Efficacy of metastatic lesion radiotherapy in patients with metastatic nasopharyngeal carcinoma: A multicenter retrospective study.

OBJECTIVE: We investigated the efficacy of metastatic lesion radiotherapy (MLRT) in patients with metastatic nasopharyngeal carcinoma (mNPC). MATERIALS AND METHODS: Patients with mNPC from three institutions were included in this study. Propensity score matching (PSM) was employed to ensure comparability between patient groups. Overall survival (OS) rates were assessed using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors were identified using univariate and multivariate Cox hazard analyses. Subgroup analyses were conducted to assess the effects of MLRT on specific patient populations. RESULTS: We analyzed data from 1157 patients with mNPC. Patients who received MLRT had significantly better OS than those who did not, both in the original (28 vs. 21 months) and PSM cohorts (26 vs. 23 months). MLRT was identified as an independent favorable predictor of OS in multivariate analyses, with hazard ratios of 0.67. The subgroup analysis results indicated that radiotherapy effectively treated liver, lung, and bone metastatic lesions, particularly in patients with a limited tumor burden. Higher total radiation doses of MLRT (biologically effective dose (BED) ≥ 56 Gy) were associated with improved OS, while neither radiation technique nor dose fractionation independently influenced prognosis. CONCLUSIONS: MLRT offers survival advantages to patients diagnosed with mNPC. Patients with limited metastatic burden derive the most benefit from MLRT, and the recommended regimen for MLRT is a minimum BED of 56 Gy for optimal outcomes.

A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome.

Hoyeraal-Hreidarsson syndrome (HHS) is the most severe form of dyskeratosis congenita (DC) and is caused by mutations in genes involved in telomere maintenance. Here, we identified male siblings from a family with HHS carrying a hemizygous mutation (c.1345C > G, p.R449G), located in the C-terminal nuclear localization signal (NLS) of the DKC1 gene. These patients exhibit progressive cerebellar hypoplasia, recurrent infections, pancytopenia due to bone marrow failure, and short leukocyte telomere lengths. Single-cell RNA sequencing analysis suggested defects in the NLRP3 inflammasome in monocytes and the activation and maturation of NK cells and B cells. In experiments using induced pluripotent stem cells (iPSCs) from patients, DKC1_R449G iPSCs had short telomere lengths due to reduced levels of human telomerase RNA (hTR) and increased cytosolic proportions of DKC1. Treatment with dihydroquinolizinone RG7834 and 3'deoxyanosine cordycepin rescued telomere length in patient-derived iPSCs. Together, our findings not only provide new insights into immunodeficiency in DC patients but also provide treatment options for telomerase insufficiency disorders.

Identification of genes associated with cancer stem cell characteristics in head and neck squamous cell carcinoma through co-expression network analysis.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a type of invasive malignancy and the seventh most common cancer in the worldwide. Cancer stem cells (CSCs) are self-renewal cells in tumors and can produce heterogeneous tumor cells, which play an important role in the development of HNSCC. In our research, we aimed to identify genes related to the CSCs characteristics in HNSCC. METHODS: Messenger RNA (mRNA) expression-based stiffness index (mRNAsi) can be used as a quantitative characterization of CSCs. We used one-class logistic regression machine learning algorithm (OCLR) to calculate the mRNAsi and investigate the relationship between mRNAsi and clinical characteristics of HNSCC. Then, a weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network was constructed to screen hub genes related to mRNAsi of HNSCC. RESULTS: The results indicated that the score of mRNAsi in HNSCC tissues is higher than in paracancer tissues, while the mRNAsi was not statistically correlated with the prognosis and clinical characteristics of HNSCC. Six positive and six negative hub genes related to mRNAsi of HNSCC were selected, which may act as therapeutic targets for inhibiting CSCs within HNSCC. CONCLUSIONS: In conclusion, our research selected 12 hub genes related to mRNAsi of HNSCC through weighted gene co-expression network analysis. These genes may become therapeutic targets to inhibit the CSCs of HNSCC in the future.

A retrospective cohort study of low-dose intensity-modulated radiotherapy for unresectable liver metastases.

