Immunotyping of peripheral blood lymphocytes by flow cytometry reveals Th cell as a potential prognostic biomarker for extranodal NK/T-cell lymphoma.

This study aimed to explore the distribution, characteristics and prognostic value of baseline peripheral blood lymphocyte subsets in patients with extranodal NK/T-cell lymphoma (NKTCL). We conducted this cross-sectional study of 205 newly-diagnosed NKTCL patients receiving first-line chemotherapy and radiation at our institute between 2010 and 2020. Baseline peripheral blood lymphocytes were detected using flow cytometry, and the clinical value was analyzed. Compared with healthy controls, patients with NKTCL presented with a distinct peripheral immunity with higher levels of cytotoxic CD8+ T cells (33.230 ± 12.090% vs. 27.060 ± 4.010%, p < 0.001) and NKT cells (7.697 ± 7.219% vs. 3.550 ± 2.088%, p < 0.001) but lower proportions of suppressive regulatory T cells (Treg, 2.999 ± 1.949% vs. 3.420 ± 1.051%, p = 0.003) and CD4+ helper T cells (Th, 33.084 ± 11.361% vs. 37.650 ± 3.153%, p < 0.001). Peripheral lymphocytes were differentially distributed according to age, stage, and primary site in patients with NKTCL. The proportion of Th cells/lymphocytes was associated with tumor burden reflected by stage (p = 0.037), serum lactate dehydrogenase (p = 0.0420), primary tumor invasion (p = 0.025), and prognostic index for NK/T-cell lymphoma (PINK) score (p = 0.041). Furthermore, elevated proportions of T cells (58.9% vs. 76.4%, p = 0.005), Th cells (56.3% vs. 68.8%, p = 0.047), or Treg cells (49.5% vs. 68.9%, p = 0.040) were associated with inferior 5-year progression-free survivals (PFS) via univariable survival analysis. Multivariate cox regression revealed elevated Th cells as an independent predictor for unfavorable PFS (HR = 2.333, 95% CI, 1.030-5.288, p = 0.042) in NKTCL. These results suggested the proportion of Th cells positively correlated with tumor burden and was a potential non-invasive biomarker for inferior survival for patients with NKTCL.

Clinical features, prognostic stratification, and treatment of advanced-stage non-nasal type extranodal natural killer/T-cell lymphoma: a multi-institutional real-world study.

The present study aimed to investigate the clinical features, prognosis, and treatment of advanced-stage non-nasal type extranodal natural killer/T-cell lymphoma (ENKTCL). This real-world study retrospectively reviewed 56 newly diagnosed advanced-stage non-nasal type ENKTCL patients from two large-scale Chinese cancer centers in the last 10-15 years and screened 139 newly diagnosed advanced-stage nasal type ENKTCLs admitted during the same period for comparison. The non-nasal type ENKTCLs exhibited significantly higher Ki-67 expression levels compared to nasal type disease (P = 0.011). With a median follow-up duration of 75.03 months, the non-nasal group showed slightly inferior survival outcomes without statistically significant differences compared to the nasal group (median overall survival (OS): 14.57 vs. 21.53 months, 5-year OS: 28.0% vs. 38.5%, P = 0.120). Eastern Cooperative Oncology Group (ECOG) score ≥ 2 (hazard ratio (HR) = 2.18, P = 0.039) and lactic dehydrogenase (LDH) elevation (HR = 2.44, P = 0.012) were significantly correlated with worse OS in the non-nasal group. First-line gemcitabine-based chemotherapy regimens showed a trend toward slightly improved efficacy and survival outcomes compared to non-gemcitabine-based ones in the present cohort of non-nasal ENKTCLs (objective response rate: 91.7% vs. 63.6%, P = 0.144; complete response rate: 50.0% vs. 33.3%, P = 0.502; median progression-free survival: 10.43 vs. 3.40 months, P = 0.106; median OS: 25.13 vs. 9.30 months, P = 0.125), which requires further validation in larger sample size studies. Advanced-stage non-nasal type patients could achieve comparable prognosis with nasal cases after rational therapy. The modified nomogram-revised index (including age, ECOG score, and LDH) and modified international prognostic index (including age, ECOG score, LDH, and number of extranodal involvement) functioned effectively for prognostic stratification in non-nasal type ENKTCLs.

Treatment and prognosis of newly diagnosed advanced-stage extranodal natural killer / T cell lymphoma: a single-center real-world study across two decades.

