Hyalinizing clear cell carcinoma of the salivary gland is a rare neoplasm, accounting for only less than 1% of malignancies arising from the salivary gland. It is molecularly defined by the expression of the EWSR-ATF1 fusion oncogene. To date, there has been no previous studies published yet in the Philippines regarding the existence of this tumor. In this paper, we present a case of a 70-year-old elderly female who had a 10-year history of a gradually enlarging left lateral neck mass. Histopathologic examination showed a tumor arranged of cords, nests, and trabeculae of monomorphic round cells with abundant clear to lightly eosinophilic cytoplasm surrounded by thick hyalinized collagen bundles. Immunohistochemistry and molecular studies were done which revealed a positive p63 staining, negative SMA and S100, and an EWSR1 rearrangement in Fluorescence in situ hybridization (FISH), thus, confirming the diagnosis.

Lung cancer is the malignancy with the highest incidence and mortality burden globally, ranking first in both morbidity and mortality among all types of malignant tumors. Pathologically, lung cancer is classified into non-small cell lung cancer (NSCLC) and small cell lung cancer, with NSCLC accounting for approximately 85% of cases. Due to the often subtle or nonspecific clinical manifestations in early-stage disease, many patients are diagnosed at a locally advanced or metastatic stage, where treatment options are limited and prognosis remains poor. Therefore, molecular targeted therapy focusing on driver genes has become a key strategy to improve the survival outcomes of patients with advanced NSCLC. The epidermal growth factor receptor (EGFR) is one of the most common driver genes in NSCLC. While EGFR mutations occur in approximately 12% of advanced NSCLC patients globally, the incidence rises to 55.9% in Chinese patients. Among EGFR mutations, P-loop and αC-helix compressing (PACC) mutations account for about 12.5%. Currently, EGFR tyrosine kinase inhibitors (TKIs) have become the first-line standard treatment for advanced NSCLC patients with classical EGFR mutations, with efficacy well-established through clinical studies and real-world evidence. However, with rapid advancements in NSCLC precision medicine and deeper exploration of the EGFR mutation spectrum, EGFR PACC mutations have emerged as a key clinical focus. The structural characteristics of these mutations lead to significant variability in responses to EGFR TKIs, leaving therapeutic options still limited, while detection challenges persist due to the sensitivity constraints of current testing technologies, driving increasing demand for improved diagnostic and treatment approaches. The current clinical evidence primarily stems from retrospective analyses and small-scale exploratory studies, while prospective, large-scale, high-level evidence-based medical research specifically targeting this mutation subtype remains notably insufficient. This evidence gap has consequently led to the absence of standardized guidelines or expert consensus regarding optimal treatment strategies for advanced NSCLC with EGFR PACC mutations. As a clinical consensus specifically addressing EGFR PACC-mutant NSCLC, this document provides a comprehensive framework encompassing the clinical rationale for EGFR PACC mutation testing, therapeutic strategies for advanced-stage disease, management of treatment-related adverse events, and follow-up protocols. The consensus underscores the pivotal role of EGFR PACC mutation detection in precision medicine implementation while offering evidence-based recommendations to guide personalized therapeutic decision-making. By establishing clear clinical pathways encompassing molecular testing, therapeutic intervention, and long-term monitoring for EGFR PACC-mutant NSCLC, this consensus aims to meaningfully improve patient survival outcomes while serving as a robust, evidence-based foundation for developing personalized clinical management approaches.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; ErbB Receptors/antagonists & inhibitors* ; Mutation ; Lung Neoplasms/pathology* ; Protein Kinase Inhibitors/therapeutic use* ; Molecular Targeted Therapy ; Consensus

