Multicenter phase II study of moderate low-dose radiotherapy in indolent non-Hodgkin lymphoma: CLCG-iNHL-01 protocol.

Background: Radiotherapy is an effective treatment for indolent non-Hodgkin lymphoma (iNHL); however, the optimal radiotherapy dose remains to be determined. We hypothesize that a suitable dose may exist between 4 and 24 Gy. Methods: This prospective multicenter phase II trial intends to recruit 73 sites of iNHL patients, who will receive involved-site radiotherapy of 12 Gy in four fractions. The primary objective is the 6-month clinical complete response rate. Tumor tissue, blood and conjunctival specimens will be collected to identify potential predictive biomarkers. Discussion: The CLCG-iNHL-01 trial will evaluate the efficacy and toxicity of 12 Gy in patients with iNHL and provide information on a novel hypofractionation regimen of low-dose radiotherapy. Clinical Trial Registration: NCT05543070 (ClinicalTrials.gov).

Evidence of cure for extranodal nasal-type natural killer/T-cell lymphoma with current treatment: an analysis of the CLCG database.

Survival from extranodal nasal-type NK/T-cell lymphoma (ENKTCL) has substantially improved over the last decade. However, there is little consensus as to whether a population of patients with ENKTCL can be considered "cured" of the disease. We aimed to evaluate the statistical "cure" of ENKTCL in the modern treatment era. This retrospective multicentric study reviewed the clinical data of 1,955 patients with ENKTCL treated with non-anthracycline-based chemotherapy and/or radiotherapy in the China Lymphoma Collaborative Group multicenter database between 2008 and 2016. A non-mixture cure model with incorporation of background mortality was fitted to estimate cure fractions, median survival times and cure time points. The relative survival curves attained plateau for the entire cohort and most subsets, indicating that the notion of cure was robust. The overall cure fraction was 71.9%. The median survival was 1.1 years in uncured patients. The cure time was 4.5 years, indicating that beyond this time, mortality in ENKTCL patients was statistically equivalent to that in the general population. Cure probability was associated with B symptoms, stage, performance status, lactate dehydrogenase, primary tumor invasion, and primary upper aerodigestive tract site. Elderly patients (>60 years) had a similar cure fraction to that of younger patients. The 5-year overall survival rate correlated well with the cure fraction across risk-stratified groups. Thus, statistical cure is possible in ENKTCL patients receiving current treatment strategies. Overall probability of cure is favorable, though it is affected by the presence of risk factors. These findings have a high potential impact on clinical practice and patients' perspective.

Outcome and risk prediction of early progression in patients with extranodal natural killer/T cell lymphoma from the CLCG study.

Recently, progression-free survival at 24 months (PFS24) was defined as clinically relevant for patients with extranodal NK/T cell lymphoma. Herein, the clinical data from two independent random cohorts (696 patients each in the primary and validation datasets) were used to develop and validate a risk index for PFS24 (PFS24-RI), and evaluate its ability to predict early progression. Patients achieving PFS24 had a 5-year overall survival (OS) of 95.8%, whereas OS was only 21.2% in those failing PFS24 (P<0.001). PFS24 was an important predictor of subsequent OS, independent of risk stratification. The proportion of patients achieving PFS24 and 5-year OS rates correlated linearly among risk-stratified groups. Based on multivariate analysis of the primary dataset, the PFS24-RI included five risk factors: stage II or III/IV, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group score ≥2, primary tumor invasion, and extra-upper aerodigestive tract. PFS24-RI stratified the patients into low-risk (0), intermediate-risk (1-2), high-risk (≥3) groups with different prognoses. Harrell's C-index of PFS24-RI for PFS24 prediction was 0.667 in the validation dataset, indicating a good discriminative ability. PFS24-RI calibration indicated that the actual observed and predicted probability of failing PFS24 agreed well. PFS24-RI provided the probability of achieving PFS24 at an individual patient level.

Risk-based, response-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma in the modern chemotherapy era: A China Lymphoma Collaborative Group study.

We aimed to determine the survival benefits of chemotherapy (CT) added to radiotherapy (RT) in different risk groups of patients with early-stage extranodal nasal-type NK/T-cell lymphoma (ENKTCL), and to investigate the risk of postponing RT based on induction CT responses. A total of 1360 patients who received RT with or without new-regimen CT from 20 institutions were retrospectively reviewed. The patients had received RT alone, RT followed by CT (RT + CT), or CT followed by RT (CT + RT). The patients were stratified into different risk groups using the nomogram-revised risk index (NRI). A comparative study was performed using propensity score-matched (PSM) analysis. Adding new-regimen CT to RT (vs RT alone) significantly improved overall survival (OS, 73.2% vs 60.9%, P < .001) and progression-free survival (PFS, 63.5% vs 54.2%, P < .001) for intermediate-risk/high-risk patients, but not for low-risk patients. For intermediate-risk/high-risk patients, RT + CT and CT + RT resulted in non-significantly different OS (77.7% vs 72.4%; P = .290) and PFS (67.1% vs 63.1%; P = .592). For patients with complete response (CR) after induction CT, initiation of RT within or beyond three cycles of CT resulted in similar OS (78.2% vs 81.7%, P = .915) and PFS (68.2% vs 69.9%, P = .519). For patients without CR, early RT resulted in better PFS (63.4% vs 47.6%, P = .019) than late RT. Risk-based, response-adapted therapy involving early RT combined with CT is a viable, effective strategy for intermediate-risk/high-risk early-stage patients with ENKTCL in the modern treatment era.