INTRODUCTION: Although there is now a consensus on asparaginase-based chemotherapy regimens in treatment of advanced-stage extranodal natural killer / T cell lymphomas (ENKTCLs), patient survival in the real-world setting is still not optimistic according to previous literature reports, and the optimal chemotherapeutic regimens and integration of different therapeutic methods under the concept of combined-modality treatment still need to be further explored and verified. METHODS: Newly diagnosed stage Ⅲ / Ⅳ ENKTCL patients from Chinese National Cancer Center in the last two decades were retrospectively collected and analyzed. Overall survival (OS) and progression-free survival (PFS) were determined as primary endpoints. Log-rank tests and Cox proportional hazard models were performed to test for survival differences between subgroups and examine the univariable and multivariable associations. RESULTS: The study included 83 newly diagnosed stage Ⅲ / Ⅳ ENKTCL patients and reported a median OS of 26.07 months and an estimated 5-year OS of 41.3% with a median follow-up of 82.13 months. First-line asparaginase- compared to non-asparaginase-based regimens significantly prolonged PFS (P=0.007; HR=0.48, P=0.020) and showed a tendency to improve OS (P=0.064; HR=0.74, P=0.359). Gemcitabine-based regimens also exhibited a trend towards improved PFS (P=0.048; HR=0.59, P=0.164) and OS (P=0.008; HR=0.67, P=0.282) compared to non-gemcitabine-based ones. The asparaginase and gemcitabine combinations yielded a 5-year OS of 55.0% and led to significantly superior PFS (P=0.020; HR=0.40, P=0.022) and slightly better OS (P=0.054; HR=0.79, P=0.495) compared to the remaining regimens. First-line combined-modality treatment integrating chemotherapy and radiotherapy improved PFS (P=0.051) and OS (P=0.036) compared to chemotherapy alone. Four autologous hematopoietic stem cell transplantation recipients reached a median OS of 58.34 months. CONCLUSION: Asparaginase and gemcitabine alone brought favorable impact on PFS and OS; and the asparaginase and gemcitabine combination chemotherapy yielded the optimal efficacy, response duration and survival outcomes. Combined-modality treatment including potent chemotherapy supplemented by radiotherapy and/or consolidative transplantation could improve prognosis in newly diagnosed advanced-stage ENKTCLs.

Intensive therapy can improve long-term survival in newly diagnosed, advanced-stage extranodal NK/T-cell lymphoma: A multi-institutional, real-world study.

The study investigated the treatment and prognosis of advanced-stage extranodal natural killer/T-cell lymphoma (ENKTL). With a median follow-up of 75.03 months, the median overall survival (mOS) for the 195 newly diagnosed stage III/IV ENKTL patients was 19.43 months, and estimated 1-, 2-, 3- and 5-year OS were 59.5%, 46.3%, 41.8% and 35.1%, respectively. Chemotherapy (CT) + radiotherapy (RT) compared to CT alone (P = .007), and hematopoietic stem cell transplantation (HSCT) compared to non-HSCT (P < .001), both improved OS. For patients ≤60 years and ineligible for HSCT, other therapies with complete remission led to comparable OS (P = .141). Nine patients ever treated with chidamide achieved a median progression-free survival (mPFS) and mOS of 53.63 (range, 3.47-92.33) and 54.80 (range, 5.50-95.70) months, and four with chidamide maintenance therapy (MT) achieved a mPFS and mOS of 55.83 (range, 53.27-92.33) and 60.65 (range, 53.70-95.70) months, possibly providing an alternative option for non-HSCT patients. Non-anthracycline (ANT)- compared to ANT-, asparaginase (Aspa)- compared to non-Aspa- and gemcitabine (Gem)- compared to non-Gem-based regimens, prolonged PFS (P = .031; P = .005; P = .009) and OS (P = .010; P = .086; P = .003), respectively. Multivariate analysis demonstrated that Gem-based regimens improved PFS (HR = 0.691, P = .061) and OS (HR = 0.624, P = .037). Gem + Aspa combinations slightly improved PFS and OS compared to regimens containing Gem or Aspa alone (P > 0.05). First-line "intensive therapy," including CT (particularly Gem + Aspa regimens), RT, HSCT and alternative chidamide MT, was proposed and could improve long-term survival for advanced-stage ENKTLs. Ongoing prospective clinical studies may shed further light on the value of chidamide MT.

Comparing the role of different treatment modalities in locoregionally advanced olfactory neuroblastoma: The 20-year clinical experience of a single institution.

