Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy.

Background: Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups. Patients and methods: A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation. Results: Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-γ signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-ß signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P = 0.01). Conclusions: This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.

[Different care models and symptom progression of Alzheimer's disease in China].

Objective: To compare the differences of cognitive function, daily living ability and neuropsychiatric symptoms in patients with sporadic type of Alzheimer's disease (AD) under different care modes, and find the most favorable care mode for delaying the progress of disease. Methods: One hundred and twenty cases of AD patients were divided into three groups: Spouse Care Group, Adult Child Care Group and Nursing Home Group. Medical history collection and scale evaluation were carried out by trained specialists on 3 groups of patients and caregivers. Assessment included socio-demographic data, including name, gender, age, course of the disease, the year of education and the way of care, Mini mental state examination (MMSE), Activity of Daily Living (ADL), Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-Cog), Neuropsychiatric Inventory (NPI), and the Relevant Outcome Scale for Alzheimer's disease (ROSA). All the evaluations were completed upon enrollment. The differences in cognitive function, daily living ability and neuropsychiatric symptoms were compared among the three groups. Results: There was no significant difference in age, gender, education duration and course of disease between the three groups (P>0.05). The MMSE average scores of Spouse Care Group, Adult Child Care Group and Nursing Home Group were 19±7, 15±6, 13±7 respectively. The ADAS-Cog median scores of Spouse Care Group, Adult Child Care Group and Nursing Home Group were 17.32(9.78, 26.50), 30.00(16.10, 38.55), 33.15 (16.28, 50.68). The NPI median total scores of Spouse Care Group, Adult Child Care Group and Nursing Home Group were 5.00(1.00, 13.00), 9.00(4.00, 20.00), 19.50(8.50, 28.50) respectively. The ADL average scores of Spouse Care Group, Adult Child Care Group and Nursing Home Group were 21±9, 25±9, 35±11. The difference of MMSE, ADAS-Cog, ADL and NPI was statistically significant among the three groups (P<0.05). No significant difference was found in care burden among the three groups (P>0.05). Conclusions: The AD patients with spouse care tend to suffer from mild diseases severitys, no matter in terms of cognitive function, daily living ability or neuropsychiatric symptoms. Close, familiar and comprehensive care plays an important role in delaying the progress of AD.

A Bayesian network meta-analysis comparing concurrent chemoradiotherapy followed by adjuvant chemotherapy, concurrent chemoradiotherapy alone and radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: Given the lack of studies, whether the addition of adjuvant chemotherapy (AC) to concurrent chemoradiotherapy (CCRT) is superior to CCRT alone for locoregionally advanced nasopharyngeal carcinoma (NPC) remains unclear. The main objective of this Bayesian network meta-analysis was to determine the efficacy of CCRT + AC when compared with CCRT alone. PATIENTS AND METHODS: We systematically searched databases and extracted data from randomized, controlled trials involving NPC patients randomly assigned to receive CCRT + AC, CCRT, or radiotherapy (RT). Overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) with hazard ratios (HRs) were investigated. A Bayesian network for different outcomes was established to incorporate all evidence. Multiple treatment comparisons based on the network integrated the efficacy of CCRT + AC, CCRT, and RT. RESULTS: Eight studies involving 2144 patients were analyzed. In the network meta-analysis, CCRT + AC and CCRT were both significantly better than RT alone for all outcomes, except that no significant difference was found between CCRT and RT for LRFS. Though ranking probabilities showed that CCRT + AC was ranked superior to CCRT for OS, LRFS, and DMFS, no significant differences were found between CCRT+AC and CCRT for all outcomes [OS: HR = 0.86, 95% credible interval (CrI) 0.60-1.16; LRFS: HR = 0.72, 95% CrI 0.43-1.15; DMFS: HR = 0.86, 95% CrI 0.62-1.16]. CONCLUSIONS: No significant improvement was found following CCRT + AC compared with CCRT alone. Whether the omission of additional AC can reduce toxic effects without adversely affecting survival in patients with locoregionally advanced NPC should be further explored, in addition to the precise patient status that would benefit from AC following CCRT.

Comparison of radiological and clinical features of temporal lobe necrosis in nasopharyngeal carcinoma patients treated with 2D radiotherapy or intensity-modulated radiotherapy.

