Objective:To analyze the clinical characteristics of adverse reactions caused by dinutuximab β for the treatment of neuro-blastoma(NB)in China and to provide safety evidence for the rational use of dinutuximab β in clinical practice.Methods:Clinical data were retrospectively collected from 16 pediatric patients with NB who had been treated with dinutuximab β at Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine from January 2022 to November 2023,and the adverse reactions caused by dinutuximab β were summarized and analyzed.Results:The male-to-female ratio was 5:3 among the 16 children with NB.The retroperitoneum was the main initial site of involvement,accounting for 75%.Thirteen(81.25%)patients had high-risk NB.The adverse reactions caused by dinutuximab β mainly included decreased hemoglobin,fever,vomiting,and diarrhea.The inci-dence of adverse reactions was highest in the first course of treatment,and the median time of adverse reactions was 2-5 days.Conclu-sion:Targeted monitoring should be carried out at an early stage during dinutuximab β administration.Adverse reactions should be de-tected and managed early to ensure the safety of medication for children.

Objective:To explore the differences between the Phoenix sepsis scoring system including Phoenix sepsis score (PSS) and Phoenix-8 organ dysfunction score (hereinafter referred to as Phoenix-8) and the commonly used pediatric sepsis scores in evaluating clinical characteristics and prognostic analysis of pediatric patients with severe sepsis diagnosed under traditional standards, namely the diagnostic criteria from the 2005 International Pediatric Sepsis Consensus Conference.Methods:This study was a retrospective observational study. From December 2020 to March 2023, 202 pediatric patients with severe sepsis meeting the inclusion criteria were admitted to the Children's Hospital of Nanjing Medical University. Based on the sepsis diagnostic criteria outlined in the International Consensus Criteria for Pediatric Sepsis and Septic Shock (2024), the pediatric patients were categorized into a sepsis group and a non-sepsis group. Sepsis group was further subdivided into a death subgroup and a survival subgroup based on the outcomes. The age, hospitalization costs, disease outcome indicators (e.g., mortality rate and incidence of septic shock), major organ (e.g., heart, liver, lungs, and kidneys) damage and their correlations, as well as PSS, Phoenix-8 and commonly used pediatric sepsis scores (e.g., pediatric sequential organ failure assessment (pSOFA), pediatric risk of mortality score Ⅲ (PRISM Ⅲ), pediatric logistic organ dysfunction-2 score (PELOD-2), pediatric multiple organ dysfunction score (P-MODS), pediatric critical illness score (PCIS), and pediatric early warning score (PEWS)) were collected and compared. Receiver operating characteristic (ROC) curve and precision-recall curve were plotted to evaluate the predictive ability of PSS, Phoenix-8, and commonly used pediatric sepsis scores for mortality risk in pediatric patients with severe sepsis under traditional standards. Predictive performance was quantified using the area under the ROC curve (AUROC). Univariate logistic regression analysis was employed to quantify the odds ratios of PSS and Phoenix-8 for predicting mortality risk. Patients with severe sepsis under traditional standards were further stratified into subgroups based on complications and comorbidities, including central nervous system (CNS) diseases, multiple infections, cardiovascular system diseases, shock, and malignancies. The Hosmer-Lemeshow goodness-of-fit test was used to assess calibration of PSS and Phoenix-8, and the DeLong test was used to compare whether there were statistically significant differences in the AUROC of PSS and Phoenix-8 for predicting mortality risk among different subgroups of pediatric patients. Results:Compared with those in non-sepsis group, pediatric patients in sepsis group were significantly older ( Z=-2.92, P<0.05) with higher incidences of septic shock and mortality, hospitalization costs, PRISM Ⅲ, PEWS, pSOFA, PELOD-2, PSS, and Phoenix-8 (with χ2 values of 21.28 and 13.64, respectively, Z values of -1.99, -5.33, -5.10, -8.55, -6.91, -10.98, and -9.93, respectively, P<0.05), and lower PCIS ( Z=-3.34, P<0.05). Compared with those in survival subgroup, hospitalization costs, PSS, Phoenix-8, PRISM Ⅲ, PEWS, pSOFA, PELOD-2, and P-MODS of pediatric patients in death subgroup was significantly higher (with Z values of -2.50, -3.50, -2.47, -5.11, -3.84, -2.94, -3.61, and -3.04, respectively, P<0.05). Compared with those in survival subgroup, the incidences of lung damage and liver damage of pediatric patients in death subgroup were also significantly higher (with χ2 values of 6.20 and 10.94, respectively, P<0.05), and 64.7% (97/150) of patients exhibited two or more concurrent organ damage. For predicting mortality risk in pediatric patients with severe sepsis under traditional standards, the AUROC values for PRISM Ⅲ, PCIS, PEWS, pSOFA, PELOD-2, P-MODS, PSS, and Phoenix-8 were approximately 0.70, with optimal cutoff values of 17.5, 91.0, 5.5, 4.5, 2.5, 4.5, 3.5, and 4.5, respectively; PELOD-2 demonstrated the highest sensitivity (0.83); while PRISM Ⅲ, PSS, and Phoenix-8 showed high specificity (>0.80). Univariate logistic regression analysis showed that for every 1-point increase in the PSS within 24 hours of pediatric intensive care unit admission, the relative risk of mortality increased by 63.7% (with odds ratio of 1.64, 95% confidence interval of 1.34-1.99, P<0.05). Similarly, for every 1-point increase in the Phoenix-8, the relative risk of mortality increased by 37.5% (with odds ratio of 1.38, 95% confidence interval of 1.18-1.60, P<0.05). The AUROC values (around 0.80) of PSS and Phoenix-8 for predicting mortality risk in pediatric patients with severe sepsis combined with CNS diseases, multiple infections, and cardiovascular system diseases were relatively high. In contrast, the AUROC values (0.60-0.80) for predicting mortality risk in pediatric patients with severe sepsis combined with shock or malignant tumors were moderate. All models passed the Hosmer-Lemeshow goodness-of-fit test ( P>0.05). The DeLong test indicated no statistically significant differences in predictive ability between PSS and Phoenix-8 across subgroups of pediatric patients ( P>0.05). Conclusions:PSS and Phoenix-8 exhibited higher specificity than most of the commonly used pediatric sepsis scores in predicting mortality risk under traditional standards. Both scores performed much better in predicting the mortality risk in pediatric patients with severe sepsis combined with CNS diseases, multiple infections, and cardiovascular system diseases.

Small cell lung cancer (SCLC) is the thoracic malignant tumor and accounts for about 15% of lung malignancies and transfer often occurs by the time of diagnosis. Extensive stage-small cell lung cancer (ES-SCLC) accounts for about 2/3 of all SCLC. For many years, radiotherapy has occupied an important position in the treatment of SCLC, especially in the treatment of ES-SCLC, because SCLC is more sensitive to radiotherapy. However, in recent years, immune checkpoint inhibitor has shown more excellent antitumor activity in the treatment of ES-SCLC and become the mainstream argument for the treatment of ES-SCLC. However, will radiotherapy be buried by the times among the therapeutic approaches for ES-SCLC? In this article, we will review the clinical progress of radiotherapy, immunotherapy and combination therapy for ES-SCLC.
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Humans ; Small Cell Lung Carcinoma/therapy* ; Lung Neoplasms/therapy* ; Immunotherapy ; Neoplasm Staging ; Radiotherapy/methods* ; Combined Modality Therapy

Purpose To investigate the correlation between tumor budding in penile squamous cell carcinoma(SCC)and its clinicopathological features.Methods Clinical data and pathological slides from 69 cases of penile SCC were collected.Tumor budding was examined microscopically,and statistical analyses were performed to assess the relationship between tumor budding and various clinicopathological features.Results Among the 69 cases of pe-nile SCC,41 cases exhibited low-grade tumor budding and 28 cases displayed high-grade tumor budding.Tumor bud-ding was significantly correlated with tumor size,urethral invasion,invasion of the urethral corpus spongiosum,inva-sion of the penile corpus cavernosum,tumor necrosis,nerve invasion,vascular tumor thrombus,and pathological T stage(all P＜0.05).In contrast,no significant association was found between tumor budding and HPV-related versus non-HPV-related penile SCC(P＞0.05).Log-rank survival analysis indicated that patients with high-grade tumor bud-ding had a significantly lower survival rate compared to those with low-grade tumor budding(P＜0.05).Conclusion Tumor budding is a distinct pathological feature of penile SCC,and high-grade tumor budding is associated with a more aggressive biological behavior.

