The Pattern of Time to Onset and Resolution of Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitors in Cancer: A Pooled Analysis of 23 Clinical Trials and 8,436 Patients / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The occurrence pattern of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) in cancer treatment remains unclear. @*Materials and Methods@#Phase II-III clinical trials that evaluated ICI-based treatments in cancer and were published between January 2007 and December 2019 were retrieved from public electronic databases. The pooled median time to onset (PMT-O), resolution (PMT-R), and immune-modulation resolution (PMT-IMR) of irAEs were generated using the metamedian package of R software. @*Results@#Twenty-two eligible studies involving 23 clinical trials and 8,436 patients were included. The PMT-O of all-grade irAEs ranged from 2.2 to 14.8 weeks, with the longest in renal events. The PMT-O of grade ≥ 3 irAEs was significantly longer than that of all-grade irAEs induced by programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) inhibitors (27.5 weeks vs. 8.4 weeks, p < 0.001) and treatment of nivolumab (NIV) plus ipilimumab (IPI) (7.9 weeks vs. 6.0 weeks, p < 0.001). The PMT-R of all-grade irAEs ranged from 0.1 to 54.3 weeks, with the shortest and longest in hypersensitivity/infusion reaction and endocrine events, respectively. The PMT-IMR of grade ≥ 3 irAEs was significantly shorter than that of all-grade irAEs caused by PD-1/PD-L1 blockade (6.9 weeks vs. 40.6 weeks, p=0.002) and NIV+IPI treatment (3.1 weeks vs. 5.9 weeks, p=0.031). @*Conclusion@#This study revealed the general and specific occurrence pattern of ICI-induced irAEs in pan-cancers, which was deemed to aid the comprehensive understanding, timely detection, and effective management of ICI-induced irAEs.

The Pattern of Time to Onset and Resolution of Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitors in Cancer: A Pooled Analysis of 23 Clinical Trials and 8,436 Patients / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The occurrence pattern of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) in cancer treatment remains unclear. @*Materials and Methods@#Phase II-III clinical trials that evaluated ICI-based treatments in cancer and were published between January 2007 and December 2019 were retrieved from public electronic databases. The pooled median time to onset (PMT-O), resolution (PMT-R), and immune-modulation resolution (PMT-IMR) of irAEs were generated using the metamedian package of R software. @*Results@#Twenty-two eligible studies involving 23 clinical trials and 8,436 patients were included. The PMT-O of all-grade irAEs ranged from 2.2 to 14.8 weeks, with the longest in renal events. The PMT-O of grade ≥ 3 irAEs was significantly longer than that of all-grade irAEs induced by programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) inhibitors (27.5 weeks vs. 8.4 weeks, p < 0.001) and treatment of nivolumab (NIV) plus ipilimumab (IPI) (7.9 weeks vs. 6.0 weeks, p < 0.001). The PMT-R of all-grade irAEs ranged from 0.1 to 54.3 weeks, with the shortest and longest in hypersensitivity/infusion reaction and endocrine events, respectively. The PMT-IMR of grade ≥ 3 irAEs was significantly shorter than that of all-grade irAEs caused by PD-1/PD-L1 blockade (6.9 weeks vs. 40.6 weeks, p=0.002) and NIV+IPI treatment (3.1 weeks vs. 5.9 weeks, p=0.031). @*Conclusion@#This study revealed the general and specific occurrence pattern of ICI-induced irAEs in pan-cancers, which was deemed to aid the comprehensive understanding, timely detection, and effective management of ICI-induced irAEs.

The evolution of the nasopharyngeal carcinoma staging system over a 10-year period: implications for future revisions / 中华医学杂志(英文版)

