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With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK), and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; p

The aim of this study was to explore predictors and construct a nomogram for risk stratification in primary extragastric mucosa-associated lymphoid tissue (MALT) lymphoma.Extragastric MALT lymphoma cases newly diagnosed between November 2010 and April 2020 were assessed to construct a progression-free survival (PFS)-related nomogram. We also performed external validation of the nomogram in an independent cohort.We performed multivariate analyses of 174 patients from 3 hospitals who were included in the training cohort. Stage, hepatitis B virus surface antigen (HBsAg) status, and Ki67 expression were significantly associated with PFS. These three factors were used to construct a nomogram, which was shown to have a C-index of 0.89. Two risk groups (low risk and high risk) were identified by the prognostic model. The 5-year PFS was 98.9% for the low-risk group and 69.3% for the high-risk group (p 0.001). The overall survival (OS) could also be effectively distinguished by the nomogram, resulting in an OS of 100% for the low-risk group and 94.6% for the high-risk group (p = 0.01). These results were validated and confirmed in an independent cohort with 165 patients from another three hospitals. The 5-year PFS rates were 94.8% and 66.7% for the low-risk and high-risk groups, respectively (p 0.001). The 5-year OS rates were 97.9% and 88.4%, respectively (p = 0.016).The nomogram could well distinguish the prognosis of low- and high-risk patients with extragastric MALT lymphoma and is thus recommended for clinical use.

The outcomes of patients with diffuse large B-cell lymphoma (DLBCL) vary widely, and about 40% of them could not be cured by the standard first-line treatment, R-CHOP, which could be due to the high heterogeneity of DLBCL. Here, we aim to construct a prognostic model based on the genetic signature of metabolic heterogeneity of DLBCL to explore therapeutic strategies for DLBCL patients. Clinical and transcriptomic data of one training and four validation cohorts of DLBCL were obtained from the GEO database. Metabolic subtypes were identified by PAM clustering of 1,916 metabolic genes in the 7 major metabolic pathways in the training cohort. DEGs among the metabolic clusters were then analyzed. In total, 108 prognosis-related DEGs were identified. Through univariable Cox and LASSO regression analyses, 15 DEGs were used to construct a risk score model. The overall survival (OS) and progression-free survival (PFS) of patients with high risk were significantly worse than those with low risk (OS: HR 2.86, 95%CI 2.04–4.01, p < 0.001; PFS: HR 2.42, 95% CI 1.77–3.31, p < 0.001). This model was also associated with OS in the four independent validation datasets (GSE10846: HR 1.65, p = 0.002; GSE53786: HR 2.05, p = 0.02; GSE87371: HR 1.85, p = 0.027; GSE23051: HR 6.16, p = 0.007) and PFS in the two validation datasets (GSE87371: HR 1.67, p = 0.033; GSE23051: HR 2.74, p = 0.049). Multivariable Cox analysis showed that in all datasets, the risk model could predict OS independent of clinical prognosis factors (p < 0.05). Compared with the high-risk group, patients in the low-risk group predictively respond to R-CHOP (p = 0.0042), PI3K inhibitor (p < 0.05), and proteasome inhibitor (p < 0.05). Therefore, in this study, we developed a signature model of 15 DEGs among 3 metabolic subtypes, which could predict survival and drug sensitivity in DLBCL patients.

Background The high heterogeneity of de novo metastatic nasopharyngeal carcinoma (dmNPC) makes its prognosis and treatment challenging. We aimed to accurately stage dmNPC and assess the patterns of treatment strategies for different risk groups. Methods The study enrolled a total of 562 patients, 264 from 2007 to 2013 in the training cohort and 298 from 2014 to 2017 in the validation cohort. Univariate and multivariate Cox regression analyses were conducted to determine the independent variables for overall survival (OS). Recursive partitioning analysis (RPA) was applied to establish a novel risk-stratifying model based on these variables. Results After pairwise comparisons of OS, three risk groups were generated: low-risk (involved lesions ≤ 4 without liver involvement), intermediate-risk (involved lesions ≤ 4 with liver involvement or involved lesions > 4 with Epstein–Barr virus (EBV)-DNA 4 with EBV-DNA > 62,000 copies/ml). The 3-year OS rate differed significantly between groups (80.4%, 42.0%, and 20.4%, respectively, all P P = 0.0032 and P = 0.0014, respectively). However, it provided no survival benefits for the high-risk group (P = 0.6). Patients did not benefit from concurrent chemotherapy during LRRT among the three subgroups (P = 0.12, P = 0.13, and P = 0.3, respectively). These results were confirmed with the validation cohort. Conclusions The novel RPA model revealed superior survival performance in subgroup stratification and could facilitate more effective treatment strategies for dmNPC.

Purpose Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare form of extranodal DLBCL. In this study, we aimed to determine the patterns of relapse and the optimal treatment strategy for PB-DLBCL in the rituximab era. Methods We retrospectively collected data from Chinese Southwest Oncology Group-affiliated institutes. Patients diagnosed with PB-DLBCL from 2008 to 2019 and treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) or R-CHOP-like regimens were included. Results A total of 135 PB-DLBCL patients treated with R-CHOP or R-CHOP-like regimens were eligible for this study. With a median follow-up of 43 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 84.7% and 69.6%, respectively. Continuous treatment failure was observed, especially affecting the breast and central nervous system (CNS). Consolidative RT significantly reduced the risk of breast relapse (p = 0.013). Relapse in CNS were detected in 13 (9.6%) patients, of whom 4 had received intrathecal prophylaxis and 9 had not received CNS prophylaxis. None of the patients who received high-dose methotrexate (HD-MTX) had CNS relapse. CNS relapse risk was reduced by HD-MTX (p = 0.036). Furthermore, we screened the genetic mutation profile of PB-DLBCL and found that MYD88 and/or CD79B mutations were present in all patients with CNS relapse, whereas patients with MYD88 and/or CD79B mutations who received HD-MTX did not experience CNS relapse. Conclusions Our results indicate that consolidative RT decreased the risk of breast relapse. Prophylactic HD-MTX reduced the risk of CNS relapse, especially in patients with MYD88/CD79B mutations.

Limei Zhang,1,2,&ast; He Huang,1,3,&ast; Zhao Wang,1,3,&ast; Xiaojie Fang,1,3 Huangming Hong,4 Yungchang Chen,4 Fangfang Li,1,3 Yuyi Yao,1,3 Zegeng Chen,1,3 Fei Pan,1,3 Xiaoqian Li,1,3 Meiting Chen,1,3 Robert Peter Gale,5 Yang Liang,1,2,&ast; Tongyu Lin1,3,4,&ast; 1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 2Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, People’s Republic of China; 3Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, People’s Republic of China; 4Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 5Department of Immunology and Inflammation, Haematology Research Centre, Imperial College London, London, UK&ast;These authors contributed equally to this workCorrespondence: Tongyu LinDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of ChinaEmail linty@sysucc.org.cnYang LiangDepartment of Hematologic Oncology, Sun Yat-sen University Cancer, State Key Laboratory of Oncology in South China, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of ChinaEmail liangyang@sysucc.org.cnBackground: The management of primary intestinal diffuse large B cell lymphoma (PI-DLBCL) in elderly patients (aged > 60 years) remains controversial. We conducted a retrospective study to assess the efficacy of different treatment strategies and prognostic factors for elderly Chinese patients with PI-DLBCL.Patients and Methods: Forty-six untreated elderly patients with PI-DLBCL were included in this retrospective study. Twenty-four patients were treated with surgery (prior to chemotherapy) plus chemotherapy (SCT). The other 22 patients did not undergo surgery before chemotherapy (CT).Results: Patients treated with SCT had a higher overall response rate of 91.7% than patients receiving CT, but the difference between groups was not significant (P=0.581). Regarding survival, SCT resulted in a greater 3-year overall survival (OS) rate (87.3% vs 56.9%, P=0.130) and significantly higher 3-year event-free survival (EFS) rate (74.1% vs 27.3%, P=0.002) than CT. The univariate analysis showed that male sex, advanced Lugano stage, poor performance status and chemotherapy alone were associated with a shorter EFS. Only the male sex was correlated with a shorter OS. The multivariate analysis showed that sex (P=0.040) and treatment strategy (P=0.022) were independent prognostic factors for EFS.Conclusion: Surgery plus chemotherapy produced a better outcome for EFS, but not OS, than chemotherapy alone in elderly Chinese patients with PI-DLBCL.Keywords: PI-DLBCL, surgery, chemotherapy, survival, prognostic factors