Risk-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma: analysis from a multicenter study.

The optimal combination and sequence of radiotherapy (RT) and chemotherapy (CT) for extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) are not well-defined. The aim of this study was to create a risk-adapted therapeutic strategy for early-stage NKTCL. A total of 1273 early-stage patients from 10 institutions were reviewed. Patients received CT alone (n = 170), RT alone (n = 253), RT followed by CT (n = 209), or CT followed by RT (n = 641). A comprehensive comparative study was performed using multivariable and propensity score-matched analyses. Early-stage NKTCL was classified as low risk or high risk based on 5 independent prognostic factors (stage, age, performance status, lactate dehydrogenase, primary tumor invasion). RT alone and RT with or without CT were more effective than CT alone (5-year overall survival [OS], 69.6% and 67.7% vs 33.9%, P < .001). For low-risk patients, RT alone achieved a favorable OS (88.8%); incorporation of induction or consolidation CT did not provide additional benefit (86.9% and 86.3%). For high-risk patients, RT followed by CT resulted in superior OS (72.2%) compared with induction CT and RT (58.3%, P = .004) or RT alone (59.6%, P = .017). After adjustment, similar significant differences in OS were still observed between treatment groups. New CT regimens provided limited benefit in early-stage NKTCL. Risk-adapted therapy involving RT alone for low-risk patients and RT consolidated by CT for high-risk patients is a viable, effective strategy for early-stage NKTCL.

Optimizing the combination of chemotherapeutic drugs along with radiotherapy for extranodal NK/T-cell lymphoma.

Background: Extranodal natural killer/T-cell lymphoma (ENKTCL) has a unique treatment principle. However, the optimal combination of drugs along with radiotherapy (RT) is unknown. Design: Retrospective cohort study. Objectives: We screened multiple drug combinations to identify the most efficacious therapeutic combinations. Methods: We reviewed 3105 patients who received 40 chemotherapy regimens with different combinations of 9 drug classes and/or RT. Least absolute shrinkage and selection operator and multivariable Cox regression analyses were used to screen efficacious single drugs and identify optimal combinations for overall survival (OS). Inverse probability of treatment weighting (IPTW) and multivariable analyses were used to compare survival between treatment regimens. Results: Screening and validation revealed RT, asparaginase (ASP), and gemcitabine (GEM) to be the most efficacious single modality/drug. RT remained an important component of first-line treatment, whereas ASP was a fundamental drug of non-anthracycline (ANT)-based regimens. Addition of RT to non-ANT-based or ASP/GEM-based regimens, or addition of an ASP-drug into ANT-based or GEM/platinum-based regimens, improved 5-year OS significantly. Use of ASP/GEM-based regimens was associated with significantly higher 5-year OS (79.9%) compared with ASP/ANT-based (69.2%, p = 0.001), ASP/methotrexate-based (63.5%, p = 0.011), or ASP/not otherwise specified-based (63.2%, p < 0.001) regimens. The survival benefit of ASP/GEM-based regimens over other ASP-based regimens was substantial across risk-stratified and advanced-stage subgroups. The survival benefits of a combination of RT, ASP, and GEM were consistent after adjustment for confounding factors by IPTW. Conclusion: These results suggest that combining ASP/GEM with RT for ENKTCL is an efficacious and feasible therapeutic option and provides a rationale and strategy for developing combination therapies.

Characteristics and prognosis of distant metastasis after primary treatment for early-stage extranodal nasal-type natural killer/T-cell lymphoma from the China Lymphoma Collaborative Group database.

This study aimed to investigate the characteristics and prognosis of distant metastasis (DM) after primary treatment for early-stage extranodal nasal-type natural killer (NK)/T-cell lymphoma (ENKTCL). A total of 1619 patients from the China Lymphoma Collaborative Group database were retrospectively reviewed. The cumulative incidence of DM was assessed using Fine and Gray's competing risk analysis. The correlation between DM sites was evaluated using phi coefficients, while DM sites were classified using hierarchical clustering. Regression analysis was used to assess the linear correlation between DM-free survival (DMFS) and overall survival (OS). The 5-year cumulative DM rate was 26.2%, with the highest annual hazard rate being in the first year (14.9%). The most frequent DM sites were the skin and soft tissues (SSTs, 32.4%) and distant lymph nodes (LNs, 31.3%). DM sites were categorized into four subgroups of distinct prognosis - distant LN, SST, extracutaneous site, and lymphoma-associated hemophagocytic lymphohistiocytosis. SST or distant LN, solitary metastasis, and late-onset DM demonstrated a relatively favorable prognosis. Contemporary chemotherapy significantly decreased DM rates and improved DMFS. Decreased DM rates were further associated with increased OS probabilities. Our findings improve the understanding of the variable clinical behaviors of early-stage ENKTCL based on four distinct DM sites and thus provide guidance for future therapeutic decisions, metastatic surveillance, and translational trial design.

