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Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2's role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/ß-catenin phosphorylation. AKT/ß-catenin phosphorylation facilitates ß-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and ß-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/ß-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.
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Infecções por Helicobacter , Helicobacter pylori , Células-Tronco Neoplásicas , Proteínas Proto-Oncogênicas c-akt , Neoplasias Gástricas , Animais , Feminino , Humanos , Masculino , Camundongos , beta Catenina/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fosforilação , Proteína Fosfatase 2/metabolismo , Proteína Fosfatase 2/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genéticaRESUMO
The gene encoding the NUAK family kinase 1 (NUAK1) is frequently amplified and its expression is upregulated, activating oncogenic signaling in various cancers. However, little is known about its role in gastric cancer (GC). We investigate the mechanistic links among NUAK1, Hedgehog signaling, and tumorigenesis in GC. NUAK1 overexpression is validated in local and public GC cohorts. Patient-derived xenograft and transgenic mouse models demonstrate that NUAK1 depletion or inhibition dramatically ameliorates gastric tumorigenesis. NUAK1 upregulates GLI1 expression by activating STAT5-mediated transcription and stabilizing GLI1 protein. NUAK1 depletion or inhibition impairs cancer cell expansion, tumor formation, and chemotherapy resistance in in vitro and in vivo models. Clinicopathological analysis confirms that upregulated NUAK1 expression correlates with poor prognosis and chemotherapy resistance in human GC. Our findings demonstrate that the signaling axis NUAK1/STAT5/GLI1 promotes cancer cell expansion and tumorigenesis and indicate that NUAK1 is an attractive therapeutic target and prognostic factor in GC.
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Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Fatores de Transcrição SOXB1 , Fator de Transcrição STAT5 , Transdução de Sinais , Neoplasias Gástricas , Proteína GLI1 em Dedos de Zinco , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamento farmacológico , Humanos , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição STAT5/metabolismo , Fator de Transcrição STAT5/genética , Animais , Linhagem Celular Tumoral , Camundongos , Proliferação de Células/efeitos dos fármacos , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição SOXB1/genética , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Masculino , Feminino , Carcinogênese/patologia , Carcinogênese/genéticaRESUMO
BACKGROUND: Increasing evidence suggests that DXS253E is critical for cancer development and progression, but the function and potential mechanism of DXS253E in colorectal cancer (CRC) remain largely unknown. In this study, we evaluated the clinical significance and explored the underlying mechanism of DXS253E in CRC. METHODS: DXS253E expression in cancer tissues was investigated using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The Kaplan-Meier plot was used to assess the prognosis of DXS253E. The cBioPortal, MethSurv, and Tumor Immune Estimation Resource (TIMER) databases were employed to analyze the mutation profile, methylation, and immune infiltration associated with DXS253E. The biological functions of DXS253E in CRC cells were determined by CCK-8 assay, plate cloning assay, Transwell assay, flow cytometry, lactate assay, western blot, and qRT-PCR. RESULTS: DXS253E was upregulated in CRC tissues and high DXS253E expression levels were correlated with poor survival in CRC patients. Our bioinformatics analyses showed that high DXS253E gene methylation levels were associated with the favorable prognosis of CRC patients. Furthermore, DXS253E levels were linked to the expression levels of several immunomodulatory genes and an abundance of immune cells. Mechanistically, the overexpression of DXS253E enhanced proliferation, migration, invasion, and the aerobic glycolysis of CRC cells through the AKT/mTOR pathway. CONCLUSIONS: We demonstrated that DXS253E functions as a potential role in CRC progression and may serve as an indicator of outcomes and a therapeutic target for regulating the AKT/mTOR pathway in CRC.