Stomach hemorrhage and perforation are very severe and common complications in patients with primary gastric diffuse large B-cell lymphoma (PG-DLBCL) during treatment with immunochemotherapy. However, no relevant clinical studies have been performed on the prevention of these serious complications.Patients diagnosed with PG-DLBCL were enrolled in this retrospective study. The prevention group received standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) treatment without prednisone combined with antacids and anti-Helicobacter pylori (Hp) therapy. These patients received R-CHOP-based treatment until the complete recovery of gastric ulcers, as proven by gastroscopy. The control group received a standard R-CHOP regimen. Toxicity and survival were the main endpoints.A total of 52 patients received preventative treatment, while 146 patients did not. Among patients with stage I, II-1, and II-2 disease, the prevention group had a lower rate of hemorrhage and perforation (0/40) than the control group (10/78, p = 0.044). At a median follow-up time of 25 months, the 5-year event-free survival (EFS) rates were 97.1% in the prevention group and 66.1% in the control group (p = 0.025), and the 5-year overall survival (OS) rates were 100% and 72.0%, respectively (p = 0.021). However, the differences in the 5-year EFS and OS of patients with disseminated disease were not statistically significant.Preventative treatment can decrease the risk of hemorrhage and perforation in patients with localized PG-DLBCL during immunochemotherapy, leading to better EFS and OS in these patients. However, preventative treatment failed to reduce the risk of gastric hemorrhage and perforation and did not improve survival (EFS and OS) in advanced-stage patients.

Background Lymphoepithelioma-like carcinoma (LELC) is a rare and unique subtype of cancer that histologically resembles undifferentiated nasopharyngeal carcinoma (NPC). The population-based analysis of LELC and the optimal treatment remains unclear. Materials and methods This real-world, retrospective study investigated 770 patients with LELC for primary site, treatment, and survival outcomes from 2005 to 2019 from five cancer centres in China. The overall survival (OS) of different subgroups was appraised by log-rank tests and Kaplan–Meier analysis. Results Primary sites LELC included the lung (597 cases, 77.5%), salivary gland (115 cases, 14.9%), and others. The median progression-free survival (PFS) of LELC patients was 47.4 months. The median overall survival (OS) was not reached. The 5-year survival rate for LELC patients was 77.8%. Most patients in stages I and II received surgery. The majority of patients in stage III received surgery and radiotherapy. More than half of the patients in stage IV received chemotherapy. Among relapsed or metastatic cases receiving chemotherapy, patients who received immunotherapy at any time presented with a superior OS than those without immunotherapy (P P Conclusion Our data provide treatment patterns and outcomes for LELC from various primary sites. Randomized controlled studies are necessary to further define the standard of care for patients with LELC. Trial registration This clinical trial was registered at ClinicalTrials.gov (No. NCT04614818).

Whether primary tumor surgery is better than no surgery in patients with de novo stage IV breast cancer remains controversial. This study combined prospective clinical trials and a multicenter cohort to evaluate the impact of locoregional surgery in de novo stage IV breast cancer. The GRADE approach was used to assess the quality of evidence in meta-analysis, and propensity score matching analysis was used in the cohort study. This study was registered with PROSPERO CRD42016043766 and ClinicalTrials.gov NCT04456855. A total of 1110 patients from six trials and 353 patients from the cohort study were included. The meta-analysis showed that compared with no surgery, locoregional surgery did not prolong overall survival (hazard ratio [HR] = 0.90, P = 0.40; moderate-quality) but had a significantly longer locoregional progression-free survival (HR = 0.23, P

Purpose To assess the efficacy and safety of cyclin-dependent kinases 4 and 6 inhibitors (CDKi) combined with endocrine therapy (ET) in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and compare the efficacy of different CDKi (palbociclib, ribociclib, or abemaciclib). Materials and Methods This study based on randomized Phase 2 or 3 trials of CDKi plus ET compared with placebo plus ET for women with HR+/HER2-ABC and identify relevant randomized clinical trials (RCTs) published prior to February 2020. The primary endpoint was progression-free survival (PFS), the secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit response (CBR) and safety. The PROSPERO registry number is 42018081105. Results The results from eight trials including 4580 participants were pooled. Evidence indicated that the PFS of CDKi group was significantly prolonged (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.50-0.60, P < 0.01) compared with placebo group. The ORR and CBR were better (risk ratio [RR] 1.47, 95% CI 1.30-1.67, P < 0.01; 1.24, 95% CI 1.15-1.35, P < 0.01) in the CDKi group. The OS of CDKi group (HR 0.75, 95% CI 0.67-0.85, P < 0.01) was significantly longer than ET alone. Subgroup analyses confirmed that the benefit was consistent across most subgroups. Subgroup analyses showed no statistically significant difference of PFS among three CDKi: palbociclib vs ribociclib (HR 0.55, 95% CI 0.49-0.60, P = 0.34), palbociclib vs abemaciclib (HR 0.53, 95% CI, 0.47-0.59, P = 0.61), and ribociclib vs abemaciclib (HR 0.56, 95% CI, 0.51-0.62, P = 0.72). Treatment-related grade 3 or 4 hematologic adverse events (AEs) were more frequently in CDKi group. Conclusion CDKi combined with ET can significantly prolong PFS and improve the ORR, CBR and OS in patients with HR+/HER2- ABC. However, the advantage of different CDKi has not been established.

Sio Teng Lam,1,2,* He Huang,1,* Xiaojie Fang,1 Zhao Wang,1 Huangming Hong,3 Quanguang Ren,1 Ying Tian,1 Suxia Lin,4 Tongyu Lin1 1Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China; 2Department of Medical Oncology, Centro Hospitalar Conde De Sao Januario, Macau, People’s Republic of China; 3Department of Medical Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 4Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tongyu LinDepartment of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, People’s Republic of ChinaTel +86-20-87343363Fax +86-20-87343294Email tongyulin@hotmail.comPurpose: Programmed death ligand 1 (PD-L1) has been proposed as an important prognostic factor in many types of cancer. However, the role of predicting the prognosis of PD-L1 in extranodal natural killer/T-cell lymphoma (ENKTL) was controversial. Combining other biomarkers might enhance its predictive power. This study aims to evaluate the prognostic value of PD-L1 in conjunction with tumor-infiltrating FoxP3+Tregs for ENKTL after non-anthracycline-based chemotherapy.Patients and Methods: A total of 81 patients with ENKTL were included in this study. Clinicopathological characteristics were collected, and prognostic significance of PD-L1 in neoplastic cells (nPD-L1) and tumor-infiltrating FoxP3+Tregs were evaluated.Results: Patients with nPD-L1-positive had significantly inferior overall survival (OS) and progression-free survival (PFS) compared with nPD-L1-negative (3-year OS, 37.2% vs 67.3%, p = 0.014; 3-year PFS, 31.0% vs 61.8%, p =0.010, respectively). Patients who had low FoxP3+Tregs had significantly inferior OS and PFS compared with high FoxP3+Tregs (3-year OS, 36.4% vs 63.0%, p = 0.004; 3-year PFS, 31.7% vs 56.3%, p = 0.020, respectively). The results of multivariate analysis showed that nPD-L1 positivity (HR 6.629, 95% CI 1.966– 22.350, p=0.002) and low FoxP3+Tregs (HR 7.317, 95% CI 2.154– 24.855, p=0.001) were independent predictors of inferior OS. Using these 2 variables, we constructed a new prognostic model that singled out 3 groups with different risk profiles: group 1, no adverse factors; group 2, 1 adverse factor; and group 3, 2 adverse factors. The 3-year OS rates of group 1, group 2, and group 3 were 93.3%, 46.6% and 20.8%, respectively (p< 0.001), and the 3-year PFS rates were 86.7%, 40.8% and 15.0%, respectively (p=0.001).Conclusion: This study is the first to validate the prognostic value of nPD-L1 and tumor-infiltrating FoxP3+Tregs in ENKTL; the new immunological prognostic model might be used to stratify ENKTL patients in clinical trials for new therapeutic strategies.Keywords: extranodal natural killer/T-cell lymphoma, PD-L1, FoxP3+Tregs, prognosis

Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment. Herein, we find that overexpression of Rac1 is associated with multi-drug resistance to the neoadjuvant chemotherapy (NAC). Mechanistically, Rac1 activates aldolase A and ERK signaling which up-regulates glycolysis and especially the non-oxidative pentose phosphate pathway (PPP). This leads to increased nucleotides metabolism which protects breast cancer cells from chemotherapeutic-induced DNA damage. To translate this finding, we develop endosomal pH-responsive nanoparticles (NPs) which deliver Rac1-targeting siRNA together with cisplatin and effectively reverses NAC-chemoresistance in PDXs from NAC-resistant breast cancer patients. Altogether, our findings demonstrate that targeting Rac1 is a potential strategy to overcome acquired chemoresistance in breast cancer., Acquired resistance to chemotherapy can lead to multi-drug resistance and poor prognosis in cancer. Here, the authors show that Rac1 increases glycolysis and non-oxidative pentose phosphate pathway activity leading to neoadjuvant chemotherapy (NAC) resistance, thus its inhibition sensitizes resistant breast cancer PDXs to NAC.