OBJECTIVE: To evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) for the treatment of unresectable liver metastases. METHODS: Twenty-five patients with unresectable liver metastases treated with IMRT were enrolled from January 2003 to September 2016. The median longest diameter of the lesions was 3.3 cm (range, 1.6-16.7 cm). The fraction dose ranged from 2 to 5.2 Gy, with a median total dose of 50 Gy (range, 30-60 Gy). RESULTS: The median follow-up was 9.2 months (range, 2.1-48.8 months). The overall survival rates at 1 and 2 years were 46.4% and 27.4%, respectively. The 1-year local control rate was 69.8%. The 1-year progression-free survival rate was 26.3%. One patient had grade 4 liver dysfunction. One case of grade 4 leukopenia and one case of grade 3 leukopenia occurred, and one case of grade 3 leukopenia and thrombocytopenia was observed. CONCLUSION: IMRT may be a promising and safe treatment for unresectable liver metastases and can be used as a treatment option.

Survival benefit of higher fraction dose delivered by three-dimensional conformal radiotherapy in hepatocellular carcinoma smaller than 10 cm in size.

Objective: Even in early-stage hepatocellular carcinoma (HCC), patients are often ineligible for surgical resection, transplantation, or local ablation due to advanced cirrhosis, donor shortage, or difficult tumor location. To compare the safety and efficacy of different fractions on the survival of patients with tumors smaller than 10 cm in size, hepatocellular carcinoma (HCC) patients ineligible for curative therapies were treated with three-dimensional conformal radiotherapy (3DCRT). Methods: A total of 198 HCC patients who had tumors smaller than 10 cm and were not eligible for surgical resection or local ablation therapy received 3DCRT. Participants were separated into two groups. The treatment for Group A (n=111) was a median total dose of 53 Gy with a fraction of 2.5-4.9 Gy given three times a week, while treatment for Group B (n=87) was a median total dose of 52 Gy with a fraction of 5.0-7.0 Gy given three times a week. Propensity score matching (PSM) was conducted, and after the PSM, 81 pairs of patients arose. The Kaplan-Meier method was adopted to analyze overall survival; multivariate analysis was applied to identify the prognostic factors of survival. Results: The median follow-up time was 19.7 months (ranging from 1 to 186 months). The median survival for Group A patients versus Group B patients was 14.4 versus 24.8 months (P=0.003), respectively. The overall survival rates at 1, 3, and 5 years were 57.7%, 30.6%, and 18.9% for Group A patients and 73.6%, 43.7%, and 33.3% for Group B patients, respectively (P=0.009). In addition, the results in the PSM model appeared to be similar between the two groups. After PSM, the association between four independent prognostic factors and worse overall survival was discovered as follows: tumor size (>5 cm), Child-Pugh class B, portal vein tumor thrombosis, and fraction of 2.5-4.9 Gy/fx. The two groups also shared similar toxicities. Conclusions: Higher fraction dose radiotherapy delivered by 3DCRT was effective, as it offered a survival benefit without aggravating the toxicities in patients with small- to medium-sized HCC tumors who were ineligible for curative therapies.

Clinical Effect of Radiotherapy Combined with Chemotherapy for Non-Surgical Treatment of the Esophageal Squamous Cell Carcinoma.