Objective:To explore the differences between the Phoenix sepsis scoring system including Phoenix sepsis score (PSS) and Phoenix-8 organ dysfunction score (hereinafter referred to as Phoenix-8) and the commonly used pediatric sepsis scores in evaluating clinical characteristics and prognostic analysis of pediatric patients with severe sepsis diagnosed under traditional standards, namely the diagnostic criteria from the 2005 International Pediatric Sepsis Consensus Conference.Methods:This study was a retrospective observational study. From December 2020 to March 2023, 202 pediatric patients with severe sepsis meeting the inclusion criteria were admitted to the Children's Hospital of Nanjing Medical University. Based on the sepsis diagnostic criteria outlined in the International Consensus Criteria for Pediatric Sepsis and Septic Shock (2024), the pediatric patients were categorized into a sepsis group and a non-sepsis group. Sepsis group was further subdivided into a death subgroup and a survival subgroup based on the outcomes. The age, hospitalization costs, disease outcome indicators (e.g., mortality rate and incidence of septic shock), major organ (e.g., heart, liver, lungs, and kidneys) damage and their correlations, as well as PSS, Phoenix-8 and commonly used pediatric sepsis scores (e.g., pediatric sequential organ failure assessment (pSOFA), pediatric risk of mortality score Ⅲ (PRISM Ⅲ), pediatric logistic organ dysfunction-2 score (PELOD-2), pediatric multiple organ dysfunction score (P-MODS), pediatric critical illness score (PCIS), and pediatric early warning score (PEWS)) were collected and compared. Receiver operating characteristic (ROC) curve and precision-recall curve were plotted to evaluate the predictive ability of PSS, Phoenix-8, and commonly used pediatric sepsis scores for mortality risk in pediatric patients with severe sepsis under traditional standards. Predictive performance was quantified using the area under the ROC curve (AUROC). Univariate logistic regression analysis was employed to quantify the odds ratios of PSS and Phoenix-8 for predicting mortality risk. Patients with severe sepsis under traditional standards were further stratified into subgroups based on complications and comorbidities, including central nervous system (CNS) diseases, multiple infections, cardiovascular system diseases, shock, and malignancies. The Hosmer-Lemeshow goodness-of-fit test was used to assess calibration of PSS and Phoenix-8, and the DeLong test was used to compare whether there were statistically significant differences in the AUROC of PSS and Phoenix-8 for predicting mortality risk among different subgroups of pediatric patients. Results:Compared with those in non-sepsis group, pediatric patients in sepsis group were significantly older ( Z=-2.92, P<0.05) with higher incidences of septic shock and mortality, hospitalization costs, PRISM Ⅲ, PEWS, pSOFA, PELOD-2, PSS, and Phoenix-8 (with χ2 values of 21.28 and 13.64, respectively, Z values of -1.99, -5.33, -5.10, -8.55, -6.91, -10.98, and -9.93, respectively, P<0.05), and lower PCIS ( Z=-3.34, P<0.05). Compared with those in survival subgroup, hospitalization costs, PSS, Phoenix-8, PRISM Ⅲ, PEWS, pSOFA, PELOD-2, and P-MODS of pediatric patients in death subgroup was significantly higher (with Z values of -2.50, -3.50, -2.47, -5.11, -3.84, -2.94, -3.61, and -3.04, respectively, P<0.05). Compared with those in survival subgroup, the incidences of lung damage and liver damage of pediatric patients in death subgroup were also significantly higher (with χ2 values of 6.20 and 10.94, respectively, P<0.05), and 64.7% (97/150) of patients exhibited two or more concurrent organ damage. For predicting mortality risk in pediatric patients with severe sepsis under traditional standards, the AUROC values for PRISM Ⅲ, PCIS, PEWS, pSOFA, PELOD-2, P-MODS, PSS, and Phoenix-8 were approximately 0.70, with optimal cutoff values of 17.5, 91.0, 5.5, 4.5, 2.5, 4.5, 3.5, and 4.5, respectively; PELOD-2 demonstrated the highest sensitivity (0.83); while PRISM Ⅲ, PSS, and Phoenix-8 showed high specificity (>0.80). Univariate logistic regression analysis showed that for every 1-point increase in the PSS within 24 hours of pediatric intensive care unit admission, the relative risk of mortality increased by 63.7% (with odds ratio of 1.64, 