Neoplasia endócrina múltiple y enfermedad inflamatoria intestinal de inicio muy temprano. Una asociación inesperada / Multiple endocrine neoplasia and very early onset in flammatory bowel disease. An unexpected association

Resumen La enfermedad inflamatoria intestinal de inicio muy temprano (VEOIBD) es una entidad rara en pediatría. Es conocida su asociación con inmunodeficiencias prima rias de origen monogénico. Presentamos el caso de una paciente con diagnóstico de VEOIBD a quien se le realizó una secuenciación masiva del exoma. El resultado del estudio permitió identificar una variante patogénica en el proto oncogen RET, asociada con enfermedad neoplasia endocrina múltiple tipo 2A. No hay reportes de asociación de variantes en el proto oncogen RET con VEOIBD. No se puede adjudicar la presencia de estas dos entidades clínicas a una única causa genética.

Abstract Very early onset inflammatory bowel disease (VEOI BD) is a rare entity in pediatrics. Its association with pri mary immunodeficiencies of monogenic origin is known. We present the case of a patient diagnosed with VEOIBD who underwent massive paralleled exome sequencing. The result of the study showed a pathogenic variant in the RET proto-oncogene, associated with multiple endo crine neoplasia type 2A disease. There are no previous reports of association of RET proto-oncogene variants with VEOIBD. The presence of these two clinical entities cannot be attributed to a single genetic cause.

Relationship between GLI1 expression and tumor immune infiltration and clinical prognosis of gastric cancer / 中国现代普通外科进展

Objective:To investigate the correlation between the expression of GLI1 and im-mune invasion and clinical prognosis in gastric cancer.To study the effect of GLI1 expression on drug resistance in gastric cancer.Methods:The expression difference of GLI1 in gastric cancer and normal tissues was analyzed by using TCGA database,and the effect of clinical features and GLI1 gene ex-pression level on prognosis of patients with gastric cancer was analyzed.The correlation between GLI1 gene expression and tumor immune cell infiltration in gastric cancer tissues was analyzed to explore its influence on drug resistance of chemotherapy drugs and targeted drugs.Clinical samples were collect-ed to analyze the difference of GLI1 expression in gastric cancer and paracancer tissues.Results:The expression of GLI1 in gastric cancer tissues was 1.7 times that in normal tissues,and the overall sur-vival and disease-free survival of patients with high expression are shorter than those with low ex-pression(P＜0.05).The interstitial score,immune score and abundance of immunoinfiltrating cells were higher in the high expression of GLI1 in gastric cancer tissues.High expression of GLI1 reduces drug sensitivity and is positively correlated with the expression of immune checkpoint markers PDCD1(P＜0.05).GLI1 expression was significantly increased in patients with subdifferentiated gastric cancer.Conclusions:GLI1 expression is associated with the prognosis and immune infiltration of patients with gastric cancer,and it may lead to poor prognosis of patients by regulating chemotherapy resis-tance,which may be a potential therapeutic target and molecular marker for gastric cancer.

Biological function and action mechanism of prefoldin 5 and its advancements in malignant tumors / 肿瘤研究与临床

Prefoldin (PFDN), a hexameric chaperone complex, is crucial for the correct folding of nascent proteins. PFDN5, a subunit of PFDN, also known as MM-1, plays an essential role in regulating cell migration and senescence. Emerging evidences suggest that PFDN-5 deletion or mutation significantly contributes to the initiation and progression of multiple cancers and the prognosis of patients. In this paper, recent researches on the biological underpinnings of PFDN-5 and its anti-cancer prospect are reviewed, aiming to provide a novel potential therapeutic target for the treatment of malignancies.

Analysis of the predictive value of the protein level of oncogenes C-myc,N-ras,PLK 1,and FGF2 in the serum of hepatitis B-related liver cancer patients on the prognosis after TACE / 国际检验医学杂志

