Full-spectral genome analysis of natural killer/T cell lymphoma highlights impacts of genome instability in driving its progression.

BACKGROUND: Natural killer/T cell lymphoma (NKTCL) is a clinically and genetically heterogeneous disease with poor prognosis. Genome sequencing and mutation characterization provides a powerful approach for patient stratification, treatment target discovery, and etiology identification. However, previous studies mostly concentrated on base-level mutations in primary NKTCL, whereas the large-scale genomic alterations in NKTCL and the mutational landscapes in relapsed/refractory NKTCL remain largely unexplored. METHODS: Here, we assembled whole-genome sequencing and whole-exome sequencing data from 163 patients with primary or relapsed/refractory NKTCL and compared their somatic mutational landscapes at both nucleotide and structure levels. RESULTS: Our study not only confirmed previously reported common NKTCL mutational targets like STAT3, TP53, and DDX3X but also unveiled several novel high-frequency mutational targets such as PRDM9, DST, and RBMX. In terms of the overall mutational landscape, we observed striking differences between primary and relapsed/refractory NKTCL patient groups, with the latter exhibits higher levels of tumor mutation burden, copy number variants (CNVs), and structural variants (SVs), indicating a strong signal of genomic instability. Complex structural rearrangements such as chromothripsis and focal amplification are also significantly enriched in relapsed/refractory NKTCL patients, exerting a substantial impact on prognosis. Accordingly, we devised a novel molecular subtyping system (i.e., C0-C4) with distinct prognosis by integrating potential driver mutations at both nucleotide and structural levels, which further provides an informative guidance for novel treatments that target these specific driver mutations and genome instability as a whole. CONCLUSIONS: The striking differences underlying the mutational landscapes between the primary and relapsed/refractory NKTCL patients highlight the importance of genomic instability in driving the progression of NKTCL. Our newly proposed molecular subtyping system is valuable in assisting patient stratification and novel treatment design towards a better prognosis in the age of precision medicine.

Development and validation of a novel prognostic nomogram for advanced diffuse large B cell lymphoma.

Advanced diffuse large B cell lymphoma (DLBCL) is a common malignant tumor with aggressive clinical features and poor prognosis. At present, there is lack of effective prognostic tool for patients with advanced (stage III/IV) DLBCL. The aim of this study is to identify prognostic indicators that affect survival and response and establish the first survival prediction nomogram for advanced DLBCL. A total of 402 patients with advanced DLBCL were enrolled in this study. COX multivariate analysis was used to obtain independent prognostic factors. The independent prognostic factors were included in the nomogram, and the nomogram to predict the performance of the model was established by R rms package, C-index (consistency index), AUC curve and calibration curve. The training and validation cohorts included 281 and 121 patients. In the training cohort, multivariate analysis showed that Ki-67 (70% (high expression) vs ≤ 70% (low expression), p < 0.001), LDH (lactate dehydrogenase) (elevated vs normal, p = 0.05), FER (ferritin) (elevated vs normal, p < 0.001), and ß2-microglobulin (elevated vs normal, p < 0.001) were independent predictors and the nomogram was constructed. The nomogram showed that there was a significant difference in OS among the low-risk, intermediate-risk and high-risk groups, with 5-year survival rates of 81.6%, 44% and 6%, respectively. The C-index of the nomogram in the training group was 0.76. The internal validation of the training group showed good consistency. In the internal validation cohort of the training group, the AUC was 0.828, and similar results were obtained in the validation group, with a C-index of 0.74 and an AUC of 0.803. The proposed nomogram provided a valuable individualized risk assessment of OS in advanced DLBCL patients.

Discontinuation and nonpublication of nasopharyngeal carcinoma clinical trials.

