American journal of cancer research最新文献

Induction chemotherapy followed by concomitant chemoradiation is the standard therapy for patients with locoregionally advanced NPC. There is a limitation of clinical studies that compare different induction regimens. The purpose of this work is to analyze the efficacy of two distinct chemotherapy regimens, docetaxel, cisplatin, and 5-fluorouracil (TPF) and gemcitabine/cisplatin (GP), in treating patients with loco-regionally advanced nasopharyngeal carcinoma (NPC). We analyzed 81 patients initially presented with stage III-IVA NPC from January 2019 to June 2023. Participants were randomized in 1:1 ratio to obtain GP regimen or TPF regimen followed by concurrent CRT. The overall response rate was 97.5% after induction chemotherapy in both groups (In GP arm, 78% of patients achieved complete remission compared to 70% of patients treated with TPF regimen). The satisfactory tumor response to induction chemotherapy was linked with significant enhanced progression free survival [CI (3.37-13.92), HR=2.16, P=0.001] and overall survival [CI (3.717-9.443), HR=1.873, P=0.001]. The GP regimen was both efficacious and well-tolerated. Leucopenia and neutropenia (Grade 3-4) were significantly lower in GP group contrasted to in TPF group. There was no significant difference in the 3-year DFS and OS between GP and TPF protocols.

HER2-positive breast cancer is highly aggressive, with a significant risk of recurrence and metastasis, leading to a poor prognosis. While most early-stage HER2-positive breast cancer patients benefit from combining trastuzumab monoclonal antibody with chemotherapy, the therapeutic response to various drug combinations varies across the HER2+ patient population. Therefore, predicting the prognosis and treatment response of HER2+ breast cancer patients to specific regimens is crucial for selecting appropriate precision individualized therapies. HER2DX is the first genomic tool designed to guide the treatment of HER2+ breast cancer patients. The three scores provided by HER2DX inform the entire treatment process, including predicting survival outcomes, recurrence, metastasis, and treatment responses like Pathological Complete Response Rate (pCR). It offers recommendations on follow-up intervals, treatment plans, and the duration of drug therapy. This review examines the literature and analyzes studies applying HER2DX to guide the comprehensive treatment and predict prognosis in HER2+ breast cancer patients, aiming to promote the widespread use of HER2DX in individualized treatment.

Colorectal cancer (CRC) is a lethal malignancy and a leading cause of cancer-related mortality worldwide. Chromosomal instability (CIN) is a key driver of genomic instability in CRC and is characterized by aneuploidy and somatic copy-number alterations. This study aimed to predict CIN in CRC using histological data from whole slide images (WSIs). CRC samples from TCGA were analyzed, with tumor regions segmented into tiles and nuclei for feature extraction using convolutional neural network (CNN) and morphologic analysis. Binary classification models were developed to distinguish high and low aneuploidy scores (AS) based on slide-level features. The analysis included 313 patients with 315 WSIs, resulting in over 350,000 tumor tiles and nearly 2.7 million tumor cell nuclei. The ResNet18-SSL model, pre-trained on histopathological images, demonstrated superior accuracy in tile-based AS prediction, while DenseNet121 excelled in nucleus-based prediction. Combining CNN-based and morphological features enhanced the classification accuracy of nucleus-based predictions. Additionally, significant correlations were observed between morphological features and copy-number signatures. Unsupervised clustering of nuclear features revealed that distinct groups are significantly correlated with CIN and TP53 mutations. This study underscores the potential of histological features from WSIs to predict CIN in CRC samples. Nuclear feature analysis, combined with deep-learning techniques, offers a robust method for CIN prediction, highlighting the importance of further research into the relationships between histological and molecular phenotypes.

KRAS mutations occur in ~40-50% of mCRC and are associated with aggressive disease that is refractory to anti-EGFR therapies. Pancreatic cancer harbors ~90% KRAS driver gene mutation frequency. Small molecules targeting KRAS G12C gained FDA approval for KRAS G12C-mutated NSCLC. ONC212, a fluorinated imipridone with nM anti-cancer activity has preclinical efficacy against pancreatic cancer and other malignancies. MRTX1133, identified as a noncovalent selective KRAS G12D inhibitor that suppresses G12D signaling by binding to the switch II pocket thereby inhibiting protein-protein interactions. We investigated cell viability, drug synergies, pERK suppression and cytokine, chemokine or growth factor alterations following treatment with 5-Fluorouracil (5-FU) or ONC212 plus MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines. IC50 sensitivities ranged from 7 to 12 µM for 5-FU, 0.2-0.8 µM for ONC212, and > 100 nM to > 5,000 nM for MRTX1133 (G12D N = 4: LS513 > 100, HPAF-II > 1,000, SNUC2B > 5,000, PANC-1 > 5,000). For non-G12D, the range of IC50 for MRTX1133 was > 1,000 to > 5,000 nM for CRC lines with G12V, G13D, or WT KRAS (N = 7). Synergies between MRTX1133 plus 5-FU or ONC212 were observed regardless of KRAS G12D mutation with combination indices of < 0.5 indicating strong synergy. Observed synergies were greater with MRTX1133 plus ONC212 compared to MRTX1133 plus 5-FU. pERK was suppressed with mutant but not wild-type KRAS at nM MRTX1133 doses. Immunostimulatory profiles included reduction in IL8/CXCL8, MICA, Angiopoietin 2, VEGF and TNF-alpha and increase in IL-18/IL-1F4 with MRTX treatments and combinations. Our studies reveal preclinical activity of MRTX1133 alone or synergies when combined with 5-FU or ONC212 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation. The results suggest that KRAS G12V and KRAS G13D should be further considered in clinical trials including combination therapies involving MRTX1133 and 5-FU or ONC212.

