Cluster-based radiomics reveal spatial heterogeneity of bevacizumab response for treatment of radiotherapy-induced cerebral necrosis.

Background: Bevacizumab is used in the treatment of radiation necrosis (RN), which is a debilitating toxicity following head and neck radiotherapy. However, there is no biomarker to predict if a patient would respond to bevacizumab. Purpose: We aimed to develop a cluster-based radiomics approach to characterize the spatial heterogeneity of RN and map their responses to bevacizumab. Methods: 118 consecutive nasopharyngeal carcinoma patients diagnosed with RN were enrolled. We divided 152 lesions from the patients into 101 for training, and 51 for validation. We extracted voxel-level radiomics features from each lesion segmented on T1-weighted+contrast and T2 FLAIR sequences of pre- and post-bevacizumab magnetic resonance images, followed by a three-step analysis involving individual- and population-level clustering, before delta-radiomics to derive five radiomics clusters within the lesions. We tested the association of each cluster with response to bevacizumab and developed a clinico-radiomics model using clinical predictors and cluster-specific features. Results: 71 (70.3%) and 34 (66.7%) lesions had responded to bevacizumab in the training and validation datasets, respectively. Two radiomics clusters were spatially mapped to the edema region, and the volume changes were significantly associated with bevacizumab response (OR:11.12 [95% CI: 2.54-73.47], P = 0.004; and 1.63[1.07-2.78], P = 0.042). The combined clinico-radiomics model based on textural features extracted from the most significant cluster improved the prediction of bevacizumab response, compared with a clinical-only model (AUC:0.755 [0.645-0.865] to 0.852 [0.764-0.940], training; 0.708 [0.554-0.861] to 0.816 [0.699-0.933], validation). Conclusion: Our radiomics approach yielded intralesional resolution, enabling a more refined feature selection for predicting bevacizumab efficacy in the treatment of RN.

Secondary correction of nasal deformities in cleft lip patients using acellular dermal matrix grafting on the nasal tip with open rhinoplasty.

Secondary nasal deformities in patients with unilateral cleft lip represent surgical challenges. Open rhinoplasty involving repositioning of the lower lateral cartilage has been shown to be a suitable technique for patients with cleft lip and nose deformities. This study aimed to explore a particular method of rhinoplasty and to assess the aesthetic outcomes for secondary unilateral cleft lip and nose deformities following its use. Fifty-seven patients treated for secondary unilateral cleft lip nasal deformities from January 2012 to December 2018 were enrolled in the study. Open rhinoplasty combined with a reverse-U incision and acellular dermal matrix grafting on the nasal tip was performed in all patients by the same surgeon. In our follow-up study we evaluated the results by measuring angles on photographs and scoring the appearance before and after operation. Data were statistically analysed using the t test. Appearances were improved in all patients. Both the alar base-nasal tip-columellar base angle and the nostril axis angles were smaller postoperatively (p < 0.001). According to the outcome scores, most patients (53/57) agreed that there was an obvious improvement in the appearance of their noses following surgery, and overall they were satisfied with the results of the revision procedure. A distinct improvement in nasal appearance can be achieved with this rhinoplasty. Our surgical method is effective and reliable in patients with secondary unilateral cleft lip and nose deformities, and is worth promoting in the clinic.

Improving myopia awareness via school-based myopia prevention health education among Chinese students.

AIM: To investigate the myopia awareness level, knowledge, attitude, and skills at baseline and to implement and evaluate the efficacy of myopia prevention health education among Chinese students. METHODS: A total of 1000 middle school students from 2 middle schools were invited to participate in the study, and myopia prevention health education was conducted. The students were assessed at baseline, followed by a survey. The efficacy of health education was evaluated using the self-comparison method pre- and post-health education. RESULTS: The study included 957 and 850 pre- and post-health education participants, respectively. The baseline knowledge of all respondents on myopic symptoms (87.5%), myopia is a risk of eyes (72.9%), myopia prevention (91.3%), myopia increases with age (86.7%), performing periodic eye examinations (92.8%), and one first, one foot, and one inch (84.8%) significantly increased after health education (P<0.001 for all). However, the percentage of students who still did not think it necessary to take breaks after 30-40min of continuous near work was 27.0%. The opinion that "myopia can be cured" was still present in 38.3%. CONCLUSION: Implementing school-based myopia prevention health education improves knowledge, attitudes, and skills regarding myopia among Chinese middle school students.