Clinical characteristics, treatment, and survival of 30 patients with gastrointestinal natural killer/T-cell lymphoma.

BACKGROUND: The gastrointestinal (GI) tract is the second most frequent extranasal involvement site for ENKTL. This study aimed to explore the clinicopathological features, treatment models, survival outcomes, and prognosis of gastrointestinal ENKTL (GI-ENKTL). METHODS: The clinical data of GI-ENKTL patients were extracted from the China Lymphoma Collaborative Group (CLCG) database and were analyzed retrospectively. RESULTS: A total of 30 patients were enrolled, with a male/female ratio of 4:1 and a median age of 42 years. Twenty-nine patients received chemotherapy, of whom 15 patients received asparaginase-based (ASP-based) regimens. Moreover, seven received surgery and three received radiotherapy. The overall response an d complete remission rates were 50.0% and 30.0% for the whole cohort, 50.0% and 37.5% for patients treated with ASP-based regimens, and 50.0% and 25.0% for those treated with non-ASP-based regimens, respectively. The median follow-up was 12.9 months and the 1-year overall survival rate was 40.0% for the whole cohort. For those patients in an early stage, ASP-based regimens resulted in a superior 1-year progression-free survival rate compared to non-ASP-based regimens (100.0% vs. 36.0%, p = .07). However, ASP-based regimens did not improve survival in patients at an advanced stage. CONCLUSION: GI-ENKTL still has a poor prognosis, even in the era of modern asparaginase-based treatment strategies.

Effectiveness and Safety of Iguratimod Monotherapy or Combined With Methotrexate in Treating Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Objectives: We aimed to estimate the effectiveness and safety of iguratimod (IGU) monotherapy or in combination with methotrexate (MTX) in treating rheumatoid arthritis (RA) to provide an evidence-primarily-based foundation for clinical application. Methods: We conducted a systematic review of the meta-analysis using eight databases and two clinical trial websites searching for randomized controlled trials (RCTs) from conception to 15 March 2022, based on outcomes of patients with RA treated with IGU. The evidence quality assessment of primary outcomes was evaluated by the GRADE tool, and RevMan 5.3 and StataMP 14.0 were used to perform this research. Results: A total of 4302 patients with RA from 38 RCTs was included in this research. Pooled results demonstrated as follows: 1) Compared with methotrexate (MTX) alone, IGU alone was superior in improving ACR20 and DAS28-ESR, while having no significant difference in ACR50 and ACR70 [ACR20: (RR 1.15, 95% CI 1.05-1.27, p = 0.004); ACR50: (RR 0.97, 95% CI 0.66-1.44, p = 0.88); ACR70: (RR 0.92, 95% CI 0.45-1.90, p = 0.83); DAS28-ESR: mean difference (MD) -0.15, 95% CI -0.27 to -0.03, p = 0.01]. 2) Compared with MTX alone, IGU + MTX was more effective in improving ACR20, ACR50, ACR70, and DAS28-ESR. [ACR20: (RR 1.24, 95% CI 1.14-1.35, p < 0.00001); ACR50: (RR 1.96, 95% CI 1.62-2.39, p <0.00001); ACR70: (RR 1.91, 95% CI 1.41-2.57, p < 0.0001)]; [DAS28-ESR: (MD) -1.43, 95% CI -1.73 to -1.12, p < 0.00001]. 3) Compared with MTX + leflunomide (LEF), ACR20, ACR50, ACR70, and DAS28-ESR of IGU + MTX had no significant difference [ACR20: (RR 1.06, 95% CI 0.94-1.19, p = 0.38); ACR50: (RR 1.10, 95% CI 0.66-1.84, p = 0.72); ACR70: (RR 1.20, 95% CI 0.45-3.20, p = 0.71); DAS28-ESR: (MD -0.02, 95% CI -0.13 to -0.10, p = 0.77)]. 4) Compared with MTX + hydroxychloroquine (HCQ), IGU + MTX was superior in improving DAS28-ESR (MD -2.16, 95% CI -2.53 to -1.79, p < 0.00001). 5) Compared with MTX + tripterygium glycosides (TGs), IGU + MTX was more effective in improving DAS28-ESR (MD -0.94, 95% CI -2.36 to 0.48, p = 0.19). 6) There were no significant differences in adverse events (AEs) between the groups of IGU vs. MTX (RR 0.96, 95% CI 0.71-1.31, p = 0.80), IGU + MTX vs. MTX (RR 1.10, 95% CI 0.90-1.35, p = 0.34), IGU + MTX vs. MTX + HCQ (RR 0.64, 95% CI 0.29-1.42, p = 0.27), and IGU + MTX vs. MTX + TGs (RR 0.75, 95% CI 0.28-2.02, p = 0.57). The incidence of AEs in the IGU + MTX group was lower than the MTX + LEF group (RR 0.83, 95% CI 0.71-0.98, p = 0.03). Conclusion: Compared to the MTX alone subgroup, IGU alone offers clear advantages in improving ACR20 and DAS28-ESR, despite the insufficient evidence for DAS28-ESR findings. IGU + MTX shows clear benefits in improving ACR20, ACR50, ACR70, and DAS28-ESR scores compared to standard therapies. When the intervention (IGU alone or IGU + MTX) lasted for 52 weeks, it demonstrated superior efficacy in improving ACR20 of patients without prominent adverse events. Notably, IGU or IGU + MTX has apparent advantages in improving ACR20 of first-visit RA, and IGU + MTX has obvious advantages in improving DAS28-ESR of refractory RA. Furthermore, IGU + MTX does not increase the risk of leukopenia, but it can decrease the risk of liver function tests (LFTs), regardless of the age or the stage of RA. Clinical Trial Registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier CRD42022295217.

