Optimize the dose of oxaliplatin for locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by radical surgery and adjuvant chemotherapy.

BACKGROUND: Addition of oxaliplatin to capecitabine remains controversial for locally advanced rectal cancer (LARC). And cumulative oxaliplatin dose (COD) varied among clinical trials showing different therapeutic effects of this regimen. The objective of this study was to explore how COD affected tumor metastasis and patient survival. METHODS: Totally 388 patients diagnosed with stage cII-III rectal cancer and treated with neoadjuvant chemoradiotherapy followed by radical surgery plus adjuvant chemotherapy were consecutively enrolled into this study and retrospectively reviewed. After grouping by total chemotherapy cycle (TCC), influences of COD on adverse effects and patients' survivals were analyzed in each group. Univariate and multivariate survival analyses were performed through Kaplan-Meier approach and COX proportional hazards model, respectively. Age, gender, anemia, differentiation, carcinoembryonic antigen, carbohydrate antigen 19-9, pretreatment clinical stage and postsurgical pathologic stage were used as covariates. RESULTS: COD < 460 mg/m2 emerged as an independent predictor of poorer overall, metastasis-free and disease-free survivals, in patients treated with TCC ≤ 7. The hazard ratios were 1.972, 1.763 and 1.637 (P values were 0.021, 0.028 and 0.041), respectively. But it was note-worthy that COD ≥460 mg/m2 increased incidence of acute toxicities from 38.4 to 70.8% (P < 0.001). And in patients treated with TCC ≥ 8, COD failed to be a prognosticator. CONCLUSIONS: For LARC patients treated with insufficient TCC (≤ 7), oxaliplatin of ≥460 mg/m2 might be needed to improve survival, though it might resulted in more acute toxicities.

The expression of long noncoding RNA CRCAL-3 in colorectal cancer and its impacts on cell proliferation and migration.

Long noncoding RNAs (lncRNAs) have been implicated in colorectal cancer (CRC). And lncRNA RP11-138J23.1 (CRCAL-3) was previously reported as a candidate regulator of CRC development. But its regulating functions have not been fully elucidated. Here, we analyzed RNA sequencing data from the Cancer Genome Atlas (TCGA) and 253 CRC patients treated in our hospital to assess expression dysregulation of CRCAL-3, and the correlation between CRCAL-3 expression and disease progression. Further, polymerase chain reaction (PCR) assay on different cell lines and knockdown experiments by small interfering RNA were performed to assess functions of CRCAL-3 in proliferation and migration of CRC cells. As a result, analyses on TCGA datasets showed an upregulated CRCAL-3 expression in 14 solid tumors, including CRC. PCR assay on 253 cases of CRC tissue and 114 cases of normal adjacent tissue confirmed this expression upregulation. Also, CRCAL-3 expression was exhibited by survival analyses on the 253 CRC patients, to have a negative correlation with patients' overall and progression-free survivals. PCR assay on different cell lines showed that CRC cells expressed a higher level of CRCAL-3, compared with normal colonic epithelial cells. In vitro knockdown of CRCAL-3 resulted in an obvious retardation of proliferation and migration in two CRC cell lines (HCT116 and DLD-1). Moreover, CRCAL-3 knockdown was observed in xenograft models to repress cell proliferation and enhance cisplatin sensitivity. Taking these results together, CRCAL-3 emerged as a biomarker for early diagnosis, prognosis prediction, and individualized treatment of CRC.

The prognostic significance of PD-L1 and PD-1 expression in patients with nasopharyngeal carcinoma: a systematic review and meta-analysis.