BACKGROUND: The clinical value of different treatment modalities, especially systemic chemotherapy (CT) in patients with locoregionally advanced olfactory neuroblastoma (LA ONB) remains unclear. METHODS: Patients with LA ONB from 2000 to 2020 at our center were collected retrospectively. The entire cohort was divided into combined systemic and local therapy (CSLT) versus local therapy (LT) groups (grouping method 1), and the same cohort was divided into neoadjuvant chemotherapy (NAC) versus non-NAC groups (grouping method 2). CSLT group included patients treated with CT + LT. LT group included patients treated with surgery (SG), radiotherapy (RT), concurrent chemoradiotherapy (CCRT), or any combination of the above methods. LT group was further divided into mono-modality local therapy (MOLT) group and multi-modality local therapy (MULT) group. MOLT group included patients treated with RT alone or SG alone. MULT group included patients treated with SG + RT/CCRT, or CCRT alone. NAC group included patients treated with NAC + LT ± adjuvant chemotherapy (ADC). Non-NAC group included patients who received LT ± ADC. RESULTS: A total of 111 patients with LA ONB were included. The median follow-up was 80.2 months (range, 2.1-254.9). The 5- and 10-year OS rates were 70.2% and 61.3%, respectively. In univariate analysis, patients treated with NAC (n = 43) had significantly better overall survival (OS) compared with those without NAC (n = 68) (p = 0.041). Patients in MULT group (n = 45) had significantly improved OS (p = 0.004) and PFS (p = 0.003) compared with those in MOLT group (n = 15). Multivariate analysis identified NAC and CSLT (n = 51) were independent prognostic factors for superior OS (p = 0.020, p = 0.046). CONCLUSIONS: Our study suggested that CSLT, especially a combination of NAC and LT, improved the survival of patients with LA ONB. Multiple treatment modalities yielded better PFS and OS compared to single-modality treatment.

Prognostic Assessment and Risk Stratification in Patients With Postoperative Major Salivary Acinar Cell Carcinoma.

OBJECTIVE: To investigate the clinicopathological features and prognosis of postoperative major salivary acinar cell carcinoma (MSACC) and develop a prognostic model. STUDY DESIGN: Retrospective cohort analysis of a public database. SETTING: Patients with MSACC were identified from the Surveillance, Epidemiology, and End Results database (1975-2019). METHODS: Overall survival (OS) was evaluated using Kaplan-Meier curves and a log-rank test. Univariate and multivariate Cox analyses were performed to explore independent prognostic factors. The prognostic model was constructed using screened variables and further visualized with a nomogram and web calculator, and assessed by concordance index, the area under the curve, calibration curve, and decision-making curve analysis. RESULTS: An upward trend in the incidence of MSACC was observed throughout the study period. A total of 1398 patients were enrolled (training cohort: 978; validation cohort: 420), and the 5- and 10-year OS rates were 97.7% and 81.6%, respectively. Age, marital status, sex, histological grade, T stage, and lymph node status were identified as prognostic factors for OS. A novel nomogram was developed and showed excellent discrimination and clinical applicability. Additionally, a web calculator was designed to dynamically predict patient survival. Based on the nomogram-based score, a risk stratification system was constructed to distinguish patients with different risks. The OS of high-risk patients was significantly lower than that of the low-risk subgroup. CONCLUSION: Long-term survival in postoperative MSACC was influenced by 6 prognostic factors. The proposed model enables individualized survival prediction and risk stratification, prompting us to be vigilant in high-risk subgroups and consider timely adjustment of subsequent treatment.

Comparison analysis of first-line asparaginase- versus non-asparaginase-based regimens for early-stage extranodal NK/T-cell lymphoma.

The present study investigated the efficacy and toxicity profile of first-line asparaginase (ASP)-based versus non-ASP-based regimens in treating early-stage extranodal NK/T-cell lymphoma (ENKTCL) in non-anthracycline therapy era. This multi-center, real-world retrospective study consisted 305 newly diagnosed localized ENKTCL patients who were treated with sequential chemoradiation between 2010 and 2020 in China: 190 cases received ASP-based regimens and 115 cases received non-ASP-based regimens. Propensity score matching and multivariable analyses were used to compare survivals and toxicities between the two treatment groups. Non-ASP-based regimens achieved comparable survivals compared with ASP-based regimens in the entire cohort. The 5-year overall survival (OS), progression-free survival (PFS) rates were 84.7% and 73.5% for non-ASP-based regimens, and 87.7% (P=0.464) and 74.6% (P=0.702) for ASP-based regimens. The non-inferior survivals of non-ASP-based regimens were consistent after adjustment using PSM and multivariable analyses. However, survival benefits of ASP varied in different treatment modalities. Among patients receiving sequential chemotherapy and radiation (CT+RT±CT), ASP-based regimens achieved higher complete remission rate (54.3 vs. 34.5%, P=0.047) and more favorable survivals compared with non-ASP-based regimens (5-year OS, 87.0 vs. 69.0%, P=0.028). However, for patients receiving sequential radiation and chemotherapy (RT+CT), non-ASP-based regimens achieved comparable favorable survivals as ASP-based regimens. Besides, liver injury, malnutrition, and coagulative dysfunction were significantly more commonly documented in ASP-based regimens. These findings suggested that ASP was an effective agent in treating ENKTCL, especially among those receiving induction CT and RT. For patients who received upfront RT, non-ASP-based regimens might be a comparably effective and more tolerable treatment option.