Objective To investigate the predictive value of serum oncogene[proliferation-related gene(C-myc),transformation gene(N-ras),silk/threonine kinase 1(PLK1),fibroblast growth factor 2(FGF2)]protein levels in patients with hepatitis B associated hepatocellular carcinoma(HCC)after hepatic arterial chemoem-bolization(TACE).Methods A total of 127 patients with hepatitis B-associated hepatocellular carcinoma ad-mitted to a hospital from July 2016 to January 2021 were selected and divided into death group and survival group according to the follow-up results.The serum oncogene C-myc,N-ras,PLK1 and FGF2 protein levels were determined by double-antibody sandwich enzyme-linked immunosorbent assay.Univariate and multivari-ate Cox analysis were used to analyze the risk factors of serum oncogene C-myc,N-ras,PLK1 and FGF2 pro-tein levels in patients with hepatitis B-associated hepatocellular carcinoma after TACE.The receiver operating characteristic curve was used to evaluate the prognostic value of the serum oncogene C-myc,N-ras,PLK1 and FGF2 protein levels,and the patients were divided into high expression group and low expression group ac-cording to the corresponding cutoff value.Kaplan-Meier survival curve was used to evaluate the prognosis of different serum oncogene C-myc,N-ras,PLK1 and FGF2 protein level.Results Multivariate Cox regression a-nalysis indicated that TNM stage Ⅲ to Ⅳ(HR=2.998,95％CI:1.239-7.257),portal vein metastasis(HR=3.737,95％CI:1.941-7.193),abdominal metastasis(HR=3.482,95％CI:1.709-7.097),Child-Pugh grade B(HR=2.587,95％CI:1.045-6.406),high serum oncogene C-myc protein level(HR=1.224,95％CI:1.090-1.374),high serum oncogene N-ras protein level(HR=1.218,95％CI:1.097-1.353),high serum oncogene PLK1 protein level(HR=1.237,95％CI:1.110-1.379)and high serum oncogene FGF2 protein level(HR=1.141,95％CI:1.060-1.228)were independent risk factors for the prognosis of hepatitis B-asso-ciated hepatocellular carcinoma patients after TACE(all P＜0.05).The overall survival rate of low expression group of serum oncogene C-myc,N-ras,PLK1,FGF2 protein level was significantly higher than that of high expression group of serum oncogene C-myc,N-ras,PLK1,FGF2 protein level,the difference was statistically significant(all P＜0.001).Conclusion Serum oncogene C-myc,N-ras,PLK1,FGF2 protein levels have predic-tive value for the prognosis of patients with HBV-related liver cancer after TACE.

Mechanisms of the role of proto-oncogene activation in promoting malignant transformation of mature B cells / 中南大学学报(医学版)

Malignant tumors continue to pose a significant threat to human life and safety and their development is primarily due to the activation of proto-oncogenes and the inactivation of suppressor genes.Among these,the activation of proto-oncogenes possesses greater potential to drive the malignant transformation of cells.Targeting oncogenes involved in the malignant transformation of tumor cells has provided a novel approach for the development of current antitumor drugs.Several preclinical and clinical studies have revealed that the development pathway of B cells,and the malignant transformation of mature B cells into tumors have been regulated by oncogenes and their metabolites.Therefore,summarizing the key oncogenes involved in the process of malignant transformation of mature B cells and elucidating the mechanisms of action in tumor development hold significant importance for the clinical treatment of malignant tumors.

Mast cells in oral lichen planus and oral lichenoid lesions related to dental amalgam contact

Abstract The aim of this study was to analyze the expression of mast cell markers toluidine blue, c-kit, and tryptase and presence of mononuclear inflammatory cells in oral lichen planus (OLP) and oral lichenoid lesions related to dental amalgam. Nineteen specimens of OLP, OLLC, and healthy oral mucosa were selected. Mononuclear inflammatory cells were analyzed. Histochemical and immunohistochemical analyses were performed using toluidine blue, anti-c-kit and anti-tryptase reagents, and the results were quantified in areas A and B of connective tissue. Mast cells of all OLP and OLLC samples were positive for toluidine blue, c-kit, and tryptase. The density of toluidine blue+, c-kit+ and tryptase+ mast cells was higher in tissue with OLP and OLLC compared with healthy controls (p < 0.05). No difference was noted in mast cells density between OLP and OLLC (p > 0.05). The density of tryptase+ mast cells was higher in the subepithelial region (area A) than the region below it (Area B) in OLLC (p = 0.047). The mononuclear inflammatory cell density was higher in OLLC compared to OLP, but without statistical significance (p > 0.05). A positive statistical correlation was found between mononuclear immune cells and density of c-kit+ and tryptase+ mast cells in OLP (r = 0.943 and r = 0.886, respectively). Our data demonstrate that the etiopathogenesis process of OLP and OLLC modulates the expansion and degranulation of mast cells; mast cells density, however, was similar between OLP and OLLC. The distribution of mast cells appears to vary along the lamina propria.

