs between NSCLC tissues and non-tumor tissues from the same patients. In addition, cases with somatic mutation showed higher levels of PD-L1 expression than cases with germline mutation in rs4143815 GG. In conclusion, we demonstrated that the rs4143815 and rs4742098 SNPs in the 3'-UTR of PD-L1 were associated with tumor PD-L1 expression in NSCLCs.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Genotipo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Regiones no TraducidasRESUMEN
Glucosidase II beta subunit (GluIIß), encoded from PRKCSH, is a subunit of the glucosidase II enzyme responsible for quality control of N-linked glycoprotein folding and suppression of GluIIß led to inhibitory effect of the receptor tyrosine kinase (RTKs) activities known to be critical for survival and development of cancer. In this study, we investigated the effect of GluIIß knockout on the global gene expression of cancer cells and its impact on functions of immune cells. GluIIß knockout lung adenocarcinoma A549 cell line was generated using CRISPR/Cas9-based genome editing system and subjected to transcriptomic analysis. Among 23,502 expressed transcripts, 1068 genes were significantly up-regulated and 807 genes greatly down-regulated. The KEGG enrichment analysis showed significant down-regulation of genes related extracellular matrix (ECM), ECM-receptor interaction, cytokine-cytokine receptor interaction and cell adhesion molecules (CAMs) in GluIIß knockout cells. Of 9 CAMs encoded DEG identified by KEGG enrichment analysis, real time RT-PCR confirmed 8 genes to be significantly down-regulated in all 3 different GluIIß knockout clones, which includes cadherin 4 (CDH4), cadherin 2 (CDH2), versican (VCAN), integrin subunit alpha 4 (ITGA4), endothelial cell-selective adhesion molecule (ESAM), CD274 (program death ligand-1 (PD-L1)), Cell Adhesion Molecule 1 (CADM1), and Nectin Cell Adhesion Molecule 3 (NECTIN3). Whereas PTPRF (Protein Tyrosine Phosphatase Receptor Type F) was significantly decreased only in 1 out of 3 knockout clones. Microscopic analysis revealed distinctively different cell morphology of GluIIß knockout cells with lesser cytoplasmic and cell surface area compared to parental A549 cells and non-targeted transfected cells.Further investigations revealed that Jurkat E6.1 T cells or human peripheral blood mononuclear cells (PBMCs) co-cultured with GluIIß knockout A549 exhibited significantly increased viability and tumor cell killing activity compared to those co-cultured with non-target transfected cells. Analysis of cytokine released from Jurkat E6.1 T cells co-cultured with GluIIß knockout A549 cells showed significant increased level of angiogenin and significant decreased level of ENA-78. In conclusion, knockout of GluIIß from cancer cells induced altered gene expression profile that improved anti-tumor activities of co-cultured T lymphocytes and PBMCs thus suppression of GluIIß may represent a novel approach of boosting anti-tumor immunity.
Asunto(s)
Moléculas de Adhesión Celular , Leucocitos Mononucleares , alfa-Glucosidasas , Humanos , Células A549 , Moléculas de Adhesión Celular/genética , Perfilación de la Expresión Génica , Citocinas , Adhesión Celular , Molécula 1 de Adhesión CelularRESUMEN
BACKGROUND: Non-small cell lung cancers (NSCLC) harboring Human Epidermal Growth Factor Receptor 2 (HER2) mutations represent a distinct subset with unique therapeutic challenges. Although immune checkpoint inhibitors (ICIs) have been transformative in lung cancer treatment, the efficacy of ICIs in HER2-mutated NSCLC remains to be established. METHODS: We systematically searched for real-world studies investigating the use of ICIs in treating HER2-mutated NSCLC, sourced from the PubMed, Cochrane Library, and Embase databases. Outcomes including objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) were extracted for further analysis. RESULTS: Twelve studies involving 260 patients were enrolled in this meta-analysis. Pooled data revealed an ORR of 0.26 (95% CI 0.17-0.34), a DCR of 0.68 (95% CI 0.55-0.81), and a median PFS (mPFS) of 5.36 months (95% CI 3.50-7.21). Notably, in the subgroup receiving combined immune and chemotherapy, the ORR increased to 0.37 (95% CI 0.26-0.49), the DCR to 0.79 (95% CI 0.70-0.87), and the mPFS to 7.10 months (95% CI 5.21-8.99). CONCLUSIONS: ICIs demonstrate promising anti-tumor activity and safety in patients with HER2-mutated NSCLC. Furthermore, the combined regimen of ICIs and chemotherapy may provide a significant therapeutic option for this patient population.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inmunoterapia , Bases de Datos Factuales , Inhibidores de Puntos de Control InmunológicoRESUMEN
Lung cancer has been one of the leading causes of death over the past century. Unfortunately, the reliance on conventional methods to diagnose the phenotypic properties of tumors hinders early-stage cancer diagnosis. However, recent advancements in identifying disease-specific nucleotide biomarkers, particularly microRNAs, have brought us closer to early-stage detection. The roles of miR-155, miR-197, and miR-182 have been established in stage I lung cancer. Recent progress in synthesizing nanomaterials with higher conductivity has enhanced the diagnostic sensitivity of electrochemical biosensors, which can detect low concentrations of targeted biomarkers. Therefore, this review article focuses on exploring electrochemical biosensors based on microRNA in lung cancer.
Asunto(s)
Técnicas Biosensibles , Neoplasias Pulmonares , MicroARNs , Nanoestructuras , Humanos , MicroARNs/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Nanoestructuras/química , Técnicas Biosensibles/métodos , Biomarcadores de Tumor/genética , Técnicas ElectroquímicasRESUMEN
Multiple primary lung cancers (MPLCs) are becoming more and more common and these patients can benefit from minimally invasive surgery. Here, we report a case of a patient diagnosed with synchronous MPLCs who underwent bilateral thoracoscopic pulmonary resections in a two-stage strategy, and achieved a good surgical outcome and high quality of life. A 66-year-old female was found to have one major ground-glass nodule (GGN) in the right upper lobe and eight minor GGNs in the left upper and lower lobes. The patient underwent right upper lobe resection and systematic mediastinal lymph node dissection via single-utility port thoracoscopic surgery in September 2018. Pathology was lepidic predominant adenocarcinoma pT1bN0M0, IA2. Regular high-resolution computed tomography examination during 36 months after right upper lobectomy showed gradually increasing diameter and solid component of multiple GGNs in left lung. The patient underwent thoracoscopic multiple pulmonary resections using an intraoperative localization technique in a hybrid operating room in October 2021 and all eight nodules in the left lung were resected. Two segmentectomies and four wedge resections were performed, and the pathological results of the eight nodules included four adenocarcinomas, three adenocarcinomas in situ, and one alveolar epithelial hyperplasia. The two operations were successful with no intra- or postoperative 90-day complications. During more than 20 months of follow-up after the second operation, the patient had well recovered pulmonary function and physical status with a Karnofsky performance status score of 90 and no local recurrence or metastasis. A two-stage surgical strategy for synchronous MPLCs is therefore feasible. The surgical strategy, timing of intervention, and extent of pulmonary resection should be individually designed according to the location and characteristics of each nodule. Intraoperative localization of small GGNs is very important to ensure that all nodules are completely and accurately resected during the operation.