Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are important treatments for EGFR mutant non-small cell lung cancer (NSCLC). However, the first and second generation EGFR-TKI face clinical limitations due to acquired resistance, such as the T790M mutation. Irreversible EGFR-TKI can significantly prolong the survival of patients by enhancing the inhibition of drug-resistant mutations through the covalent binding mechanism. This article systematically reviews the mechanism of action, clinical research progress and future direction of irreversible EGFR-TKI, focusing on their potential to overcome drug resistance, combination treatment strategies and biomarker guided personalized treatment, in order to provide references for clinical practice.

Objective: To investigate the clinicopathological features, genetic characteristics, and differential diagnosis of glomangiomatosis with uncertain malignant potential. Methods: Two cases of glomangiomatosis with uncertain malignant potential were collected at Henan Provincial People's Hospital from 2013 and 2023. Immunohistochemistry and next generation sequencing (DNA-seq) were used to detect the related protein and gene variation. Patients were followed up. Results: Case 1 was male, 34 years old; and case 2 was female, 28 years old. Both had tumor recurrence in the original site. There were multiple nodules at right calf and ankle, involving superficial subcutaneous tissue and deep interfascicular muscles; some nodules were borderless and painful. Microscopically, the tumor was nodular with fibrous pseudocapsule, some had indistinct borders and diffuse infiltration to the surrounding adipose tissue. The tumor cells were round to ovoid with inconspicuous nucleoli, partly surrounding small irregularly dilated thin-walled blood vessels. The recurrent tumors showed epithelioid morphology in some of the tumor cells, with eosinophilic cytoplasm, some apparent nucleoli, mild to moderate nuclear atypia, and brisk mitotic figures. Focally, perimuscular cell differentiation was noted. The small lesion showed intravascular tumor thrombus. NGS revealed BRAF V600E mutation in case 1, and BRAF V600E mutation combined with PDGFRB gene amplification in case 2. Conclusions: Glomangiomatosis with uncertain malignant potential is a rare variant of glomus tumor. It has a unique growth pattern morphologically, BRAF V600E mutation, and invasive biological behavior.

Objective: To investigate the clinicopathological features of SMARCA4-deficient uterine sarcoma. Methods: Five cases of SMARCA4-deficient uterine sarcoma at the Department of Pathology, the First Affiliated Hospital of Nanjing Medical University from 2018 to 2024 were collected. The morphological and immunohistochemical features were observed and analyzed. A follow-up study was also carried out. Results: Five female patients, aged 24, 54, 56, 61, and 41 years, respectively, presented with vaginal bleeding or abdominal pain. All patients had imaging findings of intracavitary lesion in the uterus, with tumor sizes ranging from 3.0 cm to 8.8 cm. The patients were followed up for 2 to 14 months. Case 1 died 9 months after surgery, whereas the remaining four patients were still alive. Histologically, the tumor cells exhibited a diffuse growth pattern, with an infiltration depth involving more than half of the myometrium. Portions of the interstitium appeared sclerosed. Benign endometrial glandular structures were observed in a leaf-like or fissured pattern, resembling those of uterine adenosarcoma. The tumor cells were large epithelioid with abundant or faintly eosinophilic cytoplasm, and the nuclei were moderately to markedly atypia with prominent nucleoli and brisk mitosis. Rhabdoid cells were seen. Some areas showed small round blue cells, with occasional spindle cells and myxoid stroma. Additionally, widespread or focal lymphovascular space invasion was observed within the myometrium. All five cases exhibited absence of SMARCA4 (BRG1) expression and retained SMARCB1 (INI1). Claudin4 expression was negative. There was no deficient expression of mismatch repair proteins MLH1, PMS2, MSH2 and MSH6. p53 showed wild-type expression. Ki-67 index ranged from 30% to 60%. CKpan, CK7, ER, PR, and PAX8 were negative. Conclusions: SMARCA4-deficient uterine sarcoma is rare, highly aggressive, and has a poor prognosis. The tumor exhibits a broad morphological spectrum, with rhabdoid cells and adenosarcoma-like structures serving as important diagnostic clues. The absence of BRG1 expression lends support to a definitive diagnosis.

