A novel approach to evaluation of tumor response for advanced pulmonary adenocarcinoma using the intertumoral heterogeneity response score.

Treatment response and prognosis estimation in advanced pulmonary adenocarcinoma are challenged by the significant heterogeneity of the disease. The current Response Evaluation Criteria in Solid Tumors (RECIST) criteria, despite providing a basis for solid tumor response evaluation, do not fully encompass this heterogeneity. To better represent these nuances, we introduce the intertumoral heterogeneity response score (THRscore), a measure built upon and expanding the RECIST criteria. This retrospective study included patients with 3-10 measurable advanced lung adenocarcinoma lesions who underwent first-line chemotherapy or targeted therapy. The THRscore, derived from the coefficient of variation in size for each measurable tumor before and 4-6 weeks posttreatment, unveiled a correlation with patient outcomes. Specifically, a high THRscore was associated with shorter progression-free survival, lower tumor response rate, and a higher tumor mutation burden. These associations were further validated in an external cohort, confirming THRscore's effectiveness in stratifying patients based on progression risk and treatment response, and enhancing the utility of RECIST in capturing complex tumor behaviors in lung adenocarcinoma. These findings affirm the promise of THRscore as an enhanced tool for tumor response assessment in advanced lung adenocarcinoma, extending the RECIST criteria's utility.

Development and validation of a novel risk stratification model and a survival rate calculator for diffuse large B-cell lymphoma in the rituximab era: a multi-institutional cohort study.

BACKGROUND: This study aimed to develop and validate a novel risk stratification model and a web-based survival rate calculator to improve discriminative and predictive accuracy for diffuse large B-cell lymphoma (DLBCL) in the rituximab era. METHODS: We retrospectively collected pre-treatment data from 873 primary DLBCL patients who received R-CHOP-based immunochemotherapy regimens at the Cancer Hospital, Chinese Academy of Medical Sciences, from January 1, 2005, to December 31, 2018. An independent cohort of 175 DLBCL patients from Fujian Cancer Hospital was used for external validation. FINDINGS: Age, ECOG PS, number of extranodal sites, Ann Arbor stage, bulky disease, and LDH levels were screened to develop the nomogram and web-based survival rate calculator. The C-index of the nomogram in the training, internal validation, and external validation cohorts was 0.761, 0.758, and 0.768, respectively. The risk stratification model generated based on the nomogram effectively stratified patients into three distinct risk groups. K-M survival curves demonstrated that the novel risk stratification model exhibited a superior level of predictive accuracy compared to IPI, R-IPI, and NCCN-IPI both in training and two validation cohorts. Additionally, the area under the curve (AUC) value of the novel model (0.763) for predicting 5-year overall survival rates was higher than those of IPI (0.749), R-IPI (0.725), and NCCN-IPI (0.727) in the training cohort. Similar results were observed in both internal and external validation cohort. CONCLUSIONS: In conclusion, we have successfully developed and validated a novel risk stratification model and a web-based survival rate calculator that demonstrated superior discriminative and predictive accuracy compared to IPI, R-IPI, and NCCN-IPI in the rituximab era.

Identification of novel prognostic autoantibodies in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone via a high-throughput antigen microarray.

BACKGROUND: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is a standard first-line treatment for diffuse large B-cell lymphoma (DLBCL). However, 20%-40% of patients survive less than 5 years. Novel prognostic biomarkers remain in demand. METHODS: Baseline plasma autoantibodies (AAbs) were assessed in 336 DLBCLs. In the discovery phase (n = 20), a high-density antigen microarray (∼21,000 proteins) was used to expound AAb profiles. In the verification phase (n = 181), with a DLBCL-focused microarray, comparative results based on event-free survival at 24 months (EFS24) and lasso Cox regression models of progression-free survival (PFS) and overall survival (OS) were integrated to identify potential biomarkers. They were further validated by enzyme-linked immunosorbent assay in validation phase 1 (n = 135) and a dynamic cohort (n = 12). In validation phase 2, a two-AAb-based risk score was established. They were further validated in an immunohistochemistry cohort (n = 55) and four independent Gene Expression Omnibus datasets (n = 1598). RESULTS: Four AAbs (CREB1, N4BP1, UBAP2, and DEAF1) were identified that showed associations with EFS24 status (p < .05) and superior PFS and OS (p < .05). A novel risk score model based on CREB1 and N4BP1 AAbs was developed to predict PFS with areas under the curve of 0.72, 0.71, 0.76, and 0.82 at 1, 3, 5, and 7 years, respectively, in DLBCL treated with R-CHOP independent of the International Prognostic Index (IPI) and provided significant additional recurrence risk discrimination (p < .05) for the IPI. CREB1 and N4BP1 proteins and messenger RNAs were also associated with better PFS and OS (p < .05). CONCLUSIONS: This study identified a novel prognostic panel of CREB1, N4BP1, DEAF1, and UBAP2 AAbs that is independent of the IPI in DLBCL.

