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.

Osteoporotic Goat Spine Implantation Study Using a Synthetic, Resorbable Ca/P/S-Based Bone Substitute.

One primary purpose of the present study is to clarify whether the highly porous, resorbable Ca/P/S-based bone substitute used in this study would still induce an osteoporotic bone when implanted into the osteoporotic vertebral defects of ovariectomized (OVX) goats, or the newly-grown bone would expectantly be rather healthy bone. The bone substitute material used for the study is a synthetic, 100% inorganic, highly porous and fast-resorbable Ca/P/S-based material (Ezechbone® Granule CBS-400). The results show that the OVX procedure along with a low calcium diet and breeding away from light can successfully induce osteoporosis in the present female experimental goats. The histological examination reveals a newly-formed trabecular bone network within the surgically-created defect of the CBS-400-implanted (OVX_IP) goat. This new trabecular bone network in the OVX_IP goat appears much denser than the OVX goat and comparable to the healthy control goat. Histomorphometry show that, among all the experimental goats, the OVX_IP goat has the highest trabecular thickness and lowest trabecular bone packet prevalence. The differences in trabecular plate separation, trabecular number and trabecular bone tissue area ratio between the OVX_IP goat and the control goat are not significant, indicating that the trabecular bone architecture of the OVX_IP goat has substantially recovered to the normal level in about 6 months after implantation without signs of osteoporosis-related delay in the bone maturing process. The quick and nicely recovered trabecular architecture parameters observed in the OVX_IP goat indicate that the present Ca/P/S-based bone substitute material has a high potential to treat osteoporotic fractures.

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.

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.

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.

Risk-dependent curability of radiotherapy for elderly patients with early-stage extranodal nasal-type NK/T-cell lymphoma: A multicenter study from the China Lymphoma Collaborative Group (CLCG).

BACKGROUND: The purpose of this study was to determine the curability of early-stage extranodal nasal-type NK/T-cell lymphoma (NKTCL) in response to radiotherapy and non-anthracycline-based chemotherapy in elderly patients. METHODS: In this multicenter study from the China Lymphoma Collaborative Group (CLCG) database, 321 elderly patients with early-stage NKTCL were retrospectively reviewed. Patients received radiotherapy alone (n = 87), chemotherapy alone (n = 59), or combined modality therapy (CMT, n = 175). Patients were classified into low- or high-risk groups using four prognostic factors. Observed survival in the study cohort vs expected survival in age- and sex-matched individuals from the general Chinese population was plotted using a conditional approach and subsequently compared using a standardized mortality ratio (SMR). RESULTS: Radiotherapy conveyed a favorable prognosis and significantly improved survival compared to chemotherapy alone. The 5-year overall survival (OS) and progression-free survival (PFS) were 61.2% and 56.4%, respectively, for radiotherapy compared with 44.7% and 38.3%, respectively, for chemotherapy alone (P < 0.001). The combination of a non-anthracycline-based chemotherapy regimen and radiotherapy significantly improved PFS compared to combination of an anthracycline-based chemotherapy regimen and radiotherapy (71.2% vs 44.2%, P = 0.017). Low-risk patients following radiotherapy (SMR, 0.703; P = 0.203) and high-risk patients who achieved PFS at 24 months (SMR, 1.490; P = 0.111) after radiotherapy showed survival equivalent to the general Chinese population. CONCLUSIONS: Our findings indicate a favorable curability for this malignancy in response to radiotherapy and non-anthracycline-based chemotherapy, providing a risk-adapted follow-up and counsel scheme in elderly patients.

Risk-adapted survival benefit of IMRT in early-stage NKTCL: a multicenter study from the China Lymphoma Collaborative Group.

This study evaluated the survival benefit of intensity-modulated radiation therapy (IMRT) compared with 3-dimension conformal radiation therapy (3D-CRT) in a large national cohort of patients with early-stage extranodal nasal-type natural killer/T-cell lymphoma (NKTCL). This retrospective study reviewed patients with early-stage NKTCL treated with high-dose radiation therapy (RT; ≥45 Gy) at 16 Chinese institutions. Patients were stratified into 1 of 4 risk groups based on the number of risk factors: low risk (no factors), intermediate-low risk (1 factor), intermediate-high risk (2 factors), and high-risk (3-5 factors). Of the 1691 patients, 981 (58%) received IMRT, and 710 (42%) received 3D-CRT. Unadjusted 5-year overall survival (OS) and progression-free survival (PFS) were 75.9% and 67.6%, respectively, for IMRT compared with 68.9% (P = .004) and 58.2% (P < .001), respectively, for 3D-CRT. After propensity score match and multivariable analyses to account for confounding factors, IMRT remained significantly associated with improved OS and PFS. The OS and PFS benefits of IMRT persisted in patients treated with modern chemotherapy regimens. Compared with 3D-CRT, IMRT significantly improved OS and PFS for high-risk and intermediate-high-risk patients but provided limited benefits for low-risk or intermediate-low-risk patients. A risk-adapted survival benefit profile of IMRT can be used to select patients and make treatment decisions.