BACKGROUND: Whether PD-L1/PD-1 expression plays a significant role in the prognosis of NPC is still controversial. The present study mainly aimed to investigate the prognostic significance of PD-L1/PD-1 expression in patients with NPC. METHODS: A systematical research was performed in the PubMed, Web of Science, EMBASE, and the Cochrane Library databases up to January 06, 2019. Eighteen studies met eligible criteria were included in the meta-analysis. Quality assessment of included articles was evaluated by Newcastle-Ottawa quality assessment scale (NOS). Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were used to elucidated the primary endpoint, overall survival (OS), and the secondary endpoints. Furthermore, the relationship between clinicopathological features of NPC and PD-L1/PD-1 expression was estimated by relative ratios (RRs) and 95% CIs. RESULTS: A total of 1836 patients from 15 included studies concerning PD-L1 and 678 patients from six studies regarding PD-1 were included in the meta-analysis. Pooled results revealed that PD-L1 expression in NPC did not correlate with OS (HR 1.34 95% CI 0.93-1.93, p = 0.11), DFS (HR 1.82, 95% CI 0.86-3.85, p = 0.12), PFS (HR 1.19, 95% CI 0.46-3.08, p = 0.72), and DMFS (HR 2.26, 95% CI 0.60-8.56, p = 0.23). Meanwhile, no statistically significant differences existed between the expression level of PD-1 in tumor infiltrating lymphocytes (TILs) and the OS in NPC, with the pooled HR 1.29 (95% CI 0.68-2.42, p = 0.44). In subgroup analysis, higher expression of PD-L1 in immune cells correlated with better OS in patients with NPC, with a pooled HR 0.68 (95% CI 0.47-0.99, p = 0.04). Among the clinicopathological features included in our study, we found that the positive expression of PD-L1 in NPC associated with the higher expression of PD-1 (RR 1.25, 95% CI 1.02-1.52, p = 0.03). CONCLUSIONS: Our meta-analysis indicated that higher/positive expression of PD-L1/PD-1 may not serve as suitable biomarkers for the prognosis of NPC, which was not in consistent with some previous studies about the prognostic value of PD-L1/PD-1 in other types of tumors. Despite the positive results in subgroup analysis and study about clinicopathological features, it may still need corroboration of prospective and large-scale studies.

Fractionated radiation therapy alters energy metabolism and induces cellular quiescence exit in patient-derived orthotopic xenograft models of high-grade glioma.

Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of biological consequences beyond the classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 5 PDOX models (P < 0.05) accompanied by γH2AX positivity in >95 % tumor cells in tumor core and >85 % in the invasive foci as well as ∼30 % apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species accumulation, were detected together with the enrichment of CD133+ tumor cells. The latter was caused by the entry of quiescent G0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies.

Identifying FGA peptides as nasopharyngeal carcinoma-associated biomarkers by magnetic beads.

Early diagnosis and treatment is known to improve prognosis for nasopharyngeal carcinoma (NPC). The study determined the specific peptide profiles by comparing the serum differences between NPC patients and healthy controls, and provided the basis for the diagnostic model and identification of specific biomarkers of NPC. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) can be used to detect the molecular mass of peptides. Mass spectra of peptides were generated after extracting and purification of 40 NPC samples in the training set, 21 in the single center validation set and 99 in the multicenter validation set using weak cationic-exchanger magnetic beads. The spectra were analyzed statistically using FlexAnalysis™ and ClinProt™ bioinformatics software. The four most significant peaks were selected out to train a genetic algorithm model to diagnose NPC. The diagnostic sensitivity and specificity were 100% and 100% in the training set, 90.5% and 88.9% in the single center validation set, 91.9% and 83.3% in the multicenter validation set, and the false positive rate (FPR) and false negative rate (FNR) were obviously lower in the NPC group (FPR, 16.7%; FNR, 8.1%) than in the other cancer group (FPR, 39%; FNR, 61%), respectively. So, the diagnostic model including four peptides can be suitable for NPC but not for other cancers. FGA peptide fragments identified may serve as tumor-associated biomarkers for NPC.

Increased pretreatment levels of serum LDH and ALP as poor prognostic factors for nasopharyngeal carcinoma.