The practicability of different preparation of mandibular molar restored by modified endocrown with intracanal extension: Computational analysis using finite element models.

BACKGROUND AND OBJECTIVE: Post-core-crown (PCC) and endocrown are two common restorative methods for severely damaged molars, but exhibit disadvantages. This study aimed to explore the practicability of modified endocrown with a 2 mm intracanal extension (MED) to restore defective teeth using finite element analysis (FEA). METHODS: Five groups of numerical models of mandibular molars restored by three MEDs, a PCC, and a routine endocrown after root canal treatment were devised by FEA software. We constructed 4 mm, 3 mm, and 2 mm thickness of MED restorations to restore mandibular molars that were prepared to 1 mm, 2 mm, and 3 mm from the cemento-enamel junction (CEJ). Furthermore, PCC and routine endocrown were used to compare the stress distribution with MED. Lithium disilicate glass-ceramics (EMAX) and resin nanoceramics (LU) were considered restorative materials, and a vertical load of 600 N and an oblique load of 200 N were applied to the restorations. RESULTS: In three MEDs by LU, 2 mm thickness of restoration generated the highest stress on prepared teeth, while the thickness of EMAX did not significantly influence the stress value. MED by LU generated higher stress around the CEJ, and reduced the stress on the middle and lower root compared to MEDs by EMAX, PCC by EMAX, and PCC by LU. MED by EMAX caused lower stress around the CEJ, and generated higher stress in the chamber walls after extended root canals compared with MED by LU, endocrowns by LU, and endocrowns by EMAX. There was an evident stress concentration at the last but one layer, which was a thin area of the tooth root in all restorative models. CONCLUSIONS: The use of modified endocrown may be considered an effective restorative method to restore defective mandibular molar, but suitable restorative material must be selected based on the tooth preparation method and deficiencies in the tooth structure.

Micro-CT Evaluation of Different Root Canal Irrigation Protocols on the Removal of Accumulated Hard Tissue Debris: A Systematic Review and Meta-Analysis.

Accumulated hard tissue debris (AHTD) is an inevitable by-product during endodontic treatment and is difficult to remove completely using traditional syringe and needle irrigation (SNI). Adjunctive irrigation is proposed to assist the clean-up of AHTD. This systematic review and meta-analysis aimed to evaluate the AHTD removal efficacy of different root canal irrigation devices using micro-computed tomography (Micro-CT). A literature search was carried out within the main scientific databases until 20 June 2022. All results were screened with detailed eligibility criteria. Eleven studies were included for analysis. SNI, passive ultrasonic irrigation (PUI), negative pressure systems, sonically activated irrigation (SAI), mechanical-activated system and laser-activated irrigation (LAI) were assessed. PUI is superior to SNI for debris removal and LAI has better AHTD removal performance than PUI. The negative pressure system and mechanical-activated system were proved to be less effective. Registration: PROSPERO (CRD42021273892).

Efficacy and safety of CD19 CAR-T cell therapy for patients with B cell acute lymphoblastic leukemia involving extramedullary relapse.