Objective: To explore the clinicopathological and molecular genetic characteristics of anaplastic lymphoma kinase (ALK)-rearranged renal cell carcinoma (RCC), including a rare case with the TPM1-ALK gene subtype. Methods: Three cases of ALK-rearranged RCC diagnosed in the Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China from January 2020 to December 2024 were collected. Their clinical pathological and next-generation sequencing (NGS) data were analyzed. Relevant literature was also reviewed, and follow-ups were carried out. Results: Among the three patients, there were 1 female (case 1) and 2 males (cases 2 and 3), with the ages of 29,41 and 44 years, respectively. All of them were presented with space-occupying renal lesions. Case 1 (KIAA1217-ALK RCC) showed mixed cystic and solid components under the microscope, with tubular, papillary, and cribriform arrangements. The tumor cells had clear boundaries, and were cubic or low columnar, arranged in a single layer, pseudostratified or in sheets. The cytoplasm was abundant and eosinophilic, and part of the cytoplasm was vacuolated, as if there was accumulation of mucoid substances. The tumor cell nuclei were oval with prominent nucleoli. A large amount of mucus and inflammatory cell infiltration were noted in the stroma. Case 2 (TPM1-ALK RCC) showed a papillary growth pattern, with small, slender papillae accompanied by branches. The cells were arranged in a single layer, and the cytoplasm was either eosinophilic or clear. Foamy cells were aggregated in the stroma, accompanied by psammoma body-like calcifications. Case 3 (EML4-ALK RCC) was characterized by papillary and tubulocystic structures. The cytoplasm was abundant and eosinophilic. The tumor cell nuclei were large, with prominent nucleoli. There was conspicuous infiltration of lymphocytes and neutrophils in the fibromuscular stroma. The tumor cells all expressed epithelial markers, PAX8, GATA3, P504s and FH. ALK (5A4) staining showed diffuse strong expression in the cytoplasm, while TFE-3 was positive (nuclear stain) only in case 1 and case 3. The fluorescence in situ hybridization showed that ALK gene rearrangement was present in all three cases, while TFE-3 gene rearrangement/mutation was not detectable in case 1 and case 3. NGS showed the KIAA1217::ALK fusion (the fusion site in the exon 11 of KIAA1217 and exon 18 of ALK) in case 1, the TPM1::ALK fusion (the exon 8 of TPM1 and exon 20 of ALK) in case 2, and the EML4::ALK fusion (the exon 2 region of EML4 and the exon 20 region of ALK) in case 3. Conclusions: ALK-rearranged RCC has unique molecular characteristics. Its histological morphology is easily confused with that of papillary RCC and TFE3-rearranged RCC. Both immunohistochemistry and gene rearrangement tests should be used to confirm the diagnosis.

Objective: To investigate the clinicopathological and genetic characteristics of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). Methods: The forty-two MEITL cases diagnosed in the Department of Pathology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China from 2016 to 2022 was retrospectively analyzed. Clinical data were collected, and follow-up was performed. Morphological characteristics were observed. Immunohistochemistry, Epstein-Barr virus (EBV) in situ hybridization, clonal rearrangement analysis of T-cell receptor (TCR) genes, and targeted next-generation sequencing (NGS) were performed. Results: Among the 42 patients (male/female ratio of 2.8∶1.0), the age range was 32-77 years with a median age of 59.5 (52.0-65.0) years. Grossly, the tumors were presented as ulcerative or exophytic lesions, with a maximum diameter of 2-18 cm. There were 34 cases with a single lesion and 8 cases with more than 1 lesion. The tumor cells in all 42 cases were relatively monotonous in histology and small or medium in size. They had round or oval nuclei, moderately pale or clear cytoplasm, evenly distributed nuclear chromatin, inconspicuous nucleoli, and frequent mitotic figures. In one of the cases, there were moderately large cells, vacuolated nuclei, and clear nucleoli. Lymphoepithelial lesions were observed in 36 (85.7%) of the 42 cases, tumor necrosis in 4 (9.5%) cases, scattered eosinophils and/or plasma cell infiltration in the background in 9 (21.4%) cases, and a "starry sky" phenomenon in 1 (2.4%) case. The tumor cells in all cases exhibited high expression of CD3, CD2, CD7, CD8, CD56, TIA1, Granzyme B, and Perforin, while some also expressed CD4 (5/41, 12.2%), CD5 (3/41, 7.3%), CD20 (4/41, 11.9%), CD79α (2/37, 5.4%), and CD30 (1/34, 2.9%). The Ki-67 proliferation index ranged from 40% to 90%. EBER in situ hybridization tests were negative in all cases. TCR gene clonal rearrangement was detected in 96.4% (27/28) of the tested cases. Targeted NGS revealed commonly mutated genes including SETD2, STAT5B, JAK3, TP53, and CREBBP. The primary treatment was chemotherapy, with 2 cases undergoing autologous hematopoietic stem cell transplantation. Follow-up information was obtained for 29 cases, with a follow-up period of 1-73 months. The mortality was 93.1% (27/29). Conclusions: MEITL is a rare and highly aggressive peripheral T-cell lymphoma. Its clinical manifestations are diverse, and diagnosis primarily relies on a comprehensive assessment of pathological morphology, immunohistochemical profiles, and EBV infection status, supplemented by genetic testing if necessary. At present, there is no effective treatment, and its overall prognosis is poor.

