Pharmaceutical Cocrystal Discovery via 3D-SMINBR: A New Network Recommendation Tool Augmented by 3D Molecular Conformations.

Cocrystals have significant potential in various fields such as chemistry, material, and medicine. For instance, pharmaceutical cocrystals have the ability to address issues associated with physicochemical and biopharmaceutical properties. However, it can be challenging to find proper coformers to form cocrystals with drugs of interest. Herein, a new in silico tool called 3D substructure-molecular-interaction network-based recommendation (3D-SMINBR) has been developed to address this problem. This tool first integrated 3D molecular conformations with a weighted network-based recommendation model to prioritize potential coformers for target drugs. In cross-validation, the performance of 3D-SMINBR surpassed the 2D substructure-based predictive model SMINBR in our previous study. Additionally, the generalization capability of 3D-SMINBR was confirmed by testing on unseen cocrystal data. The practicality of this tool was further demonstrated by case studies on cocrystal screening of armillarisin A (Arm) and isoimperatorin (iIM). The obtained Arm-piperazine and iIM-salicylamide cocrystals present improved solubility and dissolution rate compared to their parent drugs. Overall, 3D-SMINBR augmented by 3D molecular conformations would be a useful network-based tool for cocrystal discovery. A free web server for 3D-SMINBR can be freely accessed at http://lmmd.ecust.edu.cn/netcorecsys/.

Transdermal Delivery of Metformin Utilizing Ionic Liquid Technology: Insight Into the Relationship Between Counterion Structures and Properties.

PURPOSE: The purpose of the present study was to explore the feasibility of transdermal delivery of metformin, a commonly used oral antidiabetic drug, by ionic liquid (IL) technology. METHODS: Metformin hydrochloride (MetHCl) was first transformed into three kinds of ILs with different counterions. The physicochemical properties of the obtained ILs were characterized in depth. The simulation of stable configuration and calculation of interaction energies were conducted based on density functional theory (DFT). Skin-PAMPA was used to evaluate the intrinsic transdermal permeation properties. The cytotoxicity assay of these ILs was conducted using HaCaT cells to evaluate the toxicity to skin. These metformin ILs were then formulated into transdermal patch, and the transdermal potential was further evaluated using in vitro dissolution test and skin permeation assay. Finally, the pharmacokinetic profiles of these metformin IL-containing patches were determined. RESULTS: Among all the three Met ILs, metformin dihexyl sulfosuccinate (MetDH) with proper overall physiochemical and biological properties demonstrated the highest relative bioavailability. Metformin docusate (MetD) with the highest lipophilicity and intrinsic transdermal permeability exhibited the most significant sustained release profile in vivo. Both MetDH and MetD were the promising candidates for further clinical investigations. CONCLUSIONS: Overall, the properties of ILs were closely related to the structures of counterion. IL technology provided the opportunities to finely tune the solid-state and biological properties of Metformin and facilitated the successful delivery by transdermal route.

Prospective assessment of a nasopharyngeal carcinoma risk score in a population undergoing screening.

Despite evidence suggesting the utility of Epstein-Barr virus (EBV) markers to stratify individuals with respect to nasopharyngeal carcinoma (NPC) risk in NPC high-risk regions, no validated NPC risk prediction model exists. We aimed to validate an EBV-based NPC risk score in an endemic population undergoing screening for NPC. This prospective study was embedded within an ongoing NPC screening trial in southern China initiated in 2008, with 51 235 adult participants. We assessed the score's discriminatory ability (area under the receiver-operator-characteristics curve, AUC). A new model incorporating the EBV score, sex and family history was developed using logistic regression and internally validated using cross-validation. AUCs were compared. We also calculated absolute NPC risk combining the risk score with population incidence and competing mortality data. A total of 151 NPC cases were detected in 2008 to 2016. The EBV-based score was highly discriminating, with AUC = 0.95 (95% CI = 0.93-0.97). For 90% specificity, the score had 87.4% sensitivity (95% CI = 81.0-92.3%). As specificity increased from 90% to 99%, the positive predictive value increased from 2.4% (95% CI = 1.9-3.0%) to 12.5% (9.9-15.5%). Correspondingly, the number of positive tests per detected NPC case decreased from 272 (95% CI = 255-290) to 50 (41-59). Combining the score with other risk factors (sex, first-degree family history of NPC) did not improve AUC. Men aged 55 to 59 years with the highest risk profile had the highest 5-year absolute NPC risk of 6.5%. We externally validated the discriminatory accuracy of a previously developed EBV score in a high-risk population. Adding nonviral risk factors did not improve NPC prediction.