95% confidence interval of 1.34-1.99, P<0.05). Similarly, for every 1-point increase in the Phoenix-8, the relative risk of mortality increased by 37.5% (with odds ratio of 1.38, 95% confidence interval of 1.18-1.60, P<0.05). The AUROC values (around 0.80) of PSS and Phoenix-8 for predicting mortality risk in pediatric patients with severe sepsis combined with CNS diseases, multiple infections, and cardiovascular system diseases were relatively high. In contrast, the AUROC values (0.60-0.80) for predicting mortality risk in pediatric patients with severe sepsis combined with shock or malignant tumors were moderate. All models passed the Hosmer-Lemeshow goodness-of-fit test ( P>0.05). The DeLong test indicated no statistically significant differences in predictive ability between PSS and Phoenix-8 across subgroups of pediatric patients ( P>0.05). Conclusions:PSS and Phoenix-8 exhibited higher specificity than most of the commonly used pediatric sepsis scores in predicting mortality risk under traditional standards. Both scores performed much better in predicting the mortality risk in pediatric patients with severe sepsis combined with CNS diseases, multiple infections, and cardiovascular system diseases.

Objective:To investigate the epidemic characteristics of human brucellosis and the awareness of brucellosis prevention and control knowledge among occupational populations in Xuzhou City, Jiangsu Province.Methods:The data of brucellosis cases reported from January to December 2023 in the China Disease Prevention and Control Information System's Infectious Disease Surveillance System where the current residence was Xuzhou City, were collected. The epidemiological distribution characteristics across the three dimensions (time, region, and population) were analyzed, and the etiological characteristics of Brucella strains collected from sentinel hospitals in Xuzhou City during the same period were analyzed. Meanwhile, in September 2023, a survey was conducted on the awareness of brucellosis prevention and control knowledge among occupational populations in 7 counties (cities, districts) with a high incidence of brucellosis in Xuzhou City. Binary logistic regression was used to analyze the influencing factors. Results:In 2023, a total of 124 human brucellosis cases were reported in Xuzhou City, with an annual incidence rate of 1.37/100 000. Brucellosis occurred in all months of the year, with a peak incidence from May to August, accounting for 46.77% (58/124). The incidence rate of brucellosis in Feng County, Pei County, Suining County, Xinyi City and Pizhou City (1.86/100 000) was higher than that in Gulou District, Yunlong District, Quanshan District, Jiawang District and Tongshan District (0.71/100 000), with a statistically significant difference (χ 2 = 19.15, P < 0.001). Among 124 cases of brucellosis, 81 cases (65.32%) were males and 43 cases (34.68%) were females. The incidence rate of brucellosis in males (1.78/100 000) was higher than that in females (0.96/100 000), with a statistically significant difference (χ 2 = 11.08, P < 0.001). The 55 - 64 age group reported a relatively higher number of cases (45 cases, 36.29%), with an incidence rate of 3.97/100 000. The main occupation was farmers (85 cases, 68.55%). In 2023, a total of 9 strains of Brucella were collected from the sentinel hospitals in Xuzhou City, all of which were Brucella melitensis, mainly classified as biotype 3 (7/9). In 2023, a total of 984 occupational population with brucellosis were surveyed in Xuzhou City, and the overall awareness rate of brucellosis prevention and control knowledge was 3.25% (32/984). By binary logistic regression analysis, the awareness rates of brucellosis prevention and control knowledge among veterinarians and those with high school or vocational school education, college education or above were relatively high [ OR (95% CI): 21.24 (1.52 - 297.74), 13.32 (3.48 - 50.96), 18.90 (3.68 - 97.13), P < 0.05]. Conclusions:In 2023, the incidence rate of human brucellosis in Xuzhou City is at a relatively high level, with men, middle-aged and elderly people, and farmers as the main population. The awareness rate of brucellosis prevention and control knowledge among occupational population is relatively low, and it is necessary to strengthen publicity, education, and behavioral intervention.