Cerebrospinal fluid circulating tumor DNA contributes to the detection and characterization of leptomeningeal metastasis in non-small cell lung cancer.

PURPOSE: Cerebrospinal fluid (CSF) has revealed the unique genetic characteristics of leptomeningeal metastasis (LM) from non-small cell lung cancer (NSCLC). However, the research in this area is still very limited. METHODS: Patients with LM from NSCLC (n = 80) were retrospectively analyzed. Circulating tumor DNA (ctDNA) in CSF was tested by next-generation sequencing (NGS), with paired extracranial tissue or plasma samples included for comparison. An independent non-LM cohort (n = 100) was also analyzed for comparative purposes. Clinical outcomes were compared with Kaplan-Meier log-rank test and Cox proportional hazards methodologies. RESULTS: An overwhelming 93.8% of patients carried druggable mutations in NSCLC LM, with EGFR (78.8%) being the most prevalent. Notably, 4 patients who tested negative for driver genes in extracranial samples surprisingly showed EGFR mutations in their CSF and subsequently benefited from targeted therapy. There was a clear difference in genetic profiles between CSF and extracranial samples, with CSF showing more driver gene detections, increased Copy Number Variations (CNVs), and varied resistance mechanisms among individuals. Abnormalities in cell-cycle regulatory molecules were highly enriched in LM (50.9% vs 31.0%, p = 0.017), and CDKN2A/2B deletions were identified as an independent poor prognostic factor for LM patients, with a significant reduction in median OS (p = 0.013), supported by multivariate analysis (HR 2.63, 95% CI 1.32-5.26, p = 0.006). CONCLUSIONS: CSF-based ctDNA analysis is crucial for detecting and characterizing genetic alterations in NSCLC LM. The distinct genetic profiles in CSF and extracranial tissues emphasize the need for personalized treatment approaches.

Effects of intrathecal pemetrexed on the survival of patients with leptomeningeal metastasis from lung adenocarcinoma: a propensity score matching analysis.

PURPOSE: To explore the impact of intrathecal pemetrexed (IP) on the survival of lung adenocarcinoma (LUAC) patients with leptomeningeal metastasis (LM). METHODS: We analyzed patients with LUAC and LM who received systemic therapy after LM diagnosis at the Fujian Cancer Hospital between July 2018 and March 2022. Patients who underwent IP were assigned to the IP group; those without IP treatment were designated as the non-IP group. Propensity score matching (PSM) was performed between the two groups. RESULTS: 165 patients were enrolled: 83 and 82 in the IP and non-IP groups, respectively. After 1:1 PSM, we included 114 patients in the matched cohort. Median overall survival (OS) was 13.2 months (95% CI 10.8-15.6 months) in the IP group versus 10.1 months (95% CI 5.3-14.9 months) in the non-IP group (P = 0.488). Only Eastern Cooperative Oncology Group Performance Status (ECOG PS) was confirmed as an independent predictor for OS in the matched cohort (hazard ratio (HR) 2.03; P = 0.023). Multivariate competing-risks analysis showed that IP significantly correlated with central nervous system-related death (HR 0.31; P = 0.046). When stratified by ECOG PS, IP improved survival in patients with poor ECOG PS (PS = 2) (14.3 months vs. 1.6 months; P = 0.003). CONCLUSIONS: Intrathecal pemetrexed did not enhance OS for the entire LUAC patient with LM compared to non-intrathecal chemotherapy. However, it exhibited the potential to reduce the risk of central nervous system-related mortality and improve survival in patients with poor ECOG PS.

Association between subjective well-being and all-cause mortality among older adults in China.