BACKGROUND Chemoradiotherapy (CRT) is widely accepted and is considered a standard treatment, particularly for unresectable and inoperable esophageal squamous cell carcinoma (ESCC). However, the optimal use of the combined modalities of chemotherapy (CT) and radiotherapy (RT) remains controversial. In addition, no consensus has been reached regarding the exact efficacy of consolidation chemotherapy (CCT) and the most appropriate radiotherapy dose. MATERIAL AND METHODS Clinical data from 262 ESCC patients treated with CRT (n=165) or RT alone (n=97) were collected and reviewed. The long-term outcomes were analyzed, and treatment related acute toxicity reactions were compared. RESULTS The 1-year, 3-year, and 5-year overall survival (OS) rates were 75.3%, 35.6%, and 25.3%, respectively, for the CRT group and 61.5%, 26.7%, and 17.6% for the RT-alone group (P=0.015). The concurrent chemoradiotherapy (CCRT) and sequential chemoradiotherapy (SCRT) groups exhibited similar survival outcomes (for OS, P=0.568; for progression-free survival (PFS,) P=0.145). CCT after CCRT did not influence OS (P=0.236) but was associated with a more favorable PFS (P=0.020). In addition, high-dose of 60-65 Gy tended to prolong OS compared with low-dose (<60 Gy) or excessive-dose (>65 Gy). The incidence of adverse reactions, such as esophagitis and leukopenia, in the CRT group were significantly higher than in the RT-alone group (P=0.019, P=0.001, respectively), and no significant difference was observed between patients treated with CCRT and CCT after CCRT. CONCLUSIONS Treating non-surgical ESCC patients with CCRT conferred a significant survival benefit compared with RT alone. CCT after CCRT prolongs PFS but does not increase acute toxicity. High-dose (60-65 Gy) CCRT could generate more favorable survival outcomes.

Different effects of dexmedetomidine and midazolam on the expression of NR2B and GABAA-α1 following peripheral nerve injury in rats.

Neuropathic pain is a complex, chronic pain condition and the treatment is a major clinical challenge. Recent studies have shown that two FDA approved drugs dexmedetomidine (DEX) and midazolam (MZL), may be useful in treating neuropathic pain, but the mechanism is not fully dementated. Here, we investigated the effects and mechanisms of DEX and MZL treatment in the peripheral nerve injury model. Intramuscular injection with DEX and MZL attenuated the development of mechanical allodynia and thermal hyperalgesia in rats with chronic constriction injury (CCI). Concurrently, the expression of NMDA receptor subunit 2B (NR2B), GABA (A) receptor subunit alpha1 (GABAA-α1), and Sonic Hedgehog (SHH) displayed different temporal patterns in the thalamus and the ipsilateral dorsal horn of the spinal cord after CCI. Such that (1) NR2B expression was decreased on day 1 and 14, whereas GABAA-α1 expression was increased on day 1 in the thalamus, and NR2B expression was decreased on day 1, whereas GABAA-α1 expression was increased on day 1 and day 30 in the ipsilateral spinal cord dorsal horn after DEX treatment. (2) NR2B expression was increased on day 1, then decreased on day 14 and returned to baseline on day30, whereas GABAA-α1 expression was no significant changes on day 1, 14, 30 in the thalamus, and NR2B expression was decreased on day 14 and 30, whereas GABAA-α1 expression was no changes on day 1 and 14 but increased on day 30 after MZL treatment. Furthermore, the mechanical allodynia was significantly attenuated after PUR administration. Meanwhile the expression of NR2B was significantly decreased, and the expression of GABAA-α1 was significantly increased, in the thalamus and in the ipsilateral spinal cord dorsal horn when detected on postoperative day 1, 7, and 14. Our findings indicate that DEX and MZL have different mechanisms in CCI rats, suggesting different strategies could be considered in managing neuropathic pain in different individuals. © 2018 IUBMB Life, 70(2):143-152, 2018.

Median effective effect-site concentration of sufentanil for wake-up test in adolescents undergoing surgery: a randomized trial.

BACKGROUND: To determine the median effective concentration of sufentanil as an analgesic during wake-up tests after sevoflurane anesthesia during surgery for adolescent idiopathic scoliosis (AIS). METHODS: This is a randomised controlled trial. Sixty patients aged 13-18 years scheduled for AIS surgery were randomized into six groups of 10 patients each to receive target effect-site concentrations of sufentanil of 0.19, 0.1809, 0.1723, 0.1641, 0.1563, and 0.1489 ng/ml (target concentration ratio, 1.05). Wake-up time was recorded. Median EC50 and 95% confidence interval (CI) for sufentanil target-controlled infusion (TCI) were determined using Kärber's method. The primary outcome was median EC50 for sufentanil TCI as an analgesic during the wake-up test after sevoflurane anesthesia during surgery for AIS. RESULTS: The EC50 and 95% CI of sufentanil TCI were 0.1682 ng/ml and 0.1641 ~ 0.1724 ng/ml, respectively. CONCLUSIONS: The EC50 of sufentanil TCI was 0.1682 ng/ml (95% CI: 0.1641 ~ 0.1724 ng/ml) during sevoflurane anesthesia in adolescents undergoing surgery for idiopathic scoliosis with intraoperative wake-up tests. TRIAL REGISTRATION: Clinicaltrials.gov identifier: ChiCTR-TTRCC-12002696.