Serum enzymes that play potential roles in tumor growth have recently been reported to have prognostic relevance in a diverse array of tumors. However, prognosis-related serum enzymes are rarely reported for nasopharyngeal carcinoma(NPC). To clarify whether the level of serum enzymes is linked to the prognosis of NPC, we reviewed the pretreatment data of lactate dehydrogenase(LDH), alkaline phosphatase (ALP), and glutamyl transferase (GGT) in 533 newly diagnosed NPC patients who underwent radical radiotherapy between May 2002 and October 2003 at Sun Yat-sen University Cancer Center. Patients were grouped according to the upper limit of normal values of LDH, ALP, and GGT. The Kaplan-Meier method and log-rank test were used for selecting prognostic factors from clinical characteristics and serum enzymes, and the chi-square test was applied to analyze the relationships of clinical characteristics and serum enzymes. Finally, a Cox proportional hazards model was used to identify the independent prognostic factors. We found that increased levels of LDH had poor effects on both overall survival and distant metastasis-free survival (P = 0.009 and 0.035, respectively), and increased pretreatment level of serum ALP had poor effects on both overall survival and local recurrence-free survival (P = 0.037 and 0.039, respectively). In multivariate analysis, increased LDH level was identified as an independent prognostic factor for overall survival. Therefore, we conclude that increased pretreatment serum LDH and ALP levels are poor prognostic factors for NPC.

A Nomogram to Predict Survival in Patients With Locoregional Recurrent Nasopharyngeal Carcinoma Receiving Comprehensive Treatment.

Objective: This study aimed to establish a prognostic stratified model of chemotherapy-based comprehensive treatment for patients with locoregional recurrent nasopharyngeal carcinoma (lrNPC), to help individualized treatment decision-making. Materials and Methods: This study retrospectively reviewed patients with lrNPC who received chemotherapy-based comprehensive treatment from January 1, 2010, to December 31, 2018. A total of 422 eligible patients were divided into test (n = 338) and validation (n = 84) cohorts. A LASSO cox regression model was used to identify significant prognostic factors for overall survival (OS) in the test cohort. A nomogram was then developed based on a combined consideration of clinically meaningful prognostic factors and statistically significant prognostic factors. The performance of the nomogram was assessed with Harrell's concordance index (C-index) and calibration plots. Results: Five significant factors were identified: age, albumin (ALB), T stage after recurrent (rT), neutrophil to lymphocyte ratio (NLR), and systematic immune-inflammation index (SII). The nomogram was established with these five factors. C-index was 0.636 in the test cohort and 0.610 in the validation cohort. The calibration curves for the OS rate at 3, and 5 years showed an excellent agreement in both cohorts. In addition, the corresponding risk classification system successfully classified patients into low- and high-risk groups and performed well in stratification (P < 0.001). Conclusions: The nomogram shows well prognostic performance for lrNPC patients receiving chemotherapy-based comprehensive treatment.

Individualized clinical target volume delineation and efficacy analysis in unilateral nasopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT): 10-year summary.

PURPOSE: To evaluate the long-term local control, failure patterns, and toxicities after individualized clinical target volume (CTV) delineation in unilateral nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). METHODS: Unilateral NPC was defined as a nasopharyngeal mass confined to one side of the nasopharynx and did not exceed the midline. From November 2003 to December 2017, 95 patients were retrospectively included. All patients received IMRT. The CTVs were determined based on the distance from the gross tumor. The contralateral para-pharyngeal space and skull base orifices were spared from irradiation. RESULTS: There were three local recurrences and eight regional recurrences in 10 patients during an 84-month follow-up. All local recurrences were within PGTVnx, and all in-field recurrences. No recurrences were found in traditional high-risk areas including contralateral the para-pharyngeal space and skull base orifices. The 10-year local-recurrence-free survival, regional-recurrence-free survival and overall survival were 96.2%, 90.5% and 84.7%, respectively. The dosimetry parameters of the tumor-contralateral organs were all lower than the values of the tumor-ipsilateral side (P < 0.05). The late toxicities occurred mainly in the tumor-ipsilateral organs, including radiation-induced temporal lobe injury, impaired visuality, hearing loss and subcutaneous fibrosis. CONCLUSION: Individualized CTV delineation in unilateral NPC could yield excellent long-term local control with limited out-of-field recurrences, reduced dose to tumor- contralateral organs and mild late toxicities, which is worthy of further exploration.

[Establishment of a specific serum proteomic profile model of nasopharyngeal carcinoma by MALDI-TOF MS].