SMINBR: An Integrated Network and Chemoinformatics Tool Specialized for Prediction of Two-Component Crystal Formation.

Two-component crystals such as pharmaceutical cocrystals and salts have been proven as an effective strategy to improve physicochemical and biopharmaceutical properties of drugs. It is not easy to select proper molecular combinations to form two-component crystals. The network-based models have been successfully utilized to guide cocrystal design. Yet, the traditional social network-derived methods based on molecular-interaction topology information cannot directly predict interaction partners for new chemical entities (NCEs) that have not been observed to form two-component crystals. Herein, we proposed an effective tool, namely substructure-molecular-interaction network-based recommendation (SMINBR), to prioritize potential interaction partners for NCEs. This in silico tool incorporates network and chemoinformatics methods to bridge the gap between NCEs and known molecular-interaction network. The high performance of 10-fold cross validation and external validation shows the high accuracy and good generalization capability of the model. As a case study, top 10 recommended coformers for apatinib were all experimentally confirmed and a new apatinib cocrystal with paradioxybenzene was obtained. The predictive capability of the model attributes to its accordance with complementary patterns driving the formation of intermolecular interactions. SMINBR could automatically recommend new interaction partners for a target molecule, and would be an effective tool to guide cocrystal design. A free web server for SMINBR is available at http://lmmd.ecust.edu.cn/sminbr/.

Relationship of circulating tumor cells and Epstein-Barr virus DNA to progression-free survival and overall survival in metastatic nasopharyngeal carcinoma patients.

We analyzed the number of circulating tumor cells (CTCs) and Epstein-Barr virus DNA (EBV DNA) for diagnosis, monitoring and prognosis of patients with metastatic nasopharyngeal carcinoma (mNPC). The levels of CTCs and EBV DNA were measured at baseline and after first-line chemotherapy in 148 mNPC patients prospectively enrolled between December 2014 and August 2016. We also collected 122 non-mNPC cases within the same time frame for examining CTCs and EBV DNA at baseline. In 270 NPC patients, we observed improved specificity (86.0% vs. 41.0%) and inferior sensitivity (42.3% vs. 81.3%) of CTCs as compared to EBV DNA for diagnosis of distant metastasis. mNPC patients were stratified into unfavorable and favorable prognostic groups, respectively, based on CTC of 12 at baseline and 1 after first-line chemotherapy and EBV DNA of 10,000 at baseline and 4,000 after first-line chemotherapy. Conversion of baseline unfavorable CTCs and EBV DNA to favorable after first-line chemotherapy was associated with significantly longer progression-free survival (PFS) and overall survival (OS) compared to patients with unfavorable CTCs and EBV DNA at both time points. Among patients with a complete/partial response as per imaging evaluation, favorable CTCs and EBV DNA levels after first-line chemotherapy were associated with significantly longer PFS and OS. In conclusion, our data demonstrated the number of CTCs and EBV DNA before, after and during first-line chemotherapy were strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.

Neoadjuvant or Adjuvant Chemotherapy Plus Concurrent CRT Versus Concurrent CRT Alone in the Treatment of Nasopharyngeal Carcinoma: A Study Based on EBV DNA.

BACKGROUND: The goal of this study was to explore the value of adding neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy (ACT) to concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma (NPC) with different risks of treatment failure. PATIENTS AND METHODS: A total of 2,263 eligible patients with stage III-IVb NPC treated with CCRT ± NACT or ACT were included in this retrospective study. Distant metastasis-free survival (DMFS), overall survival, and progression-free survival were calculated using the Kaplan-Meier method and differences were compared using the log-rank test. RESULTS: Patients in the low-risk group (stage N0-1 disease and Epstein-Barr virus [EBV] DNA <4,000 copies/mL) who received NACT followed by CCRT achieved significantly better 5-year DMFS than those treated with CCRT alone (96.2% vs 91.3%; P= .008). Multivariate analyses also demonstrated that additional NACT was the only independent prognostic factor for DMFS (hazard ratio, 0.42; 95% CI, 0.22-0.80; P=.009). In both the intermediate-risk group (stage N0-1 disease and EBV DNA ≥4,000 copies/mL and stage N2-3 disease and EBV DNA <4,000 copies/mL) and the high-risk group (stage N2-3 disease and EBV DNA ≥4,000 copies/mL), comparison of NACT or ACT + CCRT versus CCRT alone indicated no significantly better survival for all end points. CONCLUSIONS: The addition of NACT to CCRT could reduce distant failure in patients with low risk of treatment failure.