Radiotherapy is essential after complete response to asparaginase-containing chemotherapy in early-stage extranodal nasal-type NK/T-cell lymphoma: A multicenter study from the China Lymphoma Collaborative Group (CLCG).

PURPOSE: This study aimed to clarify the benefit of radiotherapy (RT) in patients with early-stage extranodal NK/T-cell lymphoma (NKTCL) who achieve a complete response (CR) after asparaginase-containing chemotherapy (CT). PATIENTS AND METHODS: Of 240 patients achieved a CR after asparaginase-containing CT, 202 patients received additional RT (CT + RT), and 38 patients did not (CT alone). RESULTS: Compared to CT alone, CT + RT significantly improved overall survival (OS), disease-free survival (DFS) and locoregional control (LRC). The 5-year OS, DFS and LRC rates were 84.9%, 76.2% and 84.9% for CT + RT, compared to 58.9% (P = 0.006), 43.6% (P = 0.001) and 62.1% (P = 0.026) for CT alone. The 5-year cumulative disease recurrence rate was 18.8% for CT + RT compared to 46.9% (P = 0.003) for CT alone. High-dose RT (≥50 Gy) significantly decreased the risk of locoregional recurrence. The 5-year cumulative locoregional failure rate was 35.5% for patients receiving <50 Gy compared to 8.8% for patients receiving ≥50 Gy (P = 0.028). CONCLUSIONS: For patients with early-stage NKTCL who achieve a CR after asparaginase-containing CT, omission of RT results in frequent locoregional recurrence and a poor prognosis; RT is essential to improve locoregional control and survival.

The effect of molecular weight and concentration of hyaluronan on the recovery of the rat sciatic nerve sustaining acute traumatic injury.

Acute traumatic peripheral nerve injury remains a significant clinical issue affecting mostly young individuals and their productivity in spite of advances in current medicine. Hyaluronan has been explored in this scenario for its anti-adhesive and high biocompatibility properties for decades. The molecular weight and concentration of the locally applied hyaluronan has been overlooked and not optimized. We used different molecular weights and concentrations of hyaluronan in a rat sciatic nerve crush injury model and found better overall outcomes with high molecular weight (3000 kDa) hyaluronan. The anti-inflammatory effect of the higher molecular weight hyaluronan may have a more favorable effect. We conclude that the optimization of hyaluronan is necessary when incorporating hyaluronan in the engineering of biomaterials for use in acute traumatic peripheral nerve injury.

Association of Improved Locoregional Control With Prolonged Survival in Early-Stage Extranodal Nasal-Type Natural Killer/T-Cell Lymphoma.

IMPORTANCE: The long-term survival benefit for radiotherapy (RT) in early-stage extranodal natural killer/T-cell lymphoma (NKTCL) is not known, and it is unclear whether improved locoregional control (LRC) translates into a survival benefit. OBJECTIVE: To investigate the dose-dependent effect and potential survival benefits of RT on the basis of LRC improvements. DESIGN, SETTING, AND PARTICIPANTS: Review of clinical data of patients with early-stage NKTCL at 10 institutions in China between 2000 and 2014. Radiotherapy dose as a continuous variable was entered into the Cox regression model by using penalized spline regression to allow for a nonlinear relationship between RT dose and events. Regression analysis was used to assess whether a linear correlation exists between LRC and progression-free survival (PFS) or overall survival (OS). Patients received chemotherapy (CT) alone, RT alone, or a combination. Chemotherapy alone was defined as 0 Gy. MAIN OUTCOMES AND MEASURES: The association between LRC and OS or PFS. RESULTS: A total of 1332 patients (923 [69%] male; median age, 43 years [range, 2-87 years]) were reviewed. For patients treated with RT, median dose was 50 Gy (range, 10-70 Gy); 996 (86%) received at least 50 Gy, and 164 (14%) received 10 to 49 Gy. The risk of locoregional recurrence, disease progression, and mortality decreased sharply until 50 to 52 Gy. For patients receiving RT, high-dose RT (≥50 Gy) was associated with significantly better 5-year LRC (85% vs 73%; P < .001), PFS (61% vs 50%; P = .004), and OS (70% vs 58%; P = .04) than low-dose RT (<50 Gy). Improved LRC with high-dose RT was independent of the RT/CT sequence or initial response to CT. Radiotherapy yielded a dose-dependent effect on LRC (range, 41%-87%), PFS (18%-63%), and OS (33%-71%). Dose-response regression analysis revealed a linear correlation between 5-year LRC and 5-year PFS (correlation coefficient, r = 0.994, P < .001; determination coefficient, R2 = 0.988) or 5-year OS (r = 0.985, P = .002; R2 = 0.97), which was externally validated using published data. CONCLUSIONS AND RELEVANCE: The optimal dose was 50 Gy for patients with early-stage disease. The improved LRC was associated with prolonged survival. These findings emphasize the importance of RT in optimizing first-line therapy, and provide evidence for making treatment decisions and designing clinical trials.