OBJECTIVE: To evaluate the efficacy and safety of CD19 chimeric antigen receptor (CAR) T cell therapy for patients with B cell acute lymphoblastic leukemia (B-ALL) involving extramedullary relapse. METHODS: Fifteen patients with B-ALL involving extramedullary relapse who received CD19 CAR-T cell therapy in the First Affiliated Hospital, Zhejiang University School of Medicine from January 2016 to October 2021 were enrolled in this study. The overall survival and leukemia-free survival of patients were analyzed using Kaplan-Meier curves, and the response of extramedullary lesions in different locations following the CD19 CAR-T cell therapy was observed. Cytokine release syndrome (CRS), hematological toxicity, and immune effector cell-associated neurotoxicity syndrome (ICANS) during CD19 CAR-T cell therapy were analyzed. RESULTS: The median follow-up time was 7 (3-71) months, and 11 cases (73.3%) achieved complete response, median duration of complete response was 6 (2-27) months; 3 cases (20.0%) achieved partial response; 1 case (6.7%) got progressive disease. The overall response rate was 93.3% (14/15), and the overall survival rate was 80.0% (12/15) at the end of follow-up. The cumulative incidence of relapse was 40.0% (6/15) and relapse mortality rate was 20.0% (3/15). Until last follow-up date, 9 cases (60.0%) were still in disease-free survival. Among the 15 patients, 13 cases (86.7%) developed cytokine release syndrome (CRS) after cell infusion, including 7 cases with grade 1-2 CRS, 6 cases with grade 3 CRS; 1 case suffered from reversible ICANS; 15 cases (100.0%) developed B cell dysplasia; 12 cases (80.0%) developed severe hematologic adverse reactions; 2 cases (13.3%) had abnormal liver function; 1 case (6.7%) had abnormal renal function; 4 cases (26.7%) developed infection. The adverse reactions mentioned above were well controlled. CONCLUSION: CD19 CAR-T cell therapy shows explicit efficacy and controllable adverse reactions for B-ALL patients with extramedullary relapse.

Mandibular Buccal Bifurcation Cyst: Report of Two Cases.

Mandibular buccal bifurcation cyst is a rare inflammatory odontogenic cyst. We reported two cases who complained of painful swelling of extraoral soft tissue. Intraoral examination revealed the partially erupted mandibular first molar. Cone beam computed tomography showed a well-defined cystic lesion surrounding the first molar. Histopathologic images showed the cyst wall was infiltrated by a large number of plasma cells, neutrophils and eosinophils, and lined with a thin layer of non-keratinized stratified squamous epithelium. Finally, the two patients were diagnosed as mandibular buccal bifurcation cyst and treated with cyst enucleation and curettage.

Hypoxia Alters the Proteome Profile and Enhances the Angiogenic Potential of Dental Pulp Stem Cell-Derived Exosomes.

Dental pulp stem cells (DPSCs) and their exosomes (Exos) are effective treatments for regenerative medicine. Hypoxia was confirmed to improve the angiogenic potential of stem cells. However, the angiogenic effect and mechanism of hypoxia-preconditioned DPSC-Exos are poorly understood. We isolated exosomes from DPSCs under normoxia (Nor-Exos) and hypoxia (Hypo-Exos) and added them to human umbilical vein endothelial cells (HUVECs). HUVEC proliferation, migration and angiogenic capacity were assessed by CCK-8, transwell, tube formation assays, qRT-PCR and Western blot. iTRAQ-based proteomics and bioinformatic analysis were performed to investigate proteome profile differences between Nor-Exos and Hypo-Exos. Western blot, immunofluorescence and immunohistochemistry were used to detect the expression of lysyl oxidase-like 2 (LOXL2) in vitro and in vivo. Finally, we silenced LOXL2 in HUVECs and rescued tube formation with Hypo-Exos. Hypo-Exos enhanced HUVEC proliferation, migration and tube formation in vitro superior to Nor-Exos. The proteomics analysis identified 79 proteins with significantly different expression in Hypo-Exos, among which LOXL2 was verified as being upregulated in hypoxia-preconditioned DPSCs, Hypo-Exos, and inflamed dental pulp. Hypo-Exos partially rescued the inhibitory influence of LOXL2 silence on HUVEC tube formation. In conclusion, hypoxia enhanced the angiogenic potential of DPSCs-Exos and partially altered their proteome profile. LOXL2 is likely involved in Hypo-Exos mediated angiogenesis.

Three-dimensional analysis of mandible ramus morphology and transverse stability after intraoral vertical ramus osteotomy.