Mutations in the human epidermal growth factor receptor 2 (HER-2) gene are recognized as significant but relatively rare driver alterations in non-small cell lung cancer (NSCLC). These mutations predominantly manifest as gene mutation, amplification, and protein overexpression, with an estimated prevalence from 2.8% to 15.4% among NSCLC patients in China. Research indicates that HER-2 mutations, particularly exon 20 insertions (ex20ins), are strongly correlated with aggressive tumor biology, poor prognosis, and limited responsiveness to immunotherapy, thereby exhibiting characteristics of "cold tumors". Overexpression and amplification of HER-2 are also indicative of a heightened risk of chemotherapy resistance and unfavorable survival outcomes, suggesting a distinct molecular subtype with unique biological behaviors. In recent years, novel antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (T-DXd), have demonstrated groundbreaking efficacy in HER-2-mutant advanced NSCLC patients. These ADCs have shown significant clinical benefits, including high objective response rates and progression-free survival advantages, making T-DXd the first targeted therapy approved for this patient population globally. Additionally, ADCs have exhibited therapeutic potential in patients with HER-2 overexpression, thus broadening the scope of their indications. To standardize the clinical diagnosis and treatment of HER-2 variant NSCLC, the Chinese Anti-cancer Association convened multidisciplinary experts from oncology, pulmonology, thoracic surgery, pathology, and molecular diagnostics to develop this consensus based on the latest evidences from both domestic and international studies, coupled with China's clinical practice experience. This consensus focuses on the molecular characteristics, clinical significance, diagnostic strategies, treatment options, and safety management of HER-2 alterations, addressing ten critical clinical questions in a systematic manner. It is recommended that HER-2 status be routinely tested at initial diagnosis, disease progression, or recurrence in NSCLC. Mutation detection should prioritize next-generation sequencing (NGS), while protein overexpression may be assessed using immunohistochemistry (IHC) standards for gastric cancer. Fluorescence in situ hybridization (FISH) is recommended for detecting HER-2 amplification. Regarding treatment, for HER-2-mutant patients, first-line therapy may involve chemotherapy with or without immune checkpoint inhibitors (ICIs), similar to treatment approaches for driver-gene negative populations. Upon failure of first-line treatment, trastuzumab deruxtecan, may be considered as alternative therapeutic options. For patients with HER-2 overexpression, ADCs should be considered after failure of standard systemic therapy. However, the management of HER-2 amplification remains insufficiently supported by evidence, necessitating a cautious, individualized approach. The consensus also includes detailed recommendations for screening and managing adverse effects associated with ADCs, such as interstitial lung disease (ILD), emphasizing the crucial role of safety management in ensuring treatment efficacy. The publication of this consensus aims to drive the standardization of molecular diagnosis and treatment pathways for HER-2 variant NSCLC, improve clinical outcomes and quality of life for patients, and facilitate the implementation of personalized precision treatment strategies.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/pathology* ; Receptor, ErbB-2/metabolism* ; Mutation ; Immunoconjugates/therapeutic use* ; Consensus ; Trastuzumab/therapeutic use* ; Camptothecin/analogs & derivatives*

BACKGROUND: Molecular subtyping is an essential complementarity after pathological analyses for targeted therapy. This study aimed to investigate the consistency of next-generation sequencing (NGS) results between circulating tumor DNA (ctDNA)-based and tissue-based in non-small cell lung cancer (NSCLC) and identify the patient characteristics that favor ctDNA testing. METHODS: Patients who diagnosed with NSCLC and received both ctDNA- and cancer tissue-based NGS before surgery or systemic treatment in Lung Cancer Center, Sichuan University West China Hospital between December 2017 and August 2022 were enrolled. A 425-cancer panel with a HiSeq 4000 NGS platform was used for NGS. The unweighted Cohen's kappa coefficient was employed to discriminate the high-concordance group from the low-concordance group with a cutoff value of 0.6. Six machine learning models were used to identify patient characteristics that relate to high concordance between ctDNA-based and tissue-based NGS. RESULTS: A total of 85 patients were enrolled, of which 22.4% (19/85) had stage III disease and 56.5% (48/85) had stage IV disease. Forty-four patients (51.8%) showed consistent gene mutation types between ctDNA-based and tissue-based NGS, while one patient (1.2%) tested negative in both approaches. Patients with advanced diseases and metastases to other organs would be suitable for the ctDNA-based NGS, and the generalized linear model showed that T stage, M stage, and tumor mutation burden were the critical discriminators to predict the consistency of results between ctDNA-based and tissue-based NGS. CONCLUSION ctDNA-based NGS showed comparable detection performance in the targeted gene mutations compared with tissue-based NGS, and it could be considered in advanced or metastatic NSCLC.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Circulating Tumor DNA/blood* ; High-Throughput Nucleotide Sequencing/methods* ; Female ; Male ; Lung Neoplasms/pathology* ; Middle Aged ; Mutation/genetics* ; Aged ; Adult ; Aged, 80 and over

