Thoracic Cancer最新文献

Stereotactic body radiation therapy (SBRT) is a highly effective treatment for lung cancer; however, challenges arise from tumor motion induced by respiration. The CyberKnife system, incorporating both fiducial-based and fiducial-free tracking modalities, aims to mitigate these challenges, yet tumor recognition can be compromised by overlapping bone structures. This study introduces a novel bone suppression imaging technique for kilovolt X-ray imaging using generative adversarial networks (GANs) to enhance tumor tracking in SBRT by reducing interference from bony structures. Computed tomography (CT) images, both with and without bone structures, were generated using a four-dimensional extended cardiac-torso phantom (XCAT phantom) across 56 cases. X-ray projections were captured from left and right oblique 45° angles and divided into nine segments, producing 1120 images. These images were processed through six pre-trained GAN models-CycleGAN, DualGAN, CUT, FastCUT, DCLGAN, and SimDCL-yielding bone-suppressed images on the XCAT phantom (BSI_phantom). The resulting images were evaluated against bone-shadow-free images using structural similarity index measure (SSIM), peak signal-to-noise ratio (PSNR), and Frechet inception distance (FID). Additionally, bone-suppressed images (BSI_patient) were derived from 1000 non-simulated patient images. BSI_phantom images achieved SSIM and PSNR values of 0.96 ± 0.02 and 36.93 ± 3.93, respectively. SimDCL exhibited optimal performance with an FID score of 68.93, indicative of superior image generation quality. This GAN-based bone suppression imaging technique markedly improved image recognition and refined dynamic tumor tracking, enhancing the accuracy and efficacy of SBRT.

Concurrent mutations in tumor protein p53 (TP53) or Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2-pathway components are linked to poor outcomes in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), but the impact of triple mutations remains unclear. We report a case of EGFR-, TP53-, and Cullin 3 (CUL3)-mutant NSCLC in a 43-year-old woman with widespread metastases at diagnosis, including those in the contralateral lung, distant lymph nodes, pericardium, liver, bones, left adrenal gland, and brain. She received osimertinib as first-line therapy, but pericardial effusion and liver metastases progressed rapidly over 3 months, and she was switched to carboplatin and pemetrexed. By the eighth cycle of pemetrexed, the bone metastases had progressed, resulting in disseminated intravascular coagulation (DIC) due to bone marrow carcinomatosis. The patient received third-line therapy with albumin-bound paclitaxel and fourth-line therapy with docetaxel, but further treatment was suspended owing to DIC progression. She passed away 23 months after the initiation of osimertinib. Public database analysis revealed that the EGFR/TP53/CUL3 triple mutation accounts for 0.4% of EGFR-mutant NSCLC cases, yielding significantly shorter survival than EGFR mutations alone and likely shorter than EGFR/TP53 double mutations. Gaining a deeper understanding of the clinical significance of coexisting genetic mutations in patients with EGFR-mutant NSCLC will be crucial to develop future therapies.

Background: There is no unified standard in adjuvant therapy (AT) for patients with esophageal squamous cell carcinoma (ESCC) after neoadjuvant therapy and surgery. We evaluated the significance of AT for these patients and explored its influencing factors.

Methods: ESCC patients who underwent neoadjuvant therapy and surgery from 2019 to 2022 at three centers were divided into AT (n = 227) and non-AT groups (n = 435). Baseline characteristics were balanced using propensity score matching (PSM). Primary endpoints were disease-free survival (DFS) and overall survival (OS), assessed using the Kaplan-Meier method. Subgroup analyses and univariate and multivariate Cox regression analyses were conducted to identify the prognostic factors.