BACKGROUND: To compare the imaging and clinical features of temporal lobe necrosis (TLN) in nasopharyngeal carcinoma (NPC) patients treated with two-dimensional radiotherapy (2D-RT) or those with intensity-modulated radiotherapy (IMRT). METHODS: We retrospectively analysed NPC patients who underwent 2D-RT (72 patients, 128 temporal lobes) or IMRT (36 patients, 50 lobes) and developed radiation-induced, MRI-confirmed TLN. RESULTS: White-matter lesions (WMLs), contrast-enhanced lesions, cysts and local mass effects were present in 128 out of 128 vs 48 out of 50 (P=0.078), 123 out of 128 vs 47 out of 50 (P=0.688), 10 out of 128 vs 1 out of 50 (P=0.185) and 57 out of 128 vs 13 out of 50 (P=0.023) temporal lobes, respectively, in the 2D-RT and IMRT groups. The WMLs were more extensive in the 2D-RT group (P<0.001). The maximum diameter of contrast-enhanced lesions was greater in the 2D-RT group (P<0.001), and these lesions tended to extend far away from the nasopharynx. The WMLs and enhancement had no impact on cyst development (both P=1). Local mass effects were always accompanied with contrast-enhanced lesions (P=0.024) but were not correlated with WMLs or cysts (P=0.523 and 0.341, respectively). There were no between-group differences in clinical features (all P-values>0.05), whereas the difference in the incidence of severe debility was of marginal significance (18.1% vs 5.6%, P=0.077). CONCLUSIONS: The IMRT-induced TLN was less extensive and milder than 2D-RT-induced TLN, but both had similar clinical features.

Prognostic value of magnetic resonance imaging-detected cranial nerve invasion in nasopharyngeal carcinoma.

BACKGROUND: We previously reported that magnetic resonance imaging evidence of cranial nerve invasion was an unfavourable prognostic factor in nasopharyngeal carcinoma. However, the prognostic value of this evidence in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy remains unknown. METHODS: We retrospectively analysed 749 nasopharyngeal carcinoma patients who underwent intensity-modulated radiotherapy. RESULTS: Cranial nerve invasion was observed in 299 (39.9%) patients with T3-4 disease. In T3-4 nasopharyngeal carcinoma, magnetic resonance imaging-detected cranial nerve invasion was associated with inferior 5-year overall survival, distant metastasis-free survival, and locoregional relapse-free survival (P=0.002, 0.003, and 0.012, respectively). Multivariate analyses confirmed that cranial nerve invasion was an independent prognostic factor for distant metastasis-free survival (hazard ratio, 1.927; P=0.019) and locoregional relapse-free survival (hazard ratio, 2.605; P=0.032). Furthermore, the receiver-operating characteristic curves verified that the predictive validity of T classifications was significantly improved when combined with magnetic resonance imaging-detected cranial nerve invasion in terms of death, distant metastasis, and locoregional recurrence (P=0.015, 0.021 and 0.008, respectively). CONCLUSIONS: Magnetic resonance imaging-detected cranial nerve invasion is an independent adverse prognostic factor in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.

Comparison of TNM staging systems for nasopharyngeal carcinoma, and proposal of a new staging system.

BACKGROUND: There are few systematic evaluations regarding the sixth and seventh editions of the UICC/AJCC TNM Staging System (TNM6th, TNM7th) and Chinese 2008 Staging System (TNMc2008) for nasopharyngeal carcinoma (NPC). METHODS: We classified 2333 patients into intensity-modulated radiotherapy (IMRT) cohort (n=941) and conventional radiotherapy (CRT) cohort (n=1392). Tumour staging defined by TNM6th, TNM7th and TNMc2008 was compared based on Akaike information criterion (AIC) and Harrell's concordance index (c-index). RESULTS: For T-classification, TNM6th (AIC=2585.367; c-index=0.6390385) had superior prognostic value to TNM7th (AIC=2593.242; c-index=0.6226889) and TNMc2008 (AIC=2593.998; c-index=0.6237146) in the IMRT cohort, whereas TNMc2008 was superior (AIC=5999.054; c-index=0.623547) in the CRT cohort. For N-classification, TNMc2008 had the highest prognostic value in both cohorts (AIC=2577.726, c-index=0.6297874; AIC=5956.339, c-index=0.6533576). Similar results were obtained when patients were stratified by chemotherapy types, age and gender. Using staging models in the IMRT cohort, we failed to identify better stage migrations than TNM6th T-classification and TNMc2008 N-classification. We therefore proposed to combine these categories; resultantly, stage groups of the proposed staging system showed superior prognostic value over TNM6th, TNM7th and TNMc2008. CONCLUSION: TNM6th T-classification and TNMc2008 N-classification have superior prognostic value in the IMRT era. By combining them with slight modifications, TNM criteria can be unified and its prognostic value be improved.

Prognostic value of ABO blood group in southern Chinese patients with established nasopharyngeal carcinoma.