Chronic occupational exposure to hexavalent chromium causes DNA damage in electroplating workers.

BACKGROUND: Occupational exposure to chromium compounds may result in adverse health effects. This study aims to investigate whether low-level hexavalent chromium (Cr(VI)) exposure can cause DNA damage in electroplating workers. METHODS: 157 electroplating workers and 93 control subjects with no history of occupational exposure to chromium were recruited in Hangzhou, China. Chromium levels in erythrocytes were determined by graphite furnace atomic absorption spectrophotometer. DNA damage in peripheral lymphocytes was evaluated with the alkaline comet assay by three parameters: Olive tail moment, tail length and percent of DNA in the comet tail (tail DNA%). Urinary 8-OHdG levels were measured by ELISA. RESULTS: Chromium concentration in erythrocytes was about two times higher in electroplating workers (median: 4.41 µg/L) than that in control subjects (1.54 µg/L, P < 0.001). The medians (range) of Olive tail moment, tail length and tail DNA% in exposed workers were 1.13 (0.14-6.77), 11.17 (3.46-52.19) and 3.69 (0.65-16.20), and were significantly higher than those in control subjects (0.14 (0.01-0.39), 3.26 (3.00-4.00) and 0.69 (0.04-2.74), P < 0.001). Urinary 8-OHdG concentration was 13.65 (3.08-66.30) µg/g creatinine in exposed workers and 8.31 (2.94-30.83) µg/g creatinine in control subjects (P < 0.001). The differences of urinary 8-OHdG levels, Olive tail moment, tail length and tail DNA% between these two groups remained significant (P < 0.001) even after stratification by potential confounding factors such as age, gender, and smoking status. Chromium exposure was found to be positively associated with chromium levels in erythrocytes, urinary 8-OHdG levels, Olive tail moment, tail length and tail DNA%. Positive dose-response associations were also found between chromium levels in erythrocytes and Olive tail moment, tail length and tail DNA%. CONCLUSION: The findings in this study indicated that there was detectable chromium exposure in electroplating workers. Low-level occupational chromium exposure induced DNA damage.

[Therapeutic efficacy of three-dimensional conformal radiation therapy for patients with locally advanced non-small cell lung cancer].

OBJECTIVE: To compare the treatment results of three-dimensional conformal radiotherapy (3D-CRT) and conventional radiotherapy (2D) for patients with locally advanced non-small-cell lung cancer (NSCLC). METHODS: Five hundred and twenty seven patients with stage III NSCLC treated between Jan 2000 and Dec 2006 were included in this study. Among them, 253 cases were treated with 3D-CRT, and 274 with conventional radiotherapy. In the 3D group, 159 (62.8%) patients received chemoradiotherapy, 77 with total radiotherapy dose of > 60 Gy, 49 with 50 - 60 Gy. In the 2D group, 127 (46.4%) patients received chemoradiotherapy, 48 with total radiotherapy dose of > 60 Gy, 75 with 50 - 60 Gy. RESULTS: The 1-, 3-, 5-year overall survival rates (OS) and median survival time for patients treated with 3D-CRT were 73.3%, 26.1%, 14.4% and 20.1 months, respectively, and that of patients treated with 2D radiotherapy were 61.0%, 13.8%, 8.0% and 15.6 months, respectively (P = 0.002). The 1-, 3-, 5-year cause-specific survival rates (CSS) were 79.0%, 33.3%, and 20.8% for the 3D group and 65.1%, 16.7%, 11.2%, respectively, for the 2D group (P = 0.000). The 1-, 3-, and 5-year locoregional control rates were 71.6%, 34.3% and 31.0% for patients treated with 3D radiotherapy and 57.3%, 22.1% and 19.2%, respectively, for patients treated with 2D treatment (P = 0.002). The results of multivariate analysis showed that 3D-CRT, KPS, clinical tumor response and pretreatment hemoglobin level were independently associated with increased OS and CSS. No statistically significant differences were found between the radiation complications in the two groups. CONCLUSIONS: The results of our study demonstrate that 3D-conformal radiotherapy improves the survival rate in patients with stage III NSCLC compared with that of 2D radiation therapy.

[Individualized analysis of pulse wave shape before and after a single accurate power exercise in patients with long-term chronic diseases].