Survival and prognosis of metastatic head and neck adenoid cystic carcinoma.

BACKGROUND: To investigate the clinical characteristics, treatment, and prognosis of patients with metastatic head and neck adenoid cystic carcinoma (HNACC). METHOD: The clinical data of metastatic HNACC from 1999 to 2020 at the National Cancer Center of China were retrospectively collected. RESULTS: One hundred seventy-four patients with metastatic HNACC were enrolled and median overall survival (OS) was 45.6 months. Univariate analysis indicated that smoking history, disease-free interval (DFI), number and sites of metastases, and systemic therapy were associated with OS. In the multivariate analysis, non-smokers, DFI ≥3 years, and lung metastasis were prognostic factors. Local therapy for localized disease could prolong survival in patients with both recurrent and metastatic disease. CONCLUSION: No smoking history, DFI ≥3 years, and lung metastasis were favorable prognostic factors. Local therapy for metastases could not provide survival benefits, but local therapy for localized disease may prolong survival. Whether initial systemic therapy could improve prognosis needs further exploration.

First-Line Chemoradiation With or Without Chidamide (Tucidinostat) in Patients With Intermediate- and High-Risk Early-Stage Extranodal Nasal-Type Natural Killer/T-Cell Lymphoma: A Randomized Phase 2 Study in China.

PURPOSE: We investigated the safety and efficacy profile of intensity-modulated radiation therapy (IMRT) followed by gemcitabine, dexamethasone, cisplatin (GDP), plus chidamide in the first-line setting for intermediate- and high-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type (ENKTCL). METHODS: This was an open-label, randomized phase 2 trial performed at 2 centers in China. Patients were eligible if they were newly-diagnosed with intermediate- and high-risk early-stage ENKTCL with at least one risk factor based on a nomogram-revised risk index: >60 years old, elevated serum lactate dehydrogenase, invasion of the primary tumor, stage II or Eastern Cooperative Oncology Group performance status >1 or stage II disease. Patients were treated with IMRT followed by GDP, with or without chidamide, in the first-line setting. Two-year progression-free survival (PFS) comprised the primary endpoint. Toxicities, the 2-year overall survival (OS), and the response rate comprised the secondary endpoints. RESULTS: Eligible patients (N = 74) were enrolled between May 2015 and December 2019. Among them, 37 patients were treated with IMRT + GDP + chidamide (chidamide group), whereas 37 cases were treated with IMRT + GDP (control group). Follow-up comprised a median of 43.4 months (range, 1.0-74.6 months). The objective response rate was 86.5% in the chidamide group and 78.4% in the control group (P = .359) at the end of treatment completion. The 2 year OS and PFS rates were 89.2% and 75.2% in the chidamide group versus 83.8% (P = .388) and 70.2% (P = .821) in the control group. The main adverse events were hematological toxicities and mucositis, with similar rates in the 2 groups (P > .05). CONCLUSIONS: The addition of chidamide to IMRT + GDP as first-line treatment achieved similar treatment outcomes and tolerable toxicities compared with IMRT + GDP in patients with intermediate- and high-risk early-stage ENKTCL.

Homologous Recombination Deficiency (HRD) and BRCA 1/2 Gene Mutation for Predicting the Effect of Platinum-Based Neoadjuvant Chemotherapy of Early-Stage Triple-Negative Breast Cancer (TNBC): A Systematic Review and Meta-Analysis.