OBJECTIVES: The purpose of this study was to investigate short- and long-term postoperative changes of both morphology and transverse stability in mandibular ramus after intraoral vertical ramus osteotomy (IVRO) in patients with jaw deformity using three-dimensional (3D) orthognathic surgery planning treatment software for measurement of distances and angles. STUDY DESIGN: This retrospective study included consecutive patients with skeletal Class III malocclusion who had undergone intraoral vertical ramus osteotomy and computed tomography images before (T0), immediately after (T1), and 1 year after (T2) surgery. Reference points, reference lines and evaluation items were designated on the reconstructed 3D surface models to measure distances, angles and volume. The average values at T0, T1, T2 and time-dependent changes in variables were obtained. RESULTS: After surgery, the condylar length, ramal height, mandibular body length and mandibular ramus volume were significantly decreased (P < 0.01), while clinically insignificant change was observed from T1 to T2. The angular length was increased immediately after surgery (P < 0.05), but it was decreased 1 year after surgery (P < 0.05). Lateral ramal inclination showed significant increase after surgery (P < 0.05) and maintained at T2. CONCLUSION: Changes in the morphology of the mandibular ramus caused by IVRO do not obviously bring negative effect on facial appearance. Furthermore, despite position and angle of mandibular ramus changed after IVRO, good transverse stability was observed postoperatively. Therefore, IVRO technique can be safely used without compromising esthetic results.

Development of a risk classification system combining TN-categories and circulating EBV DNA for non-metastatic NPC in 10,149 endemic cases.

BACKGROUND: The objective of this study was to construct a risk classification system integrating cell-free Epstein-Barr virus (cfEBV) DNA with T- and N- categories for better prognostication in nasopharyngeal carcinoma (NPC). METHODS: Clinical records of 10,149 biopsy-proven, non-metastatic NPC were identified from two cancer centers; this comprised a training (N = 9,259) and two validation cohorts (N = 890; including one randomized controlled phase 3 trial cohort). Adjusted hazard ratio (AHR) method using a two-tiered stratification by cfEBV DNA and TN-categories was applied to generate the risk model. Primary clinical endpoint was overall survival (OS). Performances of the models were compared against American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) 8th edition TNM-stage classification and two published recursive partitioning analysis (RPA) models, and were validated in the validation cohorts. RESULTS: We chose a cfEBV DNA cutoff of ⩾2,000 copies for optimal risk discretization of OS, disease-free survival (DFS) and distant metastasis-free survival (DMFS) in the training cohort. AHR modeling method divided NPC into six risk groups with significantly disparate survival (p < 0.001 for all): AHR1, T1N0; AHR2A, T1N1/T2-3N0 cfEBV DNA < 2,000 (EBVlow); AHR2B, T1N1/T2-3N0 cfEBV DNA ⩾ 2,000 (EBVhigh) and T1-2N2/T2-3N1 EBVlow; AHR3, T1-2N2/T2-3N1 EBVhigh and T3N2/T4N0 EBVlow; AHR4, T3N2/T4 N0-1 EBVhigh and T1-3N3/T4N1-3 EBVlow; AHR5, T1-3N3/T4 N2-3 EBVhigh. Our AHR model outperformed the published RPA models and TNM stage with better hazard consistency (1.35 versus 3.98-12.67), hazard discrimination (5.29 versus 6.69-13.35), explained variation (0.248 versus 0.164-0.225), balance (0.385 versus 0.438-0.749) and C-index (0.707 versus 0.662-0.700). In addition, our AHR model was superior to the TNM stage for risk stratification of OS in two validation cohorts (p < 0.001 for both). CONCLUSION: Herein, we developed and validated a risk classification system that combines the AJCC/UICC 8th edition TN-stage classification and cfEBV DNA for non-metastatic NPC. Our new clinicomolecular model provides improved OS prediction over the current staging system.

Evaluation of facial soft tissue thickness in asymmetric mandibular deformities after orthognathic surgery.