Objective: To observe and study the resting radial artery pulse wave and changes after a single individualized exercise in patients with long-term chronic diseases. Methods: We selected 16 patients with chronic disease (disease duration ≥5 years) who have been clearly diagnosed as hypertension and/or diabetes and/or hyperlipemia, and first completed the symptom-restricted limit cardiopulmonary exercise testing (CPET). Then a single individualized exercise with Δ50% power as the exercise intensity was completed within one week after CPET. We measured and recorded 50s pulse wave data before exercise and 10 min, 20 min, 30 min after exercise, then obtained each pulse wave characteristic point: starting point (B), main wave peak point (P1), trough of a repulse point (PL), crest of a repulse point (P2), and end point (E). The raw data of the abscissa (time T) and ordinate (amplitude Y) corresponding to each point were derived from the instrument. We treated the end point E of the previous pulse wave as the start point B of the next wave, returned TB to zero, and got the main observation indicators: YB, YP1, YPL, YP2 and TP1, TPL, TP2, TE, and calculated out ΔYP1, ΔYPL, ΔYP2, TE-TPL, (TE-TPL)/TPL, pulse rate, S1, S2 ,ΔYP2-ΔYPL and TP2-TPL as secondary observation indicators. Then calculated the occurrence rate of dicrotic wave with obvious crest. Finally we analyzed individually the 50 s pulse wave data of each patient before and after exercise, and then averaged all the data for overall analysis. Results: ①16 patients with long-term chronic diseases (males 14, females 2), ages (53.7±12.6, 28~80) years old, height (171.7±6.6, 155~183) cm, body weight (80.0±13.5, 54~98) kg. 2YB (91.5±10.8, 71.1~108.6), YP1 (203.6±24.7, 162.7~236.3), YPL (127.1±6.2, 118.2~140.3), YP2 (125.9±6.2, 115.7~137.7), TP1 ( 137.2±22.3, 103.0~197.1), TPL (368.7±29.5, 316.3~434.0), TP2 (422.7±32.8, 376.9~494.7), TE (883.4±95.0, 672.2~1003.3), ΔYP1 (112.1±33.8, 60.3~ 157.5), ΔYPL (35.5±14.2, 17.5~66.2), ΔYP2 (34.4±13.3, 20.0~62.9), TE-TPL (514.6±85.4, 341.4~621.9), (TE-TPL)/TPL (1.4±0.2, 1.0~1.7), pulse rate (68.8±8.4, 59.8~89.3), S1 (0.9±0.3, 0.4~1.4), S2 (0.0±0.0, -0.1~0.0), ΔYP2-ΔYPL (-1.2±2.6,- 6.5 ~ 2.5), TP2-TPL (54.0 ± 10.8, 33.6 ~ 81.1). ③10min after exercise, YB, YPL, YP2, TPL, TE decreased, YP1 increased. ΔYPL, TE-TPL, (TE-TPL)/TPL decreased, and ΔYP1, pulse rate, S1, ΔYP2-ΔYPL, TP2 -TPL increased (all P<0.05). The change trend of pulse wave at 20min and 30min after exercise was consistent with that at 10min after exercise, but most indicators gradually recovered to the resting level before exercise from 10 min. ④The appearance rate of dicrotic wave with obvious crest in 16 patients with long-term chronic disease at rest was 28.6%, and the appearance rate of 10 min (65.7%), 20 min (77.1%), 30 min (73.7%) after exercise was significantly increased (all P< 0.01). In 6 patients, the incidence of dicrotic waves with obvious peaks after exercise was significantly increased, and it could continue until 30 minutes. In 3 patients, the incidence increased significantly 10 minutes after exercise, and began to decrease at 20 minutes. In 1 patient, the rate of appearance only started to increase 20 minutes after exercise. In 2 patients, the incidence increased 10 minutes after exercise and then decreased. In 1 patient, the rate of occurrence increased briefly 20 minutes after exercise and then decreased. The incidence of 1 patient dropped after exercise and began to rise at 20 minutes. In 2 cases, the incidence rate did not increase after exercise, and it increased slightly after 30 minutes. Conclusion: In patients with long-term chronic diseases, the radial artery pulse wave is short and the dicrotic wave is not obvious or even disappears. After a single precise power exercise, the main wave increases, the position of the dicrotic wave decreases, and the amplitude increases. The specific response should be analyzed individually.

[Individualization analysis of pulse wave shape characteristics before and after single precise power exercise in young healthy subjects].