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OBJECTIVE: To evaluate the efficacy of acute T-cell lymphoblastic leukemia (T-ALL) in children and explore the prognostic risk factors. METHODS: The clinical data of 127 newly diagnosed children with T-ALL admitted to five hospitals in Fujian province from April 2011 to December 2020 were retrospectively analyzed, and compared with children with newly diagnosed acute precursor B-cell lymphoblastic leukemia (B-ALL) in the same period. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and event-free survival (EFS), and COX proportional hazard regression model was used to evaluate the prognostic factors. Among 116 children with T-ALL who received standard treatment, 78 cases received the Chinese Childhood Leukemia Collaborative Group (CCLG)-ALL 2008 protocol (CCLG-ALL 2008 group), and 38 cases received the China Childhood Cancer Collaborative Group (CCCG)-ALL 2015 protocol (CCCG-ALL 2015 group). The efficacy and serious adverse event (SAE) incidence of the two groups were compared. RESULTS: Proportion of male, age≥10 years old, white blood cell count (WBC)≥50×109/L, central nervous system leukemia, minimal residual disease (MRD)≥1% during induction therapy, and MRD≥0.01% at the end of induction in T-ALL children were significantly higher than those in B-ALL children (P <0.05). The expected 10-year EFS and OS of T-ALL were 59.7% and 66.0%, respectively, which were significantly lower than those of B-ALL (P <0.001). COX analysis showed that WBC≥100×109/L at initial diagnosis and failure to achieve complete remission (CR) after induction were independent risk factors for poor prognosis. Compared with CCLG-ALL 2008 group, CCCG-ALL 2015 group had lower incidence of infection-related SAE (15.8% vs 34.6%, P =0.042), but higher EFS and OS (73.9% vs 57.2%, P EFS=0.090; 86.5% vs 62.3%, P OS=0.023). CONCLUSIONS: The prognosis of children with T-ALL is worse than children with B-ALL. WBC≥100×109 /L at initial diagnosis and non-CR after induction (especially mediastinal mass has not disappeared) are the risk factors for poor prognosis. CCCG-ALL 2015 regimen may reduce infection-related SAE and improve efficacy.
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Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Criança , Humanos , Masculino , Estudos Retrospectivos , Intervalo Livre de Doença , Prognóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Linfócitos T , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resposta Patológica Completa , Neoplasia Residual/diagnóstico , Neoplasia Residual/tratamento farmacológico , Linfoma de Burkitt/tratamento farmacológicoRESUMO
AbstractObjective: To investigate the clinical characteristics and prognostic factors in childhood acute lymphoblastic leukemia with MLL gene-rearrangement-positive (MLL-r+ ALL). METHODS: The clinical data of 1 414 newly diagnosed children with ALL admitted to five hospital in Fujian province from April 2011 to December 2020 were retrospectively analyzed. The clinical characteristics and efficacy of MLL-r+ and MLL-r- subgroup were compared. The prognostic factors of MLL-r ALL were analyzed by COX regression model. RESULTS: Among all children with ALL, the proportion of patients aged less than 1 year old was 1.8%, and the detection rate of MLL-r+ was 3.4% (48/1 414). The positive detection rate of MLL-r in the age groups <1 year old, and ≥1 year old and ≤14 years old was 38.5% (10/26) and 2.7 (38/1 388), respectively, the difference was statistically significant (P<0.000). Compared with MLL-r- group, the MLL-r+ group had a higher proportion of patients with age <1 year, white blood cell (WBC) count ≥50×109/L, combined central nervous system leukemia (CNSL) and testicular leukemia(TL), while MRD <0.01% on d 33 or d 46 of induction chemotherapy was lower (all P<0.05). The expected 10-year event free survival(EFS) rate and overall survival(OS) rate of the MLL-r+ group were significantly lower than those of the MLL-r- group ï¼EFSï¼ 49.9% vs 77.0%ï¼ OS: 55.3% vs 82.9%ï¼ P<0.05). COX regression model analysis showed that age <1 year, minimal residual disease (MRD) ≥0.01% on d 33 or d 46 of induction chemotherapy were independent risk factors for worse OS and EFS in MLL-r+ ALL patients (all P<0.05). CONCLUSION: Age <1 year old, high WBC, concomitant CNSL and TL are more common in children with MLL-r+ ALL at initial diagnosis, with poor early treatment response and long-term prognosis. Age <1 year old at initial diagnosis and MRD positive after induction chemotherapy may be risk factors for poor prognosis.
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BACKGROUND & PROBLEMS: Post-operation hypothermia tends to induce complications. Sixty percent of robotic-assisted mitral valve surgery patients experienced hypothermia while admitted to our intensive care unit (ICU), resulting in prolonged ICU stays and 57% (eight) of those patients with hypothermia also experiencing cardiac arrhythmia. The causes of hypothermia in our ICU included low temperature in the operating room, delayed initiation of blanket coverage after surgery, and lack of postoperative thermal blankets, insufficient cardiopulmonary bypass rewarming time, cold ICU beds, lack of in-service training for hypothermia, and lack of procedure auditing. PURPOSE: This intervention was designed to reduce the incidence of hypothermia in ICU patients undergoing robotic-assisted mitral valve surgery upon ICU admission from 60% to 36% and the one-hour hypothermia rate from 43.3% to 26%. RESOLUTIONS: We implemented several measures including increasing the room temperature, pre-heating the ICU bed, achieving team consensus regarding prolonging the rewarming time after cardiopulmonary bypass, establishing a blanket warming area for postoperative patient use, and holding in-service training to enhance the awareness of the nurses were implemented. RESULTS: The incidence of hypothermia in ICU patients receiving robotic-assisted mitral valve surgery upon ICU admission decreased from 60% to 19.4%, while the one-hour hypothermia rate decreased from 43.3% to 19.4%. CONCLUSIONS: Using systemic interprofessional collaboration, combined thermal care can be achieved to significantly reduce the incidence of postoperative hypothermia in patients undergoing robotic-assisted mitral valve surgeries resulting in higher patient care quality and shorter ICU stays. We recommend applying this combined method to improve the quality of perioperative care for long-duration and major surgical procedures that involve large postoperative wounds and for patients who may require wider exposure during their operation.