BACKGROUND: Platinum-based agents may benefit patients with triple-negative breast cancer (TNBC) whose tumors are dysfunctional in DNA repair mechanisms associated with the homologous recombination repair (HRR) genes. The purpose of this meta-analysis was to assess the values of BRCA1/2 and homologous recombination deficiency (HRD) in the prediction of the pathological complete response (pCR) rates of patients with TNBC treated with platinum-based neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Patients with TNBC with BRCA or HRD status from platinum-based NAC trials were analyzed. The odds ratios (ORs) with 95% confidence intervals (CI) for the identified studies were calculated. RESULTS: 13 eligible studies between January 2000 and September 2021 were included through systematic literature searches of Embase, PubMed, Cochrane, and Web of Science databases. In 12 trials with BRCA status, 629 of 1266 (49.7%) patients with TNBC achieved pCR with platinum-based NAC, including 134 out of 222 (60.4%) BRCA1/2-mutated patients and 495 out of 1044 (47.4%) BRCA wildtype patients (OR, 1.62; 95% CI, 1.20-2.20). The prevalence of HRD was higher than BRCA1/2 mutations in patients with TNBC (69.2% vs. 17.5%). In six trials with HRD information, pCR rates of HRD-positive patients with TNBC were significantly higher than those of HRD-negative patients with TNBC (241/412, 58.5% vs. 60/183, 32.8%, OR, 3.01; 95% CI, 2.07-4.39, p < 0.001). CONCLUSIONS: BRCA1/2-mutated and HRD-positive patients with TNBC could benefit from platinum-based NAC. In the future, a prospective study using unified HRD testing criteria is warranted for further investigation.

Liquid biopsy in extranodal NK/T-cell lymphoma: a prospective analysis of cell-free DNA genotyping and monitoring.

Satisfactory tumor material is often hard to obtain for molecular analysis in extranodal natural killer (NK)/T-cell lymphoma (NKTCL) at present. However, the accuracy and utility of circulating cell-free DNA (cfDNA) genotyping have not been adequately assessed in NKTCL. We therefore performed targeted next-generation sequencing on tumor tissues and a series of longitudinal plasma samples prospectively collected from a cohort of high-risk NKTCL patients. Concordance of genotyping results of paired baseline tumor and cfDNA and the predictive value of dynamic cfDNA monitoring were evaluated. At baseline, 59 somatic variants in 31 genes were identified in tumor and/or plasma cfDNA among 19 out of 24 high-risk NKTCL patients (79.2%). Plasma cfDNA had a sensitivity of 72.4% for detection of somatic variants identified in tumor biopsies before treatment. Plasma cfDNA also allowed the identification of mutations that were undetectable in tumor biopsies. These results were also verified in a validation cohort of an additional 23 high-risk NKTCL patients. Furthermore, longitudinal analysis showed that patients with rapid clearance of NKTCL-related mutations from plasma had higher complete remission rates (80.0% vs 0%; P = .004) and more favorable survival (1-year progression-free survival [PFS] rate, 79.0% vs 20.0%; P = .002) compared with those with persisting or emerging mutations in plasma. In addition, low cfDNA concentration before treatment was associated with favorable survival outcome for patients with NKTCL (1-year PFS, 90.0% vs 36.4%; P = .012). In conclusion, cfDNA mirrors tumor biopsy for detection of genetic alterations in NKTCL and noninvasive dynamic plasma cfDNA monitoring might be a promising approach for tracking response and survival outcome for patients with NKTCL.

Abnormal pretreatment coagulation factor levels correlate with poor prognosis in patients with early-stage extranodal nasal-type natural/killer T cell lymphoma.

Coagulative dysfunction is frequently observed among patients with extranodal nasal-type natural killer/T cell lymphoma (NKTCL) in our clinical practice. However, the true prognostic value of coagulation factors in patients with NKTCL has not been evaluated systemically. Data for patients with stage I/II NKTCL who were treated in the Cancer Hospital, Chinese Academy of Medical Sciences, from January 2008 to January 2019 were collected retrospectively. The patients enrolled in this study were initially diagnosed as having early-stage disease. The patients' baseline characteristics and pretreatment laboratory tests for coagulation function, including fibrinogen (FIB) and D-dimer (D-D), were reviewed and analyzed. The influence of coagulative factors on the responses and prognosis of patients with early-stage NKTCL was evaluated. Among 394 patients assessed, 154 were included in this study. Abnormal coagulation function was found in nearly half of the patients (48.1%). Univariate analysis showed that reduced complete remission (CR) was associated with elevated D-D (P = 0.001) and elevated FIB levels (P = 0.006). The D-D level was demonstrated as associated with unfavorable progression-free survival (PFS) (P = 0.003) and overall survival (OS) (P = 0.002). Multivariate analysis indicated that an elevated D-D level was an independent factor for poor clinical response (P = 0.019), PFS (P = 0.046), and OS (P = 0.024). Elevated pretreatment levels of coagulation factors, especially D-D and plasma FIB, are unfavorable predictors for clinical response, OS, and PFS in early-stage NKTCL.