Effect of the intraoperative wake-up test in sevoflurane-sufentanil combined anesthesia during adolescent idiopathic scoliosis surgery: a randomized study.

STUDY OBJECTIVE: To investigate the effect of the intraoperative wake-up test on sevoflurane-sufentanil anesthesia for adolescent idiopathic scoliosis (AIS) surgery. DESIGN: Randomized, double-blind, parallel trial. SETTING: Operating room. PATIENTS: 30 ASA physical status 1 patients, aged 13 to 20 years, scheduled for AIS surgery. INTERVENTIONS: Patients were randomized to two groups: Group W patients received sevoflurane-sufentanil combined anesthesia and underwent the intraoperative wake-up test; Group NW received sevoflurane-sufentanil combined anesthesia without the wake-up test. Anesthesia was induced with an intravenous (IV) injection of midazolam, propofol, and sufentanil and maintained with sevoflurane inhalation, a target-controlled infusion (TCI) of sufentanil, and IV infusion of cisatracurium besylate. MEASUREMENTS: The primary outcome was postoperative delirium. Secondary outcomes were duration of surgery, duration of anesthesia, intraoperative blood loss and transfusion, exposure of drugs administered, time to eye opening, extubation, and consciousness. MAIN RESULTS: Postoperative delirium occurred in one patient from each group (P > 0.05). There were no significant differences between the two groups in duration of surgery (322 ± 65 min vs 336 ± 72 min), duration of anesthesia (356 ± 76 min vs 368 ± 81 min), intraoperative blood loss (1847 ± 423 mL vs 1901 ± 451 mL) and transfusion (1663 ± 398 mL vs 1649 ± 382 mL), average exposure of drugs (72 ± 13 mg vs 75 ± 15 mg for propofol, 116 ± 28 µg vs 109 ± 25 µg for sufentanil, and 22 ± 5 vs 23 ± 4 mg for cisatracurium), time to eye opening (4.7 ± 1.5 min vs 4.8 ± 1.4 min), extubation (7.5 ± 2.0 min vs 7.3 ± 2.2 min), and consciousness (8.9 ± 1.8 min vs 9.1 ± 2.1 min) (all P > 0.05). CONCLUSIONS: Sevoflurane-sufentanil combined anesthesia provides hemodynamic stability and rapid recovery from AIS surgery. There is no correlation between the intraoperative wake-up test and postoperative delirium after sevoflurane-sufentanil combined anesthesia.

No association of age-related maculopathy susceptibility protein 2/HtrA serine peptidase 1 or complement factor H polymorphisms with early age-related maculopathy in a Chinese cohort.

PURPOSE: Single nucleotide polymorphisms (SNPs) of age-related maculopathy susceptibility protein 2/HtrA serine peptidase 1 (ARMS2/HTRA1) and complement factor H (CFH) have been reported to be associated with age-related macular degeneration (AMD). The purpose of this study was to investigate the association of ARMS2/HTRA1 and CFH SNPs with early age-related maculopathy (ARM) in a Han Chinese cohort. METHODS: The cohort consisted of 315 unrelated subjects, including 158 patients with early ARM and 157 recruited controls. Early ARM was diagnosed and graded according to the Age-Related Eye Disease Study criteria. Four SNPs in ARMS2/HTRA1 and six SNPs in CFH previously reported to be associated with AMD were genotyped using TaqMan genotyping assays. Logistic regression implemented with the R statistical language was used for association analysis. RESULTS: None of the ARMS2/HTRA1 and CFH SNPs showed any significant association with early ARM (all p>0.453), with the odds ratios ranging from 0.88 to 1.17. None of the SNPs were associated with unilateral or bilateral early ARM or any grade of early ARM (all p>0.249). CONCLUSIONS: The association of ARMS2/HTRA1 and CFH SNPs in early ARM was not detected in our cohort. The findings in the current study indicated that the effects of ARMS2/HTRA1 and CFH in early ARM could be much lower compared to those in AMD.