Objective: To investigate the ability of intra- and peritumoral radiomics based on three-phase computed tomography (CT) to distinguish between malignant and benign parotid tumors.

Methods: We conducted a retrospective analysis of data from 374 patients with parotid gland tumors, all confirmed by histopathology. A total of 321 patients from Center 1 (January 2014 to January 2023) were randomly divided into the training set and internal testing set at a ratio of 7:3, whereas 53 patients from Center 2 (January 2020 to June 2022) constituted the external testing set. CT images of both the tumor and surrounding areas (2 mm and 5 mm areas surrounding the tumor) were reviewed, and their radiomic features were extracted for the construction of different radiomic models. In addition, a combined clinical-radiomic model was developed using multivariate logistic regression analysis. The model's predictive performance was evaluated using decision curve analysis (DCA) and receiver operating characteristic (ROC) curves.

Results: Among the models evaluated, Tumor + External2 model demonstrated superior predictive performance. The areas under the curve (AUCs) of this model were 0.986 in the training set, 0.827 in the internal test set, and 0.749 in the external test set. For the clinical model, independent predictive factors included symptoms, boundaries, and lymph node swelling. The combined clinical-radiomic model achieved AUCs of 0.981, 0.842, and 0.749 in the three cohorts, outperforming both the Tumor model and the clinical model individually.

Conclusion: The CT-based radiomic models incorporating intratumoral and peritumoral radiomic features can effectively distinguish malignant from benign parotid tumors, and the predictive accuracy is further improved by incorporating clinically independent predictors.

Breast cancer is a multifactorial disease driven by acquired genetic and epigenetic changes that lead to aberrant regulation of cellular signaling pathways. Receptor tyrosine kinases (RTKs), a class of critical receptors, are involved in the initiation and progression of breast cancer. RTKs are cell surface receptors with unique structures and biological characteristics, which respond to environmental signals by initiating signaling cascades such as the mitogen-activated protein kinase (MAPK) pathway, Janus kinase (JAK)/signal transducer, activator of transcription (STAT) pathway, and phosphoinositide 3-kinase (PI3K)/AKT pathway. The critical role of RTKs makes them suitable targets for breast cancer treatment. Targeted therapies against RTKs have been developed in recent years, evaluated in clinical trials, and approved for several cancer types, including breast cancer. However, breast cancer displays molecular heterogeneity and exhibits different therapeutic responses to various drug types, leading to limited effectiveness of targeted therapy against RTKs. In this review, we summarize the structural and functional characteristics of selected RTKs and discuss the mechanisms and current status of drug therapy involving different protein tyrosine kinases in breast cancer progression.

Overall colorectal cancer (CRC) incidence and mortality have been decreasing for several decades; however, since the early 1990s CRC incidence rates have nearly doubled among adults aged under 50 years. This study pilot-tested a community-based mass-media campaign aimed at improving knowledge and awareness of early-onset CRC in this population. The campaign (#CRCandMe) was deployed from June to September 2023 in Utah and Wisconsin. To evaluate its success (reach) and inform future campaigns, key performance indicators were defined (e.g., impressions, website traffic). To evaluate change in knowledge in the target population, the knowledge and awareness of participants recruited via consumer panels was assessed at baseline (n=235) and follow-up (n=161). The number of correct answers for each of seven knowledge items was calculated at baseline (pre-intervention) and follow-up (post-intervention). McNemar's test was employed to assess significant differences in the seven knowledge items between the two timepoints. The campaign delivered over 26.7 million impressions and nearly 43,000 clicks. A 15-second video ad received 221,985 plays, with 57,270 users watching to completion. Pre-survey results revealed that while 74% of participants were able to correctly identify CRC signs, only 18% could identify risk factors. Knowledge scores slightly improved from baseline to follow-up, with statistically significance for the question related to CRC signs (P=0.0004). This study demonstrated wide reach and may inform future larger-scale interventions and public health initiatives aimed at reducing CRC incidence and improving health outcomes for at-risk adults aged under 50 years.