Distant Metastasis Risk Definition by Tumor Biomarkers Integrated Nomogram Approach for Locally Advanced Nasopharyngeal Carcinoma.

Identifying metastasis remains a challenge for death control and tailored therapy for nasopharyngeal carcinoma (NPC). Here, we addressed this by designing a nomogram-based Cox proportional regression model through integrating a panel of tumor biomarkers. A total of 147 locally patients with advanced NPC, derived from a randomized phase III clinical trial, were enrolled. We constructed the model by selecting the variables from 31 tumor biomarkers, including 6 pathological signaling pathway molecules and 3 Epstein-Barr virus-related serological variables. Through the least absolute shrinkage and selection operator (LASSO) Cox proportional regression analysis, a nomogram was designed to refine the metastasis risk of each NPC individuals. Using the LASSO Cox regression model, we constructed a 9 biomarkers-based prognostic nomogram: Beclin 1, Aurora-A, Cyclin D1, Ki-67, P27, Bcl-2, MMP-9, 14-3-3σ, and VCA-IgA. The time-dependence receiver operating characteristic analysis at 1, 3, and 5 years showed an appealing prognostic accuracy with the area under the curve of 0.830, 0.827, and 0.817, respectively. In the validation subset, the concordance index of this nomogram reached to 0.64 to identify the individual metastasis pattern. Supporting by this nomogram algorithm, the individual metastasis risk might be refined personally and potentially guiding the treatment decisions and target therapy against the related signaling pathways for patients with locally advanced NPC.

Concurrent chemoradiotherapy with nedaplatin versus cisplatin in stage II-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised phase 3 trial.

BACKGROUND: Cisplatin-based concurrent chemoradiotherapy is currently considered to be the standard treatment regimen for patients with advanced nasopharyngeal carcinoma, but has well known side-effects such as gastrointestinal reactions, nephrotoxicity, and ototoxicity. Nedaplatin was developed to decrease the toxic effects induced by cisplatin, and in this trial we assessed whether a nedaplatin-based concurrent chemoradiotherapy regimen was non-inferior to a cisplatin-based regimen in patients with locoregional, stage II-IVB nasopharyngeal carcinoma. METHODS: We did an open-label, non-inferiority, phase 3, randomised, controlled trial at two centres in China. Patients aged 18-65 years with non-keratinising stage II-IVB (T1-4N1-3 or T3-4N0) nasopharyngeal carcinoma, a Karnofsky score of at least 70, and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either nedaplatin 100 mg/m2 or cisplatin 100 mg/m2 on days 1, 22, and 43 for three cycles concurrently with intensity-modulated radiotherapy. Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre and clinical stage. Patients and clinicians were not masked to treatment allocation. The primary endpoint was progression-free survival at 2 years; non-inferiority was shown if the upper limit of the 95% CI for the difference in 2-year progression-free survival between the two groups did not exceed 10%. Analyses were by both intention to treat and per protocol, including all patients who received at least one complete cycle of chemotherapy. This trial is registered with ClinicalTrials.gov, number NCT01540136, and is currently in follow-up. FINDINGS: Between Jan 16, 2012, and July 16, 2014, we randomly assigned 402 patients to nedaplatin-based (n=201) or cisplatin-based (n=201) concurrent chemoradiotherapy. In the intention-to-treat population, 2-year progression-free survival was 89·9% (95% CI 85·8-94·0) in the cisplatin group and 88·0% (83·5-94·5) in the nedaplatin group, with a difference of 1·9% (95% CI -4·2 to 8·0; pnon-inferiority=0·0048). In the per-protocol analysis (cisplatin group, n=197; nedaplatin group, n=196), 2-year progression-free survival was 89·7% (95% CI 85·4-94·0) in the cisplatin group and 88·7% (84·2-94·5) in the nedaplatin group, with a difference of 1·0% (95% CI -5·2 to 7·0; pnon-inferiority=0·0020). A significantly higher frequency of grade 3 or 4 vomiting (35 [18%] of 198 in the cisplatin group vs 12 [6%] of 200 in the nedaplatin group, p<0·0001), nausea (18 [9%] vs four [2%], p=0·0021), and anorexia (53 [27%] vs 26 [13%], p=0·00070) was observed in the cisplatin group compared with the nedaplatin group. 11 (6%) patients in the nedaplatin group had grade 3 or 4 thrombocytopenia compared with four (2%) in the cisplatin group (p=0·065). Patients in the cisplatin group had a higher frequency of any grade or grade 3 or 4 late auditory or hearing toxicities than did patients in the nedaplatin group (grade 3 or 4: three [2%] in the nedaplatin group vs 11 [6%] in the cisplatin group, p=0·030). No patients died from treatment-related causes. INTERPRETATION: Our findings show that nedaplatin-based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional, advanced nasopharyngeal carcinoma. Further investigations are needed to explore the potential use of this treatment as induction or adjuvant chemotherapy or in combination with other agents. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, Sun Yat-sen University Clinical Research 5010 Program, Sci-Tech Project Foundation of Guangzhou City, National Key Basic Research Program of China, Special Support Plan of Guangdong Province, Sci-Tech Project Foundation of Guangdong Province, Health & Medical Collaborative Innovation Project of Guangzhou City, National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, PhD Start-up Fund of Natural Science Foundation of Guangdong Province, Cultivation Foundation for the Junior Teachers in Sun Yat-sen University, and Fundamental Research Funds for the Central Universities.