Estandarización de PCR en tiempo real para detección y cuantificación de los oncogenes E7 de seis Virus del Papiloma Humano de Alto Riesgo / Real-time PCR standardization for detection and quantification of E7 oncogenes from six High-Risk Human Papillomaviruses

El cáncer de cuello uterino es causado por la infección persistente del epitelio cervical con los genotipos de alto riesgo del Virus del Papiloma Humano. Para su detección se realizan pruebas moleculares que detectan el gen L1 del VPH. Este gen puede perderse hasta en el 11 % de los casos durante la integración del ADN viral en el genoma del hospedero originando falsos negativos. Por otra parte, el oncogén E7 se expresa durante todas las etapas de progresión de la enfermedad. El objetivo de este trabajo fue estandarizar una PCR en tiempo real del oncogén E7 (E7-qPCR) para genotipificación y cuantificación de 6 VPH-AR. Los resultados muestran que la E7- qPCR amplificó VPH-16, -18, -31, -33, -35 y -45 con una alta sensibilidad con límites de detección desde 102 copias, eficiencias entre 90 y 110 %, valores R2 > 0,97 y análisis de curva de fusión que revelan productos específicos.

Cervical cancer is caused by persistent infection of the cervical epithelium with the high-risk genotypes of the Human Papilloma Virus (HR-HPV). For its detection, molecular tests are carried out that detect the L1 gene of HPV. This gene can be lost in up to 11 % of cases during the integration of viral DNA into the host genome, causing false negatives. On the other hand, the E7 oncogene is expressed during all stages of disease progression. The aim of this work was to standardize a real-time PCR of the E7 oncogene (E7-qPCR) for genotyping and quantification of 6 HR-HPV. The results show that the E7-qPCR amplified HPV-16, -18, -31, -33, -35 and -45 with high sensitivity with detection limits from 102 copies, efficiencies between 90 and 110 %, R2 values >0,97 and melting curve analysis revealing specific products.

The association of BRAF V600E gene mutation with proliferative activity and histopathological characteristics of congenital melanocytic nevi in children

Abstract Background: A lot of congenital melanocytic nevi (CMN) carry the somatic mutation in the oncogene BRAF V600E. But the detailed histopathologic characteristics and the proliferative activity of CMN with BRAF V600E gene mutation have not been systematically documented. Objective: To identify the proliferative activity and histopathological features correlating them with BRAF V600E gene mutation status in CMN. Methods: CMN were retrospectively identified from the laboratory reporting system. Mutations were determined by Sanger sequencing. The CMN were divided into a mutant group and control group according to whether there was BRAF gene mutation and were strictly matched according to gender, age, nevus size, and location. Histopathological analysis, analysis of Ki67 expression by immunohistochemistry and laser confocal fluorescence microscopy were performed. Results: The differences in Ki67 index, the depth of nevus cell involvement and the number of nevus cell nests between the mutant group and the control group was statistically significant, with p-values of 0.041, 0.002 and 0.007, respectively. Compared with BRAFV600E negative nevi, BRAF V600E positive nevi often exhibited predominantly nested intraepidermal melanocytes, and larger junctional nests, but the difference in this datasets were not statistically significant. The number of nests (p = 0.001) was positively correlated with the proportion of Ki67 positive cells. Study limitations: A small sample of patients were included and there was no follow-up. Conclusions: BRAF V600E gene mutations were associated with high proliferative activity and distinct histopathological features in congenital melanocytic nevi.

Current status and outlook of medical treatment for KRAS-mutated non-small cell lung cancer / 中华肿瘤杂志

Lung cancer remains the leading cause of cancer-related deaths in men and women worldwide, and 85% of these patients have non-small cell lung cancer. In recent years, the clinical use of targeted drug therapy and immune checkpoint inhibitors has dramatically changed the treatment landscape for advanced NSCLC. The mechanism and the value of targeted therapies have been a hot topic of research, as KRAS is one of the earliest discovered and most frequently mutated oncogenes, which is activated by binding to GTP and triggers a series of cascade reactions in cell proliferation and mitosis. The KRAS protein acts as a molecular switch and is activated by binding to GTP, triggering a series of cascade responses in cell proliferation and mitosis. Clinically, patients with KRAS mutated NSCLC have poor response to systemic medical therapy and poor prognosis. Since the first report of KRAS gene in 1982, research on KRAS targeted therapeutics has been slow, and previous studies such as farnesyltransferase inhibitors and downstream protein inhibitors of KRAS signaling pathway have not achieved the expected results, making KRAS long defined as a "non-druggable target". The deeper understanding of the crystal structure of KRAS has led to the discovery of potential therapeutic sites for KRAS and the development of several drugs directly targeting KRAS, especially KRAS G12C inhibitors such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have shown encouraging results in clinical trials. In recent years, studies on the therapeutic efficacy of immune checkpoint inhibitors for KRAS-mutated NSCLC have made some progress. In this review, we systematically introduce the basic understanding of RAS gene and clinical characteristics of KRAS mutated NSCLC patients, summarize the medical treatments for KRAS mutated NSCLC, including chemotherapy, anti-vascular drug therapy and tumor immunotherapy, and focus on the review and outlook of the research progress of KRAS targeted therapy.