Radiation-induced sarcoma of head and neck: 50 years of experience at a single institution in an endemic area of nasopharyngeal carcinoma in China.

Radiation-induced sarcoma in the head and neck (RISHN) is a rare condition whose clinical presentation and management remain difficult because of its low incidence. In this retrospective study, we analyzed the symptoms, diagnosis, and the treatment of 16,634 patients with head and neck disease, who received radiotherapy between 1960 and 2010 at the Affiliated Tumor Hospital and its predecessor, Guangxi Medical University, China. Among these patients, 16 with a first tumor of nasopharyngeal carcinoma (NPC) and 1 with squamous carcinoma of the tongue met the criteria of RISHN in the head and neck. Our epidemiological data showed that the incidence of RISHN rose from 0.06 to 0.17% from 1960 to 2010; the 3-year overall survival rate was 19.1%, and 3-year disease-free survival rate was 11.1%. The mean latency (SD) period was 93.2 (33) months. Based on the experiences at our institution, we suggest that RISHN is a rare complication after radiotherapy for head and neck tumors, especially NPC. Owing to its low incidence, it should not be a major factor affecting decisions about radiotherapy. Nevertheless, there may be a possibility of increasing incidence of RISHN after radiotherapy of NPC, as shown in our epidemiological results. Given the poor prognosis of RISHN, this possibility should be taken into serious consideration before determination of high-dose radiotherapy for patients with NPC and other head and neck tumors.

Self correction of refractive error among young people in rural China: results of cross sectional investigation.

OBJECTIVE: To compare outcomes between adjustable spectacles and conventional methods for refraction in young people. DESIGN: Cross sectional study. SETTING: Rural southern China. PARTICIPANTS: 648 young people aged 12-18 (mean 14.9 (SD 0.98)), with uncorrected visual acuity ≤ 6/12 in either eye. INTERVENTIONS: All participants underwent self refraction without cycloplegia (paralysis of near focusing ability with topical eye drops), automated refraction without cycloplegia, and subjective refraction by an ophthalmologist with cycloplegia. MAIN OUTCOME MEASURES: Uncorrected and corrected vision, improvement of vision (lines on a chart), and refractive error. RESULTS: Among the participants, 59% (384) were girls, 44% (288) wore spectacles, and 61% (393/648) had 2.00 dioptres or more of myopia in the right eye. All completed self refraction. The proportion with visual acuity ≥ 6/7.5 in the better eye was 5.2% (95% confidence interval 3.6% to 6.9%) for uncorrected vision, 30.2% (25.7% to 34.8%) for currently worn spectacles, 96.9% (95.5% to 98.3%) for self refraction, 98.4% (97.4% to 99.5%) for automated refraction, and 99.1% (98.3% to 99.9%) for subjective refraction (P = 0.033 for self refraction v automated refraction, P = 0.001 for self refraction v subjective refraction). Improvements over uncorrected vision in the better eye with self refraction and subjective refraction were within one line on the eye chart in 98% of participants. In logistic regression models, failure to achieve maximum recorded visual acuity of 6/7.5 in right eyes with self refraction was associated with greater absolute value of myopia/hyperopia (P<0.001), greater astigmatism (P = 0.001), and not having previously worn spectacles (P = 0.002), but not age or sex. Significant inaccuracies in power (≥ 1.00 dioptre) were less common in right eyes with self refraction than with automated refraction (5% v 11%, P<0.001). CONCLUSIONS: Though visual acuity was slightly worse with self refraction than automated or subjective refraction, acuity was excellent in nearly all these young people with inadequately corrected refractive error at baseline. Inaccurate power was less common with self refraction than automated refraction. Self refraction could decrease the requirement for scarce trained personnel, expensive devices, and cycloplegia in children's vision programmes in rural China.