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer with a high mortality rate in its late stages. One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor (EGFR) inhibitors. Therefore, it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy. METHODS: To evaluate the efficacy of the combination of the Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) inhibitor KN93 and EGFR inhibitors, we performed in vitro and in vivo experiments using two FAT atypical cadherin 1 ( FAT1 )-deficient (SCC9 and SCC25) and two FAT1 wild-type (SCC47 and HN12) OSCC cell lines. We assessed the effects of EGFR inhibitors (afatinib or cetuximab), KN93, or their combination on the malignant phenotype of OSCC in vivo and in vitro . The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2 (SOX2) were analyzed. Changes in the yes-associated protein 1 (YAP1) protein were characterized. Moreover, we analyzed mitochondrial dysfunction. Besides, the effects of combination therapy on mitochondrial dynamics were also evaluated. RESULTS: OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment. The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation, survival, and migration of FAT1 -mutated OSCC cells and suppressed tumor growth in vivo . Mechanistically, combination therapy enhanced the therapeutic sensitivity of FAT1 -mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins. Furthermore, combination therapy induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics, ultimately resulting in tumor suppression. CONCLUSION Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/metabolism* ; Cell Line, Tumor ; Animals ; Drug Resistance, Neoplasm/genetics* ; Cadherins/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Mice ; Mutation/genetics* ; Mice, Nude ; Protein Kinase Inhibitors/therapeutic use* ; Cetuximab/pharmacology* ; Afatinib/therapeutic use* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects*

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy (RT) following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 122 patients with ES-SCLC from three hospitals during July 2019 to December 2021 were retrospectively analyzed. Inverse probability of treatment weighting (IPTW) analysis was performed to address potential confounding factors. The primary focus of our evaluation was to assess the impact of RT on progression-free survival (PFS) and overall survival (OS). RESULTS: After IPTW analysis, 49 patients received durvalumab plus platinum-etoposide (EP) chemotherapy followed by RT (Durva + EP + RT) and 72 patients received immunochemotherapy (Durva + EP). The median OS was 17.2 months vs . 12.3 months (hazard ratio [HR]: 0.38, 95% confidence interval [CI]: 0.17-0.85, P = 0.020), and the median PFS was 8.9 months vs . 5.9 months (HR: 0.56, 95% CI: 0.32-0.97, P = 0.030) in Durva + EP + RT and Durva + EP groups, respectively. Thoracic radiation therapy (TRT) resulted in longer OS (17.2 months vs . 14.7 months) and PFS (9.1 months vs . 7.2 months) compared to RT directed to other metastatic sites. Among patients with oligo-metastasis, RT also showed significant benefits, with a median OS of 17.4 months vs . 13.7 months and median PFS of 9.8 months vs . 5.9 months compared to no RT. Continuous durvalumab treatment beyond progression (TBP) prolonged OS compared to patients without TBP, in both the Durva + EP + RT (NA vs . 15.8 months, HR: 0.48, 95% CI: 0.14-1.63, P = 0.238) and Durva + EP groups (12.3 months vs . 4.3 months, HR: 0.29, 95% CI: 0.10-0.81, P = 0.018). Grade 3 or 4 adverse events occurred in 13 (26.5%) and 13 (18.1%) patients, respectively, in the two groups; pneumonitis was mostly low-grade. CONCLUSION Addition of RT after first-line immunochemotherapy significantly improved survival outcomes with manageable toxicity in ES-SCLC.
Humans ; Small Cell Lung Carcinoma/therapy* ; Retrospective Studies ; Male ; Female ; Middle Aged ; Lung Neoplasms/therapy* ; Aged ; Antibodies, Monoclonal/therapeutic use* ; Adult ; Immunotherapy/methods* ; Aged, 80 and over