The efficacy and side effects of rigosertib combined with chemotherapy in KRAS mutant colorectal cancer mice / 中华肿瘤杂志

Objective: To investigate the effect of rigosertib (RGS) combined with classic chemotherapy drugs including 5-fluorouracil, oxaliplatin, and irinotecan in colorectal cancer. Methods: Explore the synergy effects of RGS and 5-fluorouracil (5-FU), oxaliplatin (OXA), and irinotecan (IRI) on colorectal cancer by subcutaneously transplanted tumor models of mice. The mice were randomly divided into control group, RGS group, 5-FU group, OXA group, IRI group, 5-FU+ RGS group, OXA+ RGS group and IRI+ RGS group. The synergy effects of RGS and OXA on KRAS mutant colorectal cancer cell lines in vitro was detected by CCK-8. Ki-67 immunohistochemistry and TdT-mediated dUTP nick-end labeling (TUNEL) staining were performed on the mouse tumor tissue sections, and the extracted tumor tissue was analyzed by western blot. The blood samples of mice after chemotherapy and RGS treatment were collected, blood routine and liver and kidney function analysis were conducted, and H&E staining on liver sections was performed to observe the side effects of chemotherapy and RGS. Results: The subcutaneously transplanted tumor models were established successfully in all groups. 55 days after administration, the fold change of tumor size of OXA+ RGS group was 37.019±8.634, which is significantly smaller than 77.571±15.387 of RGS group (P=0.029) and 92.500±13.279 of OXA group (P=0.008). Immunohistochemical staining showed that the Ki-67 index of tumor tissue in control group, OXA group, RGS group and OXA+ RGS group were (100.0±16.8)%, (35.6±11.3)%, (54.5±18.1)% and (15.4±3.9)%, respectively. The Ki-67 index of OXA+ RGS group was significantly lower than that in control group (P=0.014), but there was no significant difference compared to OXA group and RGS group (OXA: P=0.549; RGS: P=0.218). TUNEL fluorescence staining showed that the apoptotic level of OXA+ RGS group was 3.878±0.547, which was significantly higher than 1.515±0.442 of OXA group (P=0.005) and 1.966±0.261 of RGS group (P=0.008). Western blot showed that the expressions of apoptosis related proteins such as cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 8 in the tumor tissues of mice in the OXA+ RGS group were higher than those in control group, OXA group and RGS group. After the mice received RGS combined with chemotherapy drugs, there was no significant effect on liver and kidney function indexes, but the combined use of oxaliplatin and RGS significantly reduced the white blood cells [(0.385±0.215)×10(9)/L vs (5.598±0.605)×10(9)/L, P<0.001] and hemoglobin[(56.000±24.000)g/L vs (153.333±2.231)g/L, P=0.001] of the mice. RGS, chemotherapy combined with RGS and chemotherapy alone did not significantly increase the damage to liver cells. Conclusions: The combination of RGS and oxaliplatin has a stronger anti-tumor effect on KRAS mutant colorectal cancer. RGS single agent will not cause significant bone marrow suppression and hepatorenal injury in mice, but its side effects may increase correspondingly after combined with chemotherapy.

USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01‍‒‍1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49‍‒‍2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95% CI, 0.48‍‒‍1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39‍‒‍1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A(USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32‍‒‍0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38‍‒‍0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75‍‒‍8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88‍‒‍6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

Research Progress of BRAF Fusion in Non-small Cell Lung Cancer / 中国肺癌杂志

In advanced non-small cell lung cancer (NSCLC), V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation is highly malignant and has poor prognosis, and currently Dabrafenib in combination with Trametinib is approved for first-line treatment of patients with BRAF V600 mutation. In addition to mutations, BRAF fusion can also occur. With the development of gene detection, the detection of BRAF fusion is gradually increasing, but there is a lack of effective therapeutic strategies for BRAF fusion. In this paper, we review the clinical characteristics, mechanism of action, and clinical treatment of BRAF fusion to provide a basis for the treatment of BRAF fusion in NSCLC patients.
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Expression of PLCH1 gene in esophageal squamous cell carcinoma and its effect on cell proliferation and migration / 中国生物制品学杂志