Pretreatment quality of life as a predictor of survival for patients with nasopharyngeal carcinoma treated with IMRT.

BACKGROUND: To evaluate the prognostic significance of pretreatment quality of life for patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. METHODS: We performed a prospective, longitudinal study on 554 newly diagnosed patients with NPC from April 2011 to January 2015. A total of 501 consecutive NPC patients were included. Patients were asked to complete the EORTC QLQ-C30 (version 3.0) and QLQ-H&N35 questionnaires before treatment. RESULTS: Global health status among QLQ-C30 correlates with EBV DNA(P = 0.019). In addition, pretreatment appetite loss was significantly correlated with EBV DNA(P = 0.02). Pretreatment teeth, opening mouth, feeding tube was significantly correlated with EBV DNA, with P value of 0.003, < 0.0001, and 0.031, respectively. In multivariate analysis, pretreatment cognitive functioning of QLQ-C30 was significantly associated with LRFS, with HR of 0.971(95%CI 0.951-0.990), P = 0.004. Among scales of QLQ-H&N35 for multivariate analysis, pretreatment teeth (P = 0.026) and felt ill (P = 0.012) was significantly associated with PFS, with HR of 0.984 (95%CI 0.971-.998) and 1.004 (95%CI 1.001-1.007), respectively. Felt ill of QLQ-H&N35 was significantly associated with DMFS, with HR of 1.004(95%CI 1.000-1.007), P = 0.043. There is no QoL scale significantly associated with OS after multivariate analysis. CONCLUSIONS: In conclusion, our analysis confirms that pretreatment teeth and felt ill was significantly associated with PFS in NPC patients treated with IMRT. In addition, the posttreatment EBV DNA was significantly associated with OS.

Advanced-Stage Nasopharyngeal Carcinoma: Restaging System after Neoadjuvant Chemotherapy on the Basis of MR Imaging Determines Survival.

Purpose To evaluate the prognostic value of the restaging system after neoadjuvant chemotherapy (NACT) in patients with advanced-stage nasopharyngeal carcinoma (NPC). Materials and Methods This study was approved by the clinical research committee and a written informed consent was required before enrolling in the study. Prospectively enrolled were 412 consecutive patients with stage III-IVb NPC treated with NACT followed by concurrent chemotherapy and radiation therapy. Patients were staged before NACT and restaged after NACT. The progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated with the Kaplan-Meier method, and differences were compared by using the log-rank test. Results Post-NACT T classification (PFS, P = .001) and N classification (PFS, P < .001; DMFS, P = .001) resulted in better survival curve separations than pre-NACT T classification and N classification. Patients downstaged from N2-N3 to N0-N1 disease had a better prognosis than did patients who continued to have N2-N3 diseases (3-year PFS, 83.8% vs 66.6%, P = .001; 3-year DMFS, 88.0% vs 78.4%, P = .026). Multivariate analysis revealed that post-NACT T classification (hazard ratio [HR] = 1.67; 95% confidence interval [CI]: 1.18, 2.36; P = .003) and post-NACT N classification (HR = 1.54; 95% CI: 1.17, 2.03; P = .002) were independent prognostic factors for PFS; also, post-NACT N classification (HR = 1.48; 95% CI: 1.05, 2.07; P = .025) was an independent prognostic factor for DMFS. Multivariate analysis in patients with N2-N3 disease demonstrated that the N downstaging effects of NACT was the only independent prognostic factor for PFS (HR = 0.48; 95% CI: 0.29, 0.81; P = .006) and DMFS (HR = 0.52; 95% CI: 0.28, 0.97; P = .039). Conclusion The post-NACT stage is more representative of prognosis than the pre-NACT stage in advanced-stage NPC patients, which suggests that major clinical decisions should be based on the post-NACT stage. © RSNA, 2016 Online supplemental material is available for this article.