OBJECTIVES: The purpose of this study was to compare differences in facial soft tissue thickness in three-dimensional (3D) images before and after orthognathic surgery in patients with skeletal Class III malocclusion and to obtain a better understanding of the relationship between hard and soft tissue changes after surgery. MATERIALS AND METHOD: The present retrospective study included 31 patients with skeletal Class III malocclusion with mandibular chin deviation greater than 4 mm who had undergone cone-beam computed tomography before and 6 months after surgery. Seven bilateral points were established. Measurements were taken from software-generated multiplanar reconstructions. The predictor variables were timing (pre- and postoperatively) and side (deviated vs. nondedicated). A regression model and correlation analysis were conducted for statistical analysis. RESULTS: The difference of bilateral facial soft tissue thickness was statistically significantly different between deviated and nondeviated sides (P < 0.05), with lower values observed on the deviated side. The soft tissue thickness has become nearly symmetric at local regions of the lower thirds of the face after orthognathic surgery. However, most measurements showed a negative correlation between changes in soft tissue thickness and changes in bone tissues. CONCLUSIONS: Skeletal Class III malocclusion with facial asymmetry is accompanied by differences in soft tissue thickness when comparing Dev and N-Dev sides of the posterior region of the mandible, where soft tissues are thinner on the Dev side. Soft tissue thickness can compensate for or camouflage the underlying asymmetric mandible. In addition, the asymmetric soft tissue thickness on the lower third of the face can be partially improved by orthognathic surgery, but the amount of soft tissue thickness change is not consistent with that of hard tissue positional change.

The complete mitochondrial genome of Ophiocordyceps gracilis and its comparison with related species.

In this study, the complete mitochondrial genome of O. gracilis was sequenced and assembled before being compared with related species. As the second largest mitogenome reported in the family Ophiocordycipitaceae, the mitogenome of O. gracilis (voucher OG201301) is a circular DNA molecule of 134,288 bp that contains numerous introns and longer intergenomic regions. UCA was detected as anticodon in tRNA-Sec of O. gracilis, while comparative mitogenome analysis of nine Ophiocordycipitaceae fungi indicated that the order and contents of PCGs and rRNA genes were considerably conserved and could descend from a common ancestor in Ophiocordycipitaceae. In addition, the expansion of mitochondrial organization, introns, gene length, and order of O. gracilis were determined to be similar to those of O. sinensis, which indicated common mechanisms underlying adaptive evolution in O. gracilis and O. sinensis. Based on the mitochondrial gene dataset (15 PCGs and 2 RNA genes), a close genetic relationship between O. gracilis and O. sinensis was revealed through phylogenetic analysis. This study is the first to investigate the molecular evolution, phylogenetic pattern, and genetic structure characteristics of mitogenome in O. gracilis. Based on the obtained results, the mitogenome of O. gracilis can increase understanding of the genetic diversity and evolution of cordycipitoid fungi.

Comparison of Radiation Pneumonitis in Lung Cancer Patients Treated with HT versus IMRT and Circulating Lymphocyte Subsets as Predicting Risk Factors.

PURPOSE: We sought to compare the symptomatic radiation pneumonitis (RP) in lung cancer patients treated with helical tomotherapy (HT) versus intensity-modulated radiotherapy (IMRT), and examine the predictive value of circulating lymphocyte subsets affecting the occurrence of RP. PATIENTS AND METHODS: Circulating lymphocyte subsets, clinical characteristics, dosimetric parameters and pulmonary function were collected from 130 lung cancer patients treated with HT (n = 53) or IMRT (n = 77) from 2016 through 2020. Symptomatic RP was compared between groups. Binary logistic regression was used to identify predictors of RP. RESULTS: The IMRT group had larger planning target volume (319.9 vs 240.8 cc, P = 0.041); more ECOG performance status 0-1 (96.1% vs 79.2%, P = 0.002); more stage III-IV disease (94.8% vs 37.6%, P = 0.028); and more combined systemic therapy (85.7% vs 69.8%, P = 0.022). Grade ≥2 RP were comparable between IMRT and HT groups (16.9% vs 15.1%, P = 0.785). For stage III-IV disease, IMRT was associated with lower lung V10 (31.9% vs 35.8%, P = 0.047) and lower incidence of grade 5 RP (0% vs 9.1%, P = 0.018). All lymphocyte subsets reduced after radiotherapy. The decrease degree of total T cell count and CD4+ T cell count were larger after IMRT than HT (P = 0.043, P = 0.021). In univariate analysis, the smoking status, lower baseline FEV1, and higher total T cell count, higher CD8+ T cell count, lower total B cell count, lower CD4+/CD8+ ratio after radiotherapy were associated with the development of grade ≥2 RP. The higher CD8+T cell count after radiotherapy was the only risk factor associated with grade ≥2 RP in multivariable analysis (OR 1.003; 95% CI: 1.000-1.005; P = 0.044). CONCLUSION: IMRT was associated with lower lung V10 and less grade 5 RP than HT for stage III-IV lung cancer. Higher CD8+ T cell count after radiotherapy was associated with an increased risk of RP. HT may better preserve total T cell and CD4+ T cell than IMRT.