To determine whether inflammatory markers, derived neutrophil-to-lymphocyte ratio (dNLR), haemoglobin/platelet ratio (HPR) or platelet/lymphocyte ratio (PLR) are predictive for prognosis in angioimmunoblastic T-cell lymphoma (AITL), we derived dNLR, HPR and PLR values for 110 AITL patients and appropriate cut-off point values to define overall survival (OS) and progression-free survival (PFS). dNLR ≥ 2·2, HPR ≥ 0·4 or PLR < 100 were significant factors for shorter OS and PFS. On univariate analysis, these three parameters were significantly associated with worse OS and PFS. On multivariate analysis, only dNLR remained a significant, independent prognostic factor for both OS and PFS.

Purpose Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone administered every 3 weeks (R-CHOP-21) is the standard care for diffuse large B-cell lymphoma (DLBCL). It is unknown whether the dose-dense R-CHOP (R-CHOP-14) could improve the outcome of the disease in Asian population. Materials and Methods Newly diagnosed DLBCL patients were centrally, randomly assigned (1:1) to receive R-CHOP- 14 or R-CHOP-21. R-CHOP-14 was administered every 2 weeks, and R-CHOP-21 was administered every 3 weeks. Primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS), progression-free survival (PFS), response rate and toxicities. Results Seven hundred and two patients were randomly assigned to receive R-CHOP-14 (n=349) or R-CHOP-21 (n=353). With a median follow-up of 45.6 months, the two groups did not differ significantly in 3-year DFS (79.6% for R-CHOP-14 vs. 83.2% for R-CHOP-21, p=0.311), 3-year OS (77.5% for R-CHOP-14 vs. 77.6% for R-CHOP-21, p=0.903), or 3-year PFS (63.2% for R-CHOP-14 vs. 66.1% for R-CHOP-21, p=0.447). Patients with an International Prognostic Index (IPI) score ≥ 2 had a poorer prognosis compared to those with an IPI score < 2. Grade 3/4 hematologic and non-hematologic toxicities were manageable and similar between R-CHOP-14 and R-CHOP-21. Conclusion R-CHOP-14 did not improve the outcome of DLBCL compared to R-CHOP-21 in Asian population. With manageable and similar toxicities, both of the two regimens were suitable for Asian DLBCL patients. For high-risk patients with IPI ≥ 2, new combination regimens based on R-CHOP deserve further investigation to improve efficacy.

Background Adult sporadic Burkitt lymphoma (BL) is a rare but highly aggressive subtype of lymphoma which lacks its own unique prognostic model. Systemic inflammatory biomarkers have been confirmed as prognostic markers in several types of malignancy. Our objective was to explore the predictive value of pretreatment inflammatory biomarkers and establish a novel, clinically applicable prognostic index for adult patients with sporadic BL. Methods We surveyed retrospectively 336 adult patients with newly diagnosed sporadic BL at 8 Chinese medical centers and divided into training cohort (n = 229) and validation cohort (n = 107). The pretreatment inflammatory biomarkers were calculated for optimal cut-off value. The association between serum biomarkers and overall survival (OS) was analyzed by Kaplan–Meier curves and Cox proportional models. The risk stratification was defined based on normal LDH level, Ann Arbor stage of I and completely resected abdominal lesion or single extra-abdominal mass Results and conclusions Univariate and multivariate analyses revealed that platelets9/L, albumin

Background Burkitt lymphoma (BL) is a highly aggressive, fast-growing B-cell non-Hodgkin's lymphoma, manifested in several subtypes, including sporadic, endemic, and immunodeficiency-related forms, the mechanism of which is still not clear. Abundant evidence reported that KIF15 was involved in the progression of human cancer. The emphasis of this study is to explore the functions of KIF15 in the development of BL. Methods Firstly, tumor and normal tissues were collected for detecting expression of KIF15 in BL. Lentivirus-mediated shRNA knockdown of KIF15 was used to construct BL cell model, which was verified by qRT-PCR and Western Blot. The cell proliferation was detected by CCK8 assay, cell apoptosis and cell cycle were measured through flow cytometry. Transwell assay was conducted to detect the migration. Results We first found that KIF15 is highly expressed in BL. Knockdown of KIF15 can inhibit proliferation and migration, promote apoptosis and arrest the cell cycle. Moreover, KIF15 is involved in BL cell activity through regulating expression of apoptosis-related proteins (Caspase3, Caspase8, HTRA, IGFBP-6, p53, SMAC, sTNF-R1, TNF-β and Bcl-2) and downstream pathways, such as p-Akt, CCND1, CDK6 and PIK3CA. Conclusions These findings justify the search for small molecule inhibitors targeting KIF15 as a novel therapeutic strategy in BL.

PurposePeripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a clinically and biologically heterogeneous disease with poor prognosis. As the role of radiation therapy (RT) is still unclear, we carried out this study to evaluate the potential efficacy of RT in PTCL-NOS.MethodsPatients diagnosed with PTCL-NOS between 2000 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching was used to balance the characteristics between patients who received radiotherapy and those who did not receive radiotherapy. In addition, we validated the findings in an external validation cohort retrospectively recruited from two high-capacity cancer center in China between 2006 and 2016. Kaplan-Meier curves and Cox regression models were used for survival analysis.ResultsOf the 2,768 patients with chemotherapy records in the SEER cohort, 27.6% of 844 patients with early-stage disease and 6.8% of 1,924 patients with advanced-stage disease received RT. The application of RT was significantly associated with an improvement in overall survival (5-year OS rate 58.5 versus 35.1%, P versus 44.0%, P versus 24.4%, P = 0.089; 5-year DSS rate 32.9 versus 31.3%, P = 0.223). After adjustment, a matched cohort of 1,044 patients (348 in the RT combined with CT group and 696 in the CT alone group) was created. And RT was still significantly associated with a survival benefit in the early-stage subset, but not in the advanced-stage disease group. In the validation cohort with more comprehensive data, RT also significantly improved the survival of early-stage PTCL-NOS patients.ConclusionAdding RT was associated with significant improvement in survival in early-stage PTCL-NOS, but the survival benefit of RT was not obvious in advanced-stage disease. The incorporation of RT for treatment in early-stage PTCL-NOS should be highly considered. Further prospective studies with more comprehensive data are needed to evaluate the effectiveness and toxicity of RT in PTCL-NOS.