@#ObjectiveTo detect the gene variation and expression of PLCH1 in esophageal squamous cell carcinoma(ESCC),analyze the function of PLCH1 gene in ESCC and explore its mechanism.MethodsThe copy number variation of PLCH1 in ESCC was analyzed by GISTIC,and the expression of PLCH1 in ESCC and normal esophageal tissues was detected by TCGA database and immunohistochemistry method. The expression of PLCH1 in ESCC cell lines was detected by real-time fluorescence quantitative PCR(qPCR) and Western blot,and the effects of PLCH1 silencing on the proliferation and migration of ESCC cells were detected by MTT assay,colony formation assay and Transwell assay.Results There was significant copy number amplification of PLCH1 in ESCC(G-scores > 0. 1,P < 0. 05),and the expression levels of PLCH1 mRNA and protein in ESCC were significantly higher than those in normal tissues(F = 36. 00 ～ 1 101. 00respectively,each P < 0. 000 1). After PLCH1 silencing,the ability of proliferation,clone formation and migration of ESCC cells KYESE180 and TE-9 decreased significantly(F = 35. 49 ～ 634. 00 respectively,each P < 0. 001).Conclusion PLCH1 plays an oncogenic role in ESCC,which is of great significance for the metastasis and proliferation of ESCC,and can be used as a potential target for the treatment of ESCC.

Prognostic stratification of baseline PET metabolic parameters combined with Bcl-2/c-Myc dual expression in patients with primary gastrointestinal diffuse large B-cell lymphoma / 中华核医学与分子影像杂志

Objective:To explore whether baseline PET metabolic parameters combined with B-cell lymphoma-2 (Bcl-2)/cellular-myelocytomatosis viral oncogene (c-Myc) dual expression (DE) can improve the prognostic stratification of patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL).Methods:From March 2011 to November 2019, 74 patients (33 males, 41 females; age: 20-87 years) pathologically diagnosed with PGI-DLBCL prior to treatment in Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School and the First Affiliated Hospital of Nanjing Medical University were retrospectively included. Baseline PET/CT scans were calculated automatically using the boundaries of voxels presenting a SUV max≥2.5, and metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were determined. Expressions of Bcl-2 and c-Myc were detected at protein levels by immunohistochemistry (IHC). A predicting model comprised of MTV and DE was constructed and patients were divided into 3 groups, including low-risk group (low MTV and non-DE), mediate-risk group (high MTV or DE) and high-risk group (high MTV and DE). The distributions of progression-free survival (PFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method, log-rank test and Cox proportional hazards model. Results:Of 74 patients, 20 relapsed or progressed, 13 died, and 29.7%(22/74) patients were DE positive. Multivariate analysis revealed that MTV (hazard ratio ( HR)=9.110, 95% CI: 1.429-18.615, P=0.012) and DE ( HR=9.837, 95% CI: 1.690-57.260, P=0.011) were independent predictors of PFS, while MTV ( HR=12.470, 95% CI: 3.356-46.336, P<0.001) was the only independent predictor of OS. In the predicting model for PFS, low-risk group ( n=42) and mediate-risk group ( n=20) exhibited significant difference ( χ2=7.84, P=0.005), and mediate-risk group and high-risk group ( n=12) also exhibited significant difference ( χ2=18.72, P<0.001). Conclusions:MTV and DE can independently predict PFS of patients with PGI-DLBCL, and MTV can independently predict OS. The predicting model for PFS combining MTV with DE may further improve the ability of clinicians to stratify patients in terms of differential prognoses.

Venetoclax combined with avapritinib for treatment of refractory/relapsed acute myeloid leukemia with KIT gene mutation: report of 2 cases and review of literature / 白血病·淋巴瘤

Objective:To investigate the therapeutic efficacy of venetoclax combined with avapritinib in treatment of refractory/relapsed acute myeloid leukemia (AML) with KIT gene mutation.Methods:The clinical data of 2 AML patients with KIT gene mutation who received venetoclax combined with avapritinib admitted to Canglang Hospital of Suzhou in October 2022 and November 2022 were retrospectively analyzed, and the relevant literature was reviewed.Results:Both patients with high-risk relapsed/refractory AML and KIT gene mutation were females; the one was 53 years and the other was 17 years. Case 1 was diagnosed with AML-M 2, and genetic testing revealed positive mutations in ASXL1, KIT, and RUNX1. The patient relapsed after transplantation and then was treated with venetoclax combined with avapritinib achieving morphologic leukemia-free status (MLFS). Case 2 was diagnosed with AML, and RUNX1-RUNX1T1 (AML1-ETO) fusion gene and KIT and DX15 gene mutations were detected. The patient was treated with venetoclax combined with avapritinib regimen after relapse, and the treatment regimen significantly reduced the tumor load. Complete remission was achieved after bridging to allogeneic hematopoietic stem cell transplantation. Conclusions:AML with KIT gene mutation is heterogeneous and some patients are difficult to treat with very poor prognosis. Bridging (secondary) hematopoietic stem cell transplantation can be the better treatment choice for relapsed patients achieving MLFS or complete remission after venetoclax combined with avapritinib treatment regimen.