OBJECTIVE: To determine the specific serum peptide profile by comparing the serum differences between nasopharyngeal carcinoma patients (NPC) and normal control subjects, and to provide a diagnostic model of nasopharyngeal carcinoma. METHODS: Pre-treatment serum samples of NPC and normal control subjects were collected and assayed by MALDI-TOF MS analysis. The peptides were extracted with magnetic beads coated with WCX. Mass spectrographic data were analyzed with ClinProt(TM) software. The specific serum peptide model of NPC was established by using genetic algorithms. The sensitivity and specificity of model were tested by blind testing. RESULTS: The serum peptidome patterns of nasopharyngeal carcinoma was obtained. Differential expression of 99 peptide peaks was deteced, and the 808.99 Da, 834.61 Da, 3954.82 Da, 8141.88 Da peptide peaks showing statistically significant differences between the two groups, were used to establish the diagnostic model for nasopharyngeal cancer. The recognition rate and predictive power of the model were 90.0% and 84.3%, respectively. The sensitivity and specificity of the model were 80.0% and 64.0% determined by blind testing, respectively. CONCLUSIONS: Significant differences of serum peptide peaks are detected between NPC and normal control groups. The established specific serum peptide model may have certain application in the diagnosis of nasopharyngeal carcinoma, and provides the basis for discovering specific tumor markers of nasopharyngeal carcinoma.

Prognostic value of hepatitis B viral infection in patients with nasopharyngeal carcinoma in the intensity-modulated radiotherapy era.

BACKGROUND: Whether hepatitis B virus (HBV) infection poses risk to patients with nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era remains unclear. METHODS: 953 patients with non-metastatic, newly diagnosed NPC who received detection of serologic hepatitis B surface antigen (HBsAg) and treated with IMRT were retrospectively reviewed. 171 patients had HBV infection (HBsAg seropositive). Propensity score matching method (PSM) and stabilized inverse probability of treatment weighting (IPTW) were used to address confounding. The survival rates were evaluated by Kaplan-Meier analysis and the survival curves were compared by Log-rank test. Prognostic factors were explored by multivariate analysis. RESULTS: No significant survival differences were observed between HBsAg-negative group and HBsAg-positive group [5-year overall survival (OS), 87.7% vs. 83.9%, P=0.181; locoregional recurrence-free survival (LRFS), 83.5% vs. 78.3%, P=0.109; distant metastasis-free survival (DMFS), 80.2% vs. 77.9%, P=0.446; progression-free survival (PFS), 77.4% vs. 71.4%, P=0.153], consistent with the results of PSM and IPTW analysis. Further analyses revealed that HBV infection was an independent prognostic factor for poor OS [multivariate analysis; hazard ratio (HR), 3.74; 95% confidence interval (CI), 1.45-9.68; P=0.006], LRFS (HR, 2.86; 95% CI, 1.37-5.95); P=0.005] in patients with stage N1, DMFS (HR, 2.65; 95% CI, 1.15-6.09; P=0.022) and PFS (HR, 2.63; 95% CI, 1.34-5.14; P=0.005). Among HBsAg-positive patients, liver protection improved OS (90.3% vs. 77.2%; P=0.022). CONCLUSIONS: HBV infection is an independent risk factor for patients with stage N1 NPC in the IMRT era. Hepatic protection may benefit the survival of HBsAg-positive patients.

Treatment and Survival Outcomes Associated With Platinum Plus Low-Dose, Long-term Fluorouracil for Metastatic Nasopharyngeal Carcinoma.