BACKGROUND: Although several studies in high-income countries have suggested a positive association between subjective well-being (SWB) and mortality, studies conducted in low- and middle-income countries, such as China, are scarce. The purpose of this study is to examine the association between SWB and all-cause mortality among the older Chinese population. METHODS: Data were from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a population-based longitudinal cohort study in 22 of 31 provinces in mainland China. A total of 13,282 individuals aged 65 ≥ years who were recruited in 2002 and followed-up until 2018 were included. SWB was assessed with an eight-item tool covering life satisfaction, positive affect (including optimism, happiness, personal control and conscientiousness) and negative affect (including anxiety, loneliness and uselessness). Cox proportional hazards regression methods were carried out to estimate the association between SWB and total mortality, adjusting for a wide range of potential confounders. Subgroup analyses and interaction analyses were further conducted. RESULTS: During the 16.5 years of follow-up, 8459 deaths were identified. Greater SWB was independently associated with a reduced risk of all-cause mortality (adjusted hazard ratio [HR] = 0.85, 95% confidence interval [CI] = 0.81-0.89) after adjustment for age, sex, marital status, education level, place of residence, smoking status, drinking, exercise, diet, BMI, hypertension, diabetes, heart disease, cerebrovascular diseases and cancer. Of the eight individual SWB symptoms, only 2 items, feelings of uselessness (adjusted HR = 0.94, 95% CI = 0.89-0.99) and happiness (adjusted HR = 0.91, 95% CI = 0.86-0.95), were significantly associated with total mortality. Associations remained significant across all subgroups regardless of different characteristics. CONCLUSIONS: Higher SWB overall and 2 certain symptoms (feelings of uselessness and happiness) were independently associated with all-cause mortality risk among older Chinese adults. The association was consistent across different groups, suggesting that promoting a healthier SWB may be beneficial to all older individuals irrespective of their characteristics.

Proteomics Identifies Circulating TIMP-1 as a Prognostic Biomarker for Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, although disease stratification using in-depth plasma proteomics has not been performed to date. By measuring more than 1000 proteins in the plasma of 147 DLBCL patients using data-independent acquisition mass spectrometry and antibody array, DLBCL patients were classified into four proteomic subtypes (PS-I-IV). Patients with the PS-IV subtype and worst prognosis had increased levels of proteins involved in inflammation, including a high expression of metalloproteinase inhibitor-1 (TIMP-1) that was associated with poor survival across two validation cohorts (n = 180). Notably, the combination of TIMP-1 with the international prognostic index (IPI) identified 64.00% to 88.24% of relapsed and 65.00% to 80.49% of deceased patients in the discovery and two validation cohorts, which represents a 24.00% to 41.67% and 20.00% to 31.70% improvement compared to the IPI score alone, respectively. Taken together, we demonstrate that DLBCL heterogeneity is reflected in the plasma proteome and that TIMP-1, together with the IPI, could improve the prognostic stratification of patients.

Incidence, Survival Outcome, and Prognostic Nomogram of Patients with Angioimmunoblastic T-cell Lymphoma: a Population-based Analysis.

OBJECTIVE: Due to the rarity of angioimmunoblastic T-cell lymphoma (AITL), very limited data concerning its incidence patterns and prognostic factors are available. This study aimed to explore the incidence, characteristics, survival outcomes, and prognostic factors of AITL. METHODS: Age-adjusted incidence and temporal trends were calculated based on 1247 AITL patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-13 database. A total of 1525 AITL patients from the SEER-18 database and 43 patients from our single center were included for survival analysis and nomogram construction. RESULTS: The age-adjusted incidence for overall cohort was 0.123 [95% confidence interval (CI), 0.117-0.131) per 100 000 during 1992-2017. The overall incidence increased steeply at the rate of 15.3% (95%CI 11.0%-19.8%, P<0.001) per year during 1992-2004, but remained stable during 2004-2017 (P=0.200). Similar incidence trends were observed in age, sex, and stage subgroups. The final nomograms consisted of four variables: age at diagnosis, sex, Ann Arbor stage, and primary site. The concordance index (C-index) of the nomogram for 5-year overall survival prediction was 0.717, 0.690 and 0.820 in the training cohort, validation cohort-1 and cohort-2, respectively. Regarding the disease-specific survival (DSS), the nomogram also demonstrated a good discrimination level, with the C-index for predicting the probability of DSS at 5 years of 0.716, 0.682 and 0.813 for the three cohorts, respectively. The calibration displayed good concordance between the nomogram-predicted and actual observed outcomes. CONCLUSION: The age-adjusted incidence for AITL was low during 1992-2017. The incidence continuously increased during 1992-2004, but remained stable during 2004-2017. The nomograms as proposed may provide a favorable and accurate prognostic survival prediction in AITL.