Radiation-induced sarcoma in the head and neck region: a clinicopathologic and immunohistochemical study of 13 cases.

OBJECTIVES: To study the clinical and histological features of radiation-induced sarcoma in the head and neck (RISHN). METHODS: Medical records of 13 patients with RISHN treated at our institution between 1990 and 2011 were studied, and paraffin-embedded samples were analyzed by haematoxylin and eosin staining and immunohistochemistry to determine mitosis counts and assess expression of Ki-67, bcl-2, and survivin. RESULTS: Positive bcl-2 was observed in 12 (100%) and survivin in 10 (76.9%) patients. The Ki-67 labeling index ranged from 1% to 90%, and it showed significant positive correlation with mitosis count in RISHN tissues, based on Spearman analysis. Percentage of distal metastasis with T2b was significantly higher than T1b stage (P=0.035). CONCLUSIONS: Stage T2b may be a useful indicator for predicting distant metastasis of RISHN. The MIB-1 score may be used as a histological grading system for RISHN. In addition, bcl-2 and survivin protein may play an important role in pathogenesis and progression of RISHN.

Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: the risk factors and hepatic radiation tolerance.

PURPOSE: To identify risk factors relevant to radiation-induced liver disease (RILD) and to determine the hepatic tolerance to radiation. METHODS AND MATERIALS: The data of 109 primary liver carcinomas (PLC) treated with hypofractionated three-dimensional conformal radiation therapy (3D-CRT) were analyzed. Seventeen patients were diagnosed with RILD and 13 of 17 died of it. RESULTS: The risk factors for RILD were late T stage, large gross tumor volume, presence of portal vein thrombosis, association with Child-Pugh Grade B cirrhosis, and acute hepatic toxicity. Multivariate analyses demonstrated that the severity of hepatic cirrhosis was a unique independent predictor. For Child-Pugh Grade A patients, the hepatic radiation tolerance was as follows: (1) Mean dose to normal liver (MDTNL) of 23 Gy was tolerable. (2) For cumulative dose-volume histogram, the tolerable volume percentages would be less than: V5 of 86%, V10 of 68%, V15 of 59%, V20 of 49%, V25 of 35%, V30 of 28%, V35 of 25%, and V40 of 20%. (3) Tolerable MDTNL could be estimated by MDTNL (Gy) = -1.686 + 0.023 * normal liver volume (cm3). CONCLUSION: The predominant risk factor for RILD was the severity of hepatic cirrhosis. The hepatic tolerance to radiation could be estimated by dosimetric parameters.

Prediction of radiation-induced liver disease by Lyman normal-tissue complication probability model in three-dimensional conformal radiation therapy for primary liver carcinoma.

PURPOSE: To describe the probability of RILD by application of the Lyman-Kutcher-Burman normal-tissue complication (NTCP) model for primary liver carcinoma (PLC) treated with hypofractionated three-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS: A total of 109 PLC patients treated by 3D-CRT were followed for RILD. Of these patients, 93 were in liver cirrhosis of Child-Pugh Grade A, and 16 were in Child-Pugh Grade B. The Michigan NTCP model was used to predict the probability of RILD, and then the modified Lyman NTCP model was generated for Child-Pugh A and Child-Pugh B patients by maximum-likelihood analysis. RESULTS: Of all patients, 17 developed RILD in which 8 were of Child-Pugh Grade A, and 9 were of Child-Pugh Grade B. The prediction of RILD by the Michigan model was underestimated for PLC patients. The modified n, m, TD50 (1) were 1.1, 0.28, and 40.5 Gy and 0.7, 0.43, and 23 Gy for patients with Child-Pugh A and B, respectively, which yielded better estimations of RILD probability. The hepatic tolerable doses (TD5) would be MDTNL of 21 Gy and 6 Gy, respectively, for Child-Pugh A and B patients. CONCLUSIONS: The Michigan model was probably not fit to predict RILD in PLC patients. A modified Lyman NTCP model for RILD was recommended.