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Hipotermia , Procedimentos Cirúrgicos Robóticos , Humanos , Hipotermia/prevenção & controle , Valva Mitral/cirurgia , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Incidência , Reaquecimento/efeitos adversos , Reaquecimento/métodos , Complicações Pós-Operatórias/prevenção & controleRESUMO
Tandem mass tags (TMT) are one of the most widely used techniques in proteomics quantification due to their ability to accurately and precisely analyze up to 18 samples in a multiplexed manner. Moreover, TMT tags are introduced chemically by covalent coupling of the primary amines of digested proteins, making them universally applicable for any kind of sample. However, in addition to amine groups, the hydroxyl groups of serine, threonine, and tyrosine residues can also be labeled to some extent during TMT labeling, which compromises the analytical sensitivity and results in lower peptide identification rates compared to label-free methods. In this work, we investigated in-depth the chemical nature of TMT overlabeling and revealed that peptides simultaneously containing histidine and hydroxyl-containing residues were prone to overlabeling due to an intramolecular catalysis mediated by the histidyl imidazolyl group. Based on the understanding of the chemical mechanism, we developed a novel TMT labeling method under acidic pH that completely overcomes overlabeling. Compared to the standard labeling method provided by the TMT vendor, our method achieved comparable labeling efficiency on target groups but greatly reduced overlabeled peptides, resulting in the identification of 33.9% more unique peptides and 20.9% more proteins in proteomic analysis.
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Peptídeos , Proteômica , Proteômica/métodos , Peptídeos/química , Proteínas/química , Concentração de Íons de Hidrogênio , ProteomaRESUMO
PURPOSE: Neoadjuvant chemoimmunotherapy (nICT) is a novel and promising therapy model for locally advanced esophageal squamous cell carcinoma.The objective of this study aimed to assessed the impact of additional neoadjuvant immunotherapy on patients' short-term outcomes, particularly the incidence of anastomotic leakage (AL) and pathological response. METHODS: Patients with locally advanced esophageal squamous cell carcinoma who received neoadjuvant chemotherapy (nCT)/ nICT combination with radical esophagectomy were enrolled from three medical centers in China. The authors used propensity score matching (PSM, ration:1:1, caliper=0.01) and inverse probability processing weighting (IPTW) to balance the baseline characteristics and compare the outcomes. Conditional logistic regression and weighted logistic regression analysis were used to further evaluate whether additional neoadjuvant immunotherapy would increase the risk of postoperative AL. RESULTS: A total of 331 patients getting partially advanced ESCC receiving nCT or nICT were enrolled from three medical centers in China. After PSM/IPTW, the baseline characteristics reached an equilibrium between the two groups. After matching, there were no significant difference in the AL incidence between the two groups ( P =0.68, after PSM; P =0.97 after IPTW), and the incidence of AL in the two groups was 15.85 versus 18.29%, and 14.79 versus 15.01%, respectively. After PSM/IPTW, both groups were similar in pleural effusion and pneumonia. After IPTW, the nICT group had a higher incidence of bleeding (3.36 vs. 0.30%, P =0.01), chylothorax (5.79 0.30%, P =0.001), and cardiac events (19.53 vs. 9.20%, P =0.04). recurrent laryngeal nerve palsy (7.85 vs. 0.54%, P =0.003). After PSM, both groups were similar in palsy of the recurrent laryngeal nerve (1.22 vs. 3.66%, P =0.31) and cardiac events (19.51 vs. 14.63%, P =0.41). Weighted logistic regression analysis showed that additional neoadjuvant immunotherapy was not responsible for AL (OR=0.56, 95% CI: [0.17, 1.71], after PSM; 0.74, 95% CI: [0.34,1.56], after IPTW). The nICT group had dramatically higher pCR in primary tumor than the nCT group ( P =0.003, PSM; P =0.005, IPTW), 9.76 versus 28.05% and 7.72 versus 21.17%, respectively. CONCLUSIONS: Additional neoadjuvant immunotherapy could benefit pathological reactions without increasing the risk of AL and pulmonary complications. The authors require further randomized controlled research to validate whether additional neoadjuvant immunotherapy would make a difference in other complications, and determine whether pathologic benefits could translate into prognostic benefits, which would require longer follow-up.