Importance: The treatment of metastatic nasopharyngeal carcinoma (mNPC) is a major challenge because of drug resistance and the toxic effects of chemotherapy. Objective: To evaluate the survival and toxicity outcomes and safety associated with the use of a modified low-dose fluorouracil protocol compared with standard regimens recommended in current guidelines for treatment of mNPC. Design, Setting, and Participants: This retrospective cohort study was based on data retrieved from electronic medical records from Sun Yat-sen University Cancer Center in China for 1397 patients with mNPC diagnosed from January 1, 2006, to December 31, 2017. Data analyses were conducted from October 1, 2020, to May 1, 2021. Exposures: Patients received chemotherapy, including platinum plus low-dose, long-term fluorouracil (PFLL); cisplatin plus standard dose, short-term fluorouracil (PFSS); cisplatin plus gemcitabine (GP); cisplatin plus taxane (TP); and cisplatin plus taxane plus fluorouracil (TPF). Main Outcomes and Measures: The main outcomes included overall survival (OS); subsequent-line, treatment-free survival (sTFS), defined as the period from metastasis to the date requiring subsequent-line treatment or death; and the survival to toxicity ratio (STR), defined as person-year rate of OS divided by person-year rate of severe hematologic toxic effects. Cox regression models were used to compare the outcomes of patients receiving PFLL vs other regimens, adjusting for baseline characteristics. Results: Of 1397 patients with mNPC included in this study (1152 men; median age, 46 years [range, 18-70 years]) 134 received PFLL, 203 received GP, 330 received PFSS, 366 received TP, and 364 received TPF. A total of 764 patients died (75 in treatment group PFLL; 107 in group GP; 204 in group PFSS; 207 in group TP; and 171 in group TPF), and 979 patients had subsequent-line treatment or died, whichever occurred first (PFLL, 77; GP, 144; PFSS, 262; TP, 269; and TPF, 227). The median follow-up was 46.9 months (IQR, 25.4-82.4 months), and the 5-year OS rate among patients who received PFLL was 25.4% (95% CI, 16.7%-38.8%), which was not significantly different from that among patients who did not receive PFLL (30.2%; 95% CI, 27.1%-33.5%; P = .13) or who received GP (25.1%; 95% CI, 18.1%-35.0%; P = .81), PFSS (23.6%; 95% CI, 18.5%-30.0%; P = .80), or TP (28.1%; 95% CI, 22.8%-34.7%; P = .99) but was lower than that for patients who received TPF (40.4%; 95% CI, 34.7%-47.1%; P = .001). The 5-year sTFS among patients who received PFLL (24.1%; 95% CI, 15.4%-37.6%) was significantly higher than that among patients who did not receive PFLL (18.5%; 95% CI, 16.1%-21.3%; P = .005) or who received GP (14.3%; 95% CI, 9.1%-22.5%; P = .001) but similar to that for patients who received TPF (28.0%; 95% CI, 23.0%-34.0%; P = .74). The STR of PFLL was 0.81, substantially better than that of GP (0.41) and TPF (0.65). Conclusions and Relevance: The results of this cohort study suggest that, compared with the use of standard treatment regimens, administration of PFLL was associated with similar OS but prolonged sTFS. PFLL also had better STR than other regimens, which could indicate less severe toxic effects. Thus, PFLL may be an option for first-line treatment of mNPC.

Continuous fall in hemoglobin level is a poor prognostic factor in patients with nasopharyngeal carcinoma treated with radiotherapy.

BACKGROUND AND OBJECTIVE: Anemia can not only reduce the quality of life of patients with cancer, but also affect their survival. This study was to investigate the prognostic value of hemoglobin (Hb) level in patients with nasopharyngeal carcinoma (NPC) treated with radiotherapy. METHODS: Clinical data of 520 NPC patients received definitive radiotherapy between 2000 and 2002 at Sun Yat sen University Cancer Center were analyzed. Patients were stratified into normal Hb level and anemia groups according to their Hb levels before, during, and after radiation. Anemia was defined according to World Health Organization criteria as Hb level < 130 g/L in men and < 120 g/L in women. Hb continuous decrease group and non decrease group were defined according to Hb changes in the patients during radiotherapy. Loco regional recurrence free survival (LRFS) and overall survival (OS) rates were estimated using the Kaplan Meier method. Multivariate analysis was performed using the Cox model to analyze the prognostic factors. RESULTS: Before radiation, the 5 year LRFS rates were 60.9% in anemia group and 63.9% in normal Hb level group (P = 0.337); the 5 year OS rates were 65.2% and 71.0%, respectively (P = 0.299). During radiation, the 5 year LRFS rates were 56.7% in anemia group and 67.9% in normal Hb level group (P = 0.013); the 5 year OS rates were 61.0% and 75.9%, respectively (P = 0.001). After radiation, the 5 year LRFS rates were 59.6% in anemia group and 64.9% in normal Hb level group (P = 0.169); the 5 year OS rates were 65.0% and 71.9%, respectively (P = 0.090). The 5 year LRFS and OS rates were significantly lower in Hb continuous decrease group than in Hb non decrease group (59.1% vs. 69.3%, P = 0.032; 66.2% vs. 76.4%, P=0.011). Multivariate analysis showed that the continuous decrease of Hb was an independent prognostic factor for OS. CONCLUSION: The change in Hb level during radiotherapy is an important prognostic factor affecting the OS of NPC patients.