Enhancement of the International prognostic index with ß2-microglobulin, platelet count and red blood cell distribution width: a new prognostic model for diffuse large B-cell lymphoma in the rituximab era.

BACKGROUND: This study aimed to propose a new user-friendly, cost effective and robust risk model to facilitate risk stratification for diffuse large B-cell lymphoma (DLBCL) treated with frontline R-CHOP regimens. METHODS: Data on 998 patients with de novo DLBCL diagnosed between Jan 1st, 2005 and Dec 31st, 2018 at our center, who received frontline R-CHOP or R-CHOP-like regimens, were retrospectively collected. Patients were randomly divided into the training cohort (n = 701) and the validation cohort (n = 297). A new prognostic model for overall survival (OS) was built based on the training cohort. The performance of the new model was compared with International prognostic index (IPI), revised IPI (R-IPI) and National Comprehensive Cancer Network (NCCN)-IPI (NCCN-IPI). The new model was validated in the validation cohort. RESULTS: The multivariate analysis of the training cohort showed that the IPI, ß2-microglobulin, platelet count and red blood cell distribution width were independent factors for OS, which were incorporated into the new prognostic model. Patients were stratified into low risk, low-intermediate risk, high-intermediate risk, high risk and very high risk groups, with distinct survival outcomes. The new model achieved good C-indexes for 5-year OS prediction of 0.750 (95%CI 0.719-0.781) and 0.733 (95%CI 0.682-0.784) in the training and validation cohorts, respectively, and displayed well-fitted calibration curves. The C-index and the time-dependent ROC analysis demonstrated better performance of the new model than the IPI, R-IPI and NCCN-IPI in both training and validation cohorts. The integrated Brier score for predicting 5-year OS of the new model was lower than that of the IPI, R-IPI and NCCN-IPI in both cohorts, and decision curve analysis also showed a higher net benefit, indicating the superiority of the new model over the conventional models. CONCLUSION: The new prognostic model might be a useful predictive tool for DLBCL treated with R-CHOP regimens. Further external validation is warranted.

Associations between depressive symptoms and sleep duration for predicting cardiovascular disease onset: A prospective cohort study.

BACKGROUND: The joint effects of depressive symptoms and sleep on the risk of cardiovascular disease (CVD) are not well understood. The purpose of this study was to assess the combined impact of depressive symptoms and sleep duration on the incidence of CVD among middle-aged and older Chinese individuals. METHODS: Data were from the China Health and Longitudinal Study conducted in 2013, 2015, and 2018. A total of 9595 participants aged ≥ 45 years without a history of CVD in 2013 were included. Depressive symptoms were measured using the 10-item Center for Epidemiological Studies Depression scale (elevated depressive symptoms cutoff ≥ 10). Average sleep duration was self-reported. Logistic regression analyses adjusted for age, sex, marital status, education and other potential confounders were conducted. RESULTS: In total, 1072 (11.2%) participants reported CVD incidents over the 5-year period. Elevated depressive symptoms (OR = 1.49, 95% CI = 1.30-1.72) and short sleep duration (OR = 1.21, 95% CI = 1.05-1.40) were independently associated with an increased CVD risk in the fully adjusted model. Individuals with short sleep duration/low depressive symptoms (OR = 1.34, 95% CI = 1.12-1.60), short sleep duration/elevated depressive symptoms (OR = 1.70, 95% CI = 1.41-2.50), or long sleep duration/elevated depressive symptoms (OR = 2.13, 95% CI = 1.38-3.27) were more likely to develop CVD than those with normal sleep duration/low depressive symptoms. LIMITATIONS: Depressive symptoms and sleep duration were self-reported. CONCLUSIONS: A stronger risk of CVD was found when depressive symptoms and short or long sleep durations occurred together, suggesting that an integrated approach to sleep and depressive symptoms might be a feasible strategy for the prevention of CVD.

Anti-PD1/PDL1 IgG subclass distribution in ten cancer types and anti-PD1 IgG4 as biomarker for the long time survival in NSCLC with anti-PD1 therapy.