Objective:To investigate the epidemic characteristics of human brucellosis and the awareness of brucellosis prevention and control knowledge among occupational populations in Xuzhou City, Jiangsu Province.Methods:The data of brucellosis cases reported from January to December 2023 in the China Disease Prevention and Control Information System's Infectious Disease Surveillance System where the current residence was Xuzhou City, were collected. The epidemiological distribution characteristics across the three dimensions (time, region, and population) were analyzed, and the etiological characteristics of Brucella strains collected from sentinel hospitals in Xuzhou City during the same period were analyzed. Meanwhile, in September 2023, a survey was conducted on the awareness of brucellosis prevention and control knowledge among occupational populations in 7 counties (cities, districts) with a high incidence of brucellosis in Xuzhou City. Binary logistic regression was used to analyze the influencing factors. Results:In 2023, a total of 124 human brucellosis cases were reported in Xuzhou City, with an annual incidence rate of 1.37/100 000. Brucellosis occurred in all months of the year, with a peak incidence from May to August, accounting for 46.77% (58/124). The incidence rate of brucellosis in Feng County, Pei County, Suining County, Xinyi City and Pizhou City (1.86/100 000) was higher than that in Gulou District, Yunlong District, Quanshan District, Jiawang District and Tongshan District (0.71/100 000), with a statistically significant difference (χ 2 = 19.15, P < 0.001). Among 124 cases of brucellosis, 81 cases (65.32%) were males and 43 cases (34.68%) were females. The incidence rate of brucellosis in males (1.78/100 000) was higher than that in females (0.96/100 000), with a statistically significant difference (χ 2 = 11.08, P < 0.001). The 55 - 64 age group reported a relatively higher number of cases (45 cases, 36.29%), with an incidence rate of 3.97/100 000. The main occupation was farmers (85 cases, 68.55%). In 2023, a total of 9 strains of Brucella were collected from the sentinel hospitals in Xuzhou City, all of which were Brucella melitensis, mainly classified as biotype 3 (7/9). In 2023, a total of 984 occupational population with brucellosis were surveyed in Xuzhou City, and the overall awareness rate of brucellosis prevention and control knowledge was 3.25% (32/984). By binary logistic regression analysis, the awareness rates of brucellosis prevention and control knowledge among veterinarians and those with high school or vocational school education, college education or above were relatively high [ OR (95% CI): 21.24 (1.52 - 297.74), 13.32 (3.48 - 50.96), 18.90 (3.68 - 97.13), P < 0.05]. Conclusions:In 2023, the incidence rate of human brucellosis in Xuzhou City is at a relatively high level, with men, middle-aged and elderly people, and farmers as the main population. The awareness rate of brucellosis prevention and control knowledge among occupational population is relatively low, and it is necessary to strengthen publicity, education, and behavioral intervention.

Objective:To explore and verify the value of neoadjuvant rectal (NAR) score in predicting the prognosis of patients with middle and low locally advanced rectal cancer.Methods:A retrospective analysis of 207 patients with middle and low locally advanced rectal adenocarcinoma who received neoadjuvant radiotherapy and chemotherapy in Tianjin Medical University Cancer Institute & Hospital from January 2015 to December 2021 was performed. The neoadjuvant radiotherapy regimen was pelvic external irradiation of 45-50.4 Gy, 1.8 Gy/f, 5 times per week and concurrent oral capecitabine chemotherapy on days 1-14 and 22-36 during radiotherapy. Total mesorectal excision (TME) was then performed. The NAR score was calculated based on the initial clinical stage and postoperative pathological stage, and divided into the low (<8), medium (8-16) and high (>16) layers, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and the differences in DFS and OS among different NAR score layers were compared using the log-rank test. Some patients received consolidation chemotherapy during the interval between concurrent radiotherapy-chemotherapy and surgery, even the total neoadjuvant therapy (TNT) model. Subgroup analysis was further used to verify the predictive value of the NAR score in the strengthened neoadjuvant therapy model.Results:The median follow-up of all patients was 46.0 months (range: 19.5-88.0 months), the 3-year DFS was 79.2%, and the 3-year OS was 87.4%. Univariate analysis found that the NAR score had a significant impact on the 3-year DFS and OS. The 3-year DFS of patients with low, medium, and high NAR scores were 90.3%, 86.1% and 58.7% ( P<0.001), and the 3-year OS were 94.4%, 91.7% and 74.6%, ( P<0.001), respectively. Subgroup analysis showed that the predictive value of the NAR score also applied to the strengthened neoadjuvant therapy model. The 3-year DFS of patients with low, medium, and high NAR scores were 86.9%, 83.8% and 68.3% ( P=0.044), and the 3-year OS were 92.9%, 90.7% and 85.4% ( P=0.029), respectively. Conclusion:The NAR score can effectively predict the prognosis of patients with middle and low locally advanced rectal adenocarcinoma, whether using neoadjuvant therapy or strengthened neoadjuvant therapy followed by TME surgery.