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Doenças Cardiovasculares , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/cirurgia , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/etiologia , Fístula Anastomótica/cirurgia , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Terapia Neoadjuvante/efeitos adversos , Esofagectomia/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND & AIMS: Transformation of stem/progenitor cells has been associated with tumorigenesis in multiple tissues, but stem cells in the stomach have been hard to localize. We therefore aimed to use a combination of several markers to better target oncogenes to gastric stem cells and understand their behavior in the initial stages of gastric tumorigenesis. METHODS: Mouse models of gastric metaplasia and cancer by targeting stem/progenitor cells were generated and analyzed with techniques including reanalysis of single-cell RNA sequencing and immunostaining. Gastric cancer cell organoids were genetically manipulated with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) for functional studies. Cell division was determined by bromodeoxyuridine-chasing assay and the assessment of the orientation of the mitotic spindles. Gastric tissues from patients were examined by histopathology and immunostaining. RESULTS: Oncogenic insults lead to expansion of SOX9+ progenitor cells in the mouse stomach. Genetic lineage tracing and organoid culture studies show that SOX9+ gastric epithelial cells overlap with SOX2+ progenitors and include stem cells that can self-renew and differentiate to generate all gastric epithelial cells. Moreover, oncogenic targeting of SOX9+SOX2+ cells leads to invasive gastric cancer in our novel mouse model (Sox2-CreERT;Sox9-loxp(66)-rtTA-T2A-Flpo-IRES-loxp(71);Kras(Frt-STOP-Frt-G12D);P53R172H), which combines Cre-loxp and Flippase-Frt genetic recombination systems. Sox9 deletion impedes the expansion of gastric progenitor cells and blocks neoplasia after Kras activation. Although Sox9 is not required for maintaining tissue homeostasis where asymmetric division predominates, loss of Sox9 in the setting of Kras activation leads to reduced symmetric cell division and effectively attenuates the Kras-dependent expansion of stem/progenitor cells. Similarly, Sox9 deletion in gastric cancer organoids reduces symmetric cell division, organoid number, and organoid size. In patients with gastric cancer, high levels of SOX9 are associated with recurrence and poor prognosis. CONCLUSION: SOX9 marks gastric stem cells and modulates biased symmetric cell division, which appears to be required for the malignant transformation of gastric stem cells.
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Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Gástricas , Camundongos , Animais , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Neoplasias Gástricas/patologia , Proliferação de Células , Transformação Celular Neoplásica/patologia , Carcinogênese/patologia , Divisão Celular , Células-Tronco/metabolismoRESUMO
OBJECTIVES: To study the clinical features and prognosis of high hyperdiploid (HHD) childhood acute lymphoblastic leukemia (ALL). METHODS: A retrospective analysis was performed on the medical data of 1 414 children who were newly diagnosed with ALL and were admitted to five hospitals in Fujian Province of China from April 2011 to December 2020. According to karyotype, they were divided into two groups: HHD (n=172) and non-HHD (n=1 242). The clinical features and treatment outcome were compared between the two groups, and the factors influencing the prognosis were further explored. RESULTS: Among the 1 414 children with ALL, 172 (12.16%) had HHD. Compared with the non-HHD group, the HHD group had significantly lower proportions of children with risk factors for poor prognosis at diagnosis (age of onset ≥10 years or <1 year, white blood cell count ≥50×109/L, and T-cell phenotype) or positive fusion genes (TEL-AML1, BCR-ABL1, E2A-PBX1, and MLL gene rearrangement) (P<0.05). The HHD group had a significantly higher proportion of children with minimal residual disease (MRD) <0.01% at the end of induction chemotherapy (P<0.05). The 10-year event-free survival (EFS) rate and overall survival (OS) rate in the HHD group were significantly higher than those in the non-HHD group (P<0.05). The univariate analysis showed that the number of chromosomes of 58-66, trisomy of chromosome 10, trisomy of chromosome 17, bone marrow MRD <1% on day 15 or 19 of induction chemotherapy, and bone marrow MRD <0.01% on day 33 or 46 of induction chemotherapy were associated with a higher EFS rate (P<0.05), and trisomy of chromosome 10 was associated with a higher OS rate (P<0.05). The multivariate Cox analysis showed that trisomy of chromosome 17 was closely associated with a high EFS rate (P<0.05). CONCLUSIONS: The ALL children with HHD have few risk factors for poor prognosis at diagnosis and often have good prognosis. The number of chromosomes and trisomy of specific chromosomes are associated with prognosis in these children.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Trissomia , Criança , Humanos , Estudos Retrospectivos , Prognóstico , Resultado do Tratamento , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Neoplasia Residual , Intervalo Livre de DoençaRESUMO