Results: The median follow-up period is 36 (2-72) months. After PSM, the total population had 1-, 2-, and 3-year OS rates of 71.3%, 66.0%, and 64.1%, respectively. There were no statistically significant differences in DFS (HR: 0.79; 95% CI: 0.55-1.14, p = 0.21) or OS (HR: 0.75; 95% CI: 0.49-1.13, p = 0.17) between AT and non-AT groups. Subgroup analysis revealed that non-pCR patients benefited from AT in DFS (p = 0.042) and OS (p = 0.033). Moreover, in non-pCR patients who received AT, BMI ≥ 21.5 kg/m² and ypN0 were independent protective factors of DFS. ypN0 was an independent protective factor of OS. In terms of AT regimens, the Kaplan-Meier analysis revealed that adjuvant immunochemotherapy (AICT) provided superior survival benefits than adjuvant radiotherapy and adjuvant chemotherapy.

Conclusions: Postoperative AT benefited ESCC patients with non-pCR, while AICT may be a relatively better AT regimen in real-world data, which deserves further exploration.

Objectives: Stage III non-small cell lung cancer (NSCLC) treatment remains challenging, with a multitude of treatment options available. We assessed Stage IIIA NSCLC outcomes by treatment received.

Methods: We performed a single-institution retrospective review of NSCLC patients with Stage IIIA disease treated January 01, 2010-March 01, 2022. Demographics, treatments, outcomes, and failure patterns were collected. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier analysis. Failure patterns were assessed for differences using chi-square analysis.

Results: Of 270 Stage III NSCLC patients, 134 had Stage IIIA disease with a median follow-up of 29.9 months and a median age of 66 years (IQR 60-75). 66 (49.3%) patients were male, and 105 (78.4%) were current/former smokers (with 30 median pack-years). Patients were treated with definitive radiation with/without chemotherapy (CRT; n = 77, 57.5%), surgery with neoadjuvant chemotherapy and/or radiation (Neoadj; n = 42, 31.3%), and surgery without neoadjuvant therapy (Surg; n = 15, 11.2%). Median PFS was 25.4 months (95% CI 12.5-42.6) for CRT, 22.6 months (95% CI 12.2-44.4) for Neoadj, and 22.8 months (95% CI 5.2-NA) for Surg with no significant intergroup difference (p = 0.99). Median OS was 57.0 months (95% CI 37.4-77.5) for CRT, 51.5 months (95% CI 36.7-65.5) for Neoadj, and 35.3 months (95% CI 16.8-NR) for Surg with no significant intergroup difference (p = 0.99).

Conclusions: In this single institution retrospective study, we find no significant differences in PFS, OS, and failure patterns between patients with Stage IIIA NSCLC treated with definitive (chemo)radiation and surgery with or without neoadjuvant therapy. Further work in the immunotherapy era is needed.

Esophageal cancer (EC) is a leading cause of cancer-related mortality worldwide. Methyltransferase-like 3 (METTL3), a key enzyme involved in m6A methylation, has been implicated in the development and progression of various cancers, including EC. However, its potential mechanism of action in EC progression remains unclear. METTL3 expression was found to be upregulated in EC tissues and cells. Knockdown of METTL3 suppressed EC cell proliferation, invasion, migration, and angiogenesis, while promoting apoptosis. Mechanistically, METTL3 maintained PIK3CA mRNA expression and stability in an m6A-dependent and IGF2BP2-dependent manner, respectively. METTL3 silencing inactivated the AKT pathway by regulating PIK3CA expression. Furthermore, overexpression of PIK3CA mitigated the effects of METTL3 silencing on the malignant growth of KYSE180 and TE1 cells in vivo and in vitro. METTL3/IGF2BP2 promoted the malignant progression of EC by activating the PIK3CA/AKT pathway. Targeting the METTL3-PIK3CA axis may offer a novel therapeutic approach for EC treatment.

Background: Recognizing rare molecular variants of driver mutations poses a challenge in precision oncology, particularly for treatment of non-small cell lung cancer (NSCLC). In this study, we aimed to determine whether Oncomine Dx Target Test Multi-CDx System (ODxTT), the most widely used genetic test for NSCLC in Japan, potentially overlooks druggable EGFR mutations.