B and cyano groups co-doped g-C3N4 with multiple defects for photocatalytic nitrogen fixation in ultrapure water without hole scavengers.

B atoms and cyano groups co-doped graphite carbon nitride with nitrogen vacancies (VN-BC-CN) was explored via one-step in-situ route. A series of comprehensive experiments confirmed that B atoms and cyano groups had been doped into the framework of graphite carbon nitride, forming VN-BC-CN catalyst sample with a large number of nitrogen-vacancy defects. As electron acceptors, B and cyano groups could be used as active sites for nitrogen conversion. The defect level caused by nitrogen vacancy led to red shift of the light absorption edge, which resulted in higher separation efficiency of photo-induced carriers and faster transfer rate of photo-induced electrons for the VN-BC-CN catalyst. This VN-BC-CN catalyst had good photocatalytic nitrogen fixation performance in the ultrapure water without any hole-scavengers. The nitrogen photofixation rate of VN-BC-CN (115.53 µmol g-1 h-1) was 25.5 times that of pure carbon nitride (GCN, 4.53 µmol g-1 h-1). Moreover, NH4+ generation rate hardly decreased after 10 h reaction, and the NH4+ generation rate could reach 79.56 µmol g-1 h-1 in the fifth cycle, showing the good photocatalytic stability of the VN-BC-CN catalyst.

Efficacy and safety of apatinib in recurrent/metastatic nasopharyngeal carcinoma: A pilot study.

BACKGROUND: There is no standard-of-care for recurrent, metastatic nasopharyngeal carcinoma (rmNPC) after first-line chemotherapy. Here, we report the efficacy and safety data of apatinib in rmNPC patients. METHODS: Thirty-five biopsy-proven rmNPC patients received apatinib at 500 mg/day under a compassionate access programme. Primary end-point was objective response rate (ORR; RECIST v1.1). Kaplan-meier method was used to estimate progression-free survival (PFS) and overall survival (OS). Toxicity was assessed by CTCAE v4.0. RESULTS: 82.9% (29 of 35) of patients had poly-metastatic rmNPC. All patients, except five, were platinum-refractory; 37.1% (13 of 35) received ≥ 2 lines. Median number of apatinib cycles was 4.0 (IQR: 2.0-8.0). ORR was 31.4% (11 of 35 [95% CI: 16.9-49.3]) and disease control rate was 74.3% (26 of 35 [95% CI: 56.7-87.5]); 11 (31.4%) and 4 (11.4%) patients demonstrated response for ≥ 6 and ≥ 12 months, respectively. Median PFS and OS was 3.9 (95% CI: 3.1-5.5) months and 5.8 (95% CI: 4.5-8.0) months, respectively. Among the ≥ 12-month responders, all patients had pre-apatinib EBV DNA titer of <700 (range: 353-622) copies/ml; this was consistent with the association of PFS with pre-apatinib EBV DNA titer (adjusted HR 3.364 [95% CI: 1.428-7.923] for ≥ 4000 copies/ml, P = 0.006). 42.9% (15 of 35) of patients required dose reduction. Nonetheless, only five (14.3%) patients suffered from G3 toxicities (two haematological, one hypertension, one hand-foot syndrome and one elevated aminotransferases). CONCLUSION: Our data suggests potential efficacy of apatinib in rmNPC patients. Although incidence of severe toxicities was low, dose modification was required in 42.9% of patients.

Characteristics of stereotactic radiotherapy clinical trials registered on ClinicalTrials.gov.