Objectives: Neoadjuvant immunochemotherapy (nICT) is a novel pattern for locally advanced esophageal squamous cell carcinoma (ESCC), and the time to surgery (TTS) is recommended as 4-6 weeks. However, there were some patients with prolonged TTS(> 6 weeks). This study aimed to explore whether prolonged TTS (> 6 weeks) would affect the outcomes. Methods: Patients diagnosed with locally advanced ESCC between January 2020 and March 2022 and undergoing esophagectomy following nICT were identified based on a prospectively collected database. Primary outcome measures were pathological complete response (pCR) and disease-free survival (DFS), and the secondary outcomes were 30-day postoperative mortality and morbidity, surgical time, postoperative hospital stay, and hospital expense. Results: Total of 95 patients were included for analysis, with 52 patients in the standard TTS group and 43 patients in the prolonged TTS group. The clinical and demographic characteristics of the two groups were comparable. The prolonged group had a median 18 days longer TTS(P<0.001). The pCR rate was 23.08% (12/52) in the standard group and 16.28% (7/43) in the prolonged group (P=0.41). Multivariate regression analysis further indicated that TTS wasn't an independent factor in predicting pCR (P=0.41). The median follow-up time was 10.5 months in the standard TTS group and 11.2 months in the prolonged TTS group. A total of five recurrences occurred with two events in the standard TTS group and three events in the prolonged TTS group, and no significant difference was observed in DFS(P=0.60). Both groups were comparable in postoperative hospital stays, total hospital stay, hospital expenses, and comprehensive complications index (CCI). The complications and major complications were also similar in both groups. Spearman test further indicated that there was no linear correlation among TTS with hospital expenses, postoperative hospital stays, hospital stay, CCI index, lymph nodes moved number, or surgical time, with a p-value of 0.48, 0.63, 0.80, 0.92, 0.09, 0.38 respectively. Conclusions: Based on present evidence, TTS after completion of nICT is not of major importance concerning pathological response, disease-free survival, and short-term postoperative outcomes.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Esofagectomia , Carcinoma de Células Escamosas do Esôfago/terapia , Terapia Neoadjuvante , Neoplasias Esofágicas/cirurgia , Intervalo Livre de DoençaRESUMO
Background: This study aimed to investigate whether the difference between "lung age" and real age (L-R) could be useful for the prediction of postoperative complications and long-term survival in patients with esophageal cancer followed by minimally invasive esophagectomy (MIE). Methods: This retrospective cohort study included 625 consecutive patients who had undergone MIE. "Lung age" was determined by the calculation method proposed by the Japanese Respiratory Society. According to L-R, patients were classified into three groups: group A: L-R ⦠0 (n = 104), group B: 15 > L-R > 0 (n = 199), group C: L-R ≥ 15 (n = 322). Clinicopathological factors, postoperative complications evaluated by comprehensive complications index (CCI), and overall survival were compared between the groups. A CCI value >30 indicated a severe postoperative complication. Results: Male, smoking status, smoking index, chronic obstructive pulmonary disease, American Society of Anesthesiologists status, lung age, and forced expiratory volume in 1â s were associated with group classification. CCI values, postoperative hospital stays, and hospital costs were significantly different among groups. Multivariate analysis indicated that L-R, coronary heart disease, and 3-field lymphadenectomy were significant factors for predicting CCI value >30. Regarding the prediction of CCI value >30, area under the curve value was 0.61(95%: 0.56-0.67), 0.46 (95% CI, 0.40-0.54), and 0.46 (95% CI, 0.40-0.54) for L-R, Fev1, and Fev1%, respectively. Regarding overall survival, there was a significant difference between group A and group B + C (log-rank test: p = 0.03). Conclusions: Esophageal cancer patients with impaired pulmonary function had a higher risk of severe postoperative complications and poorer prognosis than those with normal pulmonary function. The difference between "lung age" and "real age" seems to be a novel and potential predictor of severe postoperative complications and long-term survival.
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Telomere integrity is critical for embryonic development, and core telomere-binding proteins, such as TIN2, are key to maintaining telomere stability. Here, we report that homozygous Tin2S341X resulted in embryonic lethality in mice and reduced expression of Tin2 in the derived mouse embryonic stem cells (mESCs). Homozygous mutant mESCs were able to self-renew and remain undifferentiated but displayed many phenotypes associated with alternative lengthening of telomeres (ALT), including excessively long and heterogeneous telomeres, increased ALT-associated promyelocytic leukemia (PML) bodies, and unstable chromosomal ends. These cells also showed upregulation of Zscan4 expression and elevated targeting of DAXX/ATRX and H3K9me3 marks on telomeres. Furthermore, the mutant mESCs were impeded in their differentiation capacity. Upon differentiation, DAXX/ATRX and PML bodies disassociated from telomeres in these cells, where elevated DNA damage was also apparent. Our results reveal differential responses to telomere dysfunction in mESCs versus differentiated cells and highlight the critical role of TIN2 in embryonic development.