OBJECTIVES: To determine the extent of research waste in the field of nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: In this cross-sectional study, we explored the rates, causes and predictors of discontinuation and nonpublication of NPC clinical trials. The sample was derived using the ClinicalTrials.gov advanced search function. Adjusted logistic regression was used to ascertain the effect of trial characteristics on completion and publication status. If a trial discontinuation explanation or publication status could not be determined through the systematic search, the corresponding author was emailed. RESULTS: Ultimately, 311 NPC clinical trials were included (255 [82.0 %] completed and 56 [18.0 %] discontinued trials). The most common reason for trial discontinuation was poor accrual (50 %, 23/46). Industry funding (adjusted OR, 3.12; P = 0.003) and recurrent/metastatic setting (adjusted OR, 11.95; P = 0.003) were significantly associated with increased likelihood of trial discontinuation. Of the 207 completed trials included in the publication query, 141 (68.1 %) were published in peer-reviewed journals, 10 (4.8 %) had results only available on ClinicalTrials.gov, and 56 (27.1 %) remained unpublished 3 or more years after trial completion. Radiation with or without pharmacologic interventions significantly increased the potential of publication (adjusted OR, 3.20; P = 0.048). Among published trials, the median time to publication was 28.47 months (interquartile range, 15.27-44.98 months). CONCLUSION: We identified the difficulties inherent in NPC clinical trials from completion to publication. This represents considerable research waste in NPC, thus raising ethical concerns about the concealment of clinical data and futile patient participation and attendant risks.

Primary breast diffuse large B-cell lymphoma in the rituximab era: A retrospective study of the Chinese Southwest Oncology Group.

BACKGROUND: Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of extranodal DLBCL, and the standard treatment remains controversial. In this study, we aimed to define the optimal treatment management in the rituximab era. METHODS: A total of 5089 newly diagnosed DLBCL patients treated with rituximab-containing immunochemotherapy between 2008 and 2019 from the Chinese Southwest Oncology Group-affiliated institutes were identified, of whom 135 diagnosed with PB-DLBCL were eligible for this analysis. RESULTS: PB-DLBCL accounted for 2.7% of all DLBCLs. With a median follow-up of 4.2 years, the 5-year overall survival and progression-free survival rates were 84.8% and 71.6%, respectively. Breast and central nervous system (CNS) relapses were the main cause of treatment failure. We observed that consolidative breast radiotherapy (RT) significantly decreased breast relapse risk (5-year risk, 2.9% vs. 20.1%, p = 0.007). The CNS relapse risk was lower for patients who received high-dose methotrexate (HD-MTX) than for patients who did not (5-year risk, 0% vs. 15.2%, p = 0.015). We further screened the genetic mutation profile of 20 patients from two institutes, and found that MYD88 (25%) and CD79B mutations (25%) frequently occur in PB-DLBCL. In addition, four patients with MYD88 and/or CD79B mutations experienced CNS relapse, while three patients with MYD88 and/or CD79B mutations who received HD-MTX did not experience CNS relapse. CONCLUSION: Collectively, our results indicate combined modality therapy including rituximab-containing immunochemotherapy and consolidative breast RT is a promising approach for PB-DLBCL, while HD-MTX is useful for preventing CNS relapse.

Characteristics of immunotherapy trials for nasopharyngeal carcinoma over a 15-year period.

Background: Immunotherapy has been a hotspot in nasopharyngeal carcinoma (NPC) in recent years. This study aimed to provide a comprehensive landscape of the characteristics of immunotherapy clinical trials in NPC and to determine whether contemporary studies are of sufficient quality to demonstrate therapeutic value. Methods: This is a cross-sectional analysis of NPC trials registered on ClinicalTrials.gov in the last 15 years (Jan 1, 2008-Nov 20, 2022). Only interventional trials with a primary purpose of treatment were included in the final analysis. Characteristics of immunotherapy trials were compared with those of other NPC trials. Chronological shifts in NPC immunotherapy trials were also analyzed. Results: Of the 440 NPC studies selected, 161 (36.6%) were immunotherapy trials and 279 (63.4%) were other NPC trials. NPC immunotherapy trials were more likely than other NPC trials to be phase 1-2 (82.6% vs. 66.7%, P < 0.001), single-arm (51.3% vs. 39.6%, P = 0.020), non-randomized (64.8% vs. 44.4%, P < 0.001), and enroll fewer than 50 participants (46.3% vs. 34.4%, P = 0.015). Blinding was used in 8.8% of NPC immunotherapy trials. Also, 90.7% of NPC immunotherapy trials were recruited nationally and 82.6% were Asia-centric. Although academic institutions and governments (72.7%) were the major sponsors of NPC trials, immunotherapy trials were more likely to be industry-funded than other NPC trials (34.2% vs. 11.5%, P < 0.001). The number of NPC immunotherapy trials increased exponentially after 2017, attributed to the exploration of immune checkpoint inhibitors. Immunotherapy combined with chemotherapy was the most commonly investigated regimen. Conclusion: NPC immunotherapy trials over a 15-year period were predominantly exploratory. To generate high-quality evidence and advance the clinical application of immunotherapy in NPC, more attention and concerted efforts are needed.