Establishment of an innovative staging system for extramedullary plasmacytoma.

BACKGROUND: Extramedullary plasmacytoma (EMP) is a rare malignant disease that lacks a unique clinical staging system to predict the survival of EMP patients and to design individualized treatment. Instead, clinicians have chosen to use the multiple myeloma (MM) staging system. METHODS: Forty-eight EMP patients treated between 1996 and 2014 were included in this study. The new clinical stages were established according to independent survival factors using Cox regression model. RESULTS: Lymph node metastasis and a larger primary tumor (≥5 cm) were the only two independent poor prognostic factors for overall survival (OS) and disease-free survival (P < 0.05). Stage I was defined as the disease without those two poor prognostic factors. Stage II was defined as the presence of either factor, and Stage III was defined as the presence of both factors. OS was significantly different in each stage of the new staging system (P < 0.001), with a median follow-up time for Stage I, Stage II and Stage III of 68, 23 and 14 months. The new staging system had enhanced prognostic value compared to the MM staging system (the area under ROC 0.763 versus 0.520, P = 0.044). Although no difference was observed between treatments in Stage I, the combination treatment was associated with a significantly beneficial OS in the late stages (5-year OS: 15.3 % versus 79.5 %; P = 0.032). CONCLUSIONS: The new staging system exhibited a promising prognostic value for survival and could aid clinicians in choosing the most suitable treatment for EMP patients.

With or without reirradiation in advanced local recurrent nasopharyngeal carcinoma: a case-control study.

BACKGROUND: The study aimed to evaluate the long-term outcome in patients with advanced local recurrent nasopharyngeal carcinoma (NPC) treated with or without reirradiation. METHODS: A total of 44 patients treated without reirradiation (non-RT + chemotherapy) were matched with 44 patients treated with reirradiation (re-RT+/-chemtherapy) by age, sex, Karnosky performance score (KPS), rT stage, rN stage, and time interval between initial radiation and recurrence (TI). Overall survival (OS) rate and time to progression (TTP) rate were assessed using Kaplan-Meier method, log-rank test, and Cox regression analysis. RESULTS: From March 2008 to December 2013, a total of 88 well-balanced rT3-4 N0-1 NPC patients were retrospectively analyzed. After a median follow-up of 27 months (range: 6-85), the 5-year OS rate and TTP rate was 23.4 %, 39.0 % in the non-RT + chemotherapy group and 27.5 %, 49.8 % in the re-RT+/-chemtherapy group, respectively. Multivariate analysis showed that significant toxic effect was the only significant prognosticator correlated with OS (HR: 2.15, 95 % CI = 1.02-4.53, p = 0.044). No statistically significant survival differences were observed between the two treatment groups in either univariate or multivariate analyses. CONCLUSION: Compared with reiradiation, treating advanced local recurrent NPC with chemotherapy alone warrants further validation in the view of its similar survival and more acceptable toxicities.

The impact of the cumulative dose of cisplatin during concurrent chemoradiotherapy on the clinical outcomes of patients with advanced-stage nasopharyngeal carcinoma in an era of intensity-modulated radiotherapy.