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Homeostase do Telômero , Telômero , Animais , Células-Tronco Embrionárias/metabolismo , Camundongos , Fenótipo , Telômero/genética , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismoRESUMO
Objectives: The combination of neoadjuvant chemotherapy and immunotherapy (nICT) is a novel treatment for locally advanced esophageal cancer. There is concern that nICT may increase operation difficulty, postoperative morbidity, and mortality. This study aimed to compare short-term outcomes among esophagectomy after neoadjuvant chemoradiotherapy (nCRT) and nICT and for locally advanced esophageal squamous cell carcinoma (ESCC). Methods: A retrospective analysis of a prospectively maintained database was performed to identify patients (from January 2017 through July 2021) who underwent surgery for ESCC following neoadjuvant therapy. A 1:1 propensity score matching (PSM) with a caliper 0.05 was conducted to balance potential bias. Results: A 1:1 PSM was conducted based on clinical stage, age, body mass index (BMI), and tumor location, and then 32 comparable pairs were matched. After PSM, age, gender, BMI, American Society of Anesthesiologists (ASA) status, smoking history, clinical stage, tumor location, lymphadenectomy field, pathological stage, anastomotic position, route of gastric conduit, procedure type, and operative approach were comparable between groups. Compared with the nICT group (median, 300 min), the operation time was significantly longer in the nCRT group (median, 376 min). However, both groups were comparable in intraoperative blood loss, thoracic drainage volume, intensive care unit (ICU) stay, postoperative hospital stays, and hospital cost. Further, 30-day mortality, 30-day readmission, ICU readmission, and major complications were similar in both groups. The nCRT group had an advantage in pathological response. The pathological complete response (pCR) was 18.8% (6/32) in the nICT group and 43.8% (14/32) in the nCRT group (p = 0.03). The major pathological response (MPR) was 71.9% (23/32) in the nCRT group and 34.4% (11/32) in the nICT group (p = 0.03). Conclusions: Based on our preliminary experience, esophagectomy appears to be safe and feasible following combined neoadjuvant immunotherapy with chemotherapy for locally advanced esophageal cancer.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Quimiorradioterapia Adjuvante , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Esofagectomia/efeitos adversos , Estudos de Viabilidade , Humanos , Imunoterapia/efeitos adversos , Pontuação de Propensão , Estudos RetrospectivosRESUMO
OBJECTIVES: This study aims to investigate the efficacy and feasibility of esophagectomy following combined neoadjuvant immunotherapy and chemotherapy for locally advanced esophageal cancer. METHODS: We retrospectively identified patients who were treated with neoadjuvant immunotherapy and chemotherapy (NICT, n = 27) or chemotherapy alone (NCT, n = 95) at our institution between January, 2017 and April, 2021. The primary end point was 30-day complications. Major complications were defined as Clavien-Dindo classification grade ≥ 3. Secondary end points were interval to surgery, operation time, postoperative thoracic drainage, thoracic drainage tube stay, 30-day readmission rate, and 30-day mortality. Propensity score matching (PSM) was used to reduce bias caused by potential confounding. RESULTS: All patients included successfully completed neoadjuvant therapy and underwent McKeown minimally invasive esophagectomy negative margins. Out of 122 eligible patients, 26 patients in NICT group and 52 patients in NCT group were identified by 1:2 PSM. After PSM, the clinical stage was matched and demographic characteristics of the two groups were well balanced, including age, gender, BMI, ASA status, age-adjusted Charlson index, smoking, drinking, chemotherapy regimens, neoadjuvant cycle, tumor location, lymphadenectomy, pathological stage, histologic sub-type, anastomotic position, route of gastric conduit, procedure type, and operative approach were comparable between groups after PSM. Although NICT group had a higher incidence of pneumonia and pleural effusion, however, the CCI index, other complication and major complications were comparable between the two groups. There were no significant differences in operation time, intraoperative blood loss, thoracic drainage tube stays, thoracic drainage volume, ICU stay, postoperative hospital stay and hospital cost. Furthermore, 30-day mortality, 30-day readmission, ICU readmission were similar in both groups. CONCLUSIONS: Based on our preliminary experience, esophagectomy is safe and feasible following combined neoadjuvant immunotherapy with chemotherapy for locally advanced esophageal cancer.