BACKGROUND: We aim to analyze the characteristics of stereotactic radiotherapy trials registered on ClinicalTrials.gov, and to compare completed and stopped early trials to identify predictors of trial failure. METHODS: All interventional stereotactic radiotherapy trials registered on ClinicalTrials.gov before Dec 31, 2019 were downloaded. Trial characteristics over time and between different regions were compared by Chi-square test. Binary logistic regression was used to explore characteristics associated with trials stopped early. RESULTS: A total of 760 trials were included. A higher proportion of trials were about lung cancer (20.4%), prostate cancer (14.7%) and central nervous system (14.6%). Most trials were phase1 and/or 2 trials (63.0%), single group (62.4%), nonrandomized (71.7%), open-label (95.0%) and single center (75.8%). The median sample size was 40 (0-1,716). Only 15.1% and 13.5% were funded by industry and National Institutes of Health (NIH), respectively. 15.4% stopped early with status includes "suspended", "terminated" and "withdrawn". Of the 113 "completed" trials, only 28 were published on PubMed. Compared with 2010 to 2014, trials from 2015 to 2019 were more likely to be randomized (20.0% vs. 34.4%; P=0.001), with 2 study arms (27.1% vs. 42.1%; P=0.002), industry-funded (11.0% vs. 19.1%; P=0.028) and conducted in Asia (7.6% to 15.8%; P=0.002). Trials from North America were more oriented toward phase 1 research (24.4% vs. 6.1% for Europe and 6.5% for Asia, P<0.001), nonrandomized (77.7% vs. 56.8% for Europe and 64.1% for Asia, P<0.001). Trials from Asia were more likely to have recruiting status (56.5% vs. 45.5% for Europe and 43.6% for North America, P<0.001). Multivariate regression analysis showed that randomized (OR 8.090, P=0.001), and enrollment patients ≤50 (OR 3.813, P<0.001) were associated with trials stopped early. CONCLUSIONS: Stereotactic radiotherapy trials are predominantly early-phase, small, single arm, nonrandomized and open label. Trials with randomized allocation or enrollment patients ≤50 were more likely to stop early.

Lactate dehydrogenase kinetics predict chemotherapy response in recurrent metastatic nasopharyngeal carcinoma.

BACKGROUND: Lactate dehydrogenase (LDH) is a known prognostic biomarker for the endemic variant of nasopharyngeal carcinoma (NPC). Here, we investigate whether serial changes in LDH level between chemotherapy (CT) cycles are associated with tumour response to CT. METHODS: Patients with biopsy-proven, recurrent or treatment-naïve metastatic NPC (mNPC) were recruited. All patients had received at least two cycles of platinum-based doublet or triplet CT, with serial assessment of LDH prior to every cycle of chemotherapy (CT1-6). Patients harbouring conditions that affect LDH levels (IU/L) were excluded. Tumour response was assessed after every two cycles of CT by RECIST v1.1. RESULTS: A total of 158 patients were analysed, including 77 with recurrent and 81 with treatment-naïve mNPC. High pre-CT LDH was associated with an inferior overall survival [hazard ratio 1.93 for ⩾240 versus <240 (1.34-2.77), p < 0.001], which is consistent with published literature. We found that both absolute LDH levels and LDH ratios (LDHCTn: LDHCTn-1) were associated with tumour response [partial response versus progressive disease: median value across CT1-6 = 168-190 versus 222-398 (absolute); 0.738-0.988 versus 1.039-1.406 (ratio)], albeit LDH ratio had a tighter variance between patients. Finally, we showed that an LDH ratio cut-off of 1.0 at CT1, CT3 and CT5 was predictive of progressive disease at CT2, CT4, CT6 [area under the curve of 0.73 (0.65-0.80)]. CONCLUSION: Herein, we characterised the longitudinal variation of LDH in response to CT in mNPC. Our findings suggest the potential utility of interval LDH ratio to predict subsequent tumour response to CT.

High-Dimensional Characterization of the Systemic Immune Landscape Informs on Synergism Between Radiation Therapy and Immune Checkpoint Blockade.