Regular aspirin intake and prognosis of TxN2-3M0 nasopharyngeal carcinoma: A cohort study based on propensity score matching.

OBJECTIVES: Distant metastasis is the leading cause of death in patients with N2-3 nasopharyngeal carcinoma (NPC). And aspirin is found to reduce metastasis and improve prognosis in some other malignancies, such as colorectal cancer. This study aimed to evaluate the clinical value of regular aspirin intake (RAI) in N2-3 NPC treated with standard chemoradiotherapy. MATERIALS AND METHODS: Totally 2064 patients diagnosed with TxN2-3M0 NPC from Jan. 2008 to Dec. 2015 and treated with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy were involved. According to RAI, these patients were divided into 2 groups between which a propensity score matching was made, with a ratio of 1:3 and a series of clinical characteristics (age, gender, T stage, N stage and EBV DNA) as covariates. Then survivals and acute toxicities were compared in the 464 matched patients. RESULTS: RAI appeared to bring better overall (87.7% vs. 79.6%, P = 0.031), metastasis-free (87.8% vs. 76.5%, P = 0.017) and disease-free (85.9% vs. 75.5%, P = 0.033) survivals. It simultaneously increased total incidences of myelosuppression (55.2% vs. 32.2%, P < 0.001), oral mucositis (60.3% vs. 38.2%, P < 0.001), cervical dermatitis (60.3% vs. 38.5%, P < 0.001) and xerostomia (49.1% vs. 33.3%, P = 0.002). But RAI failed to affect incidence of any grade 3/4 toxicity. CONCLUSIONS: Post-diagnosis RAI might be a tolerable approach to control distant metastasis and provide survival benefit for N2-3 NPC in combination with standard chemoradiotherapy.

Dosimetric parameters predict radiation-induced choanal stenosis in patients with nasopharyngeal carcinoma.

BACKGROUND: Radiation-induced choanal stenosis (RICS) severely decreases life quality of patients with nasopharyngeal carcinoma (NPC) and originates from nasal mucositis, which depends on radiation dose. This self-controlled study aimed to find the correlations between dosimetric parameters and RICS. METHODS: Totally 49 NPC patients treated with intensity-modulated radiotherapy from May 2010 to Aug. 2013 and diagnosed with RICS during follow-up were enrolled into this study. Minimum point dose, maximum point dose, mean dose (Dmean), dose covering ≥33% volume (D33), dose covering ≥66% volume (D66), and volume receiving ≥60 Gy (V60) were compared between the nasal cavities with and without RICS, through paired t-test. The parameters with difference would enter receiver operating characteristic analysis to determine their cutoff values. Then predicting abilities of the cutoff values were tested by Chi-square test. RESULT: The nasal cavities with RICS appeared to have higher Dmean, D33, D66 and V60, compared with those without RICS (P values were 0.014, 0.003, 0.006 and 0.010). Dmean ≥54.22 Gy, D33 ≥ 61.96 Gy, D66 ≥ 46.50 Gy and V60 ≥ 48.13% were demonstrated to be related with a higher risk of RICS. CONCLUSION: Dmean, D33, D66 and V60 of nasal cavity might be used as predictors of RICS. Their values needed to be controlled whenever possible, for ameliorating life quality of NPC patients.

Necessity of concurrent chemotherapy in N2-3 nasopharyngeal carcinoma treated with neoadjuvant chemotherapy of ≥3 cycles followed by intensity-modulated radiotherapy.