BACKGROUND: The combination of immune checkpoint inhibitors and chemotherapy (ICI + Chemo) shows promise in treatment of recurrent or metastatic nasopharyngeal carcinoma (RM-NPC), but some patients received limited benefit and the prognostic factors of the treatments remain unclear. Furthermore, ICIs efficacy in subsequent treatments needs further evaluation. METHODS: A systematic search on PubMed, Embase, the Cochrane Library, and major conference proceedings was conducted to identify relevant studies for meta-analysis. The study was designed to compare ICI + Chemo with chemotherapy in first-line treatment and identify efficacy predictors, and to evaluate ICIs alone in subsequent-line treatment for RM-NPC, with a focus on progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (AEs). RESULTS: Fifteen trials involving 1928 patients were included. Three trials compared ICI + Chemo with chemotherapy as a first-line treatment, while 12 trials evaluated ICIs alone in subsequent-line treatment of RM-NPC patients. First-line ICI + Chemo showed superior PFS (hazard ratio [HR] = 0.52, 95% confidence interval [CI], 0.43-0.63; P <0.001) and ORR (risk ratio [RR] = 1.14, 95% CI, 1.05-1.24; P <0.001) compared to chemotherapy, without increased AEs (RR = 1.01, 95% CI, 0.99-1.03; P = 0.481). Neither programmed death-ligand 1 (PD-L1) nor other factors predicted the efficacy of ICI + Chemo vs . chemotherapy. Subsequent-line ICIs alone had a median PFS of 4.12 months (95% CI, 2.93-5.31 months), an ORR of 24% (95% CI, 20-28%), with grade 1-5/grade 3-5 AEs at 79%/14%. However, ICIs alone were associated with significantly shorter PFS (HR = 1.31, 95% CI, 1.01-1.68; P = 0.040) than chemotherapy alone. CONCLUSIONS ICI + Chemo confers superior survival benefits compared to chemotherapy in first-line RM-NPC treatment, independent of PD-L1 expression or other factors. However, ICIs alone demonstrate a manageable safety profile but do not surpass chemotherapy in efficacy for subsequent-line treatment.
Humans ; Immune Checkpoint Inhibitors/adverse effects* ; Nasopharyngeal Carcinoma/drug therapy* ; Nasopharyngeal Neoplasms/drug therapy* ; Neoplasm Recurrence, Local/drug therapy*

BACKGROUND: Durvalumab after chemoradiotherapy (CRT) failed to bring survival benefits to patients with epidermal growth factor receptor ( EGFR ) mutations in PACIFIC study (evaluating durvalumab in patients with stage III, unresectable NSCLC who did not have disease progression after concurrent chemoradiotherapy). We aimed to explore whether locally advanced inoperable patients with EGFR mutations benefit from tyrosine kinase inhibitors (TKIs) and the optimal treatment regimen. METHODS: We searched the PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases from inception to December 31, 2022 and performed a meta-analysis based on a Bayesian framework, with progression-free survival (PFS) and overall survival (OS) as the primary endpoints. RESULTS: A total of 1156 patients were identified in 16 studies that included 6 treatment measures, including CRT, CRT followed by durvalumab (CRT-Durva), TKI monotherapy, radiotherapy combined with TKI (RT-TKI), CRT combined with TKI (CRT-TKI), and TKI combined with durvalumab (TKI-Durva). The PFS of patients treated with TKI-containing regimens was significantly longer than that of patients treated with TKI-free regimens (hazard ratio [HR] = 0.37, 95% confidence interval [CI], 0.20-0.66). The PFS of TKI monotherapy was significantly longer than that of CRT (HR = 0.66, 95% CI, 0.50-0.87) but shorter than RT-TKI (HR = 1.78, 95% CI, 1.17-2.67). Furthermore, the PFS of RT-TKI or CRT-TKI were both significantly longer than that of CRT or CRT-Durva. RT-TKI ranked first in the Bayesian ranking, with the longest OS (60.8 months, 95% CI = 37.2-84.3 months) and the longest PFS (21.5 months, 95% CI, 15.4-27.5 months) in integrated analysis. CONCLUSIONS: For unresectable stage III EGFR mutant NSCLC, RT and TKI are both essential. Based on the current evidence, RT-TKI brings a superior survival advantage, while CRT-TKI needs further estimation. Large randomized clinical trials are urgently needed to explore the appropriate application sequences of TKI, radiotherapy, and chemotherapy. REGISTRATION PROSPERO; https://www.crd.york.ac.uk/PROSPERO/ ; No. CRD42022298490.
Humans ; Carcinoma, Non-Small-Cell Lung/therapy* ; ErbB Receptors/genetics* ; Lung Neoplasms/drug therapy* ; Mutation/genetics* ; Protein Kinase Inhibitors/therapeutic use* ; Chemoradiotherapy ; Antibodies, Monoclonal/therapeutic use*