PURPOSE: Improved antitumor responses have been observed in patients after combination radiation therapy (RT) and immune checkpoint blockade (ICB). Whether these clinical responses are linked to the host systemic immune system has not been elucidated. METHODS AND MATERIALS: In this single-institution prospective observational study, peripheral blood was longitudinally collected from 10 patients with metastatic disease who had responded to anti-PD-1/anti-PD-L1 ICB and received RT (8-50 Gy in 1-5 fractions) upon disease progression at the following timepoints: baseline (pre-RT), 1 to 2 weeks post-RT, and post-ICB (cycle 1) on reintroduction post-RT. To thoroughly characterize the interaction between combined RT-ICB and the host immune system, we performed high-dimensional, mass cytometry-based immunophenotyping of circulating lymphocytes using a 40-marker panel addressing lineage, differentiation, activation, trafficking, cytotoxicity, and costimulatory and inhibitory functions. Phenotypic expression of circulating lymphocytes was compared across patients and time points and correlated with post-RT tumor responses. RESULTS: Foremost, we demonstrated excellent posttreatment clinical responses, including 4 local responses with >50% reduction in radiated tumor size, 1 out-of-field response, and 4 patients who resumed ICB for >1 year. Baseline and post-RT immune states were highly heterogeneous among patients. Despite this interindividual heterogeneity in baseline immune states, we observed a systemic immune reaction to RT-ICB common across patients, histology, and radiation sites; a subset of pre-existing Ki-67+ CD8+ T cells were increased post-RT and further expanded upon reintroduction of ICB post-RT (2.3-fold increase, P = .02). Importantly, RT did not alter the phenotypic profile of these Ki-67+ CD8+ T cells, which was characterized by a distinct activated and differentiated effector phenotype. CONCLUSIONS: Collectively, these findings point toward a sustained reinvigoration of host antitumor immunity after RT-ICB and suggest an expansion in activated Ki-67+ CD8+ T cells as a possible demonstration of this synergy, thereby providing new insights that may support the development of optimal sequencing strategies.

A Prospective 10-Year Observational Study of Reduction of Radiation Therapy Clinical Target Volume and Dose in Early-Stage Nasopharyngeal Carcinoma.

PURPOSE: Current guideline recommends a uniform method of delineation of subclinical disease within the primary clinical target volume (CTVp) for all stages of nasopharyngeal carcinoma (NPC). We performed a prospective observational study to investigate the outcomes with a reduced CTVp and radiation dose for early-stage NPC. METHODS AND MATERIALS: Patients with newly diagnosed, biopsy-proven World Health Organization type II-III and American Joint Committee on Cancer/Union for International Cancer Control sixth edition stage T1-2N0-1 disease were enrolled. All patients were treated with intensity modulated radiation therapy alone. We categorized CTVp into CTVp1 (high risk) and CTVp2 (low risk). CTVp1 comprised of gross tumor (on magnetic resonance imaging or contrast-enhanced computed tomography) plus a 5-mm margin (3-mm posteriorly) and was prescribed to 60 Gy in 30 fractions (fr). CTVp2 was generated from CTVp1 plus a 5-mm margin (3 mm posteriorly), excluding the maxillary and cavernous sinuses, and was prescribed to 54 Gy in 30 fr. The prescribed doses to the primary and nodal gross tumor volume (GTVp and GTVn) were 68 Gy in 30 fr and 60 to 66 Gy in 30 fr, respectively. Primary endpoint was local recurrence-free survival. This study was registered in ClinicalTrials.gov, number NCT03839602. RESULTS: From May 2001 to August 2006, 103 patients were recruited and completed IMRT. With a median follow-up of 15.2 years (range, 2.1-18.1 years), only 1 patient had local failure. Ten-year local recurrence-free survival, regional recurrence-free survival, distant metastasis-free survival, and overall survival were 90.3%, 88.3%, 90.3%, and 91.2%, respectively. Among late IMRT-related adverse events, we recorded 2 patients with G1 cranial nerve injury, 3 patients with G3 hearing loss, and 3 patients with G3 subcutaneous fibrosis. No patients had temporal lobe necrosis, brain stem injury, or trismus. CONCLUSIONS: Decreased CTV margins and radiation doses can achieve long-term tumor control with mild late toxicities for patients with early-stage NPC.