Concurrent chemotherapy (CCT) is used in locally advanced nasopharyngeal carcinoma (NPC) for improved local control, which could also be achieved by intensity-modulated radiotherapy (IMRT). And for N2-3 NPC, distant metastasis is the more important cause of death. This study aims to evaluate the value of CCT in N2-3 NPC when neoadjuvant chemotherapy (NACT) of sufficient cycles is performed to eradicate distant metastasis. It enrolled 959 patients diagnosed with TxN2-3M0 NPC from July 2011 to December 2015 and treated with NACT of 3-4 cycles and IMRT. A propensity score matching (PSM) was made between patients treated with and without CCT (called the CCT and non-CCT groups, respectively), using a series of clinical characteristics (age, gender, T stage, N stage, NACT regimen, and EBV DNA) as covariates. After PSM, the two groups of patients were compared on survivals and acute toxicities. The results indicated that no difference was seen in the overall, disease-free, recurrence-free or metastasis-free survivals between the two groups. But compared with the CCT group, the non-CCT group had a lower patient proportion of myelosuppression, nausea/vomiting, oral mucositis, cervical dermatitis, xerostomia, and grade 3/4 myelosuppression and oral mucositis (all P values were <0.001). Hence, CCT appeared to bring more acute toxicities, instead of survival benefit, to N2-3 NPC patients treated with NACT of ≥3 cycles and IMRT. It should be used with cautions in these patients.

Recombined humanized endostatin (Endostar) intravenous infusion in the treatment of refractory nasopharyngeal carcinoma: Three case reports.

RATIONALE: Refractory nasopharyngeal carcinoma is challenging to treat and at present there is no standard treatment or any good choice. PATIENT CONCERNS: Although the three patients in our case reports had already underwent multiple treatments before, they still suffered from disease recurrence of nasopharyngeal carcinoma. DIAGNOSIS: They were diagnosed as refractory nasopharyngeal carcinoma. INTERVENTIONS: A continuous infusion of Endostar, an antiangiogenic agent, combined with chemotherapy and radiation therapy was given to treat the patients. OUTCOMES: Patients showed complete or partial response to the combined therapy as evidenced by regression of tumors and decrease in plasma Epstein-Barr virus (EBV) DNA load. LESSONS: Continuous infusions of Endostar in combination with chemotherapy and/or radiation therapy showed promising efficacy and safety. The combination therapy indicates a new approach to treat refractory nasopharyngeal carcinoma.

Is long interval from neoadjuvant chemoradiotherapy to surgery optimal for rectal cancer in the era of intensity-modulated radiotherapy?: a prospective observational study.

OBJECTIVES: To evaluate the impact of interval between neoadjuvant chemoradiotherapy (NACRT) and surgery on therapeutic and adverse effects of surgery, and long-term outcome of patients with locally advanced rectal cancer (RC), in the era of intensity-modulated radiotherapy (IMRT). PATIENTS AND METHODS: Patients diagnosed with stage II-III RC and treated with IMRT-based NACRT followed by radical surgery were enrolled consecutively from April 2011 to March 2014. The data of all the patients were collected prospectively and grouped according to their NACRT-to-surgery interval. The therapeutic and adverse effects of surgery, and survivals were compared between the patients with interval ≤7 weeks and those with interval ≥8 weeks. RESULTS: A total of 231 patients were eligible for analysis, including 106 cases with interval ≤7 weeks and 125 cases with interval ≥8 weeks. The therapeutic and adverse effects of surgery were similar between these two groups of patients. However, interval ≥8 weeks appeared to lead to poorer overall, distant-metastasis-free and disease-free survivals, compared with interval ≤7 weeks. The HRs were 1.805, 1.714, and 1.796 (P-values were 0.045, 0.049, and 0.028), respectively. CONCLUSION: For patients with locally advanced RC, a long NACRT-to-surgery interval might bring a potential risk of increased distant metastasis rather than a better tumor regression in the era of IMRT.

CCR6 Is a Predicting Biomarker of Radiosensitivity and Potential Target of Radiosensitization in Rectal Cancer.