Extranodal NK/T-cell lymphoma (ENKTL) is an Epstein-Barr virus (EBV)-associated extranodal lymphoma derived from NK or T cells. It exhibits strong geographical and ethnic predispositions and is relatively prevalent in China, making it one of the common lymphoma types in our country. Most cases of this tumor exhibit aggressive biological behavior, and timely, accurate pathological diagnosis is crucial for improving cure rates and patient prognosis. However, the tumor has a broad histopathological spectrum, diverse morphological features, and lacks specific immunomarkers, which can lead to misdiagnosis or underdiagnosis in some cases. Additionally, it is necessary to integrate clinical, imaging, and laboratory findings to differentiate ENKTL from a range of EBV-positive lymphoproliferative disorders. In recent years, with the continuous advancement of molecular biology technologies, significant progress has been made in the molecular genetic research of ENKTL. This article aims to summarize the latest advances in the pathological research of ENKTL, emphasizing the diagnostic challenges, pitfalls, and strategies to avoid them, thereby enhancing pathologists' understanding of this tumor and enabling precise diagnostic stratification.

Bladder cancer is a common malignancy with high incidence and poor prognosis. N6-methyladenosine (m6A) modification is widely involved in diverse physiological processes, among which the m6A recognition protein YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) plays a crucial role in bladder cancer progression. This study aims to elucidate the molecular mechanism by which O-linked N-acetylglucosamine (O-GlcNAc) modification of YTHDF2 regulates its downstream target, period circadian regulator 1 (PER1), thereby promoting bladder cancer cell proliferation.

Increasing detection of low-risk papillary thyroid carcinoma (PTC) is associated with overdiagnosis and overtreatment. N6-methyladenosine (m6A)-mediated microRNA (miRNA) dysregulation plays a critical role in tumor metastasis and progression. However, the functional role of m6A-miRNAs in PTC remains unclear. This study aims to elucidate the regulatory mechanism of m6A-miR-139-5p expression in PTC, determine its association with PTC metastasis, and evaluate its potential as a diagnostic biomarker for PTC metastasis, thereby providing experimental evidence for precision diagnosis and therapy.

Non-small cell lung cancer (NSCLC) is associated with poor prognosis, with 30% of patients diagnosed at an advanced stage. Mutations in the EGFR and KRAS genes are important prognostic factors for NSCLC, and targeted therapies can significantly improve survival in these patients. Although tissue biopsy remains the gold standard for detecting gene mutations, it has limitations, including invasiveness, sampling errors due to tumor heterogeneity, and poor reproducibility. This study aims to develop machine learning models based on radiomic features to predict EGFR and KRAS gene mutation status in NSCLC patients, thereby providing a reference for precision oncology.

To investigate the role of circular RNA circ_0000437 in regulating biological behaviors of breast cancer cells and the molecular mechanism.