Immunotherapy for nasopharyngeal carcinoma: Current status and prospects (Review).

Nasopharyngeal carcinoma (NPC) is an epithelial tumor located in the nasopharynx and is highly associated with Epstein­Barr virus (EBV) infection. Although radiotherapy alone can cure ~90% of patients with early­stage disease, >70% of patients with NPC have locoregionally advanced or metastatic disease at the first diagnosis due to the insidious and aggressive nature of NPC. After comprehensive radiochemotherapy, 20­30% of patients with advanced NPC still fail treatment, mainly due to recurrence and/or metastasis (R/M). Conventional salvage treatments, such as radiotherapy, chemotherapy and surgery, are suboptimal and frequently accompanied by severe adverse effects and limited efficacy. In recent years, immunotherapy has emerged as a promising treatment modality for R/M NPC. An increasing number of clinical studies have investigated the safety and efficacy of immunotherapy for advanced NPC and have shown considerable progress. In the present review, the rationale for the use of immunotherapy to treat NPC was summarized and the current status, progress and challenges of NPC clinical research on different immunotherapeutic approaches were highlighted, including immune checkpoint inhibitors, vaccines, immunomodulators, adoptive cell transfer and EBV­specific monoclonal antibodies. The comprehensive overview of immunotherapy in NPC may provide insight for clinical practice and future investigation.

Harsh parenting and adolescent non-suicidal self-injury: A moderated mediation model of alienation and cognitive reappraisal.

OBJECTIVE: Harsh parenting has been shown to be associated with non-suicidal self-injury (NSSI) in adolescents. Based on the integrated theoretical model of the development of NSSI and the cognitive-emotional model of NSSI, we proposed a moderated mediation model to investigate "how" and "when" harsh parenting is associated with adolescent NSSI. Specifically, we tested whether feelings of alienation mediated the association between harsh parenting and NSSI, and whether this indirect effect was weakened by cognitive reappraisal as an adaptive emotion regulation strategy. METHODS: A total of 1638 Chinese adolescents (54.7 % girls; ages 12-19 years) completed self-report questionnaires in their classrooms. The questionnaires assessed harsh parenting, feelings of alienation, cognitive reappraisal skills, and incidents of NSSI. RESULTS: Path analyses showed that harsh parenting positively predicted NSSI, and alienation mediated this association. Both the direct effect of harsh parenting on NSSI and the indirect effect through alienation were moderated by cognitive reappraisal. Specifically, cognitive reappraisal skills weakened the direct and indirect associations between harsh parenting and NSSI. CONCLUSIONS: Adolescents may benefit from interventions that decrease feelings of alienation and increase cognitive reappraisal strategies to reduce the risk of NSSI in the context of harsh parenting.

Proposed prognostic subgroups and facilitated clinical decision-making for additional locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma: a retrospective study based on recursive partitioning analysis.

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 < 62,000 copies/ml), and high-risk (involved lesions > 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 < 0.05). Adding locoregional intensity-modulated radiotherapy (LRRT) followed by palliative chemotherapy (PCT) resulted in a significant OS benefit over PCT alone for the low- and intermediate-risk groups (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.

A study on the prevention of hemorrhage and perforation in patients with primary gastric diffuse large-B cell lymphoma during treatment with immunochemotherapy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A novel prognostic nomogram for patients with extragastric mucosa-associated lymphoid tissue lymphoma: A multicenter study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: The nomogram could well distinguish the prognosis of low- and high-risk patients with extragastric MALT lymphoma and is thus recommended for clinical use.

A novel prognostic index for sporadic Burkitt lymphoma in adult patients: a real-word multicenter study.