Background: The clinical benefit of chemotherapy or endocrine therapy maintenance in patients with metastatic breast cancer (MBC) after first-line chemotherapy, specifically hormone receptor (HR) positive MBC patients remain inconclusive. This study aims to comprehensively evaluate the clinical efficacy of chemotherapy or endocrine therapy maintenance in MBC patients. Methods: The meta-analysis of randomized clinical trials (RCTs) and propensity score matched analysis of multicentre cohort study in China were evaluated MBC patients who underwent first-line chemotherapy or endocrine therapy maintenance. The GRADE approach was used to assess quality of evidence in meta-analysis. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Findings: A total of 2,867 patients from 15 RCTs and 760 patients from multicentre cohort were included. The results from meta-analysis showed that chemotherapy maintenance significantly improved PFS (hazard ratio [HR], 0·63; 95% confidence interval (CI) 0·54-0·73; P 0·05). Additionally, treatment effect sizes were greater for OS than for PFS, and a moderate correlation between PFS and OS was identified. Interpretation: This study provided a high evidence for PFS and OS benefits of longer first-line chemotherapy and endocrine therapy maintenance in MBC patients, and there were no difference efficacy between chemotherapy and endocrine therapy maintenance for HR-positive patients. We also suggested that both PFS and OS should be evaluated to determine the effectiveness of maintenance therapy in future clinical trials. Trial Registration: This study is registered with PROSPERO Identifier: CRD42017071858, and ClinicalTrials.gov Identifier: NCT04258163. Funding Statement: This study was supported by grant 2020ZX09201021 from the National Science and Technology Major Project, grant YXRGZN201902 from the Medical Artificial Intelligence Project of Sun Yat-Sen Memorial Hospital, grants 81572596, 81972471, U1601223, 82073408, 81802656, and 82071754 from the National Natural Science Foundation of China, grant 2017A030313828 from the Natural Science Foundation of Guangdong Province, grant 201704020131 from the Guangzhou Science and Technology Major Program, grant 2017B030314026 from the Guangdong Science and Technology Department, grant 2018007 from the Sun Yat-Sen University Clinical Research 5010 Program, grant SYS-C-201801 from the Sun Yat-Sen Clinical Research Cultivating Program, and A2020558 from the Medical Scientific Research Foundation of Guangdong Province. Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: The study protocol was approved by the ethics committee of the Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.

Additional file 1: Table S1. The antibody information for the WB.

Purpose: Metastatic nasopharyngeal carcinoma (mNPC) remains incurable. This prospective study aimed to investigate whether adding cetuximab to cisplatin-based induction therapy could improve efficacy and survival for chemotherapy-naive mNPC patients. Patients and Methods: Eligible chemotherapy-naive mNPC patients were enrolled, including those initially diagnosed with mNPC (IM) and those with first-relapse metastases after radiotherapy (RM). Patients all received induction chemotherapy (IC) including docetaxel and cisplatin plus cetuximab. Those who obtained objective remission after IC would continue to receive radiotherapy concurrent with cetuximab and cisplatin, and further capecitabine as maintenance. Contemporaneous patients who received conventional therapy served as controls. Results: Forty-three patients were enrolled, including 17 IM and 26 RM patients. Thirty-nine (90.7%) patients had WHO III subtype. The overall response and complete response (CR) rates were, respectively, 79.1 and 34.9% after induction therapy and 76.7 and 46.5% after chemoradiotherapy. The 5-year overall survival (OS) and progression-free survival (PFS) rates reached 34.9 and 30%, respectively. Subgroup analysis showed that compared with RM patients, IM patients had a higher 5-year OS (58.8 vs. 19.2%) and PFS (52.9 vs. 19.2%). The IM group had a higher CR rate of induction treatment than the RM group (52.9 vs. 23.1%). No treatment-related death was observed. Twelve patients (27.9%) remained alive with disease-free survival times from 60+ to 135+ months. Control patients showed a substantially lower survival rate (5-year OS, 10.9%) and few long-term survivors. Conclusions: This regimen resulted in significantly improved efficacy and survival, which indicates a potentially curative role for chemotherapy-naive mNPC, especially in newly diagnosed patients. A phase III clinical trial (NCT02633176) is ongoing for confirmation.

In the era of asparaginase-based therapy for extranodal natural killer/T cell lymphoma (ENKTL), the clinical outcomes of ENKTL have notably improved. However, as a rare subtype of ENKTL, the therapeutic effect and prognostic factors of non-nasal type ENKTL remain unclear. Thus, we performed this study to analyze the clinical characteristics and to establish a prognostic model specifically for the non-nasal disease. We performed a retrospective study of consecutive patients newly diagnosed with non-nasal type ENKTL and mainly received asparaginase-based therapy at Sun Yat-sen University Cancer Center (SYSUCC) between January 2011 and December 2019, to analyze the prognostic factors and to propose a prognostic model. We validated the prognostic model in an independent cohort. In total, 98 non-nasal type ENKTL patients were included in the training cohort. Multivariate analyses showed that prognostic factors for OS were elevated LDH levels, involvement of bone marrow and serum total protein (TP) < 60 g/L. We developed a new prognostic model named the non-nasal type ENKTL prognostic index (NPI) by grouping the prognostic factors: group 1, no risk factors; group 2, one risk factor; and group 3, two or three risk factors, which were associated with 3-year OS rates of 84.1% (95% CI, 70.9-97.2), 46.8% (27.7-65.8), and 14.9% (0-32.9), respectively (P < 0.001). These results were validated and confirmed in an independent cohort. The new model is efficient in distinguishing non-nasal-type ENKTL patients with various outcomes in the contemporary era of asparaginase-based therapy.

This study aimed to investigate the optimal time of leucovorin rescue for HDMTX in non-Hodgkin's lymphoma (NHL) patients. Ninety-eight patients treated with HDMTX were randomly assigned to receive leucovorin at either 18 or 24 h after initiation of HDMTX infusion during the first cycle and switched to the other mode in the second cycle. All courses achieved an efficacious MTX concentration. Compared to the 18th hour group, the 24th hour group exhibited an increase in incidence of thrombocytopenia (48% versus 34.7%

Purpose To assess the efficacy and safety of cyclin-dependent kinases 4 and 6 inhibitors (CDKi) combined with endocrine therapy (ET) in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and compare the efficacy of different CDKi (palbociclib, ribociclib, or abemaciclib). Materials and Methods This study based on randomized Phase 2 or 3 trials of CDKi plus ET compared with placebo plus ET for women with HR+/HER2−ABC and identify relevant randomized clinical trials (RCTs) published prior to February 2020. The primary endpoint was progression-free survival (PFS), the secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit response (CBR) and safety. The PROSPERO registry number is 42018081105. Results The results from eight trials including 4580 participants were pooled. Evidence indicated that the PFS of CDKi group was significantly prolonged (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.50–0.60, P < 0.01) compared with placebo group. The ORR and CBR were better (risk ratio [RR] 1.47, 95% CI 1.30–1.67, P < 0.01; 1.24, 95% CI 1.15–1.35, P < 0.01) in the CDKi group. The OS of CDKi group (HR 0.75, 95% CI 0.67–0.85, P < 0.01) was significantly longer than ET alone. Subgroup analyses confirmed that the benefit was consistent across most subgroups. Subgroup analyses showed no statistically significant difference of PFS among three CDKi: palbociclib vs ribociclib (HR 0.55, 95% CI 0.49–0.60, P = 0.34), palbociclib vs abemaciclib (HR 0.53, 95% CI, 0.47–0.59, P = 0.61), and ribociclib vs abemaciclib (HR 0.56, 95% CI, 0.51–0.62, P = 0.72). Treatment-related grade 3 or 4 hematologic adverse events (AEs) were more frequently in CDKi group. Conclusion CDKi combined with ET can significantly prolong PFS and improve the ORR, CBR and OS in patients with HR+/HER2− ABC. However, the advantage of different CDKi has not been established.

The aim of this randomized phase II study was to investigate the optimal timing of the administration of thrombopoietin to prevent cytarabine-induced thrombocytopenia. Fifty-two patients who were scheduled for high-dose cytarabine treatment were randomly assigned to receive either the standard prophylactic mode (starting thrombopoietin, 15,000 units/day on days 2-11) or the pre-chemo mode (starting thrombopoietin, 15,000 units/day on days -4, -2, and 2-9) during the first cycle of chemotherapy with a switch to the other mode in the second cycle. The thrombocytopenia rate in the standard mode and the pre-chemo mode were PLT 50 × 10