BACKGROUND: The impact of cumulative dose of cisplatin on clinical outcomes of nasopharyngeal carcinoma (NPC) patients who received intensity-modulated radiotherapy (IMRT) was evaluated. METHODS: This study included 491 consecutive patients with histologically confirmed NPC who were treated with concurrent chemoradiotherapy with IMRT. The patients were divided into three groups: low- (cumulative dose≤100 mg/m2), medium- (cumulative dose>100 mg/m2 and ≤200 mg/m2), and high- (cumulative dose>200 mg/m2) dose groups. Subgroups of patients included pre-treatment levels of Epstein-Barr Virus DNA (EBV DNA)<4000 copies/ml and pre-treatment EBV DNA≥4000 copies/ml. To test for independent significance, the Kaplan-Meier with the log-rank test and the Cox proportional hazards model were used. RESULTS: The 5-year overall survival (OS) rates of the low-, medium-, and high-dose groups were 64.1%, 91.1%, and 89.4%, respectively (P=0.002). Based on multivariate analysis, patients who were in the medium- and high-dose groups had compared with the low-dose group, with an odds ratio of 0.135 (95% CI 0.045-0.405, P<0.001) and 0.225 (95% CI 0.069-0.734, P=0.013), respectively. For the low-risk patients, the cumulative dose of cisplatin significantly associated with a lower OS (P<0.001). The medium-dose group had reduced odds of death compared with the low-dose group, with an odds ratio of 0.062 (95% CI 0.001-0.347, P=0.002), according to multivariate analysis. CONCLUSIONS: The cumulative dose of cisplatin is associated with OS and distant metastasis-free survival (DMFS) among NPC patients who received IMRT.

Secular trend analysis of lung cancer incidence in Sihui city, China between 1987 and 2011.

BACKGROUND: With industrial and econom ic development in recent decades in South China, cancer incidence may have changed due to the changing lifestyle and environment. However, the trends of lung cancer and the roles of smoking and other environmental risk factors in the development of lung cancer in rural areas of South China remain unclear. The purpose of this study was to explore the lung cancer incidence trends and the possible causes of these trends. METHODS: Joinpoint regression analysis and the age-period-cohort (APC) model were used to analyze the lung cancer incidence trends in Sihui, Guangdong province, China between 1987 and 2011, and explore the possible causes of these trends. RESULTS: A total of 2,397 lung cancer patients were involved in this study. A 3-fold increase in the incidence of lung cancer in both sexes was observed over the 25-year period. Joinpoint regression analysis showed that while the incidence continued to increase steadily in females during the entire period, a sharp acceleration was observed in males starting in 2005. The full APC model was selected to describe age, period, and birth cohort effects on lung cancer incidence trends in Sihui. The age cohorts in both sexes showed a continuously significant increase in the relative risk (RR) of lung cancer, with a peak in the eldest age group (80-84 years). The RR of lung cancer showed a fluctuating curve in both sexes. The birth cohorts identified an increased trend in both males and females; however, males had a plateau in the youngest cohorts who were born during 1955-1969. CONCLUSIONS: Increasing trends of the incidence of lung cancer in Sihui were dominated by the effects of age and birth cohorts. Social aging, smoking, and environmental changes may play important roles in such trends.

Evaluation of plasma Epstein-Barr virus DNA load to distinguish nasopharyngeal carcinoma patients from healthy high-risk populations in Southern China.

BACKGROUND: The utility of circulating Epstein-Barr Virus (EBV) DNA as a tumor marker for nasopharyngeal carcinoma (NPC) detection suggests that it might improve the diagnostic performance of anti-EBV antibody markers in NPC screening. In this study, the authors evaluated whether circulating EBV DNA load is capable of distinguishing NPC patients from high-risk individuals who have positive anti-EBV antibodies. METHODS: In a population-based NPC screening trial in Sihui City and Zhongshan City, Guangdong Province, China, the authors previously identified 862 high-risk participants with 2 screening markers, immunoglobulin A (IgA) antibodies to EBV capsid antigen (VCA/IgA) and nuclear antigen-1 (EBNA1/IgA). In the current study, real-time polymerase chain reaction was used to measure the baseline plasma EBV DNA load among 825 participants (97%). Follow-up was extended to the end of 2011 to evaluate the diagnostic and predictive values of plasma EBV DNA load. RESULTS: By using 0 copies/mL as the cutoff value, plasma EBV DNA had a sensitivity of 86.8% (33 of 38 patients) for NPC detected within the first year of follow-up, yielding a positive predictive value of 30% (33 of 110 participants) and a negative predictive value of 99.3% (696 of 701 participants). The patients who had early stage NPC had lower sensitivity (81.5%; 22 of 27 patients) than those who had advanced NPC (100%; 11 of 11 patients). For the 14 patients who had NPC detected after 1 year of follow-up, only 50% (7 of 14 patients) tested positive for EBV DNA at baseline. CONCLUSIONS: The plasma EBV DNA load may improve the accuracy of diagnosing NPC in high-risk individuals, but it appears to have limited value in screening patients who have early stage NPC and predicting NPC development.