BACKGROUND: Antibodies targeting programmed cell death-1(PD1) and its ligand (PDL1) have revolutionized cancer therapy. However, little is known about the preexisted anti-PD1/PDL1 autoantibodies (AAbs) distribution in multiple cancer types, nor is their potential biomarker role for anti-PD1 therapy. METHOD: Plasma anti-PD1/PDL1 AAb IgG and subclasses (IgG1-4) were detected by enzyme-linked immune sorbent assay (ELISA) in 190 cancer patients, covering 10 cancer types (lung, breast, esophageal, colorectal, liver, prostatic, cervical, ovarian, gastric cancers and lymphoma), the comprehensive correlation of AAbs with multiple clinical parameters was analyzed. We further tested these AAbs in 76 non-small cell lung cancer (NSCLC) samples receiving anti-PD1 therapy, the association of AAbs level with survival was analyzed and validated in an independent cohort (n = 32). RESULTS: Anti-PD1/PDL1 AAb IgG were globally detected in 10 types of cancer patients. IgG1 and IgG2 were the major subtypes for anti-PD1/PDL1 AAbs. Correlation analysis revealed a distinct landscape between various cancer types. The random forest model indicated that IgG4 subtype was mostly associated with cancer. In discovery cohort of 76 NSCLC patients, high anti-PD1 IgG4 was associated with a reduced overall survival (OS, p = 0.019), not progression-free survival (PFS, p = 0.088). The negative association of anti-PD1 IgG4 with OS was validated in 32 NSCLC patients (p = 0.032). CONCLUSION: This study reports for the first time the distribution of preexisted anti-PD1/PDL1 AAb IgG and subclasses across 10 cancer types. Moreover, the anti-PD1 AAb IgG4 subclass was identified to associate with OS, which may serve as a potential biomarker for anti-PD1 therapeutic survival benefit in NSCLC patients.

The changing landscape of anti-lung cancer drug clinical trials in mainland China from 2005 to 2020.

BACKGROUND: In recent years, new drug development on lung cancer is in full swing in China. The aim of this study was to overview the changing landscape of anti-lung cancer drug clinical trials in mainland China from 2005 to 2020. METHODS: We analysed anti-lung cancer drug clinical trials registered on three websites including the China National Medical Products Administration Centre for Drug Evaluation platform, the Chinese Clinical Trial Registry and ClinicalTrials.gov. FINDINGS: A total of 1595 anti-lung cancer drug clinical trials from Jan 1st, 2005 to Dec 31st, 2020 were extracted, which included 630 (39•5%) investigator-initiated trials (IITs), 698 (43•8%) domestic industry-sponsored trials (ISTs), and 267 (16•7%) international ISTs. During the past 16 years, the number of anti-lung cancer clinical trials including IITs and domestic ISTs had a remarkable growth, however, the number of international ISTs increased slowly. The number of principal clinical trial units also increased significantly over time. Of the 1595 trials, the largest growth was observed in phase I trials during 2013-2020, with an average annual growth rate of 38•6%. 278 trials were led by principal investigators (PI) from Guangdong, followed by Beijing (n=273) and Shanghai (n=257). Among the 965 ISTs, clinical trials involving targeted drugs (588, 60•9%) accounted for the largest proportion, followed by immunotherapeutic drugs (284, 29•4%), cytotoxic drugs (75, 7•8%), and traditional Chinese medicine (18, 1•9%). In terms of targeted drugs, EGFR-TKIs remained the most studied drugs (225/588, 38•27%). As for immunotherapy, 125 out of 284 (44•01%) trials involved PD-1 inhibitors, 60 (21•13%) trials involved PD-L1 inhibitors, and seven (2•46%) trials involved CTLA-4 inhibitors. INTERPRETATION: In the past 16 years, the development of anti-lung cancer drug clinical trials has achieved much progress in mainland China. The most progress lied in targeted therapy and immunotherapy. FUNDING: This work was financially supported in part by China National Major Project for New Drug Innovation (2017ZX09304015) and Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001).

High PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor in urothelial carcinoma.

Aims: To explore the prognostic value of high PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (TIIC) in urothelial carcinoma (UC). Patients & methods: 162 UC specimens were evaluated for PD-L1 expression on TIIC and TC with the SP263 assay. High PD-L1 expression was defined as ≥25% staining. Results: High PD-L1 expression on TC in UC patients with stage T1-4 disease was associated with poor overall survival. However, high PD-L1 expression on TIIC in UC patients with stage T1-4 disease revealed favorable disease-free and overall survival; more significant differences were observed in patients with stages T2-4. Multivariate analysis revealed that high PD-L1 expression on TIIC was an independent prognostic predictor for better disease-free and overall survival. Conclusion: High PD-L1 expression on TIIC, but not on TC, is a favorable prognostic factor in UC.