Background: Stage III follicular lymphoma (FL) is currently still considered incurable after RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy and rituximab maintenance. Radiotherapy plays a vital role in early-stage FL, but the value remains unclear in stage III FL. Here, we reported the results of invasive field radiotherapy (IFRT) combined with rituximab maintenance versus rituximab maintenance alone in patients with stage III FL who achieved complete remission (CR) or partial response (PR) after induction chemotherapy. Methods: From January 2015 and January 2020, patients aged 18-70 years with CR or PR after induction chemotherapy in stage III FL, grade 1, 2 or 3a and CD20 positive in immunohistochemical feature were randomly assigned (1:1) to receive IFRT combined rituximab maintenance or rituximab maintenance alone after induction chemotherapy in multicenter. The primary endpoint was progression-free survival at 5 years. This study is registered with Chinese ClinicalTrials.gov, number ChiCTR2000032550. Results: 63 patients were randomly assigned to IFRT combined rituximab maintenance (IFRT+R arm) and 66 patients to rituximab maintenance alone (R arm) after induction chemotherapy. The dose of IFRT was 30Gy. After a medium follow-up of 48 months (range 7-72 months), the 5-year progression free survival (PFS) were significantly improved in patients with IFRT +R, with 87.8% versus 67.1% (HR, 0.32; 95% CI, 0.14-0.72, P=0.006). Patients with IFRT +R also have a better overall survival (OS), OS was 96.6% versus 80% (HR, 0.28; 95% CI, 0.09-0.92, P=0.036). Thirty-six (57%) patients in IFRT+R arm and twenty-four (36%) patients in R arm suffered toxic effects (P=0.02). Grade 3 and 4 adverse events were recorded in 17 patients (27%) in IFRT+R arm and 11 (16%) in R arm (P=0.200). Conclusion: On the basis of rituximab maintenance, IFRT demonstrated promising efficacy and manageable toxicity in stage III FL, with longer PFS and OS compared with rituximab alone. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Resistance to radiotherapy is frequently encountered in clinic, leading to poor prognosis of cancer patients. Long noncoding RNAs (lncRNAs) play important roles in the development of radioresistance due to their functions in regulating the expression of target genes at both transcriptional and posttranscriptional levels. Exploring key lncRNAs and elucidating the mechanisms contributing to radioresistance are crucial for the development of effective strategies to reverse radioresistance, which however remains challenging. Here, actin filament‐associated protein 1 antisense RNA1 (lncAFAP1‐AS1) is identified as a key factor in inducing radioresistance of triple‐negative breast cancer (TNBC) via activating the Wnt/β‐catenin signaling pathway. Considering the generation of a high concentration of reduction agent glutathione (GSH) under radiation, a reduction‐responsive nanoparticle (NP) platform is engineered for effective lncAFAP1‐AS1 siRNA (siAFAP1‐AS1) delivery. Systemic delivery of siAFAP1‐AS1 with the reduction‐responsive NPs can synergistically reverse radioresistance by silencing lncAFAP1‐AS1 expression and scavenging intracellular GSH, leading to a dramatically enhanced radiotherapy effect in both xenograft and metastatic TNBC tumor models. The findings indicate that lncAFAP1‐AS1 can be used to predict the outcome of TNBC radiotherapy and combination of systemic siAFAP1‐AS1 delivery with radiotherapy can be applied for the treatment of recurrent TNBC patients.

e17040 Background: PD-1/PD-L1 blockade significantly improved survival for bladder cancer. PD-L1 expression might not be an ideal marker for patient selection in isolation. Several studies demonstrated that alternative markers such as NLR, a biomarker of systemic inflammation response to therapy, correlated with outcomes in a variety of cancers including bladder cancer, might be a predictor for patient selection and the response to immunotherapy. However, no reporters have been made combination of NLR and PD-L1 in predicting prognosis in bladder cancer. Methods: Suitable tissue of 100 FFPE blocks of bladder cancer patients treated in Sun Yat-Sen Memorial Hospital Sun Yat-sen University were stained with PD-L1 antibody. Clinicopathological data and pretreatment complete blood count were retrospectively collected. All patients were classified into high NLR group and low NLR group at cut-off 3.0. Kaplan-Meier and Cox proportional hazard models analyses were used to assessed the predictor of combined PD-L1/NLR for disease-free survival (DFS) and overall survival (OS). Results: Patients were mostly male (79%) with high grade () lymph node positive (21%), T3-4 (33%) . The positivity of PD-L1 expression was 22% (22/100) at cut-off 1%. Univariate analysis showed that PD-L1 expression was positively associated with larger tumor size, higher grade, positive lymph node metastases. Median DFS and OS were 35 months and 37 months, respectively. Both PD-L1 expression and NLR were associated with DFS and OS. COX analysis model showed that PD-L1 and NLR were independent prognostic factors for tumor prognosis. Of interest, when patients were divided in two groups based on PD-L1/NLR: patients with PD-L1+/high NLR as group 1 and other patients as group 2, group1 had significantly shorter DFS and OS (DFS, X2 = 4.146, P = 0.042; OS, X2 = 10.274, P = 0.001). COX proportional hazards regression models indicated that PD-L1+/high NLR was correlated with a significantly shorter DFS and OS (DFS, hazard ration [ HR] = 2.572, P = 0.05; OS, HR = 3.811, P = 0.003). Conclusions: The study indicated that combined use of PD-L-1/ NLR as predictive biomarker for survival. This feasible panel may be optional maker applied to select patients for immunotherapy.

Angioimmunoblastic T-cell lymphoma (AITL) is a distinct subtype of peripheral T-cell lymphoma with unique clinical and pathological features. This study aim to design a prognostic model specifically for AITL, providing risk stratification in affected patients. A total of 115 newly diagnosed AITL patients were retrospectively analyzed. The estimated five-year overall survival (OS) rate for all patients was 45.4%. Multivariate analysis found prognostic factors for survival were bone marrow involvement, number of extranodal sites >1, and performance status >1. We categorized three risk groups: group 1, no adverse factor; group 2, one factor; and group 3, two or three factors. Five-year OS was 86.9% for Group 1, 46.3% for Group 2, and 16.2% for Group 3 (p

Current standard treatment, including non-anthracycline-based chemotherapy and optimal combining of radiotherapy, has dramatically improved outcomes of patients with extranodal natural killer/T-cell lymphoma (ENKTL) during the last decade. This study was conducted to investigate the clinical outcome of ENKTL patients with relapsed or progressive disease after initial current standard therapy.We retrospectively reviewed patients diagnosed with ENKTL at six centers in four countries (China, France, Singapore, and South Korea) from 1997 to 2015 and analyzed 179 patients who had relapsed or progressed after initial current standard therapy.After a median follow-up of 58.6 months (range 27.9-89.2), the median second progression-free survival (PFS) was 4.1 months [95% confidence interval (CI) 3.04-5.16] and overall survival (OS) was 6.4 months (95% CI 4.36-8.51). Multivariate Cox-regression analysis revealed that elevated lactate dehydrogenase, multiple extranodal sites (≥2), and presence of B symptoms were associated with inferior OS (P 0.05). OS and PFS were significantly different according to both prognostic index of natural killer lymphoma (PINK) and PINK-E (Epstein-Barr virus) models. Salvage chemotherapy with l-asparaginase (l-Asp)-based regimens showed a significantly better clinical benefit to response rate and PFS, although it did not lead to OS improvement. First use of l-Asp in the salvage setting and l-Asp rechallenge at least 6 months after initial treatment were the best candidates for salvage l-Asp containing chemotherapy.Most patients with relapsed or refractory ENKTL had poor prognosis with short survival. Further studies are warranted to determine the optimal treatment of patients with relapsed or refractory ENKTL.

7537 Background: Radiotherapy is extremely important in extranodal natural killer/T-cell lymphoma (ENKTL). [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is a routine pretreatment imaging technique used in ENKTL, while magnetic resonance imaging (MRI) plays a key role in head and neck (HN) cancer. The purpose of this study was to investigate the value of pretreatment HN-MRI and PET/CT-guided therapy in improving survival in upper aerodigestive tract ENKTL (UADT-ENKTL). Methods: We prospectively conducted a single center study on untreated patients with pathologically diagnosed UADT-ENKTL. Patients undergoing PET/CT with/without HN-MRI were decided by clinicians for staging and restaging. The patients were treated with L-asparaginase/Pegaspargase and non-anthracycline-based chemotherapy with intensity-modulated radiation therapy (IMRT). Results: We enrolled 171 patients (median age, 44 years; range, 18-75 years; 118 (69%) males) from April 2011 to March 2018. Overall, 71 patients underwent PET/CT and HN-MRI (PET/CT-MRI) and 100 patients underwent PET/CT alone. HN-MRI upgraded the clinical stages in 8 patients (8/71) undergoing PET/CT based on the Ann Arbor staging system and in 10 patients (10/71) based on the TNM staging system by detecting additional local lesions ( P=0.011 and P=0.019, respectively). With a median follow-up of 54 months, the 5-year overall survival (OS), local recurrence-free survival (LRFS) and progression-free survival (PFS) rates were 72.7%, 68.6% and 68.2%, respectively, for all patients. The 5-year LRFS rate was 100% in the PET/CT-MRI group and 64.3% in the PET/CT group ( P