Two Epstein-Barr virus-related serologic antibody tests in nasopharyngeal carcinoma screening: results from the initial phase of a cluster randomized controlled trial in Southern China.

A nasopharyngeal carcinoma (NPC) mass screening trial using a combination of immunoglobulin A antibodies to Epstein-Barr virus capsid antigen and nuclear antigen-1 by enzyme-linked immunosorbent assay in addition to indirect mirror examination in the nasopharynx and/or lymphatic palpation (IMLP) was conducted in southern China. Cantonese aged 30-59 years residing in 2 cities randomly selected by cluster sampling, Sihui and Zhongshan, were invited to participate in this screening from May 2008 through May 2010. Participants were offered fiberoptic endoscopy examination and/or pathologic biopsy if their serologic tests reached our predefined level of high risk or if results from the physical examination indicated possible cancer (i.e., were IMLP positive). A total of 28,688 individuals were voluntarily screened in the initial round. The overall NPC detection rate was 0.14% (41/28,688) with an early diagnosis rate of 68.3% (28/41) during the first year of follow-up. Thirty-eight of 41 cases (92.7%) were detected among the high-risk group, and 7 of 41 cases (17.1%) were detected among the IMLP-positive group. The 2 Epstein-Barr virus serologic tests by enzyme-linked immunosorbent assay could be a feasible alternative for NPC screening in endemic areas. Further follow-up is needed to examine whether screening has an effect on decreasing mortality from NPC in these areas.

Clinical findings and imaging features of 67 nasopharyngeal carcinoma patients with postradiation nasopharyngeal necrosis.

Postradiation nasopharyngeal necrosis is an important late effect of radiotherapy that affects prognosis in patients with nasopharyngeal carcinoma. In the present study, we reviewed the clinical and imaging features of 67 patients with pathologically diagnosed postradiation nasopharyngeal necrosis who were treated at Sun Yat-sen University Cancer Center between June 2006 and January 2010. Their clinical manifestations, endoscopic findings, and imaging features were analyzed. Early nasopharyngeal necrosis was limited to a local site in the nasopharyngeal region, and the tissue defect was not obvious, whereas deep parapharyngeal ulcer or signs of osteoradionecrosis in the basilar region was observed in serious cases. Those with osteoradionecrosis and/or exposed carotid artery had a high mortality. In conclusion, Postradiation nasopharyngeal necrosis has characteristic magnetic resonance imaging appearances, which associate well with clinical findings, but pathologic examination is essential to make the diagnosis.

Randomized study of sinusoidal chronomodulated versus flat intermittent induction chemotherapy with cisplatin and 5-fluorouracil followed by traditional radiotherapy for locoregionally advanced nasopharyngeal carcinoma.

Neoadjuvant chemotherapy plus radiotherapy is the most common treatment regimen for advanced nasopharyngeal carcinoma (NPC). Whether chronomodulated infusion of chemotherapy can reduce its toxicity is unclear. This study aimed to evaluate the toxic and therapeutic effects of sinusoidal chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) and 5-fluorouracil (5-FU) followed by radiotherapy in patients with locoregionally advanced NPC. Patients with biopsy-diagnosed untreated stages III and IV NPC (according to the 2002 UICC staging system) were randomized to undergo 2 cycles of sinusoidal chronomodulated infusion (Arm A) or flat intermittent constant rate infusion (Arm B) of DDP and 5-FU followed by radical radiotherapy. Using a "MELODIE" multi-channel programmed pump, the patients were given 12-hour continuous infusions of DDP (20 mg/m2) and 5-FU (750 mg/m2) for 5 days, repeated every 3 weeks for 2 cycles. DDP was administered from 10:00 am to 10:00 pm, and 5-FU was administered from 10:00 pm to 10:00 am each day. Chronomodulated infusion was performed in Arm A, with the peak deliveries of 5-FU at 4:00 am and DDP at 4:00 pm. The patients in Arm B underwent a constant rate of infusion. Radiotherapy was initiated in the fifth week, and both arms were treated with the same radiotherapy techniques and dose fractions. Between June 2004 and June 2006, 125 patients were registered, and 124 were eligible for analysis of response and toxicity. The major toxicity observed during neoadjuvant chemotherapy was neutropenia. The incidence of acute toxicity was similar in both arms. During radiotherapy, the incidence of stomatitis was significantly lower in Arm A than in Arm B (38.1% vs. 59.0%, P = 0.020). No significant differences were observed for other toxicities. The 1-, 3-, and 5-year overall survival rates were 88.9%, 82.4%, and 74.8% for Arm A and 91.8%, 90.2%, and 82.1% for Arm B. The 1-, 3-, and 5-year progression-free survival rates were 91.7%, 88.1%, and 85.2% for Arm A and 100%, 94.5%, and 86.9% for Arm B. The 1-, 3-, and 5-year distant metastasis-free survival rates were 82.5%, 79.1%, and 79.1% for Arm A and 90.2%, 85.2%, and 81.7% for Arm B. Chronochemotherapy significantly reduced stomatitis but was not superior to standard chemotherapy in terms of hematologic toxicities and therapeutic response.