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Neoplasias Esofágicas , Esofagectomia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Estudos de Viabilidade , Humanos , Imunoterapia/efeitos adversos , Terapia Neoadjuvante/efeitos adversos , Complicações Pós-Operatórias/etiologia , Pontuação de Propensão , Estudos RetrospectivosRESUMO
Objectives: Neoadjuvant immunochemotherapy (nICT) has been confirmed with promising pathological complete response (pCR) among locally advanced esophageal squamous cell carcinoma (ESCC). However, there were still no reliable and accurate predictors to predict the treatment response. This study aimed to explore the predictive value of inflammatory and nutritional parameters. Methods: Patients with ESCC who underwent radical surgery after nICT between January 2020 and April 2022 were included in the study. First, the least absolute shrinkage and selection operator regression (LASSO) logistic regression analysis was used to screen independent inflammatory and nutritional parameters. Secondly, univariate and multivariate logistic regression were used to screen and predict independent risk factors for pCR. Thirdly, a nomogram was constructed based on the independent predictive factors, and 30% of the included population was randomly selected as the validation cohort. We used the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) curve to evaluate the nomogram model. Results: A total of 97 ESCC patients were screened for analysis, with 20 patients with pCR (20.32%). Only the systemic immune-inflammation index (SII) was screened after LASSO-logistic regression when λ was 0.06. The cut-off value of SII was 921.80 with an area under curve (AUC) value of 0.62. We defined SII > 921.80 as high SII and SII ⦠921.80 as low SII. Further, the univariate and multivariate analysis further determined SII(OR = 3.94, 95%CI:1.26-12.42, P = 0.02) and clinical stage(OR = 0.35, 95%CI:0.12-0.98, P = 0.05) were independent predictive factors of pCR. One novel nomogram was established with an AUC value of 0.72 in the training cohort and 0.82 in the validation cohort. The Brier score of the calibration curve was 0.13. The calibration curve showed good agreement between the predicted results and the actual results in both the training cohort and the validation cohort. Compared with the clinical stage, the DCA confirmed a better clinical value of the nomogram model in both the training cohort and the validation cohort. Conclusions: High pretreatment SII and early clinical stage were independently associated with pCR among ESCC receiving nICT. We further established and validated one novel nomogram model to effectively predict pCR among ESCC after nICT.
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BACKGROUND: Combination of neoadjuvant immunotherapy and chemotherapy (nICT) is a novel treatment for locally esophageal cancer squamous cell carcinoma (ESCC). This study aimed to evaluate the potential effect of nICT on surgery safety by comparing short-term outcomes between the surgery alone group and the nICT followed by surgery group. METHODS: A retrospective analysis was performed to identify patients (from January 2017 to July 2021) who underwent surgery for ESCC with or without nICT. A propensity score matching (PSM) comparison (1:1) was conducted to reduce selection biases and balance the demographic and oncologic characteristics between groups. RESULTS: After PSM, the nICT group (n = 38) was comparable to the surgery alone group (n = 38) in the following characteristics: age, sex, BMI, ASA status, smoking, tumor location, lymph node resection, clinical stage, anastomotic location, surgical approach, and surgical approach. The operation time and incidence of postoperative pneumonia in the nICT group were higher than those in the control group (p < 0.05). However, other complications and major complications were comparable between the two groups. There was no significant difference between the two groups in intraoperative blood loss, ICU stay time, postoperative hospital stay, and hospitalization cost. The 30-day mortality, 30-day readmission, and ICU readmission rates were also similar in the nICT and control groups. In the nICT group, the pathological complete response rate in primary tumor was 18.4%, and the major pathological response rate in tumor was 42.1%. CONCLUSIONS: Based on our preliminary experience, nICT followed by surgery is safe and effective with acceptable increased operation risk, manageable postoperative complications, and promising pathological response. Further multicenter prospective trials are needed to validate our results.