Investigation into the safety of perineural application of 1,4-butanediol diglycidyl ether-crosslinked hyaluronan in a rat model.

Hyaluronan (HA) is well known for its biocompatibility and has widespread clinical use. To change its mechanical and physiologic properties to adapt to specific clinical scenarios, HA is crosslinked with chemically reactive linker molecules, most of which are toxic chemical reagents. Adverse events related to clinical use of crosslinked HA have been documented. Although approved by the FDA as dermal filler, the safety of perineural application of 1,4-butanediol diglycidyl ether (BDDE)-crosslinked HA has not been assessed critically. Concern exists owing to the vulnerability of neural tissues, because of their elongated morphology, high ratio of membrane surface area to cell volume, and complicated electrophysiologic properties. In this study, we systematically investigated the toxicity profile of BDDE-crosslinked HA, using in vitro and in vivo experiments in a rat model. The in vivo experiments included the evaluation of aspects of histopathology, electrophysiology, and neurobehavior. There were no significant changes in the treatment group compared with the control group in all aspects of the experiments, except for the increased epineurial vascular formation in the 0.5% crosslinked HA-treated group during 2 weeks of observation. Further studies involving perineural application of BDDE-crosslinked HA can be done based on our findings, which ruled out the safety concern of cytotoxicity and adverse changes in electrophysiology and neurobehavior.

Advances in noninvasive functional imaging of bone.

The demand for functional imaging in clinical medicine is comprehensive. Although the gold standard for the functional imaging of human bones in clinical settings is still radionuclide-based imaging modalities, nonionizing noninvasive imaging technology in small animals has greatly advanced in recent decades, especially the diffuse optical imaging to which Britton Chance made tremendous contributions. The evolution of imaging probes, instruments, and computation has facilitated exploration in the complicated biomedical research field by allowing longitudinal observation of molecular events in live cells and animals. These research-imaging tools are being used for clinical applications in various specialties, such as oncology, neuroscience, and dermatology. The Bone, a deeply located mineralized tissue, presents a challenge for noninvasive functional imaging in humans. Using nanoparticles (NP) with multiple favorable properties as bioimaging probes has provided orthopedics an opportunity to benefit from these noninvasive bone-imaging techniques. This review highlights the historical evolution of radionuclide-based imaging, computed tomography, positron emission tomography, and magnetic resonance imaging, diffuse optics-enabled in vivo technologies, vibrational spectroscopic imaging, and a greater potential for using NPs for biomedical imaging.

An effective method to reduce ischemia time during total knee arthroplasty.

BACKGROUND/PURPOSE: Because of controversy regarding timing of tourniquet release during total knee arthroplasty (TKA), a closed arthrotomy as a tamponade for effective hemostasis was used to save ischemia time. The study was to verify the safety and efficacy on clinical issues. METHODS: A prospective cohort study was conducted on 72 consecutive unilateral primary TKAs. They were divided into two groups according to different timing of tourniquet release. The study group was composed of 36 index procedures with an intra-operative release after a tight arthrotomy closure; while the remaining 36 TKAs with a tourniquet application throughout the procedure comprised the comparative group. In all operations, no drain was used to augment the intra-articular tamponade. RESULTS: In the study group, the tourniquet time was significantly shorter (p<0.001), and thus ischemic duration and perioperative blood loss were reduced. The postoperative course was similar on the basis of analgesics consumption and inpatient stay, but better earlier functional recovery as well as subjective performance was observed at early postoperative follow-ups. CONCLUSIONS: The results suggest that a closed tamponade with arthrotomy closure and drainage avoidance is an effective hemostasis to reduce ischemia time during TKAs.