BACKGROUND@#The classification criteria and staging groups for nasopharyngeal carcinoma described in the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging system have been revised over time. This study assessed the proportion of patients whose staging and treatment strategy have changed due to revisions of the UICC/AJCC staging system over the past 10 years (ie, from the sixth edition to the eighth edition), to provide information for further refinement.@*METHODS@#We retrospectively reviewed 1901 patients with non-metastatic nasopharyngeal carcinoma treated in our cancer center between November 2009 and June 2012. The Akaike information criterion and Harrell concordance index were applied to evaluate the performance of the staging system.@*RESULTS@#In total, 25 (1.3%) of the 1901 patients who were staged as T2a according to the sixth edition system were downgraded to T1 in the eighth edition; 430 (22.6%) staged as N0 in the sixth edition were upgraded to N1 in the eighth edition; 106 (5.6%) staged as N1/2 in the sixth edition were upgraded to N3 in the eighth edition. In addition, 51 (2.7%) and 25 (1.3%) of the study population were upstaged from stage I to stage II and stage II to stage IVa, respectively; 10 (0.5%) was downgraded from stage II to stage I. The survival curves of adjacent N categories and staging groups defined by eighth classification system were well-separated. However, there was no significant difference in the locoregional failure-free survival (P = 0.730) and disease-free survival (P = 0.690) rates between the T2 and T3 categories in the eighth edition classification system.@*CONCLUSIONS@#Modifications to the tumor-node-metastasis staging system over the past 10 years have resulted in N classification changes in numerous cases. Although the eighth edition tumor-node-metastasis staging system better predicts survival outcomes, the T classification could be simplified in future revisions.

A National Study of Survival Trends and Conditional Survival in Nasopharyngeal Carcinoma: Analysis of the National Population-Based Surveillance Epidemiology and End Results Registry / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Conditional survival (CS) provides important information on survival for a period of time after diagnosis. Currently, information on CS patterns of patients with nasopharyngeal carcinoma (NPC) is lacking. We aimed to analyze survival rate over time and estimate CS for NPC patients using a national population-based registry. MATERIALS AND METHODS: Patients diagnosed with NPC between 1973 and 2007 with at least 5-year follow-up were identified from the Surveillance Epidemiology End Results registry. Traditional survival rates and crude CS estimateswere calculated using Kaplan-Meier analysis. Risk-adjusted survival curves were plotted from the proportional hazards model using the correct group prognosis method. RESULTS: For 7,713 patients analyzed, adjusted baseline 5-year overall survival improved significantly from 36.0% in patients diagnosed in 1973-1979, 41.7% in 1980-1989, 46.6% in 1990-1999, to 54.7% in 2000-2007 (p < 0.01). CS analysis demonstrated that for every additional year survived, adjusted probability of surviving the next 5 years increased from 66.7% (localized), 54.0% (regional), and 35.3% (distant) at the time of diagnosis, to 83.7% (localized), 75.0% (regional), and 62.2% (distant) for patients who had survived 5 years. Adjusted 5-year CS differed among age, sex, tumor histology, ethnicity, and stage subgroups initially, but converged with time. CONCLUSION: Treatment outcomes of NPC patients have greatly improved over the decades. Increases in CS become more prominent in patients with distant disease than in those with localized or regional disease as patients survive longer. CS provides more dynamic prognostic information for patients who have survived a period of time after diagnosis.

Neutropenia during the First Cycle of Induction Chemotherapy Is Prognostic for Poor Survival in Locoregionally Advanced Nasopharyngeal Carcinoma: A Real-World Study in an Endemic Area / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study was to investigate the effect of neutropenia during the first cycle of induction chemotherapy (IC-1) on survival in locoregionally advanced nasopharyngeal carcinoma (LANPC). MATERIALS AND METHODS: Eligible patients (n=545) with LANPC receiving IC+concurrent chemoradiotherapy were included. Based on nadir neutrophil afterIC-1, all patientswere categorized into three groups: no/grade 1-2/grade 3-4 neutropenia. Five-year overall survival (OS) and disease-free survival (DFS) were compared between groups and subgroups stratified by IC regimen. We also explored the occurrence of IC-1–induced myelosuppression events and the minimal value of post-treatment neutrophil-to-lymphocyte ratio (post-NLRmin). Univariate/multivariate analyses were performed to investigate the effect of IC-1–induced neutropenia, timing of neutropenia, number of myelosuppression events, and high post-NLRmin on OS/DFS. RESULTS: Grade 1-2/grade 3-4 neutropeniawere associatedwith poorer OS/DFS than no neutropenia (all p < 0.05); OS/DFS were not significantly different between patients experiencing grade 1-2 vs. 3-4 neutropenia. Neutropenia had no significant effect on OS/DFS in patients receiving docetaxel–cisplatin–5-fluorouracil (TPF). Grade 1-2 (grade 3-4) neutropenia negatively influenced OS/DFS in patients receiving cisplatin–5-fluorouracil (PF) (PF and docetaxel–cisplatin [TP]; all p < 0.05). Neutropenia, two/three myelosuppression events, and high post-NLRmin (≥ 1.33) was most frequent on days 5-10, second and third week of IC-1, respectively. After adjustment for covariates, IC-1–induced neutropenia, two/three myelosuppression events, and post-NLRmin ≥ 1.33were validated as negative predictors of OS/DFS (all p < 0.05); timing of neutropenia had no significant effect. CONCLUSION: Occurrence of neutropenia, number of myelosuppression events, and high post-NLRmin during PF/TP IC-1 have prognostic value for poor survival in LANPC.