e12529 Background: Current guidelines lack definitive evidence regarding the clinical outcomes associated with different maintenance strategies for hormone-receptor (HR) positive metastatic breast cancer (MBC). We aimed to evaluate different maintenance modalities after first-line chemotherapy in this setting. Methods: We conducted a multicenter real world study to compare maintenance chemotherapy, endocrine therapy and observation in patients with HR positive MBC who achieved disease control after first-line chemotherapy. The primary endpoint was overall survival (OS), secondary endpoint was progression-free survival (PFS). We further examined the results from fourteen multicenter prospective studies in a meta-analysis. Results: A total of 928 patients were enrolled in the real world study. The median age was 48 years (range, 18 to 76 years). Of these patients, 269 received chemotherapy, 330 received endocrine therapy and 329 received observation as their maintenance treatment. OS was significantly longer in the chemotherapy group and endocrine therapy group than in the observation group (median 33.0 vs 36.0 vs 19.0 months, respectively, P < 0.001), as was PFS (median 12.0 vs 14.0 vs 8.0 months, respectively, P < 0.001). However, there was no significant difference of OS between chemotherapy group and endocrine therapy group (HR, 0.947, 95% CI: 0.743-1.207, P = 0.656), so did PFS (HR, 0.969, 95% CI: 0.787-1.194, P = 0.765). In the meta-analysis of all cohorts (2706 participants), maintenance endocrine therapy provide similar PFS and OS compare with chemotherapy, but with lower odds of G1-G2 adverse events. Conclusions: Our study provided strong evidence for OS and PFS benefits of maintenance therapy over observation after first-line chemotherapy in HR positive MBC patients. Maintenance endocrine therapy was noninferior to chemotherapy with less treatment-related toxicity, which was worthy of a clinical recommendation.

The genetic landscape of Natural killer/T-cell nasal-type lymphoma (NKTL) has been recently unraveled by discoveries describing recurring mutations altering the JAK-STAT pathway, epigenetic modifiers, the DDX3X gene and genetic predisposition in the HLA-DPB1 gene but none has employed whole-genome sequencing (WGS). Whole-genome sequencing was performed for 11 pairs of tumor-blood samples to study the association between somatic mutations and response to pembrolizumab. Interestingly, recurrent PD-L1 SRs were validated in four of the seven complete responders (CR) cases. JAK3-activating (p.A573V) mutations were also validated in another two pembrolizumab-treated patients who have achieved CR. Lastly, we also found a homozygous 3 bp insertion (p.Q131_H132insQ) in the ARID1B gene, a chromatin remodeler gene and a subunit in the SWI/SNF complex in the last remaining CR case. A recent study has also reported PBRM1-deficient and ARID2-deficient tumors correlated with better response to anti-PD1/PD-L1 therapy renal cell carcinoma. There seems to be a relationship between truncating alterations in the subunits of the SWI/SNF complex and response to PD1/PD-L1 therapy. However, the exact mechanisms behind these associations remain to be elucidated for NKTL. Analysis of the WGS data from the four remaining progressive disease (PD) patients' tumors did not reveal similar alterations in the PD-L1 and JAK3 genes. A careful inspection was also carried out on the genes associated with major histocompatibility complex and interferon gamma pathways, which are known to associate with resistance to immune checkpoint blockade in melanoma, but no further mutation in these groups of genes was found in our cohort. Furthermore, a TP53 (p.W14X) stop-gain mutation, a hallmark tumor suppressor gene, was detected in a patient who had progressive disease after given pembrolizumab. We went on to check if PD-L1 IHC staining could explain the response of these NKTL patients to pembrolizumab. In this study, tumors were stained and assessed for PD-L1 positivity by the same pathologist. All cases, except two cases, have greater than 20% of tumor cells stained positive for PD-L1. Interesting, both cases are CR. In addition, all four PD cases were strongly stained for PD-L1 with an average of 69% PD-L1 positive cells (range, 50% - 90%) but their outcomes were dismal. This suggests that there could be a companion biomarker that could be added to PD-L1 IHC positivity for better predictive power of response to PD1 blockade therapy. Here we report retrospectively, for the first time, the genomic mutational profiles of anti-PD1 blockade in 11 relapsed/refractory NKTL patients using WGS data, which provide proof-of-concept data that the response to anti-PD1 is relevant and correlates with recurrent PD-L1 and JAK3 genomic alterations in this malignancy. Disclosures No relevant conflicts of interest to declare.

7553Background: The prognosis of refractory or relapsed(R/R) non-germinal center B cell (non-GCB) subtype diffuse large B cell lymphoma (DLBCL) is dismal without established standard salvage chemot...

7552Background: The survival of patients with extranodal natural killer T-cell lymphoma (ENKTL), a rare and highly aggressive malignancy, is not accurately predicted by the routine lymphoma Ann Arb...

BACKGROUND: The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted.METHODS: We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort.FINDINGS: We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75-86), 62% (55-70), and 25% (20-34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)-which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories-significant associations with overall survival were noted (81% [95% CI 75-87%], 55% (44-66), and 28% (18-40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group.INTERPRETATION: PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy.FUNDING: Samsung Biomedical Research Institute.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare and severe malignancy. ENKTL is primarily located in the upper aerodigestive tract; the nasal/nasopharyngeal localization represents 75% of cases, and other sites involved include the skin, gastrointestinal (GI) tract, testis, bone marrow and spleen [1]. Patients with NK/T-cell lymphoma outside the upper aerodigestive tract tend to present with more aggressive clinical features and have a more unfavorable prognosis. To date, little information regarding primary GI NK/T-cell lymphomas (GINKTLs) is available. Previous studies have reported that the incidence of GINKTL is less than 0.1 cases per 100 000 persons per year [2,3]. Treatment strategies for nodal non-Hodgkin lymphoma (NHL) are well established; however, much debate and controversy remain regarding the optimal approach in GINKTL. Due to the rarity of primary GINKTL, empirical standards in the treatment of GINKTL, consisting of surgical resection of the primary tumor mass followed by chemotherapy or radiotherapy (or both), have not been evaluated prospectively. Hence we initiated a retrospective study to investigate the clinical features of GINKTL, analyze the impact of surgical resection on outcome and delineate its major prognostic factors.

Background: Rituximab (Rtx) with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) regimen could improve the survivalship in treatment of B cell lymphoma, however, also increases the possibilities of infectious disease including pulmonary pneumonia. Methods and materials: A prospective study was conducted in Sun Yat-sen University Cancer Center from Feb 2008 to Oct 2015 to analyze the addition of thyomosin (Th α1) and intravenous immunoglobulin (IVIG) supportive therapy impact in preventive role of pulmonary adverse effect (PAE) incidence rate related to Rtx based immuno-chemotherapy. Results: Out of 379 cases, 215 in Th α1 and IVIG (study) group and 164 in non Th α1 and IVIG (control) group compared; 80 (21.1%) of them developed PAE: 39 Rtx immuno-chemotherapy induced interstitial pulmonary disease (IPD) and 41 infectious pneumonia (IP) cases were developed after the 4rth median cycles (2.8 months) of R-CHOP regimen from the first exposure until prior to induced PAE and 11 cases of IP were isolated with etiology. In comparing the role of Th α1 and IVIG vs. control group; out of 41 R-CHOP induced pneumonia cases: 9 (2.4%) vs. 32 (8.4%) with p Conclusions: The B cell lymphoma patients with high risk factors along with the risk of developing infectious pneumonia may be substantially decreased by the regular implication of Th α1 and IVIG along the Rtx based chemotherapy that may result effective in improving EFS too. Disclosures No relevant conflicts of interest to declare.