Lay abstract Bladder cancer is the tenth most common form of cancer worldwide, and urothelial carcinoma is the most common type of bladder cancer. PD-L1 is a protein that can be expressed on the surface of many tissue types, including tumor cells (TC) and tumor-infiltrating immune cells (TIIC). PD-L1 can help the tumor evade the body's natural immune defense system. The expression of PD-L1 not only related to the response of immunotherapy but is also associated with the prognosis in bladder cancer. However, the prognostic significance of PD-L1 expression on TC and TIIC remains controversial. This study drew a conclusion that high PD-L1 expression on TIIC, but not on TC, is a favorable prognostic factor in urothelial carcinoma.

Minimal Residual Disease and Survival Outcomes in Patients with Mantle Cell Lymphoma: a systematic review and meta-analysis.

Background: Minimal residual disease (MRD) has shown the prognostic value in mantle cell lymphoma (MCL). To quantify the relationships between progression free survival (PFS) and overall survival (OS) with MRD status in MCL, we conducted this meta-analysis. Methods: We searched databases including Pubmed, Embase, Web of Science and the Cochrane Library up to July 15th, 2020. Data of patients' characteristics, MRD assessment and survival outcomes were extracted and analyzed. Results: Ten articles were included. For the impact of post-induction MRD status on survival outcomes, MRD positive status was associated with worse PFS (HR=1.44; 95%CI 1.27-1.62; P<0.00001) and OS (HR=1.30; 95%CI 1.03-1.64; P=0.03) compared with MRD negative status. Regarding the impact of post-consolidation MRD status on survival outcomes, MRD positivity predicted shorter PFS (HR=1.84; 95%CI 1.49-2.26; P<0.00001) and OS (HR=2.38; 95%CI 1.85-3.06; P<0.00001) than MRD negativity. Conclusions: This study indicated that MRD positivity after induction and consolidation treatments was associated with worse PFS and OS for MCL. MRD-based treatment strategies should be further explored in clinical trials and real-world practice.

R-CHOP immunochemotherapy plus surgery is associated with a superior prognosis in Chinese primary intestinal diffuse large B-cell lymphoma.

AIM: The aim of the study was to compare the therapeutic strategies and prognostic factors of patients with primary intestinal diffuse large B-cell lymphoma (PI-DLBCL). METHODS: A total of 50 PI-DLBCL patients who accepted standard first-line treatment at National Cancer Center in China were included in this retrospective study. Survival analysis was performed to evaluate the prognostic risk factors. RESULTS: The 3-year overall survival (OS) and 3-year progression-free survival (PFS) for the entire group were 76.0% and 65.9%, respectively. Univariate analysis showed that B symptom, advanced Lugano stage, elevated LDH status, poor ECOG PS and immunochemotherapy alone were significantly correlated with a poor PFS. Elevated LDH status, poor ECOG PS, advanced Lugano stage, high IPI score and immunochemotherapy alone were significantly correlated with a poor OS. Multivariate analysis revealed that ECOG PS (P= 0.035; HR = 0.233; 95% CI, 0.060-0.905), LDH level (P = 0.010; HR = 0.223; 95% CI, 0.072-0.693) and surgery (P = 0.002; HR = 5.584; 95% CI, 1.883-16.563) were independent prognostic factors for OS. LDH level (P = 0.035; HR = 0.210; 95% CI, 0.049-0.894) and surgery (P = 0.003; HR = 6.410; 95% CI, 1.903-21.593) were independent risk factors for PFS in PI-DLBCL. R-CHOP immunochemotherapy combined surgery treatment was also associated with a lower rate of refractory/relapsed (R/R) disease (P = 0.004). Furthermore, stratified analysis revealed that partial resection or radical resection combined with immunochemotherapy had no significantly difference which affect OS (P = 0.338) and PFS (P = 0.207). CONCLUSION: R-CHOP immunochemotherapy plus surgery was associated with a superior prognosis compared with R-CHOP alone in Chinese PI-DLBCL population.