Effect of Rong Huang granules of patients with non-dialysis kidney deficiency damp heat syndrome and chronic kidney disease mineral and bone metabolism disorder to serum OPG and RANKL levels / 中国免疫学杂志

Objective:To observe serum osteoprotegerin (OPG),receptor activator of NF-kB ligand (RANKL) levels and the therapeutic effect of Rong Huang granules of patients with non-dialysis chronic kidney disease mineral and bone metabolism disorder (CKD-MBD) and kidney deficiency damp heat syndrome.Methods:70 cases of non-dialysis CKD-MBD with kidney deficiency damp heat syndrome,were randomly divided into treatment group and control group,the actual completion of 61 cases,30 cases in treatment group,31 cases in the control group;and a healthy normal group of 20 cases of patients was established.Two groups of patients were given symptomatic treatment,in addition,Rong Huang granules was plused in treating at treatment group and it was used three times a day,each time blunt one bag.The course of treatment was 8 weeks.The changes of kidney deficiency damp heat syndrome,blood urea nitrogen (BUN),serum creatinine (Scr),estimated glomerular filtration rate (eGFR),serum of calcium (Ca),phosphorus (P), alkaline phosphatase (ALP),parathyroid hormone (iPTH),OPG and RANKL levels were observed in two groups of patients.Results:The total effective rate in treatment group was significantly better than the control group(P<0.01).The integral value of syndrome decreased more significantly with the course of treatment increased of two groups of patients(P<0.01).Compared with the same period of therapy,the descender in the treatment group was significantly better than that in the control group(P<0.01).The levels of BUN, Scr,eGFR,Ca,P,iPTH and ALP were improved in the treatment group after treatment(P<0.05 or P<0.01),BUN and iPTH were improved in the control group(P<0.05 or P<0.01),other indexes were not improved(P>0.05).After treatment,BUN,Scr,eGFR,Ca, P,iPTH,ALP of treatment group were significantly better than the control group(P<0.05 or P<0.01).Compared with the normal group,the levels of OPG and RANKL were significantly higher in CKD-MBD patients (P<0.01).After treatment,serum OPG level, serum RANKL level and OPG/RANKL ratio were significantly improved than before treatment in treatment group(P<0.05 or P<0.01),and in the control group,only the OPG/RANKL ratio increased(P<0.01).After treatment,OPG,RANKL and OPG/RANKL ratio in the treatment group were obviously improved compared with them in the control group(P<0.05 or P<0.01).Conclusion:The levels of OPG and RANKL in non-dialysis CKD-MBD patients with kidney deficiency damp heat syndrome were higher than those in healthy people,and the ratio of OPG/RANKL was lower than that in healthy people.Rong Huang granules can ameliorate clinical symptoms,prevent calcium and phosphorus metabolism,improve renal function,the mechanism may be related to the ameliorate of serum OPG and the decrease of serum RANKL level and the raise of ratio of OPG/RANKL.

Interhemispheric functional connectivity for Alzheimer's disease and amnestic mild cognitive impairment based on the triple network model / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

The purpose of this study was to explore the differences in interhemispheric functional connectivity in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) based on a triple network model consisting of the default mode network (DMN), salience network (SN), and executive control network (ECN). The technique of voxel-mirrored homotopic connectivity (VMHC) analysis was applied to explore the aberrant connectivity of all patients. The results showed that: (1) the statistically significant connections of interhemispheric brain regions included DMN-related brain regions (i.e. precuneus, calcarine, fusiform, cuneus, lingual gyrus, temporal inferior gyrus, and hippocampus), SN-related brain regions (i.e. frontoinsular cortex), and ECN-related brain regions (i.e. frontal middle gyrus and frontal inferior); (2) the precuneus and frontal middle gyrus in the AD group exhibited lower VMHC values than those in the aMCI and healthy control (HC) groups, but no significant difference was observed between the aMCI and HC groups; and (3) significant correlations were found between peak VMHC results from the precuneus and Mini Mental State Examination (MMSE) and Montreal Cognitive Scale (MOCA) scores and their factor scores in the AD, aMCI, and AD plus aMCI groups, and between the results from the frontal middle gyrus and MOCA factor scores in the aMCI group. These findings indicated that impaired interhemispheric functional connectivity was observed in AD and could be a sensitive neuroimaging biomarker for AD. More specifically, the DMN was inhibited, while the SN and ECN were excited. VMHC results were correlated with MMSE and MOCA scores, highlighting that VMHC could be a sensitive neuroimaging biomarker for AD and the progression from aMCI to AD.