Background and objectives: Methotrexate (MTX) is a folic acid reductase inhibitor widely used. Peripheral infusion of high dose MTX (HD-MTX) could prevent the central nervous system recurrence of leukemia and NHL. Due to the blood brain barrier, only 1-3% of MTX in the peripheral blood can enter the cerebrospinal fluid. Improving the peripheral MTX drug dosage helps to improve MTX concentration in the cerebrospinal fluid. However, high concentration of MTX has serious side effects to normal organs. Leucovorin (CF) rescue is given to reduce the toxic effect of methotrexate on normal cells. During high dose MTX therapy, monitoring of serum concentration of MTX and timely CF rescue therapy are mandatory so as to maximum the efficacy of MTX and minimize the toxicities. Due to the lack of randomized clinical trials with large sample, the safe dose and most appropriate time of leucovorin rescue treatment are of no consensus. In order to study the effect of different time of leucovorin rescue treatment on the serum concentration of MTX, we carried out this study. Patients and methods: We included patients who had pathological diagnosis of non-Hodgkin's lymphoma and indications to receive HD-MTX as single agent or component in combined regimen consecutively from October 2011 to June 2014 at our hospital. Patients were randomized to receive CF rescue at the sixth hour after MTX infusion in the first course and twelfth hour in the second course or the twelfth hour in the first course and sixth hour in the second course. A dosage of 3.5 g/m2 of MTX was provided. Adequate hydration, alkalization and monitoring of laboratory tests were administered. Intrathecal injection of MTX plus cytarabine and dexamethasone were given after MTX infusion. 100mg of CF was given at the first time, then 30mg of CF were given every 6 hours for a total of 7 times until the plasma concentration of MTX were lower than 1×10-7 mol/L. Blood samples were collected at 2, 12, 18, 24, 28, 72 hours after the beginning of MTX infusion. High performance liquid chromatography was used to test the plasma concentration of MTX. Results: There were 23 male patients and 12 female patients with a mean age of 41 years. Most of patients were diagnosed as diffuse large B cell lymphoma (65.7%). Eleven cases (31.4%) had central nervous system invasion at the time of HD-MTX treatment. Twenty-one patients (51%) had more than one extra-nodal lesion. Sixteen patients were randomly to be rescued at the sixth hour in the first course then the twelfth hour in the second course. Nineteen patients were randomly to be rescued at the twelfth hour in the first course then the sixth hour in the second course. The plasma concentration of MTX of patients rescued at the sixth hour at the time of 2, 12, 18, 24, 48 hours were 5.21±0.36×10-5 mol/L, 8.01±0.635×10-5 mol/L, 4.57±1.67×10-6 mol/L, 1.43±0.83×10-6 mol/L, 0.1±0.1×10-6 mol/L, respectively; The plasma concentration MTX of patients rescued at the twelfth hour at the time of 2, 12, 18, 24, 48 hours were 5.46±0.34×10-5 mol/L, 8.65±0.663×10-5 mol/L, 5.4±0.93×10-6 mol/L, 1.12±0.21×10-6 mol/L, 0.1±0.24×10-6 mol/L, respectively. There was no significant difference of MTX concentration level between patients treated with different CF rescue timing, P >0.05. Most of patients achieved maximal MTX concentration at the twelfth hour, and descended to be lower than the minimal effective concentration at the eighteenth hour. At the forty-eighth hour, majority of patients had MTX concentration being in a safe range. The rate of grade 3 to 4 adverse reactions including neutropenia, anemia, thrombocytopenia and grade 1 to 2 side effects including neutropenia, thrombocytopenia, mucositis, fatigue, and MTX discharge delay were higher when patients were rescued with CF at the twelfth hour, though P >0.05. Conclusion: Most of patients treated with high dose MTX reached the maximum MTX concentration at the twelfth hour after MTX infusion, and descended to be under the minimal effective concentration at the eighteenth hour, then to be in the safe range at the forty eighth hour. No significant difference of MTX concentration was found between patients rescued with CF at the sixth hour or the twelfth hour. However, adverse reactions were lower when patients were treated with CF rescue at the sixth hour. It seems a better choice to give patients CF rescue at the sixth hour after MTX infusion. Disclosures No relevant conflicts of interest to declare.

18 F-PET-CT is clinically recommended for monitoring therapeutic response in DLBCL patients. But the role of interim PET-CT remains controversial, and most of the previous researches were retrospective. We designed this study to prospectively evaluate whether interim PET-CT was a valid prognostic tool for patients with DLBCL treated with R-CHOP regimen and if yes, try to determine the more appropriate time and interpretation method for interim PET-CT. This study was a sub-study of the parental study "A prospective, multicenter randomized phase III clinical trial of intensified chemotherapy in improving the treatment efficacy of patient with diffuse large B-cell lymphoma" (NCT01793844). The sub-study included patients that have already been enrolled in the parent study at Sun Yat-Sen University Cancer Center prospectively. Patients were evaluated with PET-CT scans before treatment and after every 2 cycles of R-CHOP and after the completion of first-line treatment. Regular follow-up starts from the enrollment. Between Jan. 2008 and Aug. 2014, 221 patients in Sun Yat-Sen University Cancer Center were enrolled in this sub-study, among whom 203 patients were included in the analysis and the other 18 were excluded for lacking the necessary raw data of PET-CT scan. PET evaluation would be applying the visual criteria of International Harmonization Project(IHP) and the Deauville 5-point scale(5-PS). The results showed PET positive in 103 patients and negative in 100 patients after 2 cycles of R-CHOP chemotherapy with IHP criteria. Among the 103 patients with positive PET-2, 53 patients turned negative after 4 cycles of chemotherapy and still 50 patients remain positive. At the evaluation of end-of-first-line-treatment, 165 patients achieved CR, while 30 achieved PR and 8 PD . According to 5-PS criteria, 146 patients were PET negative with 57 were positive after 2 cycles of chemotherapy. And 173 patients were negative in PET-4 evaluation, while 30 patients remained positive. With a median follow-up of 25.46 months (range 3.60~77.33 months) and according to IHP criteria, patients with negative PET-2 had superior 3-year PFS (84.7% vs. 63.8%, p < 0.001) and OS (89.8% vs. 80.4%, p = 0.045) than those with positive results. Patients with negative PET-4 also had a better clinical outcome compared with the positive group with 3-year PFS (84.1% vs. 43.8%, p < 0.001) and OS (90.7% vs. 67.8%, p < 0.001). A further analysis showed that patients who achieved PET negative just after 2 cycles of chemotherapy (Early responder, ER) had a similar prognosis comparing with those who achieved PET negative after 4 cycles (Later responder, LR). There were no significant differences in the persistent CR rates (87.00% vs. 86.79%, p = 0.971), 3-year PFS (84.7% vs. 82.2%, p = 0.867) and 3-year OS (89.8% vs. 92.9%, p = 0.638) between the ER group and the LR group. Patients who remained PET positive after 4 cycles of chemotherapy (Interim non-responder, I-NR) had the worst prognosis. Their persistent CR rate (42.00% vs. 87.00%, p < 0.001; 42.00% vs. 86.79%, p < 0.001), 3-year PFS (43.8% vs. 84.7%, p < 0.001; 43.8% vs. 82.2%, p < 0.001) and 3-year OS (67.8% vs. 89.8%, p < 0.001; 67.8% vs. 92.9%, p = 0.002) were significantly lower, comparing with the ER and LR group. And according to 5-PS criteria, the results were similar. Patients with negative PET-2 had superior 3-year PFS (82.9% vs. 51.6%, p < 0.001) and OS (89.7% vs. 72.9%, p = 0.001) than those with positive results. Patients with negative PET-4 also had a better clinical outcome compared with the positive group with 3-year PFS (81.8% vs. 30.0%, p < 0.001) and OS (90.1% vs. 54.2%, p < 0.001). In the multivariate analysis, PET-4 with IHP criteria, PET-4 with 5-PS criteria and IPI score were independent predictive factors for PFS of patients with DLBCL. A further analysis of positive predictive value (NPV) and negative predictive value (PPV) showed PET-4 was superior than PET-2, especially interpretated with 5-PS. The PPV and NPV of PET-4 with 5-PS criteria were 70.00% and 83.82% respectively. These data indicates that Interim 18 F-FDG PET-CT scan could predict the prognosis of DLBCL patients treated with R-CHOP regimen. And it was recommended that interim 18 F-FDG PET-CT scan be done after 4 cycles of chemotherapy, and that 5-PS criteria be applied in the interpretation of interim PET-CT scan rather than IHP criteria. Disclosures No relevant conflicts of interest to declare.