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 < 10 cm. RESULTS AND CONCLUSIONS: Univariate and multivariate analyses revealed that platelets< 254 × 109/L, albumin< 40 g/L, lactate dehydrogenase≥334 U/L independently predicted unfavorable OS. We used these data as the basis for the prognostic index, in which patients were stratified into Group 1 (no or one risk factor), Group 2 (two risk factors), or Group 3 (three risk factors), which were associated with 5-year OS rates of 88.1, 72.4, and 45%, respectively. In the subgroup analysis for high-risk patients, our prognostic model results showed that high-risk patients with no more than one adverse factor presented a 5-year survival rate of 85.9%, but patients with three adverse factors had a 5-year survival rate of 43.0%. Harrell's concordance index (C-index) of the risk group score was 0.768. Therefore, the new prognostic model could be used to develop risk-adapted treatment approaches for adult sporadic BL.

Surgery and Chemotherapy versus Chemotherapy Only in Older Persons with Primary Intestinal Diffuse Large B-Cell Lymphoma.

BACKGROUND: 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.

The optimal timing of radiotherapy in the combination treatment of limited-stage extranodal natural killer/T-cell lymphoma, nasal type: an updated meta-analysis.

This study was designed to explore the relative efficacy and toxicity of upfront radiotherapy (RT) and late RT in combination treatments for patients with limited-stage extranodal natural killer/T-cell lymphoma nasal type (LS-ENKTL). We searched for clinical trials in the PubMed database that compared upfront RT with late RT in the combined treatment of patients with LS-ENKTL. We systematically evaluated the differences in survival, treatment response, and treatment-related adverse events (AEs) between these two groups. Ten retrospective studies with a total of 1752 patients were included. Upfront RT significantly prolonged the overall survival (OS) and progression-free survival (PFS) of patients compared to late RT in combination with chemotherapy (CT) (HR = 0.72, 95% CI 0.59-0.88, P = 0.001 for OS; HR = 0.57, 95% CI 0.41-0.79, P = 0.0007 for PFS). The complete remission (CR) rate in the upfront RT group was superior to that in the late RT group (HR = 1.61, 95% CI 1.09-2.37, P = 0.02). Patients experienced similar local recurrence-free survival (LRFS), objective response rates (ORR), and toxicity between these two arms (P > 0.05 for all) in the analysis of each subgroup. The survival benefit of upfront RT was not correlated with the RT dose, concurrent chemoradiotherapy (CCRT) (or not), or the CT regimen (P > 0.05 for all). Without compromises in terms of toxicity, RT dose, and treatment modality, upfront RT can significantly benefit OS, PFS, and CR compared to late RT in combination treatment. These findings verified that the upfront RT regimen is more suitable for patients with LS-ENKTL.

KIF15 is involved in development and progression of Burkitt lymphoma.

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-ß 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.

Chemotherapy Plus Radiotherapy Versus Chemotherapy Alone for Patients With Peripheral T-Cell Lymphoma, Not Otherwise Specified.

PURPOSE: Peripheral 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. METHODS: Patients 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. RESULTS: Of 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 <0.001) and disease-specific survival (5-year DSS rate 66.3 versus 44.0%, P <0.001) in the early-stage subgroup, while no apparent survival benefit of adding RT was identified in patients with advanced-stage disease (5-year OS rate 28.7 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. CONCLUSION: Adding 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.

Modified R-CODOX-M/IVAC chemotherapy regimens in Chinese patients with untreated sporadic Burkitt lymphoma.

OBJECTIVE: To characterize modified R-CODOX-M/IVAC-based chemotherapy to lower the severe adverse events in Chinese adult patients with sporadic Burkitt lymphoma. METHODS: We enrolled a retrospective cohort including 123 adult patients with untreated sporadic Burkitt lymphoma from August 2008 to September 2019 at Sun Yat-sen University Cancer Center. We studied a dose-modified and long-course R-CODOX-M/IVAC regimen utilizing a low dose of 1.0 g/m2/cycle cyclophosphamide, 2 g/m2/cycle methotrexate, 4,500 mg/m2/cycle ifosfamide, and 4.0 g/m2/cycle cytarabine. Forty-nine patients with low risk disease underwent 4-6 cycles of dose-modified R-CODOX-M-based chemotherapy. Seventy-four patients with high risk disease underwent 6-8 cycles of dose-modified alternating R-CODOX-M/IVAC regimens. RESULTS: The objective remission was 87.0%. The event-free survival rate and overall survival at 3 years were 81.2% and 92.1%, respectively. Major grade 3-4 adverse events included leukopenia (91.9%), anemia (58.5%), thrombocytopenia (73.2%), and febrile neutropenia (48.8%). A total of 26.0% and 37.4% of patients received red blood cell and platelet transfusions, respectively. We observed 4 cases (3.3%) of septic shock after chemotherapy. Two treatment-related deaths occurred from severe infection. CONCLUSIONS: The modified R-CODOX-M/IVAC chemotherapy regimen was effective for sporadic Burkitt lymphoma in the Chinese population, with a lower toxicity than standard regimens.