Objective: To observe and study the resting radial artery pulse wave and the pulse wave changes after a single individualized exercise in young healthy normal subjects. Methods: We selected 16 young healthy graduate students, advanced training doctors, and visiting scholars from Fuwai Hospital without any disease diagnosis and low daily exercise. They first completed the symptom-restricted limit cardiopulmonary exercise testing (CPET). A single individualized exercise with Δ50% power as the exercise intensity was completed within one week after CPET. We measured and recorded 50 s pulse wave data before exercise and 10 min, 20 min, 30min after exercise, let the instrument automatically fix the point and then manually recheck to obtain each pulse wave characteristic point: starting point (B), main wave peak point (P1), trough of a repulse point (PL), crest of a repulse point (P2), and end point (E), and the raw data of the abscissa (time T) and ordinate (amplitude Y) corresponding to each point were derived from the instrument. We treated the end point E of the previous pulse wave as the start point B of the next wave, returned TB to zero, and got the main observation indicators: YB, YP1, YPL, YP2 and TP1, TPL, TP2, TE, and calculated out ΔYP1 (YP1-YB), ΔYPL (YPL-YB), ΔYP2 (YP2-YB), TE-TPL, (TE-TPL)/TPL, pulse rate, S1 (the slope of main wave ascending branch), S2 (the slope of dicrotic ascending branch), ΔYP2-ΔYPL and TP2-TPL as secondary observation indicators; defined the dicrotic wave with obvious crest as YP2>YPL, and calculated the occurrence rate of dicrotic wave with obvious crest (number of waveforms with YP2>YPL in 50 s /total number of waveforms×100%). We analyzed individually the 50 s pulse wave data of each subject before and after exercise, and then averaged all the data for overall analysis. Results: ①16 healthy young subjects (males 10, females 6), age (30.6±6.4, 24~48) years old; height (170.4±8.2, 160~188) cm; body mass (63.9±12.8, 43~87) kg. ②YB (87.2±5.8, 78.1~95.9), YP1 (223.5±15.8, 192.7~242.3), YPL (122.8±7.8, 110.0~133.8), YP2 (131.4±4.9, 116.7~137.5), TP1 (126.2±42.2, 94.2~280.0), TPL (360.2±44.8, 311.5~507.3), TP2 (432.4±50.8, 376.2~589.0), TE (899.7±86.9, 728.3~1042.0). ΔYP1 (136.3±19.9, 96.8~ 158.6), ΔYPL (35.7±10.7, 16.0~55.7), ΔYP2 (44.3±8.1, 22.5~56.5), TE-TPL (539.5±79.3, 405.9~691.3), (TE-TPL)/TPL (1.5±0.3, 0.8~2.0), pulse rate (67.3±6.6, 57.6~82.4), S1 (1.1±0.2, 0.6~1.4), S2 (0.1±0.1, 0.0~0.2), ΔYP2-ΔYPL (8.6±6.1, 0.9 ~19.8), TP2-TPL (72.3±19.9, 38.3~108.4). ③10 min after exercise, YPL (97.0±13.2 vs 122.8±7.8), YP2 (109.6±12.8 vs 131.4±4.9), ΔYPL (6.6±9.8 vs 35.7±10.7), ΔYP2 (19.3±11.2 vs 44.3±8.1), TE (667.8±123.1 vs 899.7±86.9), TE-TPL (330.2±128.4 vs 539.5±79.3), (TE-TPL)/TPL (1.0±0.4 vs 1.5±0.3) decreased, while the pulse rate (92.2± 14.0 vs 67.3±6.6), ΔYP2-ΔYPL (12.7±9.7 vs 8.6±6.1), TP2-TPL (98.0±38.1 vs 72.3±19.9) increased (all P<0.05). The trend of pulse wave changes at 20 min and 30 min after exercise was consistent with that at 10 min after exercise, but from 20 min, most of the indicators gradually recovered to the resting level before exercise. ④The incidence of dicrotic waves with obvious peaks in 16 young healthy persons at rest was 94.5%, and increased at 10 min (96.3%), 20 min (98.5%), and 30 min (99.8%) after exercise (all P<0.01). Among them, the incidence of dicrotic waves with obvious peaks before and after exercise was maintained at about 100% in 10 subjects. The appearance rate of 2 cases had reached 100% before exercise, but it decreased at 10 minutes after exercise, and then continued to increase, at 30 minutes recovered to 100%. Three subjects had a low resting rate and started to increase after exercise. In 1 case, the rate was low only 20 minutes after exercise, considering the influence of human factors. Conclusion: The influence of exercise on the pulse wave of normal people is mainly reflected in the dicrotic wave. On the whole, after a single precise power exercise, the position of the dicrotic wave is reduced, the amplitude is deepened, and the appearance rate of the dicrotic wave with obvious crest is generally increased, and this change can be maintained for at least 30 minutes. From an individual point of view, the response trend of each subject is different.

Validation of nomogram-revised risk index and comparison with other models for extranodal nasal-type NK/T-cell lymphoma in the modern chemotherapy era: indication for prognostication and clinical decision-making.

Derived from our original nomogram study by using the risk variables from multivariable analyses in the derivation cohort of 1383 patients with extranodal NK/T-cell lymphoma, nasal-type (ENKTCL) who were mostly treated with anthracycline-based chemotherapy, we propose an easily used nomogram-revised risk index (NRI), validated it and compared with Ann Arbor staging, the International Prognostic Index (IPI), Korean Prognostic Index (KPI), and prognostic index of natural killer lymphoma (PINK) for overall survival (OS) prediction by examining calibration, discrimination, and decision curve analysis in a validation cohort of 1582 patients primarily treated with non-anthracycline-based chemotherapy. The calibration of the NRI showed satisfactory for predicting 3- and 5-year OS in the validation cohort. The Harrell's C-index and integrated Brier score (IBS) of the NRI for OS prediction demonstrated a better performance than that of the Ann Arbor staging system, IPI, KPI, and PINK. Decision curve analysis of the NRI also showed a superior outcome. The NRI is a promising tool for stratifying patients with ENKTCL into risk groups for designing clinical trials and for selecting appropriate individualized treatment.

Progression-free survival at 24 months and subsequent survival of patients with extranodal NK/T-cell lymphoma: a China Lymphoma Collaborative Group (CLCG) study.