This study aims to establish the S_(180) tumor-bearing mice model, and to investigate the influence of Shenqi Erpi Granules(SQEPG) on immune function, as well as the drug's tumor-suppressive effect and mechanism. SPF grade KM mice(half male and half female) were randomly divided into 6 groups: a control group, a model group, a cyclophosphamide group(50 mg·kg~(-1)), as well as SQEPG groups in low-, medium-, and high-dose(5.25, 10.5, 21 g·kg~(-1)). The control group and the model group were given distilled water, and the other 4 groups were given the corresponding drugs by gavage. The administration continued for 10 days before the mice were sacrificed. The antitumor and immune regulation effects of SQEPG were evaluated. The effect of SQEPG on delayed type hypersensitivity reaction(DTH), carbon clearance index, and serum hemolysin antibody level was observed to reflect the effect on the immune function of tumor-bearing mice. Tumor weight was recorded to calculate the tumor suppression rate and the immune organ index. Hematoxylin-eosin(HE) staining was used to detect morphological changes in tumor tissues. Flow cytometry was employed to detect the percentage of CD4~+ and CD8~+ T-cells in the spleen tissues and the tumor tissue apoptosis levels. Immunohistochemistry was conducted to detect the KI67 protein expression level of tumor tissues. ELISA resorted to the detection of the following expression levels in tumor tissues: tumor necrosis factor-α(TNF-α), interleukin-2(IL-2), interferon-γ(IFN-γ). Western blot was performed to detect the expression levels of caspase-3, B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), cyclin-dependent kinases 4(CDK4), G_1/S-specific cyclin D1(cyclin D1), and vascular endothelial growth factor A(VEGFA). The results showed that, compared with the model group, the SQEPG could increase the swelling of the auricle of the tumor-bearing mice; significantly increase the phagocytic index of carbon granule contour(P<0.05 or P<0.01), and the middle dose of SQEPG could significantly increase the antibody level of hemolysin(P<0.05); different doses of SQEPG significantly inhibit the growth of the tumor, and decrease the mass of the tumor tissues(P<0.05 or P<0.01); the low dose of SQEPG significantly decreased spleen index(P<0.05), low and high doses of SQEPG increased thymus index, while medium doses of SQEPG decreased thymus index. High doses of SQEPG significantly elevated the levels of CD4~+ and CD8~+ T-cells in the spleens of the homozygous mice(P<0.01 or P<0.001), and increased the apoptosis rate of the cells of the tumor tissues(P<0.05); Meanwhile, high-dose SQEPG elevated the levels of immunity factors such as IL-2, IFN-γ and TNF-α in the serum of tumor-bearing mice(P<0.01); medium-and high-dose SQEPG significantly lowered the rate of positive expression of KI67 protein in tumor tissues(P<0.01). Compared with the model group, high-dose SQEPG significantly up-regulated the expression of caspase-3 and Bax proteins in tumor tissues(P<0.05), and significantly down-regulated the expression of CDK4, cyclin D1, and VEGFA proteins(P<0.05 or P<0.01). In conclusion, SQEPG has the effect of improving immune function and inhibiting tumor growth in tumor-bearing mice. Its mechanism of tumor-suppressive effects may be related to apoptosis promotion, cell cycle progression block, and tumor cell proliferation inhibition.