PURPOSE: This study aimed to explore the functions and mechanisms of C-C motif chemokine receptor 6 (CCR6), a gene associated with progression and metastasis of colorectal cancer (CRC), in radiosensitivity of rectal cancer (RC). MATERIALS AND METHODS: RNA sequencing and immunohistochemical analysis on CCR6 expression were performed in pretreatment tissues of RC patients exhibiting different therapeutic effects of radiotherapy. Colonogenic survival assay was conducted in different CRC cell lines to assess their radiosensitivity. And the impact of CCR6 expression on radiosensitivity was validated through RNA interference. The DNA damage repair (DDR) abilities of cell lines with different CCR6 expression were evaluated through immunofluorescence-based γH2AX quantification. RESULTS: The CCR6 mRNA level was higher in patients without pathologic complete remission (pCR) than in those with pCR (fold changed, 2.11; p=0.004). High-level expression of CCR6 protein was more common in the bad responders than in the good responders (76.3% vs. 37.5%, p < 0.001). The CRC cell lines with higher CCR6 expression (LoVo and sw480) appeared to be more radioresistant, compared with the sw620 cell line which had lower CCR6 expression. CCR6 knockdown made the LoVo cells more sensitive to ionizing radiation (sensitization enhancement ratio, 1.738; p < 0.001), and decreased their DDR efficiency. CONCLUSION: CCR6 might affect the RC radiosensitivity through DDR process. These findings supported CCR6 as a predicting biomarker of radiosensitivity and a potential target of radiosensitization for RC patients.

Surrogate endpoints shortening the therapeutic evaluation duration for different subgroups of patients with nasopharyngeal carcinoma receiving intensity-modulated radiotherapy: A retrospective analysis of 830 patients stratified by the 8th edition of the UICC/AJCC staging system and plasma Epstein-Barr viral.

Purpose: Investigating surrogate endpoints shortening the time of therapeutic evaluation in nasopharyngeal carcinoma (NPC) after radical treatment. Patients and Methods: We retrospectively analyzed 830 patients receiving intensity-modulated radiotherapy (IMRT) from 2008 to 2010 and being stratified by the 8th edition of UICC/AJCC staging system and the plasma Epstein-Barr virus DNA (EBV DNA). The annual rates of overall survival (OS), progression-free survival (PFS), loco-regional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were sequentially calculated using the life table and compared by the McNemar method. Results: The time of shortening therapeutic evaluation by surrogate endpoints: OS, PFS, LRFS and DMFS could be shortened to 1-year (100% vs 100%, P=1) in patients with stage I; OS, PFS, LRFS and DMFS could be shortened to 3-year (96.9% vs 96.1%, P = 1; 94.6% vs 92.2%, P = 0.125; 96.9% vs 95.3%, P = 0.5) and 4-year (92.2% vs 91.2%, P = 0.125) in stage II; In the high EBV DNA group , OS and DMFS could be shortened to 1-year (100% vs 100%, P = 1;100% vs 100%, P = 0.25) in stage II; OS and PFS could be shortened to 3-year (94.3% vs 91.4%, P = 1;82.9% vs 74.3%, P = 0.25) in stage III; OS could be shortened to 4-year (75% vs 72.7%, P = 1) in stage IVA. Conclusions: The time of therapeutic evaluation could be shortened to <5-year in stages I-II patients. The year of surrogate endpoints could be ahead in stages II-IVA with high EBV DNA.

A Prognostic Score for Nasopharyngeal Carcinoma with Bone Metastasis: Development and Validation from Multicenter.

Background: To establish a prognostic score based on clinical routine factors to stratify nasopharyngeal carcinoma patients with bone metastasis into risk groups with different survival rates. Materials and Methods: Total 276 patients from multicenter were retrospectively analyzed. Kaplan-Meier method and Cox regression were used to confirm independent risk factors, which were checked for internal validity by bootstrapping method. The prognostic score, deriving from the corresponding regression coefficients in Cox model, classified patients into low and high risk groups. Finally, two independent cohorts were used for external validation. Results: In development cohort, six risk factors were identified: age>46 year-old (point=1), N>0 stage (point=2), anemia (point=2), bone metastasis free interval≤12 months (point=1), without radiotherapy to primary sites (point=1), and without radiotherapy to first metastasis sites (point=1). The derived prognostic score divided patients into low (score, 0-4) and high (score, 5-8) risk groups, with highly significant differences of 5-year overall survival rates (high vs. low risk: 24.6% vs. 58.2%, HR 3.47, P<0.001). Two external validations presented congruent results. Conclusion: A feasible and applicative prognostic score was successfully established and validated to discriminate bone metastatic nasopharyngeal carcinoma into low/high risk groups, which will be useful for individual treatment.