Materials and methods: Among 418 patients who underwent molecular testing using ODxTT at our hospital, 267 were diagnosed with adenocarcinoma. No mutations were reported in 82 of these cases. For these 82 cases, we searched for EGFR mutations in exons 18-21 by examining the binary alignment map file. Once a mutation was identified, its pathological significance was evaluated using the ClinVar database to determine whether ODxTT had overlooked any actionable EGFR mutations.

Results: Mutations in EGFR exons 19 and 18 were identified in six and four cases, respectively. Three, six, and none of these variants were detectable using the Cobas EGFR Mutation Test v2, Lung Cancer Compact Panel, and Amoy Dx, respectively. Of the 10 patients, five were subsequently treated with EGFR TKI; three showed partial response, one had stable disease, and one had progressive disease.

Conclusions: ODxTT failed to identify 10 actionable EGFR mutations, accounting for 12.2% (10/82) of the cases initially reported as not carrying actionable mutations. Therefore, comprehensive genomic profiling should be actively performed early in cases with high clinical suspicion of EGFR mutations.

Background: The epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) has a unique "cold" immune profile. DNA damage repair (DDR) genes are closely related to tumorigenesis and the effectiveness of immunotherapy in many tumors. However, the role and mechanism of DDR in the genesis and progression of EGFRm NSCLC remain unclear.

Methods: This study included 101 EGFRm NSCLC samples from The Cancer Genome Atlas (TCGA) dataset and a GSE31210 dataset (external set) from the GEO database. Cluster analysis was used to identify different subtypes of EGFRm NSCLC based on the expression of DDR genes. Univariate and LASSO regression analysis was used to develop a DDR-based predictive model. The prognostic significance of this model was assessed using Cox regression, Kaplan-Meier, and receiver operating characteristic (ROC) curve analyses. Bioinformatics analysis was performed to investigate the clinicopathological characteristics and immune profiles associated with this model. In vitro experiment was performed to testify the role of DDR genes in EGFRm NSCLC.

Results: We identified two subtypes of EGFRm NSCLC: DDR-activated and DDR-suppressed. The DDR-activated subtype showed more aggressive clinical behavior and poorer prognosis and was more responsive to immunotherapy. A prognostic model for EGFRm NSCLC was constructed using four DDR genes: CAPS, FAM83A, IGLV8-61, and SLC7A5. The derived risk score could serve as an independent prognostic indicator. High- and low-risk patients exhibited distinct clinicopathological characteristics, immune profiles, and responses to immunotherapy. The T-cell inflammation and Tumor Immune Dysfunction and Exclusion (TIDE) scores differed between the high- and low-risk subgroups, with both showing enhanced effectiveness of immunotherapy in the low-risk subgroup. Targeted therapy such as BI.2536, an inhibitor of polo-like kinase 1, could be effective for patients with high-risk EGFRm NSCLC. Meanwhile, in vitro detection approved the role of DDR genes in EGFRm NSCLC response.

Conclusion: This study demonstrated a diversity of DDR genes in EGFRm NSCLC and developed a predictive model using these genes. This model could assist in identifying potential candidates for immunotherapy and in assessing personalized treatment and prognosis of patients with EGFRm NSCLC.

Objective: Malignant mesothelioma (MM) is a rare malignant tumor. To explore the clinicopathological characteristics and efficacy of Chinese population with MM in the real-world.

Methods: Two hundred and forty-eight patients diagnosed with MM between September 2007 and August 2024 from three large medical centers (Beijing Hospital, Peking University Cancer Hospital, and Chinese Academy of Medical Sciences Cancer Hospital) were retrospectively analyzed. Kaplan-Meier and Cox regression were performed. Breast cancer gene 1-associated protein 1 (BAP1) status was evaluated.