Interferon, interleukin 2 combined with lenalidomide for elderly acute myeloid leukemia with minimal residual disease-positive: report of 1 case and review of literature / 白血病·淋巴瘤

Objective:To investigate the effect of interferon, interleukin 2 (IL-2) combined with lenalidomide in the treatment of acute myeloid leukemia (AML) with minimal residual disease (MRD)-positive.Methods:The clinical data of 1 elderly AML patient with persistent MRD positive treated with interferon, IL-2 combined with lenalidomide in the Affiliated Cancer Hospital of Zhengzhou University in December 2019 were retrospectively analyzed, and the relevant literature was reviewed.Results:The 72-year-old male patient was diagnosed as AML-M 2b with c-kit mutation, the low-risk group according to laboratory related examinations, flow cytometry, genetic testing. The patient did not achieve remission after 1 cycle of standard VA (venetoclax + azacitidine) regimen, and achieved complete remission (CR) after another 1 cycle of IA (idarubicin + cytarabine) induction regimen, followed by consolidation therapy with medium dosage cytarabine and D-CAG (decitabine + cytarabine + aclarubicin + granulocyte colony-stimulating factor) regimen, during which the AML1-ETO fusion gene progressively increased. After programmed death receptor 1 (PD-1) inhibitor-based combination therapy, the AML1-ETO fusion gene remained negative for more than 1 month, and then increased again; subsequently, the patient was treated with the ITI (interferon, thalidomide, and interleukin-2) regimen, and the AML1-ETO fusion gene remained negative for more than 7 months; thalidomide was changed to lenalidomide after the increase again, and AML1-ETO fusion gene remained negative again for 2 years until May 2023. Conclusions:Interferon, IL-2 combined with lenalidomide have a significant therapeutic efficacy in reversing MRD positive and have mild adverse reactions, which can be used as a new option for refractory AML.

Clinical characteristics and prognosis analysis of TCF3-PBX1 fusion gene-positive childhood B-cell precursor acute lymphoblastic leukemia / 白血病·淋巴瘤

Objective:To investigate the clinical characteristics and prognostic factors of TCF3-PBX1 fusion gene-positive childhood B-cell precursor acute lymphoblastic leukemia (B-ALL).Methods:The clinical data of 1 287 newly diagnosed children with B-ALL who were admitted to five hospital in Fujian province (Fujian Medical University Union Hospital, the First Affiliated Hospital of Xiamen University, Zhangzhou Affiliated Hospital of Fujian Medical University, Quanzhou First Hospital Affiliated to Fujian Medical University, Nanping First Hospital of Fujian Province) from April 2011 to December 2020 were retrospectively analyzed. According to the results of TCF3-PBX1 fusion gene testing, all the patients were divided into TCF3-PBX1-positive group and TCF3-PBX1-negative group. The clinical characteristics, early treatment response [minimal residual disease (MRD) at middle stage and end of induction chemotherapy] and long-term efficacy [overall survival (OS) and event-free survival (EFS)] of the patients in both groups were compared. Kaplan-Meier method was used for survival analysis. The prognostic factors of TCF3-PBX1-positive B-ALL were analyzed by using Cox proportional hazards model. Among 83 children with TCF3-PBX1-positive B-ALL, the treatment regimens, risk stratification and efficacy evaluation of 62 cases were performed by using Chinese Children's Leukemia Group (CCLG)-ALL 2008 regimen and 21 cases were performed by using Chinese Children's Cancer Group (CCCG)-ALL 2015 regimen, and the efficacy and incidence of serious adverse events (SAE) between the two groups compared.Results:Among 1 287 B-ALL patients, 83 patients (6.4%) were TCF3-PBX1-positive. The proportion of patients with initial white blood cell count (WBC)≥50×10 9/L in the TCF3-PBX1-positive group was higher than that in the TCF3-PBX1-negative group, while the proportions of patients with MRD ≥1% on induction chemotherapy day 15 or day 19, and MRD ≥0.01% on induction chemotherapy day 33 or day 46 in the TCF3-PBX1-positive group were lower than those in the TCF3-PBX1-negative group (all P < 0.05). Univariate Cox regression analysis showed that MRD ≥1% on induction chemotherapy day 15 or day 19 and TCF3-PBX1 ≥0.01% on induction chemotherapy day 33 or day 46 were risk factors for OS and EFS (all P < 0.05). Multivariate analysis showed that MRD ≥1% on induction chemotherapy day 15 or day 19 was an independent risk factor for OS ( HR = 10.589, 95% CI 1.903-58.933, P = 0.007) and EFS ( HR = 10.218, 95% CI 2.429-42.980, P = 0.002). TCF3-PBX1≥0.01% on induction chemotherapy day 33 or day 46 was an independent risk factor for EFS ( HR = 6.058, 95% CI 1.463-25.087, P = 0.013) but not for OS ( HR = 3.550, 95% CI 0.736-17.121, P = 0.115). The 10-year EFS and OS rates of the TCF3-PBX1-positive group were 84.6% (95% CI 76.9%-93.1%) and 89.1% (95% CI 82.1%-96.6%), and the differences between the two groups were not statistically significant (both P > 0.05). Among 80 children who received standardized treatment, compared with children who were treated with CCLG-ALL 2008 regimen, the incidence of infection-related SAE was lower in children who were treated with CCCG-ALL 2015 regimen [0 (0/21) vs. 20.3% (12/59), χ2 = 5.22, P = 0.022], but there were no statistical differences in treatment-related mortality, relapse rate, EFS and OS between the two groups (all P > 0.05). Conclusions:Children with TCF3-PBX1-positive B-ALL have a good prognosis, and MRD≥1% at middle stage of induction chemotherapy and TCF3-PBX1≥0.01% at the end of induction chemotherapy may be influencing factors for poor prognosis. CCCG-ALL 2015 regimen can reduce infection-related SAE while achieving good efficacy.