BACKGROUND: ABO blood group is associated with aetiology of nasopharyngeal carcinoma (NPC); however, the effect of it on survival of patients diagnosed with NPC has not been explored. METHODS: We retrospectively analysed two cohorts of southern Chinese patients with WHO histological type III: intensity-modulated radiotherapy (IMRT) cohort, 924 patients; and conventional radiotherapy (CRT) cohort, 1193 patients. Associations of ABO blood group with survival were estimated using Cox regression. RESULTS: In IMRT cohort, we observed significant associations of blood type A with overall survival (OS) and distant metastasis-free survival (DMFS), compared with type O, after adjusting for prognostic factors. Compared with non-A blood types (B, AB, and O), type A patients had significantly lower OS and DMFS (adjusted hazard ratio (HR)=1.49, 95% CI 1.03-2.17, P=0.036; HR=1.68, 95% CI 1.13-2.51, P=0.011, respectively); similar results were obtained in CRT cohort. Subgroup analyses of the entire population showed that lower OS conferred by blood type A was not significantly modified by age, smoking status, drinking status, immunoglobulin A against Epstein-Barr virus viral capsid antigen (VCA-IgA) titre, or chemotherapy; however, lower OS was not observed in female patients or patients with early clinical stage disease. CONCLUSION: ABO blood group is associated with survival in NPC; patients with blood type A had significantly lower OS and DMFS than patients with non-A blood types.

Prognostic impact of family history in southern Chinese patients with undifferentiated nasopharyngeal carcinoma.

BACKGROUND: Family history of cancer is associated with developing nasopharyngeal carcinoma (NPC); however, the impact of it on survival among established NPC patients remains unknown. METHODS: We retrospectively analysed 1773 southern Chinese patients. Associations between a first-degree family history of NPC and overall survival (OS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) were estimated by Cox regression. RESULTS: Among 1773 patients, 207 (11.7%) reported a first-degree family history of NPC. Compared with patients without a family history, the adjusted hazard ratios among those with it were 0.60 (95% confidence interval (CI), 0.37-0.98; P=0.040) for OS, 0.52 (95% CI, 0.24-1.12; P=0.096) for LRFS and 0.51 (95% CI, 0.27-0.97; P=0.040) for DMFS. There were trends for improving OS, LRFS and DMFS with increasing number of affected relatives (Ptrend: 0.050, 0.114 and 0.044, respectively). But no significant benefits of family history in second- or third-degree relatives were observed. In subgroup analysis, we observed the effects of family history with restriction to male patients and those of advanced stage and treated with conventional radiotherapy and addition of chemotherapy. CONCLUSION: A first-degree family history of NPC is associated with improved survival of patients.

Significant efficacies of neoadjuvant and adjuvant chemotherapy for nasopharyngeal carcinoma by meta-analysis of published literature-based randomized, controlled trials.

BACKGROUND: We carried out this meta-analysis to demonstrate efficacies of neoadjuvant chemotherapy (NACT) and adjuvant chemotherapy (AC) for nasopharyngeal carcinoma (NPC) patients based on randomized, controlled trials (RCTs). PATIENTS AND METHODS: We comprehensively searched electronic databases and manuscripts for RCTs and extracted data from eligible studies for meta-analysis. Overall survival (OS) with hazard ratios (HRs), locoregional recurrence rate (LRR) and distant metastasis rate (DMR) with relative risks (RRs) were concerned using random and/or fixed-effects models. Subgroup and sensitivity analyses were also carried out. RESULTS: Six trials in NACT group (n = 1418) and five in AC group (n = 1187) were eligible. HR of death for NACT was 0.82 [95% confidence interval (CI) 0.69-0.98, P = 0.03], corresponding to an absolute survival gain of 5.13% after 3 years. Significant reduction of DMR (P = 0.0002; RR 0.69, 95% CI 0.56-0.84) was also found from NACT. But no decrease in LRR (P = 0.49; RR 0.90, 95% CI 0.66-1.22) was observed. Patients receiving additional AC had lower LRR (P = 0.03; RR 0.71, 95% CI 0.53-0.96). But no benefit of OS and DMR were seen in AC. CONCLUSIONS: NACT can effectively enhance OS and reduce DMR, not LRR in NPC. And AC only helps to better control locoregional recurrence of NPC.

Staging of laryngeal carcinoma: comparison of high-frequency sonography and contrast-enhanced computed tomography.