Objective:To evaluate the impact of postoperative radiotherapy (RT) and associated risk factors on the prognosis of patients undergoing postmastectomy breast reconstruction (PMBR) for breast cancer.Methods:A retrospective analysis was conducted on 1593 breast cancer patients who underwent PMBR at Tianjin Medical University Cancer Institute & Hospital between January 2010 and October 2023. Patients were divided into an RT group ( n = 351) and a non-RT group ( n =1242) based on whether postoperative radiotherapy was administered. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoint was the incidence of revision surgery. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used for pairing. Continuous variables were compared between the two groups using the independent samples t-tests, while categorical variables were compared using chi-square tests, and survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards model was used to analyze survival influencing factors, and include propensity factors with P<0.2 in univariate analysis into multivariate analysis. Results:In the RT group, there were 3 deaths (0.9%) and 21 cases of disease progression (6.0%); in the non-RT group, 7 patients died (0.56%) and 40 experienced disease progression (3.22%). The median OS was 20.1 months (range: 0.1-164.9), and the median PFS was 19.5 months (range: 0.1-160.9). Pregnancy-associated breast cancer and higher N stage were identified as significant risk factors for OS, while neoadjuvant therapy, absence of adjuvant chemotherapy or endocrine therapy, and higher T stage were significant risk factors affecting patients' PFS. Radiotherapy significantly reduced the survival risk for PMBR patients with pregnancy-associated breast cancer or those receiving neoadjuvant therapy ( P=0.019, 0.027). Compared with other reconstruction methods, implant-based reconstruction was associated with a lower incidence of postmastectomy revision surgery(10.5% vs. 17.0%, P<0.001). Even after radiotherapy, the revision surgery incidence for implant-based reconstruction remained lower than that of other methods (12.2% vs. 14.2%, P=0.591). Compared with other reconstruction types, expander-based reconstruction was associated with an increased incidence of revision surgery (31.9% vs. 10.9%, P<0.001). Conclusions:Postmastectomy radiotherapy can reduce survival risk in PMBR patients with pregnancy-associated breast cancer or who received neoadjuvant therapy, showing positive effects on OS and PFS in high-risk patients. Pregnancy, higher T/N stage, and specific treatment strategies are critical factors influencing the prognosis of PMBR patients. Implant-based reconstruction is associated with a lower incidence of revision surgery, which remains low even after RT, whereas expander-based reconstruction may increase the long-term risk of revision surgery.

Purpose To investigate the correlation between tumor budding in penile squamous cell carcinoma(SCC)and its clinicopathological features.Methods Clinical data and pathological slides from 69 cases of penile SCC were collected.Tumor budding was examined microscopically,and statistical analyses were performed to assess the relationship between tumor budding and various clinicopathological features.Results Among the 69 cases of pe-nile SCC,41 cases exhibited low-grade tumor budding and 28 cases displayed high-grade tumor budding.Tumor bud-ding was significantly correlated with tumor size,urethral invasion,invasion of the urethral corpus spongiosum,inva-sion of the penile corpus cavernosum,tumor necrosis,nerve invasion,vascular tumor thrombus,and pathological T stage(all P＜0.05).In contrast,no significant association was found between tumor budding and HPV-related versus non-HPV-related penile SCC(P＞0.05).Log-rank survival analysis indicated that patients with high-grade tumor bud-ding had a significantly lower survival rate compared to those with low-grade tumor budding(P＜0.05).Conclusion Tumor budding is a distinct pathological feature of penile SCC,and high-grade tumor budding is associated with a more aggressive biological behavior.