Limited evidence supports the use of early endpoints to evaluate the success of initial treatment of extranodal NK/T-cell lymphoma (ENKTCL) in the modern era. We aim to analyze progression-free survival at 24 months (PFS24) and subsequent overall survival (OS) in a large-scale multicenter cohort of patients. 1790 patients were included from the China Lymphoma Collaborative Group (CLCG) database. Subsequent OS was defined from the time of PFS24 or progression within 24 months to death. OS was compared with age- and sex-matched general Chinese population using expected survival and standardized mortality ratio (SMR). Patients who did not achieve PFS24 had a median OS of 5.3 months after progression, with 5-year OS rate of 19.2% and the SMR of 71.4 (95% CI, 62.9-81.1). In contrast, 74% patients achieved PFS24, and the SMR after achieving PFS24 was 1.77 (95% CI, 1.34-2.34). The observed OS rate after PFS24 versus expected OS rate at 5 years was 92.2% versus 94.3%. Similarly, superior outcomes following PFS24 were observed in early-stage patients (5-year OS rate, 92.9%). Patients achieving PFS24 had excellent outcome, whereas patients exhibiting earlier progression had a poor survival. These marked differences suggest that PFS24 may be used for study design and risk stratification in ENKTCL.

First-line non-anthracycline-based chemotherapy for extranodal nasal-type NK/T-cell lymphoma: a retrospective analysis from the CLCG.

The present study investigated the survival benefit of non-anthracycline (ANT)-based vs ANT-based regimens in a large-scale, real-world cohort of patients with extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTCL). Within the China Lymphoma Collaborative Group (CLCG) database (2000-2015), we identified 2560 newly diagnosed patients who received chemotherapy with or without radiotherapy. Propensity score matching (PSM) and multivariable analyses were used to compare overall survival (OS) and progression-free survival (PFS) between the 2 chemotherapy regimens. We explored the survival benefit of non-ANT-based regimens in patients with different treatments in early-stage disease and in risk-stratified subgroups. Non-ANT-based regimens significantly improved survivals compared with ANT-based regimens. The 5-year OS and PFS were 68.9% and 59.5% for non-ANT-based regimens compared with 57.5% and 44.5% for ANT-based regimens in the entire cohort. The clinical advantage of non-ANT-based regimens was substantial across the subgroups examined, regardless of stage and risk-stratified subgroup, and remained significant in early-stage patients who received radiotherapy. The survival benefits of non-ANT-based regimens were consistent after adjustment using multivariable and PSM analyses. These findings provide additional evidence supporting non-ANT-based regimens as a first-line treatment of patients with ENKTCL.

Risk-Dependent Conditional Survival and Failure Hazard After Radiotherapy for Early-Stage Extranodal Natural Killer/T-Cell Lymphoma.

Importance: Prognosis of early-stage extranodal natural killer/T-cell lymphoma (NKTCL) is usually estimated and stratified at diagnosis, but how the prognosis actually evolves over time for patients who survived after curative treatment is unknown. Objective: To assess conditional survival and failure hazard over time based on risk categories, previous survival, and treatment. Design, Setting, and Participants: This retrospective cohort study reviewed the clinical data of 2015 patients with early-stage NKTCL treated with radiotherapy identified from the China Lymphoma Collaborative Group multicenter database between January 1, 2000, and December 31, 2015. Patients were stratified into low-, intermediate- and high-risk groups according to a previously established prognostic model. Median follow-up was 61 months for surviving patients. Data analysis was performed from December 1, 2017, to January 30, 2018. Exposures: All patients received radiotherapy with or without chemotherapy. Main Outcomes and Measures: Conditional survival defined as the survival probability, given patients have survived for a defined time, and annual hazard rates defined as yearly event rate. Results: A total of 2015 patients were included in the study (mean [SD] age, 43.3 [14.6] years; 1414 [70.2%] male); 1628 patients (80.8%) received radiotherapy with chemotherapy, and 387 (19.2%) received radiotherapy without chemotherapy. The 5-year survival rates increased from 69.1% (95% CI, 66.6%-71.4%) at treatment to 85.3% (95% CI, 81.7%-88.2%) at year 3 for conditional overall survival and from 60.9% (95% CI, 58.3%-63.3%) at treatment to 84.4% (95% CI, 80.6%-87.6%) at year 3 for conditional failure-free survival. The annual hazards decreased from 13.7% (95% CI, 13.0%-14.3%) for death and 22.1% (95% CI, 21.0%-23.1%) for failure at treatment to less than 5% after 3 years (death: range, 0%-3.9% [95% CI, 3.7%-4.2%]; failure: 1.2% [95% CI, 1.0%-1.4%] to 4.2% [95% CI 3.9%-4.6%]). Intermediate-risk (11.4% [95% CI, 10.5%-12.3%]) and high-risk (21.6% [95% CI, 20.0%-23.2%]) patients had initially higher but significantly decreased death hazards after 3 years (<6%, range: 0%-5.9% [95% CI, 5.2%-6.7%]), whereas low-risk patients maintained a constantly lower death hazard of less than 5% (range, 0%-4.8%; 95% CI, 4.4%-5.3%). In high-risk patients, radiotherapy combined with non-anthracycline-based regimens were associated with higher conditional overall survival before year 3 compared with anthracycline-based regimens (hazard ratio [HR] for death, 1.49; 95% CI, 1.13-1.95; P = .004 at treatment; HR, 1.60; 95% CI, 1.07-2.39; P = .02 at 1 year; and HR, 1.77; 95% CI, 0.94-3.33; P = .07 at 2 years) or radiotherapy alone (HR, 2.42; 95% CI, 1.73-3.39; P < .001 at treatment; HR, 1.82; 95% CI, 1.05-3.17; P = .03 at 1 year; and HR, 2.69; 95% CI, 1.23-5.90; P = .01 at 2 years). Conclusions and Relevance: The survival probability increased and the hazards of failure decreased in a risk-dependent manner among patients with early NKTCL after radiotherapy. These dynamic data appear to provide accurate information on disease processes and continual survival expectations and may help researchers design additional prospective clinical trials and formulate risk-adapted therapies and surveillance strategies.