AIM: To evaluate the accuracy of high-frequency sonography on pretherapeutic T-staging in patients with laryngeal carcinoma. MATERIALS AND METHODS: Thirty-six consecutive patients with laryngeal carcinoma undergoing surgical resection were included in this study. All patients underwent ultrasonographic examination and contrast-enhanced computed tomography before surgery. These imaging interpretations were evaluated independently and then compared with the reference of postoperative pathological examination. McNemar's test was used for comparing the data obtained separately from ultrasonography and computed tomography. RESULTS: There was one T2 stage tumour of an aryepiglottic fold undetected by sonography. Sonography failed to stage five tumours correctly; the T-staging accuracy was 83.3%. Contrast-enhanced computed tomography failed to stage four patients correctly; the T-staging accuracy was 88.8%. There was no difference between the pretherapeutic staging accuracy of ultrasonography and contrast-enhanced computed tomography (p=0.735). CONCLUSION: Ultrasonography has a reliable pretherapeutic staging accuracy of laryngeal carcinoma. It can be a non-invasive complementary technique for pretherapeutic staging of laryngeal carcinoma.

Analysis of the stability and degradation products of triptolide.

Triptolide is the major active ingredient of the Chinese herbal remedy Tripterygium wilfordii Hook F. (TwHF). As triptolide content is used to estimate the potency of preparations of TwHF, assessment of its stability is warranted. The accelerated stability of triptolide was investigated in 5% ethanol solution in a light-protected environment at pH 6.9, within a temperature range of 60-90 degrees C. The observed degradation rate followed first-order kinetics. The degradation rate constant (K25 degrees C) obtained by trending line analysis of Arrhenius plots of triptolide was 1.4125 x 10(-4) h(-1). The times to degrade 10% (t1/10) and 50% (t1/2) at 25 degrees C were 31 and 204 days, respectively. Stability tests of triptolide in different solvents and different pH conditions (pH4-10) in a light-protected environment at room temperature demonstrated that basic medium and a hydrophilic solvent were the major factors that accelerated the degradation of triptolide. Triptolide exhibited the fastest degradation rate at pH 10 and the slowest rate at pH 6. In a solvent comparison, triptolide was found to be very stable in chloroform. The stability of triptolide in organic polar solvents tested at both 100% and 90% concentration was greater in ethanol than in methanol than in dimethylsulphoxide. Stability was also greater in a mixture of solvent:pH6 buffer (9:1) than in 100% solvent alone. An exception was ethyl acetate, which is less polar than the other solvents tested, but permitted more rapid degradation of triptolide. Two of the degradation products of triptolide were isolated and identified by HPLC and mass spectroscopy as triptriolide and triptonide. This suggested that the decomposition of triptolide occurred at the C12 and C13 epoxy group and the C14 hydroxyl. The opening of the C12 and C13 epoxy is an irreversible reaction, but the reaction occurring on the C14 hydroxyl is reversible. These results show that the major degradation pathway of triptolide involves decomposition of the C12 and C13 epoxy group. Since this reaction is very slow at 4 degrees C at pH 6, stability is enhanced under these conditions.

Detection of Duchenne muscular dystrophy carriers by dosage analysis using the DMD cDNA clone 8.

Deletion screening in 11 unrelated DMD patients has been performed using DMD cDNA clones 1-8. Of these 11 patients, 6 exhibit deletions of the cDNA clone 8. The carriership of 18 female relatives from these six DMD families has been investigated by dosage analysis. It is shown that dosage analysis is an available method to determine the carrier status of the female relatives of DMD patients showing a deletion within a DMD cDNA clone.

Clinical application of modified Anyang type 2 esophageal intubation instrument--a new esophageal intubation method.

The preliminary experience in the clinical use of Anyang Type 2 esophageal intubation instrument, designed by ourselves, in 11 patients with severe esophageal obstruction due to advanced carcinoma of the esophageal was reported. The diagnosis of all 11 cases was confirmed by barium-meal roentgenography. After intubation, all the patients could take liquid or soft diet by mouth. There was no operative mortality and the patients survived 2 to 14 months (mean 5.7 months). All of them could take food by mouth before death. The clinical application proved that the intubation has been a safe and suitable management.

Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat.

The stroke-prone spontaneously hypertensive rat (SHRSP) is a well-characterized model for primary hypertension in humans. High blood pressure in SHRSP shows polygenic inheritance, but none of the loci responsible have previously been identified. To locate genes controlling this quantitative trait, we mapped a large collection of DNA polymorphisms in a cross between SHRSP and the normotensive WKY strain. Here we report strong genetic evidence that a gene, Bp1, having a major effect on blood pressure maps to rat chromosome 10 with a LOD score of 5.10 and is closely linked to the rat gene encoding angiotensin-converting enzyme (ACE), an enzyme that plays a major role in blood pressure homeostasis and is an important target of anti-hypertensive drugs. We also find significant, albeit weaker, linkage to a locus, Bp2, on chromosome 18. We discuss the implications of genetic dissection of quantitative disease-related phenotypes in mammals.