Pretreatment body mass index and clinical outcomes in cancer patients following immune checkpoint inhibitors: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to evaluate the association between pretreatment body mass index (BMI) and clinical outcomes in cancer patients treated with immune checkpoint inhibitors (ICIs). METHODS: Systematical searches of PubMed, Embase, and the Cochrane Library databases were carried out. Studies reporting on the association between BMI and outcomes of ICIs were included. The intended outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and immune-related adverse events (irAEs). Quantitative analyses and dose-response meta-analyses were performed under random effect models. RESULTS: Twenty-two eligible studies involving 5686 cancer patients treated with ICIs were identified. Compared to those with lower BMI, patients with higher BMI obtained a significant benefit on OS (HR = 0.698, 95% CI 0.614-0.794, P < 0.001; I2 = 45.9%) and PFS (HR = 0.760, 95% CI 0.672-0.861, P < 0.001; I2 = 37.9%). Most stratified analyses for OS and PFS also showed similar pooled risk estimates. For an increment of every 5 kg/m2 in BMI, the risk for death reduced by approximately 15.6% (HR = 0.844, 95% CI 0.752-0.945, P = 0.003). Moreover, patients with higher BMI had a remarkably better ORR (OR = 0.468, 95% CI 0.263-0.833, P = 0.010; I2 = 73.6%) than that of those with lower BMI. However, no statistically significant differences were found in the incidence of any grade irAEs (P = 0.073) and ≥ 3 grade irAEs (P = 0.105) between higher and lower BMI. CONCLUSION: Higher BMI is significantly associated with improved outcomes in patients treated with ICIs. Further large-scale prospective research is warranted to better illuminate the association between BMI and outcomes from ICIs.

Autoantibody profiling identifies predictive biomarkers of response to anti-PD1 therapy in cancer patients.

Background: Programmed cell death protein 1 (PD1) inhibitors have revolutionized cancer therapy, yet many patients fail to respond. Thus, the identification of accurate predictive biomarkers of therapy response will improve the clinical benefit of anti-PD1 therapy. Method: We assessed the baseline serological autoantibody (AAb) profile against ~2300 proteins in 10 samples and ~4600 proteins in 35 samples with alveolar soft part sarcoma (ASPS), non-small-cell lung cancer (NSCLC) and lymphoma using Nucleic Acid Programmable Protein Arrays (NAPPA). 23 selected potential AAb biomarkers were verified using simple, affordable and rapid enzyme linked immune sorbent assay (ELISA) technology with baseline plasma samples from 12 ASPS, 16 NSCLC and 46 lymphoma patients. SIX2 and EIF4E2 AAbs were further validated in independent cohorts of 17 NSCLC and 43 lymphoma patients, respectively, using ELISA. The IgG subtypes in response to therapy were also investigated. Results: Distinct AAb profiles between ASPS, NSCLC and lymphoma were observed. In ASPS, the production of P53 and PD1 AAbs were significantly increased in non-responders (p=0.037). In NSCLC, the SIX2 AAb was predictive of response with area under the curve (AUC) of 0.87, 0.85 and 0.90 at 3 months, 4.5 months, 6 months evaluation time points, respectively. In the validation cohort, the SIX2 AAb was consistently up-regulated in non-responders (p=0.024). For lymphoma, the EIF4E2 AAb correlated with a favorable response with AUCs of 0.68, 0.70, and 0.70 at 3 months, 4.5 months, and 6 months, respectively. In the validation cohort, the AUCs were 0.74, 0.75 and 0.66 at 3 months, 4.5 months, and 6 months, respectively. The PD1 and PD-L1 IgG2 AAbs were highly produced in ~20% of lymphoma responders. Furthermore, bioinformatics analysis revealed antigen functions of these AAb biomarkers. Conclusion: This study provides the first evidence that AAb biomarkers selected using high-throughput protein microarrays can predict anti-PD1 therapeutic response and guide anti-PD1 therapy.

Diagnostic value of serum glypican-3 alone and in combination with AFP as an aid in the diagnosis of liver cancer.