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BACKGROUND: The value of indocyanine green (ICG) fluorescence imaging in tracing metastatic lymph nodes (LNs) has rarely been reported. We aimed to evaluate the clinical implications of fluorescence imaging-guided lymphadenectomy and the sensitivity of fluorescent lymphography to detect metastatic LN stations in gastric cancer (GC). MATERIALS AND METHODS: This analysis pooled data from two randomized controlled trials (FUGES-012 and FUGES-019 studies) on laparoscopic ICG tracer-guided lymphadenectomy for GC between November 2018 and October 2020. Patients who received ICG injection using either the intraoperative subserosal or preoperative submucosal approaches 1 day before surgery and underwent fluorescence imaging-guided lymphadenectomy were defined as the ICG group. Patients who underwent conventional lymphadenectomy without ICG injection and intraoperative imaging were defined as the non-ICG group. RESULTS: Among 514 enrolled patients, the ICG and non-ICG groups included 385 and 129, respectively. A significantly higher mean number of LNs was retrieved in the ICG group than in the non-ICG group (49.9 vs. 42.0, P < 0.001). The ICG group showed a lower LN noncompliance rate than that in the non-ICG group (31.9% vs. 57.4%, P < 0.001). The sensitivity of fluorescence imaging for detecting all metastatic LN stations was 86.8%. The negative predictive value was 92.2% for nonfluorescent stations. For detecting all metastatic stations, subgroup analysis revealed 97.7%, 91.7%, 86.2%, and 84.3% sensitivities for pT1, pT2, pT3, and pT4a tumors, respectively. Regardless of gastrectomy type, the diagnostic accuracy for detecting all metastatic stations in the D1+ and D2 stations for cT1-cT2 disease reached 100%. CONCLUSION: ICG fluorescence imaging, using either the subserosal or submucosal approaches, assisted in the thorough dissection of potentially metastatic LNs, as recommended for individualized laparoscopic lymphadenectomy for GC.
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Laparoscopia , Neoplasias Gástricas , Estudos de Coortes , Humanos , Verde de Indocianina , Excisão de Linfonodo , Linfonodos , Imagem Óptica , Biópsia de Linfonodo Sentinela , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/cirurgiaRESUMO
OBJECTIVE: To analyze the gene mutations of children with juvenile myelomonocytic leukemia (JMML) and their correlation with clinical characteristics. METHODS: The genetic mutation results and clinical data of 19 children with JMML in Fujian from January 2015 to December 2018 were collected and analyzed retrospectively. According to the results of gene mutation, they were divided into PTPN11 gene mutation group and non-PTPN11 gene mutation group, and the clinical characteristics and prognosis of children with JMML between two groups were compared. RESULTS: Among the 19 children with JMML, 14 cases were male and 5 cases were female, and male/female ratio was 2.8â¶1. The median age at diagnosis was 13(3-48) months, and 14 cases (73.68%) were less than 2 years old. Abdominal distension and pyrexia were the common initial symptoms, and all the children with JMML had splenomegaly. The median white blood cell count was 39.82(4.53-103.4)×109/Lï¼and monocyte count was 4.37(1.04-23.12)×109/L. HbF was higher than the normal high value of the same age in 8 cases (42.11%). All JMML children's Philadelphia chromosome and BCR-ABL1 fusion gene were negative. Among the 19 patients, there were 1 case without any JMML related gene mutation, 7 cases (36.84%) with PTPN11 mutation, 6 cases (31.58%) with K-Ras mutation, 2 cases with NF1 mutation (10.53%), 2 cases with N-Ras mutation (10.53%), and 1 case (5.26%) with NF1 and N-Ras mutations simultaneously. Fifteen patients who only received supporting therapy all died, with a median survival time 9.2 (0.4-58.1) months. Whereas, among the four JMML children who received hematopoietic stem cell transplantation(HSCT), three cases survived and only one case died. Compared with the non-PTPN11 gene mutation group, the proportion of patients with hemoglobin F higher than the normal value of the same age was higher, and the median survival time was shorter in PTPN11 gene mutation group, and the differences were statistically significant (P=0.048 and 0.046, respectively). CONCLUSION: JMML is more common in male infancy and toddlerhood, and the main gene mutation types are PTPN11 and Ras mutations. Because the JMML children with PTPN11 mutations show particularly rapid disease progression, if there is no timely intervention, most children die in a short period of time. Therefore, early HSCT may improve the prognosis of the children with JMML.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil , Criança , Feminino , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/genética , Masculino , Mutação , Prognóstico , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Estudos Retrospectivos , Proteínas ras/genéticaRESUMO
This study investigated stress and other factors associated with colorectal cancer (CRC) outpatients with temporary colostomies in Taiwan. Temporary colostomies have been incorporated as a defecation alternative to maintain physical function and are accompanied by chemotherapy/radiotherapy in CRC patients. A cross-sectional study was conducted, and a convenience sampling approach was adopted to recruit 110 discharged CRC patients with temporary colostomies from a medical centre in southern Taiwan. The mean score of the Stress of Colostomy Patients Scale was 66.49 (out of 120). Demographic attributes were found to have an impact on different stress types. Stress of changes in familial and social interaction was affected by age, employment status, educational level and colostomy assistant caregiver. The stress of colostomy care was impacted by the factor of employment status, and the stress of changes of self-concept was impacted by the factors of educational level and self-perception of disease. The results provide post-operative information regarding stress and stress types among CRC patients with temporary colostomies, serve as a reference for clinical assessment, practice and care, and generate up-to-date knowledge and comprehension of learning how to live with a temporary colostomy.