Esophageal squamous cell carcinoma (ESCC) poses a significant global health challenge, necessitating early detection, timely diagnosis, and prompt treatment to improve patient outcomes. Endoscopic examination plays a pivotal role in this regard. However, despite the availability of various endoscopic techniques, certain limitations can result in missed or misdiagnosed ESCCs. Currently, artificial intelligence (AI)-assisted endoscopic diagnosis has made significant strides in addressing these limitations and improving the diagnosis of ESCC and precancerous lesions. In this review, we provide an overview of the current state of AI applications for endoscopic diagnosis of ESCC and precancerous lesions in aspects including lesion characterization, margin delineation, invasion depth estimation, and microvascular subtype classification. Furthermore, we offer insights into the future direction of this field, highlighting potential advancements that can lead to more accurate diagnoses and ultimately better prognoses for patients.
Humans ; Artificial Intelligence ; Esophageal Squamous Cell Carcinoma/diagnosis* ; Esophageal Neoplasms/diagnosis* ; Precancerous Conditions/diagnosis*

BACKGROUND: Peripheral helper T (T PH ) cells are uniquely positioned within pathologically inflamed non-lymphoid tissues to stimulate B-cell responses and antibody production. However, the phenotype, function, and clinical relevance of T PH cells in hepatocellular carcinoma (HCC) are currently unknown. METHODS: Blood, tumor, and peritumoral liver tissue samples from 39 HCC patients (Sep 2016-Aug 2017) and 101 HCC patients (Sep 2011-Dec 2012) at the Third Affiliated Hospital of Sun Yat-sen University were used. Flow cytometry was used to quantify the expression, phenotype, and function of T PH cells. Log-rank tests were performed to evaluate disease-free survival and overall survival in samples from 39 patients and 101 patients with HCC. T PH cells, CD19 + B cells, and T follicular helper (T FH ) cells were cultured separately in vitro or isolated from C57/B6L mice in vivo for functional assays. RESULTS: T PH cells highly infiltrated tumor tissues, which was correlated with tumor size, early recurrence, and shorter survival time. The tumor-infiltrated T PH cells showed a unique ICOS hi CXCL13 + IL-21 - MAF + BCL-6 - phenotype and triggered naïve B-cell differentiation into regulatory B cells. Triggering programmed cell death protein 1 (PD-1) induced the production of C-X-C motif chemokine ligand 13 (CXCL13) by T PH cells, which then suppressed tumor-specific immunity and promoted disease progression. CONCLUSION Our study reveals a novel regulatory mechanism of T PH cell-regulatory B-cell-mediated immunosuppression and provides an important perspective for determining the balance between the differentiation of protumorigenic T PH cells and that of antitumorigenic T FH cells in the HCC microenvironment.
Carcinoma, Hepatocellular/metabolism* ; Liver Neoplasms/metabolism* ; Humans ; T-Lymphocytes, Helper-Inducer/metabolism* ; Animals ; Mice ; Male ; Female ; Mice, Inbred C57BL ; Middle Aged ; B-Lymphocytes, Regulatory/metabolism* ; Flow Cytometry ; Interleukin-21 ; Aged ; Chemokine CXCL13/metabolism*