Background: CD20-antibody (rituximab) plus CHOP chemotherapy (R-CHOP) have become the first-line regimen for CD20 positive DLBCL since the introduction of rituximab at the end of 1990s. Our group (Chinese south-west oncology group, CSWOG) planned to evaluate the efficacy and toxicity of biweekly schedule of RCHOP (RCHOP-14) compared to triweekly RCHOP (RCHOP-21) for DLBCL. Purpose: RCHOP-14 vs. RCHOP-21 for untreated diffuse large B-cell lymphoma (DLBCL), compare the 5-year disease-free survival (DFS), overall survival (OS), response rate and the side effects. Patients and methods: Patients older than 18 years, newly diagnosed of CD20-positive DLBCL with adequate organ function were recruited. All patients were randomized into two groups after provided written informed consent, and received RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. The RCHOP-14 group was administered every 2 weeks, patients received prophylactic granulocyte colony-stimulating after each chemotherapy cycle. The control group RCHOP-21 was administered every 3 weeks. The planned cycles of chemotherapy was 6 to 8 cycles. Patients received imaging evaluation at the baseline and every 2 cycles of chemotherapy. Radiotherapy was recommended to treat local residue or bulky tumor. Vital signs, physical examination, and laboratory studies were documented at each follow-up visit. Results: From January 2008 to December 2014, a total of 702 patients with newly diagnosed DLBCL were recruited in 14 cancer centers of CSWOG. There were 407 males (58.0%) , 295 females (42.0%) , and median age of 52 years (range 18-80 years). 353 assigned to the RCHOP-21 group and 349 assigned to the RCHOP-14 group, patients in the two groups totally received 3989 cycles of chemotherapy, an average of 5.70 cycles per patient. There was no significant difference between the RCHOP-21 and RCHOP-14 groups in terms of sex, age, Ann Arbor stage, International Prognostic Index, B symptoms, extranodal involvement and seropositive status for hepatitis-B surface antigen. Overall, 496 (70.7%) achieved CR, 136 (19.4%) PR, 16 (2.3%) SD and 50 (7.1%) PD. For RCHOP-21 group, the incidence of CR, PR and PD was 72.8%, 18.4%, 6.5%, respectively, the response rate was 91.2%, and relapse rate was 22.6%. For RCHOP-14 group, the incidence of CR, PR and PD was 69.1%, 20.9%, 7.7%, respectively, the response rate was 90.0%, relapse rate was 16.8%, and the results were no significant difference. With the median follow-up of 35.95 months, the 5-year DFS, OS, and PFS of RCHOP-21 compared with RCHOP-14 was 72.2% vs.72.8%, p=0.306; 68.9% vs62.3%, p=0.856; and 53.8% vs. 54.4%, p=0.357,respectively. The most common side effect was bone marrow suppression including 83.6% granulopenia and 46.7% grade III/IV granulopenia, Febrile Neutropenia 24.9%; 69.1% anemia and 12.6% grade III/IV anemia; 50.6% thrombocytopenia and 11.5% grade III/IV thrombocytopenia. Other side effects included: 18.6% pneumonia, 6.8% interstitial pneumonia, 17.1% other site of infection, 17.5% ALT/AST increasing, 17.4% peripheral neuritis, 13.1% fatigue, 11.9% nausea, 13.1% vomiting, 4.6% oral ulcer. There were no significant difference between the two groups about the above side effects. There were 32 patients (9.1%) in RCHOP-21 and 40 patients (11.5%) in RCHOP-14 delayed the chemotherapy because of severe side effects. High score of IPI, insufficient chemotherapy cycles and relapse during chemotherapy were independent prognosis factors in multivariate analysis. Conclusion: RCHOP-14 did not showed superior effective than RCHOP-21. The side effects were similar with prophylactic GCSF in RCHOP-14 regimen. Therefore, RCHOP-21 is still the standard treatment for DLBCL. Disclosures No relevant conflicts of interest to declare.

Predictive value of therapeutic monitoring with plasma Epstein-Barr virus DNA in Extranodal NK/T cell lymphoma, nasal type Background: Predictive tumor markers are essential for extranodal NK/T cell lymphoma, nasal type (ENKTL), which pursues an aggressive clinical course with poorer prognosis. This prospective study was conducted to evaluate the dynamic monitoring value of circulating EBV DNA concentration for the prediction of ENKL during treatment. Method: Patients with untreated, centrally reviewed diagnosis of ENKTL were included in our study. Plasma Epstein-Barr virus (EBV) DNA levels were collected before and/or every 2 cycles of chemotherapies for circulating EBV DNA measurement by a real-time PCR assay. Result: From Jan 2002 to Aug 2012, 113 newly diagnostic ENKTL patients enrolled. The positive rate of circulating EBV DNA is 61.9% (70/113) with a median concentration of 1.21×103copies/ml. Patients who had initial positive circulating EBV-DNA had more lymph nodes invasion, higher IPI and KPI score. The more advance of the stage, the higher rate of the circulating EBV-DNA positive. When divided the positive group as low and high-dose ones by the cut-off value as 2×104copies/ml, the CR rate of the high-dose group is much lower and the 5-year OS is significantly better than the low-dose group and the negative group. After two cycles of chemotherapy, 45 patients were tested circulating EBV-DNA and 53.33% (24/45) patients became negative EBV-DNA candidates. There were 87.5% (21/24) patients obtained complete remission at the end of the treatment, comparing as 42.86% (9/21) in the still positive EBV-DNA groups(P= 0.002). There is a tendency that the patients whose circulating EBV-DNA become negative after two cycles will have better prognosis (5-year OS: 75% vs 46%, P=0.074). The similar situation of CR rate and OS happened in the EBV-DNA detection of completion of total chemotherapy. 7 of 13 relapsed pts of ＞1×103copies/ml EBV-DNA at the time of recurrent, and the survival outcome was dismal for them compared to the other 6 pts of ≤1×103copies/ml（5- year OS: 0% vs 80%, P=0.001） Conclusion: Circulating EBV-DNA level can predict the efficacy of treatment as a dynamic marker of ENKL. Patients with early positive detection of EBV-DNA after 2 cycles of chemotherapy maybe received more aggressive treatments. Disclosures No relevant conflicts of interest to declare.

Purpose: Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is a rare and highly aggressive disease. The Ann Arbor staging system had been unsuitable to proper staging of ENKTL. This study was conducted to establish a new staging system specified for ENKTL, which can identify poor prognostic patients. Patients and Methods: Patients with untreated, centrally reviewed diagnosis of ENKTL were included in our study. The new staging system was established based on the study of single center consecutive patients treated with CHOP-like regimens with or without involved field radiotherapy (IFRT), then we initinated a multicenter confirmation study and conducted a multicenter prospective study to validate the new staging system. Results: From Jan 1997 to June 2006, 134 consecutive patients treated in the cancer center of Sun Yat-sen University were analyzed. The following was a summary of the classification system developed: stage I: lesions confined within nasal cavity or nasopharynx without local invasiveness (paranasal sinuses or bony or skin invasion); stage II: localized disease with local invasiveness; stage III: localized disease with regional lymph node involvement (cervical lymph nodes); and stage IV: disseminated disease (lymph nodes on both sides of diaphragm, multiple extranodal site). The distribution of stage I to IV using the new system and Ann Arbor system were 39.6%, 23.9%, 23.1%, 13.4% and 63.4%, 23.1%, 5.2%, 8.2%, respectively. The 5-year OS rate of stage I to IV using the new system were 29.5%, 23.4%, 21.3% and 0.07% compared with 23.8%, 21.3%, 0.0% and 0.0% using the Ann Arbor system. In the multicenter confirmation study conducted in 18 centers in China, 722 patients were analyzed. The results showed that the distribution of the new system compared with Ann Arbor system from stage I to IV were 24.1%, 34.9%, 18.3%, 22.7% vs 59.1%, 19.0%, 6.9%, 15.0%, respectively, and the 5-year OS rate of stage I to IV were 56.0%, 48.3%, 33.8%, 26.1% vs 50.7%, 39.1%, 10.8%, 28.0%, respectively. For the multicenter prospective study, 233 newly diagnosed ENKTL patients treated with non-CHOP-like regimens were enrolled and showed a balanced distribution of 17.2%, 39.9%, 19.3%, 23.6% vs 53.6%, 25.3%, 6.9%, 14.2% from stage I to IV and superior 5-year OS rate: 82%, 73%, 67%, 54% vs 75.2%, 65.6%, 46.9%, 73.8% from stage I to IV using the new system in compared with the Ann Arbor system. Conclusions: The new staging system with a more balanced distribution and a superior prognostic discrimination as compared with Ann Arbor staging system no matter for CHOP-like or non-CHOP-like regimens, is more suitable for ENKTL and can be recommended used in the future. Disclosures No relevant conflicts of interest to declare.