Intervention effect of Qingshen Granules on oxidative stress in patients with chronic renal failure of damp-heat syndrome / 中成药

AIM To observe the changes of serum ROS,MDA,SOD levels in chronic renal failure (CRF) patients with damp-heat syndrome and to explore the intervention effect of Qingshen Granules (Hedyotis diffusae Herba,Salviae miltiorrhizae Radix et Rhizoma,Artemisiae scopariae Herba,etc.) on oxidative stress.METHODS Seventy cases of CRF patients with damp-heat syndrome were randomly and equally divided into control group and treatment group.Sixty cases completed the study,thirty-one cases in the treatment group,twenty-nine cases in the control group.Twenty other cases served as the normal group.The treatment group and the control group were given the basic treatment of western medicine and retention enema of TCM.The treatment group was added Qingshen Granules for eight weeks.The levels of U-Pro/24 h,Scr,BUN,estimated glomerular filtration rate (eGFR),serum ROS,MDA and SOD were measured before and after the treatment,and were compared with the normal group.RESULTS Both total effective rates on disease and on traditional Chinese medicine syndrome in the treatment group were 83.87％,significantly higher than those in the control group (51.72％ and 48.28％),respectively.The levels of U-Pro/24 h,Scr and BUN were obviously lower in the treatment group after the treatment,and eGFR was obviously higher as compared with those in the control group.Before the treatment,the levels of ROS and MDA in the treatment and control groups were significantly higher than those in the normal group,and the level of SOD was significantly lower;the levels of ROS and MDA were reduced in the treatment group after the treatment,and the level of SOD was increased;these changes in the treatment group were more significant than those in the control group.CONCLUSION Qingshen Granules can ameliorate clinical symptoms in CRF patients with damp-heat syndrome,decrease the levels of U-Pro/24 h,Scr and BUN,increase eGFR level,inhibit oxidative stress,and enhance antioxidant capacity,ultimately delay the development of renal fibrosis.

Dosimetric benefit to organs at risk following margin reductions in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy / 癌症

<p><b>INTRODUCTION</b>It is important to decrease the radiation exposure of normal tissue in intensity-modulated radiation therapy (IMRT). Minimizing planning target volume (PTV) margins with more precise target localization techniques can achieve this goal. This study aimed to quantify the extent to which organs at risk (OARs) are spared when using reduced margins in the treatment of nasopharyngeal carcinoma (NPC).</p><p><b>METHODS</b>Two IMRT plans were regenerated for 40 patients with NPC based on two PTV margins, which were reduced or unchanged following cone beam computed tomography online correction. The reduced-margin plan was optimized based on maximal dose reduction to OARs without compromising target coverage. Dosimetric comparisons were evaluated in terms of target coverage and OAR sparing.</p><p><b>RESULTS</b>Improvements in target coverage occurred with margin reduction, and significant improvements in dosimetric parameters were observed for all OARs (P < 0.05) except for the right optic nerve, chiasm, and lens. Doses to OARs decreased at a rate of 1.5% to 7.7%. Sparing of the left parotid and right parotid, where the mean dose (Dmean) decreased at a rate of 7.1% and 7.7%, respectively, was greater than the sparing of other OARs.</p><p><b>CONCLUSIONS</b>Significant improvements in OAR sparing were observed with margin reduction, in addition to improvement in target coverage. The parotids benefited most from the online imaging-guided approach.</p>

Prognostic scoring system for locoregional control among the patients with nasopharyngeal carcinoma treated by intensity-modulated radiotherapy / 癌症