Mechanism of Bcl-2 BH4 selective inhibitor BDA-366 on NK/T cell lymphoma cells / 国际肿瘤学杂志

Objective:To investigate the inhibitory effect and killing mechanism of Bcl-2 BH4 selective inhibitor BDA-366 on NK/T cell lymphoma (NK/TCL) .Methods:Human NK cell leukemia cell line YT and human NK/TCL cell line NK92 cells were treated with 0, 0.05, 0.10, 0.20, 0.30, 0.40, 0.50 μmol/L BDA-366. CCK-8 assay was used to calculate the half inhibitory concentration (IC 50) value of BDA-366 on these cells. The apoptosis levels of cells in control group and IC 50 BDA-366 treated group were detected by flow cytometry. Western blotting was used to detect the expression levels of apoptosis-related proteins in cells of control group and 1/2 IC 50, IC 50, 2× IC 50 BDA-366 treated groups. TMRE and Fluo-3 fluorescent probe were used to detect mitochondrial membrane potential of control group and IC 50 BDA-366 treated group, and the intracellular Ca 2+ concentration of control group, IC 50, 2× IC 50 BDA-366 treated groups. NOD-SCID mice in control group and 10 mg/kg BDA-366 intraperitoneal injection group were weighed and HE staining was performed to evaluate the toxicity of BDA-366 in vivo. Results:The IC 50 of BDA-366 for YT and NK92 cells were 0.065 and 0.086 μmol/L respectively. The apoptosis rates of YT cells in the control group and 0.065 μmol/L BDA-366 group were (6.62±1.59) % and (34.60±3.06) % respectively. The apoptosis rates of NK92 cells in the control group and 0.086 μmol/L BDA-366 group were (5.57±0.88) % and (29.18±0.90) % respectively, both with statistically significant differences ( t=14.05, P<0.001; t=32.58, P<0.001). The relative expression of Bax in NK92 cells of the control group, 0.043, 0.086 and 0.172 μmol/L BDA-366 groups were 0.85±0.00, 1.26±0.04, 1.51±0.18, 1.15±0.10 ( F=20.70, P<0.001), the relative expression of Bax in BDA-366 groups were higher than that in the control group (all P<0.05). The fluorescence intensity of TMRE of YT cells in the control group and 0.065 μmol/L BDA-366 group were 8 372.00±330.47 and 6 419.67±311.34, and that of NK92 cells in the control group and 0.086 μmol/L BDA-366 group were 9 169.00±535.72 and 7 311.67±295.52 respectively, and there were statistically significant differences ( t=7.45, P=0.002; t=5.26, P=0.006). In YT cells, the intracellular Ca 2+ concentrations of 0.065 and 0.130 μmol/L BDA-366 groups were significantly higher than that of the control group (5 791.67±220.45, 6 729.33±585.39, 4 874.67±112.61, F=19.16, P=0.003) ( P=0.039; P=0.002). In NK92 cells, the intracellular Ca 2+ concentrations of 0.086 and 0.172 μmol/L BDA-366 groups were significantly higher than that of the control group (4 553.67±17.62, 4 740.33±254.50, 4 185.67±17.67, F=10.96, P=0.010) ( P=0.039; P=0.007). There was no statistically significant difference in body weight change on day 12 compared with day 0 of NOD-SCID mice between BDA-366 group and control group [ (3.18±0.01) g vs. (2.73±0.58) g, t=0.60, P=0.570], and HE staining showed no abnormal morphology of heart, liver, spleen, lung and kidney in BDA-366 group. Conclusion:BDA-366 promotes NK/TCL cells apoptosis in vitro, but does not cause weight loss and morphological changes of organs by HE staining in vivo. The inhibitory effect of BDA-366 on NK/TCL cells may be achieved by increasing Bax expression, inducing Ca 2+ release and reducing mitochondrial membrane potential.