Low initial trough concentration of rituximab is associated with unsatisfactory response of first-line R-CHOP treatment in patients with follicular lymphoma with grade 1/2.

For follicular lymphoma (FL) with grade 1/2, the complete response (CR) rate of the first-line R-CHOP treatment was significantly low. In this study, we assessed the rationality of the administration of rituximab for FL patients with grade 1/2 based on concentration-response relationship analyses. Thus, we conducted a prospective pharmacokinetic (PK) study in 68 FL patients with grades 1-3 treated with R-CHOP at 21-day intervals. Plasma rituximab concentrations were quantified using ELISA and the population PK modeling was established with Phoenix® NLMETM. The first cycle trough concentration (C1-trough) of rituximab was a significant independent risk factor for achieving CR in matched-pair logistic regression analysis, rather than the concentrations in later cycles; the recommendatory minimum optimal C1-trough was 13.60 µg/mL. Patients with grade 1/2 had significantly lower C1-trough compared with grade 3 (12.21 µg/mL vs. 23.45 µg/mL, P < 0.001), only 30% patients with grade 1/2 could reach 13.60 µg/mL, compared with 91.67% in patients with grade 3, which was in accord with its unsatisfactory CR rates (43.33% vs. 76.32%). The stage indicating the tumor burden (the target) was a crucial influence factor for C1-trough, accounting for 40.70% of its variability, 70% patients with grade 1/2 were stage IV in this study, since the systemic therapy only started at the disseminated disease stage. The initial dose of 1800 mg was recommended by Monte Carlo simulation for patients with grade 1/2. In summary, low C1-trough accounted for low-grade FL's unsatisfactory CR rate, designing the first dosage of rituximab should be a very important component of individualized therapy for FL.

Combination of crizotinib and chemotherapy in patients with relapsed or refractory anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL).

Our aim was to explore the role of crizotinib, targeted anaplastic lymphoma kinase (ALK), on r/r systemic anaplastic large cell lymphoma (sALCL). The treated group prospectively screened 20 patients. After taking crizotinib in the first week, 16 patients who were tolerant and sensitive received the combination of crizotinib with chemotherapy. The control group included 27 patients receiving chemotherapy in the same hospital during the same period. The objective remission rates of the treated and control group were 81.3% and 74.1% (p = .869), respectively. The progression-free survival rates at two years in treated and control group were 68.7% and 45.0% (HR = 0.42, 95% CI 0.17-0.99, p < .05), respectively. The overall survival rates at two years in the treated and control group were 86.1% and 78.9% (p = .385, HR = 0.51, 95% CI 0.11-2.30), respectively. The main adverse events included elevated transaminase, diarrhea, and vision abnormalities. Thus, the combination of crizotinib with chemotherapy might be effective in ALK-positive and crizotinib sensitive r/r sALCL patients.

A proposal for a prognostic index for non-nasal type natural killer/T cell lymphoma after asparaginase-based treatment.

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.

Platelet-derived alpha-granules are associated with inflammation in patients with NK/T-cell lymphoma-associated hemophagocytic syndrome.

Due to the variable overlap of multiple symptoms, accurate early diagnosis of NK/T-cell lymphoma-associated hemophagocytic syndrome (NK/T-LAHS) is difficult, making the prognosis extremely poor. Hemophagocytic syndrome (HPS) is now diagnosed primarily based on the hemophagocytic lymphohistiocytosis (HLH)-2004 diagnostic criteria, and platelet count is one of the baseline evaluations. However, in our study, the data showed that decreased platelets were not only a clinical feature of HPS but also the key cells that regulate inflammation by releasing α-granules containing upregulated platelet factor 4 (PF4) and downregulated platelet-derived growth factors (PDGFs). Furthermore, we found that angiopoietin-4 (ANG-4), which has significant differential expression, has been less reported, that may affect hematopoiesis and proinflammatory responses and can be used as diagnostic biomarkers together with PF4 and PDGFs.