The prognostic value of T category for locoregional control in patients with nasopharyngeal carcinoma (NPC) has decreased with the extensive use of intensity-modulated radiotherapy (IMRT). We aimed to develop a prognostic scoring system (PSS) that incorporated tumor extension and clinical characteristics for locoregional control in NPC patients treated with IMRT. The magnetic resonance imaging scans and medical records of 717 patients with nonmetastatic NPC treated with IMRT at Sun Yat-sen University Cancer Center between January 2003 and January 2008 were reviewed. Age, pathologic classification, primary tumor extension, primary gross tumor volume (GTV-p), T and N categories, and baseline lactate dehydrogenase (LDH) level were analyzed. Hierarchical cluster analysis as well as univariate and multivariate analyses were used to develop the PSS. Independent prognostic factors for locoregional relapse included N2-3 stage, GTV-p ≥26.8 mL, and involvement of one or more structures within cluster 3. We calculated a risk score derived from the regression coefficient of each factor and classified patients into four groups: low risk (score 0), intermediate risk (score >0 and ≤1), high risk (score >1 and ≤2), and extremely high risk (score >2). The 5-year locoregional control rates for these groups were 97.4%, 93.6%, 85.2%, and 78.6%, respectively (P < 0.001). We have developed a PSS that can help identify NPC patients who are at high risk for locoregional relapse and can guide individualized treatments for NPC patients.

Long-term outcome and late toxicities of simultaneous integrated boost-intensity modulated radiotherapy in pediatric and adolescent nasopharyngeal carcinoma / 癌症

The application of simultaneous integrated boost-intensity modulated radiotherapy (SIB-IMRT) in pediatric and adolescent nasopharyngeal carcinoma (NPC) is underevaluated. This study aimed to evaluate long-term outcome and late toxicities in pediatric and adolescent NPC after SIB-IMRT combined with chemotherapy. Thirty-four patients (aged 8-20 years) with histologically proven, non-disseminated NPC treated with SIB-IMRT were enrolled in this retrospective study. The disease stage distribution was as follows: stage I, 1 (2.9%); stage III, 14 (41.2%); and stage IV, 19 (55.9%). All patients underwent SIB-IMRT and 30 patients also underwent cisplatin-based chemotherapy. The prescribed dose of IMRT was 64-68 Gy in 29-31 fractions to the nasopharyngeal gross target volume. Within the median follow-up of 52 months (range, 9-111 months), 1 patient (2.9%) experienced local recurrence and 4 (11.8%) developed distant metastasis (to the lung in 3 cases and to multiple organs in 1 case). Four patients (11.8%) died due to recurrence or metastasis. The 5-year locoregional relapse-free survival, distant metastasis-free survival, disease-free survival, and overall survival rates were 97.1%, 88.2%, 85.3%, and 88.2%, respectively. The most common acute toxicities were grades 3-4 hematologic toxicities and stomatitis. Of the 24 patients who survived for more than 2 years, 16 (66.7%) and 15 (62.5%) developed grades 1-2 xerostomia and ototoxicity, respectively. Two patients (8.3%) developed grade 3 ototoxicity; no grade 4 toxicities were observed. SIB-IMRT combined with chemotherapy achieves excellent long-term locoregional control in pediatric and adolescent NPC, with mild incidence of late toxicities. Distant metastasis is the predominant mode of failure.

Locoregional extension patterns of nasopharyngeal carcinoma and suggestions for clinical target volume delineation / 癌症

Clinical target volume (CTV) delineation is crucial for tumor control and normal tissue protection. This study aimed to define the locoregional extension patterns of nasopharyngeal carcinoma (NPC) and to improve CTV delineation. Magnetic resonance imaging scans of 2366 newly diagnosed NPC patients were reviewed. According to incidence rates of tumor invasion, the anatomic sites surrounding the nasopharynx were classified into high-risk (>30%), medium-risk (5%-30%), and low-risk (<5%) groups. The lymph node (LN) level was determined according to the Radiation Therapy Oncology Group guidelines, which were further categorized into the upper neck (retropharyngeal region and level II), middle neck (levels III and Va), and lower neck (levels IV and Vb and the supraclavicular fossa). The high-risk anatomic sites were adjacent to the nasopharynx, whereas those at medium-or low-risk were separated from the nasopharynx. If the high-risk anatomic sites were involved, the rates of tumor invasion into the adjacent medium-risk sites increased; if not, the rates were significantly lower (P<0.01). Among the 1920 (81.1%) patients with positive LN, the incidence rates of LN metastasis in the upper, middle, and lower neck were 99.6%, 30.2%, and 7.2%, respectively, and skip metastasis happened in only 1.2% of patients. In the 929 patients who had unilateral upper neck involvement, the rates of contralateral middle neck and lower neck involvement were 1.8% and 0.4%, respectively. Thus, local disease spreads stepwise from proximal sites to distal sites, and LN metastasis spreads from the upper neck to the lower neck. Individualized CTV delineation for NPC may be feasible.