Diagnostic value of BRAF V600E mutation detection in BSRTC categories Ⅰ and Ⅲ thyroid nodules / 中华核医学与分子影像杂志

Objective:To evaluate the value of B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation detection in the differentiating malignant from benign with Bethesda system for reporting thyroid cytopathology (BSRTC) categories Ⅰ and Ⅲ nodules. Methods:From January 2019 to December 2020, a total of 264 nodules from 263 patients (79 males, 184 females; median age 46 years) were retrospectively enrolled and all patients underwent BRAF V600E mutation detection, fine-needle aspiration cytology (FNAC) and thyroid nodulectomy in the Affiliated Drum Tower Hospital of Nanjing University Medical School. Thirteen nodules of 12 patients had repeat aspirate samples and 51 nodules were examined with multiple genes assay in formalin fixed paraffin embedded tissues. Taken the postoperative histopathological results as the gold standard, the diagnostic efficiency of BRAF V600E mutation was analyzed by comparing the results of multiple genes assay and BRAF V600E mutation detection of repeated puncture samples. Results:Of 264 nodules, 230 were malignant (papillary thyroid cancer (PTC)) and 34 were benign, with BSRTC categories Ⅰ (nondiagnostic) and Ⅲ (follicular lesion) nodules of 58 and 206. The sensitivities of BRAF V600E mutation detection in BSRTC categories Ⅰ and Ⅲ nodules were 77.1%(37/48) and 78.0%(142/182), the specificities were 9/10 and 91.7%(22/24), the positive predictive values were 97.4%(37/38) and 98.6%(142/144), the negative predictive values were 45.0%(9/20) and 35.5%(22/62), and the accuracy rates were 79.3%(46/58) and 79.6%(164/206). The diagnostic concordance of BRAF V600E mutation detection was 90.2%(46/51) in the preoperative and postoperative samples of 51 nodules with preoperative BRAF V600E wild type but postoperative pathology confirmed as PTC and was 11/13 in repeat puncture samples. Conclusion:BRAF V600E mutation detection is an effective diagnostic method for BSRTC categories Ⅰ and Ⅲ nodules.

Significance of BRAF V600E mutation in prediction of the efficacy of apatinib for radioactive iodine-refractory differentiated thyroid cancer / 中华核医学与分子影像杂志

Objective:To investigate the significance of B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation in the prediction of response to apatinib treatment in advanced radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Methods:Twenty patients (10 males, 10 females, age: 51.5(46.3, 65.0) years) with advanced RAIR-DTC from Peking Union Medical College Hospital between March 2016 and March 2023 were retrospectively enrolled, and all patients were treated with apatinib and underwent genetic sequencing (including BRAF V600E and telomerase reverse transcriptase (TERT) promoter). The serological and imaging data, progression-free survival (PFS) and overall survival (OS) data were collected during apatinib treatment. The Kaplan-Meier survival analysis (log-rank test) was performed, and Mann-Whitney U test were used to analyze the differences of duration of response (DOR) between mutation group and wild-type group. Then univariate and multivariate Cox regression analyses were conducted. Results:The PFS (35.3 vs 9.2 months, χ2=7.53, P=0.006) and DOR (25.8(7.4, 35.2) vs 8.2(2.5, 13.4) months, U=23.00, P=0.046) of the BRAF V600E mutation group were longer than those of the wild-type group. Univariate Cox regression analysis showed that the BRAF V600E mutation group had better PFS benefit (hazard ratio ( HR)=0.22 (95% CI: 0.06-0.72), P=0.013), and the risk of disease progression or death in patients with lung metastasis and bone or brain metastasis was 3.06(95% CI: 1.10-8.54, P=0.033) times higher than that in patients with lung metastasis alone. Further, multivariate cox regression analysis showed that only BRAF V600E mutation was an independent predictor of PFS ( HR=0.23 (95% CI: 0.07-0.80), P=0.021), suggesting that RAIR-DTC patients with BRAF V600E mutation might have better efficacy of apatinib. There was no significant difference in PFS ( χ2=1.34, P=0.247) and OS ( χ2=0.19, P=0.664) between TERT promoter mutation group and wild-type group. Conclusion:RAIR-DTC patients with BRAF V600E mutation have longer PFS and DOR after apatinib treatment than those with BRAF V600E wild-type, suggesting that BRAF V600E may be a potential biomarker to guide tyrosine kinase inhibitor (TKI) therapy and help to refine TKI treatment indications.