Locoregional radiotherapy in patients with distant metastases of nasopharyngeal carcinoma at diagnosis.

Systemic chemotherapy is the basic palliative treatment for metastatic nasopharyngeal carcinoma (NPC); however, it is not known whether locoregional radiotherapy targeting the primary tumor and regional lymph nodes affects the survival of patients with metastatic NPC. Therefore, we aimed to retrospectively evaluate the benefits of locoregional radiotherapy. A total of 408 patients with metastatic NPC were included in this study. The mortality risks of the patients undergoing supportive treatment and those undergoing chemotherapy were compared with that of patients undergoing locoregional radiotherapy delivered alone or in combination with chemotherapy. Univariate and multivariate analyses were conducted. The contributions of independent factors were assessed after adjustment for covariates with significant prognostic associations (P < 0.05). Both locoregional radiotherapy and systemic chemotherapy were identified as significant independent prognostic factors of overall survival (OS). The mortality risk was similar in the group undergoing locoregional radiotherapy alone and the group undergoing systemic chemotherapy alone [multi-adjusted hazard ratio (HR) = 0.9, P = 0.529]; this risk was 60% lower than that of the group undergoing supportive treatment (HR = 0.4, P = 0.004) and 130% higher than that of the group undergoing both systemic chemotherapy and locoregional radiotherapy (HR = 2.3, P < 0.001). In conclusion, locoregional radiotherapy, particularly when combined with systemic chemotherapy, is associated with improved survival of patients with metastatic NPC.

Camrelizumab Plus Apatinib in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma: An Open-Label, Single-Arm, Phase II Study.

PURPOSE: Immune checkpoint inhibitors combined with antiangiogenic therapy reportedly have potential synergistic antitumor activity. We investigated the activity and safety of this regimen for recurrent/metastatic nasopharyngeal carcinoma (NPC). METHODS: This single-arm, Simon two-stage study enrolled patients with recurrent/metastatic NPC who were refractory to at least first-line systemic therapy and treatment-naive to immune checkpoint inhibitors. The patients received camrelizumab 200 mg once every 3 weeks and apatinib 250 mg once per day. The primary end point was the objective response rate. Key secondary end points included disease control rate, progression-free survival, duration of response, overall survival, and safety. RESULTS: Between October 14, 2020, and December 23, 2021, 58 patients were enrolled, and all were included in the efficacy and safety analysis set. The objective response rate was 65.5% (95% CI, 51.9 to 77.5), and the disease control rate was 86.2% (95% CI, 74.6 to 93.9). The median duration of response was not reached, and the median progression-free survival was 10.4 months (95% CI, 7.2 to 13.6), with a median follow-up duration of 12.4 months (range, 2.1-19.9 months). Treatment-related adverse events (TRAEs) of grade 3 or higher were reported in 34 (58.6%) patients, with the most common being hypertension (19.0%), nasopharyngeal necrosis (15.5%), headache (12.1%), AST elevation (10.3%), and creatine phosphokinase elevation (10.3%). Sixteen (27.6%) patients discontinued apatinib treatment before progression because of unbearable TRAEs, and the most common complication was nasopharyngeal necrosis (9/16; 56.3%). Recurrent nasopharyngeal lesions (odds ratio, 5.94 [95% CI, 1.45 to 24.24]) and reirradiation (odds ratio, 5.33 [95% CI, 1.15 to 24.79]) were significantly positively correlated with nasopharyngeal necrosis. CONCLUSION: Camrelizumab plus apatinib had promising antitumor activity in patients with refractory recurrent/metastatic NPC who failed first-line therapy. Moderate to severe TRAEs were experienced by 58.6%, including nasopharyngeal necrosis associated with local recurrence and a history of reirradiation.