BACKGROUND: Recently, a series of studies have been published to examine the possible diagnostic and prognostic values of glypican-3 (GPC3) in liver cancer with conflicting results observed. Thus, the present study aimed to assess the values of preoperative serum GPC3 alone and in combination with AFP for the diagnosis of liver cancer. METHODS: An enzyme-linked immunoassay was used to quantify serum GPC3 in hepatocellular carcinoma group (HCC, n = 210), intrahepatic cholangiocarcinoma group (ICC, n = 36), combined hepatocellular cholangiocarcinoma group (cHCC-CC, n = 8), metastatic liver cancer group (MLC, n = 10) and normal controls (NC, n = 134). RESULTS: The area under the curve (AUC) of GPC3 for HCC versus NC was 0.879, with a sensitivity of 79.52% at an optimal cutoff value of 0.0414 ng/mL; when GPC3 was combined with AFP, the AUC and sensitivity were increased to 0.925 and 88.10%, respectively. In addition, 43 of 68 AFP-negative patients had elevated GPC3 levels. Furthermore, the positive rate of GPC3 was significantly higher than the that of AFP for HCC in early stage. CONCLUSIONS: Serum GPC3 was superior to AFP for the diagnosis of early-stage HCC, and may be complementary to AFP for distinguishing HCC from NC.

Development and Validation of a Novel Risk Stratification Model for Cancer-Specific Survival in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogenous disease. Identifying more precise and individual survival prognostic models are still needed. This study aimed to develop a predictive nomogram and a web-based survival rate calculator that can dynamically predict the long-term cancer-specific survival (CSS) of DLBCL patients. A total of 3,573 eligible patients with DLBCL from 2004 to 2015 were extracted from the Surveillance, Epidemiology and End Results (SEER) database. The entire group was randomly divided into the training (n = 2,504) and validation (n = 1,069) cohorts. We identified six independent predictors for survival including age, sex, marital status, Ann Arbor stage, B symptom, and chemotherapy, which were used to construct the nomogram and the web-based survival rate calculator. The C-index of the nomogram was 0.709 (95% CI, 0.692-0.726) in the training cohort and 0.700 (95% CI, 0.671-0.729) in the validation cohort. The AUC values of the nomogram for predicting the 1-, 5-, and 10- year CSS rates ranged from 0.704 to 0.765 in both cohorts. All calibration curves revealed optimal consistency between predicted and actual survival. A risk stratification model generated based on the nomogram showed a favorable level of predictive accuracy compared with the IPI, R-IPI, and Ann Arbor stage in both cohorts according to the AUC values (training cohort: 0.715 vs 0.676, 0.652, and 0.648; validation cohort: 0.695 vs 0.692, 0.657, and 0.624) and K-M survival curves. In conclusion, we have established and validated a novel nomogram risk stratification model and a web-based survival rate calculator that can dynamically predict the long-term CSS in DLBCL, which revealed more discriminative and predictive accuracy than the IPI, R-IPI, and Ann Arbor stage in the rituximab era.

Changes in Expression of Multiple Checkpoint Molecules and Infiltration of Tumor Immune Cells after Neoadjuvant Chemotherapy in Gastric Cancer.

It remains unclear that how tumor immune micro-environment will change following neoadjuvant chemotherapy (NACT) in locally advanced gastric cancer (LAGC). In this study, we aimed to characterize the changes in tumor-infiltrating immune cells and checkpoint molecules following NACT and investigate the prognostic value of these changes in LAGC. Paired tumor samples (pre-NACT and post-NACT) of 60 patients were retrospectively identified and analyzed by multiplex immunohistochemistry with a panel including CD4, CD8, FOXP3, PD-1, PD-L1, and TIM3. Following NACT, the overall median expression levels of CD4, CD8, PD1, PD-L1 and TIM3 were significantly increased (P = 0.008 for PD-L1 and P < 0.001 for all the other markers), while the median FOXP3 expression level remained stable (P = 0.120). Individually, the majority of patients presented increased expression of the markers, while 8.5%, 11.9%, 16.9%, 25.4%, 22.0% and 42.2% of patients had decreased expression of CD4, CD8, PD-1, PD-L1, TIM3 and FOXP3, respectively. Changes in expression between baseline and post-NACT of TIM3, PD-1, and PD-L1 showed strongly positive pairwise correlations with each other (P < 0.001). Multivariate analysis demonstrated that high upregulation levels of CD8 (HR = 0.73, P = 0.028), PD-1 (HR = 0.76, P = 0.027), and PD-L1 (HR = 0.67, P = 0.038) following NACT were beneficial prognostic factors of OS. NACT increase the expression of multiple checkpoint molecules and infiltration of CD4+, CD8+ immune cells in LAGC with the levels of changes in checkpoint molecules positively related with each other. This may raise the possibility of applying immunotherapy with chemotherapy or even dual checkpoint inhibitors in LAGC.