Study on the mechanism of Fangxia Dihuang Formula(FXDH) in treating breast cancer complicated with depression through the regulation of M1/M2 microglial polarization via the PERK/eIF2α axis. In addition to control group and 4T1 group, a mouse model of breast cancer complicated with depression was established using 4T1 cells combined with corticosterone. The mice were divided into model group, PERK/eIF2α signaling axis agonist(CCT020312, 2 mg·kg~(-1)·d~(-1)) group, CCT020312(2 mg·kg~(-1)·d~(-1)) + FXDH(13.65 g·kg~(-1)·d~(-1)) group, FXDH(13.65 g·kg~(-1)·d~(-1)) group, FXDH(13.65 g·kg~(-1)·d~(-1)) + Capecitabine Tablets(CAP, 390 mg·kg~(-1)·d~(-1)) group, and Fluoxetine Hydrochloride Capsules(FXT, 2.6 mg·kg~(-1)·d~(-1)) + CAP(390 mg·kg~(-1)·d~(-1)) group, with continuous intervention for 21 d. Depression-like behaviors in mice were assessed through sugar preference test and open field test. Hematoxylin-eosin(HE) staining was used to evaluate the morphology of tumor and hippocampal DG region neurons. Nissl staining was employed to detect changes in Nissl bodies in the hippocampal CA3 region. Immunofluorescence was used to observe cluster of differentiation 86(CD86)/ionized calcium-binding adapter molecule 1(Iba-1) and cluster of differentiation 206(CD206)/Iba-1 in hippocampal tissue. Real-time fluorescence quantitative polymerase chain reaction(RT-qPCR) was used to detect the mRNA expression of M1-type microglia [interleukin-6(IL-6), tumor necrosis factor-α(TNF-α)] and M2-type [arginase-1(Arg-1), IL-10] in hippocampal tissue. Western blot was used to detect the protein expression of key factors in the PERK/eIF2α axis, including PERK, eIF2α, activating transcription factor 4(ATF4), and C/EBP homologous protein(CHOP) in hippocampal tissue. The results showed that compared to model group/CCT020312 + FXDH group, FXDH group increased sugar preference index, total movement distance, central zone distance, and central zone entries; reduced tumor mass and volume; tumor cells were sparsely arranged, with a smaller nuclear-to-cytoplasmic ratio and reduced nuclear division figures, increased Nissl body count, and alleviated neuronal nuclear pyknosis; increased CD206-positive M2-type microglia expression, decreased CD86/Iba-1-positive M1-type microglia expression; reduced IL-6 and TNF-α mRNA expression, and increased Arg-1 and IL-10 mRNA expression; downregulated PERK, eIF2α, ATF4, and CHOP protein expression levels. The results indicate that the mechanism of FXDH in treating breast cancer complicated with depression may be related to inhibiting the activity of the PERK/eIF2α axis, reducing the proportion of M1-type microglia, increasing the proportion of M2-type microglia, thereby suppressing neuronal immune inflammation, improving depressive symptoms, and subsequently delaying the progression of breast cancer.

This study aimed to explore the expression of lysosomal-associated membrane protein 5 (LAMP5) and microRNA (miR)-302a-3p in oral squamous cell carcinoma (OSCC) and their functional mechanism on the invasion and metastasis of OSCC.

Nasopharyngeal carcinoma（NPC） is a distinct type of head and neck cancer closely associated with Epstein-Barr virus（EBV） infection and exhibits significant geographic variations in its incidence. Despite recent advancements in radiotherapy techniques and precision medicine for NPC, the overall survival rate remains unsatisfactory due to tumor metastasis, recurrence, and drug resistance. Single-cell RNA sequencing（scRNA-seq） is an emerging technology that allows for the analysis of gene expression at single-cell resolution, providing a clearer understanding of tumor cell subpopulations, the evolutionary trajectory of tumor cells, and the functional roles and interactions of cells within the tumor microenvironment. This provides new ideas for the development of precision medicine in NPC. Here, we review the applications of scRNA-seq in exploring the mechanisms of NPC pathogenesis, tumor heterogeneity, the tumor microenvironment, drug resistance, and therapeutic response.

The evolving stratified treatment approach based on molecular genetic alterations and minimal residual disease (MRD) monitoring has established a strong foundation for clinically managing Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). However, with the growing use of immune-targeted therapies and the increased sensitivity of detection technologies, discrepancies in MRD assessment have emerged in some patients with Ph(+) ALL, particularly where BCR:: ABL1-based MRD levels remain consistently elevated compared to those detected by alternative methods. Research suggests that this persistent BCR:: ABL1 positivity may not solely reflect residual lymphoblasts but may also indicate the involvement of multilineage hematopoietic cells. This distinct biological feature has been termed Ph(+) ALL with multilineage involvement. Currently, the absence of standardized diagnostic criteria and prognostic frameworks for this subtype poses significant challenges in clinical decision-making. Therefore, this article offers a comprehensive review of its molecular and pathological characteristics, potential prognostic biomarkers, patterns of disease evolution, and clinical implications, with the goal of informing more accurate diagnostic and therapeutic strategies.