Laryngeal squamous cell carcinoma (LSCC) is a prevalent head and neck neoplasm with escalating global morbidity and mortality rates. Despite the increasing burden of LSCC, the drugs currently approved for its treatment are limited. Therefore, it is necessary to identify novel and promising drugs that target LSCC. Cucurbitacin E (CuE) is a naturally oxygenated tetracyclic triterpenoid that suppresses several cancers. However, its anti-LSCC activity and the molecular mechanisms of action remain unclear. This study explored its impact on LSCC, revealing cell viability attenuation and apoptosis enhancement in vitro. Further investigations indicated that CuE significantly decreased mitochondrial membrane potential, thereby promoting cytochrome c release, increasing cleaved-Caspase 3 and cleaved-PARP levels, and triggering mitochondria-dependent apoptosis. Concurrently, exposure of LSCC cells to CuE enhanced endoplasmic reticulum (ER) stress, mobilized the protein kinase RNA-like endoplasmic reticulum kinase/initiation factor 2a/ATF4/C-EBP homologous protein pathway, and induced LSCC cell apoptosis. Finally, CuE markedly elevated intracellular reactive oxygen species (ROS) levels. When ROS were eliminated with N-acetylcysteine, CuE-mediated mitochondrial dysfunction, ER stress, and cell apoptosis were nearly abolished. Similar outcomes were observed in murine LSCC models. Together, these results highlight that CuE suppresses proliferation while triggering apoptosis in LSCC cells via ROS-regulated mitochondrial dysfunction and the ER stress pathway. Hence, CuE may serve as a promising candidate for LCSS treatment.

Although a significant improvement in progression-free survival (PFS) has been reported in the thyroid transcription factor 1 (TTF-1) positive patients under treatment for non-squamous non-small cell lung cancer (NS-NSCLC), including immune checkpoint inhibitor therapy, the association between TTF-1 expression and adverse event occurrence remains unclear. Therefore, this study investigated the impact of TTF-1 and its adverse events on PFS during pembrolizumab plus pemetrexed and platinum chemotherapy for NS-NSCLC. Patients who received the pembrolizumab plus pemetrexed and platinum chemotherapy from 1/1/2018 to 12/31/2022 and whose TTF-1 expression was measured were included in the study. This was a retrospective study conducted using electronic medical records. The mean age of the 79 patients was 67.5 ± 8.4 years, with 75.95% patients being male. Among them, 59.49% were TTF-1 positive. PFS comparison between TTF-1-positive and -negative patients showed a trend toward longer PFS for TTF-1 positive patients, though the results were statistically insignificant (P = 0.190). Proportional hazards analysis indicated significant PFS extension from treatment interruption, as adverse events related to cancer therapy stopped (hazard ratio [HR] = 0.32, P = 0.005) and the number of anticancer agents used (HR = 0.01, P < 0.001). Additionally, pembrolizumab plus pemetrexed and platinum chemotherapy for TTF-1-positive NS-NSCLC significantly extended PFS after treatment discontinuation as related adverse events stopped (827 vs. 210 days, P = 0.021). Measurement of TTF-1 may accordingly serve as a predictor of treatment response to the pembrolizumab plus pemetrexed and platinum chemotherapy. It may also be a predictor of patient prognosis when treatment is discontinued due to related adverse events.

Background: VMA21 has been shown to be dysregulated in a number of cancers. However, no study has yet explored whether VMA21 is involved in the regulation of triple-negative breast cancer (TNBC), especially from the level of immune escape.

Methods: The Gene Expression Omnibus (GEO) database was accessed to obtain the microarray dataset identified as GSE38959, which was then subjected to an analysis aimed at identifying genes that are differentially expressed (DEGs). The researchers examined the expression of VMA21 in TNBC cell lines. After knockdown of VMA21 in TNBC cells, cell proliferation, invasion, and migration were assessed by clone formation, cell scratch, and Transwell assay, respectively. The effect of VMA21 on immune cell function was explored by cell co-culture method, which was used to assess how TNBC cells with suppressed VMA21 expression affected CD8+ T cytotoxic potential and cytokine secretion. The effect of VMA21 on TCIRG1 protein stability and ubiquitination was assessed using immunoprecipitation. The effects of VMA21 knockdown on tumor xenograft growth and CD8+ T cell immune infiltration in mice were further evaluated.

Results: VMA21 expression is significantly elevated across various cell lines of TNBC. Furthermore, the perturbation of VMA21 notably suppresses key cell viability parameters in TNBC cells, including their proliferation, invasiveness, and migratory abilities. The modulation of VMA21 in TNBC cells can lead to a substantial augmentation in CD8+ T cell effectiveness. VMA21 stabilizes TCIRG1 protein expression by inhibiting its ubiquitination degradation. Further, VMA21 is involved in regulating TNBC cell proliferation, invasion and immune escape by promoting TCIRG1 expression.

Conclusions: VMA21 is able to regulate TCIRG1 protein stability by binding to TCIRG1 protein in the form of ubiquitination, which ultimately promotes the malignant behavior as well as immune escape of TNBC cells.