Effect of primary tumor invasion on treatment and survival in extranodal nasal-type NK/T-cell lymphoma in the modern chemotherapy era: a multicenter study from the China Lymphoma Collaborative Group (CLCG).

We evaluated the effect of primary tumor invasion (PTI) on treatment selection in 1356 patients with extranodal nasal-type NK/T cell lymphoma who received non-anthracycline-based chemotherapy from the updated dataset of China Lymphoma Collaborative Group. 760 (56.0%) patients had PTI. PTI showed most prominent effect in stage I disease, with 5-year overall survival (OS) of 83.0% in PTI-absent patients and 69.5% in PTI-present patients (p < .001). Radiotherapy ± chemotherapy achieved higher OS in PTI-absent stage I patients (approximately 85%). Either radiotherapy alone or chemotherapy alone was associated with an unfavorable OS in PTI-present patients (approximately 55%). Compared to radiotherapy alone, combined modality treatment improved OS in PTI-present patients (78.3% vs. 56.6%; p = .001) but showed similar OS in PTI-absent patients (85.3% vs. 83.3%; p = .560). These findings were confirmed in multivariate analyses. PTI was a robust prognostic factor and indicator for additional chemotherapy in stage I NKTCL patients.

Effect of age as a continuous variable on survival outcomes and treatment selection in patients with extranodal nasal-type NK/T-cell lymphoma from the China Lymphoma Collaborative Group (CLCG).

PURPOSE: The aim of this study was to determine the impact of analyzing age as a continuous variable on survival outcomes and treatment selection for extranodal nasal-type NK/T-cell lymphoma. RESULTS: The risk of mortality increased with increasing age, without an apparent cutoff point. Patients' age, as a continuous variable, was independently associated with overall survival after adjustment for covariates. Older early-stage patients were more likely to receive radiotherapy only whereas young-adult advanced-stage patients tended to receive non-anthracycline-based chemotherapy. A decreased risk of mortality with radiotherapy versus chemotherapy only in early-stage patients (HR, 0.347, P < 0.001) or non-anthracycline-based versus anthracycline-based chemotherapy in early-stage (HR, 0.690, P = 0.001) and advanced-stage patients (HR, 0.678, P = 0.045) was maintained in patients of all ages. CONCLUSIONS: These findings support making treatment decisions based on disease-related risk factors rather than dichotomized chronological age. PATIENTS AND METHODS: Data on 2640 patients with extranodal nasal-type NK/T-cell lymphoma from the China Lymphoma Collaborative Group database were analyzed retrospectively. Age as a continuous variable was entered into the Cox regression model using penalized spline analysis to determine the association of age with overall survival (OS) and treatment benefits.

[mRNA expression levels of p53 and DNA damage and repair genes in peripheral blood lymphocytes of benzene-exposed workers].

OBJECTIVE: To investigate the relationship between the mRNA expression levels of p53-mediating DNA damage and repair genes in the peripheral blood lymphocytes of workers and their exposures to benzene in their working environment. METHODS: The mRNA expression levels of p53 and related genes were determined by SYBR Green I chimeric fluorescence quantitative real-time RT-PCR analysis in peripheral blood lymphocytes of 72 workers, who were classified into group A (46 direct exposure to benzene) and group B (26 indirect exposure to benzene) based on their positions, and 29 controls. The differences of gene expression levels were analyzed by software REST 2005. Meanwhile, the peripheral blood leukocytes, hemoglobin and platelet of workers and controls were counted. Benzene content was measured in the samples of toluene, used as raw material, and spraying agents and benzene, toluene and xylene concentrations in the air of workplaces were monitored. RESULTS: There were no significant differences in the mRNA expression levels of p53, Ku80, Ape1 and Mdm-2 between group A or group B and control group (P > 0.05). The expression up-regulation of p21 mRNA was found, but without significant difference (P > 0.05). However, the mRNA expression levels of Rad51, Bcl-2, Bax, Xpa and Xpc in group A and Rad51 in group B were downregulated significantly (P < 0.05 or P < 0.01). Moreover, both the counts of white blood cell, hemoglobin and platelet in group A were (4.93 +/- 1.27) x 10(9)/L, (123.97 +/- 11.80) g/L and (124.02 +/- 41.22) x 10(9)/L respectively and platelet in group B (135.80 +/- 39.44) x 10(9)/L were significantly lower than in control group (P < 0.05 or P < 0.01). CONCLUSION: The mRNA expression levels of some p53-mediating DNA damage and repair genes are downregulated in the workers chronically exposed to low benzene concentration. The working environment impacts on health of group A workers are greater than the ones of group B.