Results: Chinese population with MM had a lower diagnostic age, higher proportion of youth and female, more advanced stage and lower expression of characteristic markers. The median progression-free survival (mPFS) and median overall survival (mOS) were 8.90 and 25.60 months for the first-line treatment, and 3.28 and 19.50 months for the second-line. The first-line immunotherapy provided a relatively higher objective response rate (33.3% vs. 20.5%, p = 0.402) and a trend to prolong mPFS (12.10 vs. 9.20 months, p = 0.345) and mOS (NA vs. 23.90, p = 0.185) compared with chemotherapy. Bevacizumab combined with chemotherapy relatively prolonged mPFS (10.47 vs. 7.93 months, p = 0.074) and mOS (31.30 vs. 23.20 months, p = 0.673) than chemotherapy alone. Carboplatin relatively improved mPFS than cisplatin (10.87 vs. 8.87 months, p = 0.185). Age and histologic type were predictors for PFS, and gender, histologic subtype, and CK5/6 were prognosis factors for OS. Briefly, 17.78% patients existed BAP1 deletions and correlated with OS benefit.

Conclusion: Chinese population with MM present unique clinicopathologic characteristics and could benefit from the first-line immunotherapy and bevacizumab combined with chemotherapy. Gender, histologic subtype, and CK5/6 are prognosis factors for OS. BAP1 deletions correlate with OS benefit.

Adjuvant osimertinib administered over a 3-year period in patients diagnosed with stage IB-IIIA non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations has not only shown improvement in event-free survival but also demonstrated a prolonged overall survival (OS), leading to its approval as a standard treatment in this context. Meanwhile, no targeted studies have been conducted on the efficacy of adjuvant immune checkpoint inhibitors in these patients. Although studies such as IMPOWER-010 and KEYNOTE-091 have included a small number of patients with positive driver genes, no definitive conclusions regarding the OS benefit have been established. Neoadjuvant targeted therapy is not currently recommended because of insufficient evidence, characterized by a low depth of pathological response and no reported improvement in survival outcomes. The same is true for neoadjuvant immunotherapy in patients with EGFR mutations. Although numerous issues such as refining patient population selection, determining appropriate combination therapy regimens, establishing primary endpoints, assessing the influence of perioperative complications, and accurately evaluating the clinical application of circulating tumor DNA in various scenarios exist, several promising ongoing trials, including ADAURA2 and NEOADURA, are expected to provide valuable insights that will help address these questions. Here, we summarize the available evidence and clinical issues that need to be considered to optimize clinical decision-making for patients with EGFR-mutant NSCLC.

Objective: To explore the clinical value of molecular residual disease detection based on circulating tumor DNA (ctDNA-MRD) in the perioperative period of esophageal squamous cell carcinoma (ESCC) and to analyze the tumor escape mechanisms in MRD-positive cases.

Methods: A total of 35 ESCC patients were prospectively enrolled. Preoperative and postoperative (1 month after surgery) blood and surgical tissue samples were analyzed. ctDNA variants were tracked in plasma to assess ctDNA-MRD, and whole-transcriptome sequencing was performed on MRD-positive and MRD-negative tissue samples.

Results: Preoperative blood ctDNA was positive in 54.3% of patients, with a 31.6% positive predictive value for recurrence. One month postsurgery, the positive rate of ctDNA was 17.1%, with an 83.3% predictive value for recurrence. Both preoperative and postoperative ctDNA positivity were significant prognostic indicators (HR = 2.78, p < 0.05; HR = 4.42, p < 0.001). Multivariate analysis confirmed ctDNA as an independent prognostic factor (HR = 303.75, p < 0.001). Transcriptomic analysis revealed increased macrophage (W = 15 848; p < 0.01) and follicular helper T (Tfh) cell (W = 10 935; p < 0.01) levels in MRD-positive patients, suggesting a potential link to immune escape in tumors.

Conclusions: Plasma ctDNA measured 1 month postoperatively in ESCC patients can effectively detect MRD, and ctDNA-MRD serves as an independent risk factor for postoperative recurrence. The mechanism underlying MRD positivity may involve the polarization of Tfh cells and macrophages, aiding tumor cells in immune escape through the bloodstream.