Fragmentation landscape of cell-free DNA revealed by deconvolutional analysis of end motifs.

Cell-free DNA (cfDNA) fragmentation is nonrandom, at least partially mediated by various DNA nucleases, forming characteristic cfDNA end motifs. However, there is a paucity of tools for deciphering the relative contributions of cfDNA cleavage patterns related to underlying fragmentation factors. In this study, through non-negative matrix factorization algorithm, we used 256 5' 4-mer end motifs to identify distinct types of cfDNA cleavage patterns, referred to as "founder" end-motif profiles (F-profiles). F-profiles were associated with different DNA nucleases based on whether such patterns were disrupted in nuclease-knockout mouse models. Contributions of individual F-profiles in a cfDNA sample could be determined by deconvolutional analysis. We analyzed 93 murine cfDNA samples of different nuclease-deficient mice and identified six types of F-profiles. F-profiles I, II, and III were linked to deoxyribonuclease 1 like 3 (DNASE1L3), deoxyribonuclease 1 (DNASE1), and DNA fragmentation factor subunit beta (DFFB), respectively. We revealed that 42.9% of plasma cfDNA molecules were attributed to DNASE1L3-mediated fragmentation, whereas 43.4% of urinary cfDNA molecules involved DNASE1-mediated fragmentation. We further demonstrated that the relative contributions of F-profiles were useful to inform pathological states, such as autoimmune disorders and cancer. Among the six F-profiles, the use of F-profile I could inform the human patients with systemic lupus erythematosus. F-profile VI could be used to detect individuals with hepatocellular carcinoma, with an area under the receiver operating characteristic curve of 0.97. F-profile VI was more prominent in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy. We proposed that this profile might be related to oxidative stress.

Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

BACKGROUND: The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. METHODS: For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. FINDINGS: The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). INTERPRETATION: The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. FUNDING: Institut National du Cancer and Ligue Nationale Contre le Cancer.

Preclinical evaluation of the VEGF/Ang2 bispecific nanobody BI 836880 in nasopharyngeal carcinoma models.

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is endemic to parts of Asia and overexpression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α are common in NPC. Anti-vascular agents have known clinical activity in patients with recurrent/ metastatic NPC and in this study, we investigated the anti-tumor effect of BI 836880, a humanized bispecific nanobody against VEGF and angiopoietin-2 (Ang2), in preclinical models of EBV-positive and EBV-negative NPC. The efficacy of BI 836880 was also compared with bevacizumab, a recombinant humanized monoclonal antibody against VEGF. We found that BI 836880 could exert growth-inhibitory effect on endothelial cells (HUVEC-C) and the EBV-negative NPC cell line (HK1), but to a lesser extent in the EBV-positive NPC cell lines, C17C and C666-1. In patients-derived xenograft (PDX) models of NPC - Xeno-2117 and Xeno-666, BI 836880 could suppress tumor growth and Ki67, as well as induce tumor necrosis and reduce microvessel density. Moreover, treatment with BI 836880 increased the level of macrophage infiltration in both PDX tumor models of NPC, suggesting that BI 836880 may exert immunomodulatory effect on the NPC immune microenvironment. When compared with bevacizumab, BI 836880 appeared to show at least comparable activity as bevacizumab in terms of its anti-proliferative and anti-angiogenic effects. This study showed that BI 836880 has anti-proliferative, anti-angiogenic and possibly immunomodulatory effect in clinical models of NPC, therefore the dual targeting of VEGF and Ang2 signaling in NPC should be further investigated.

The effect of material assignment in nasal cavity on dose calculation for nasopharyngeal carcinoma (NPC) using Acuros XB.

PURPOSE: To evaluate the effect of material assignment in nasal cavity on dose calculation for the volumetric modulated arc therapy (VMAT) of nasopharyngeal carcinoma (NPC) using Acuros XB (AXB) algorithm. METHODS: The VMAT plans of 30 patients with NPC were calculated using AXB with material auto-assignment of nasal cavity to lung and reassignment to air respectively. The doses to the planning target volumes (PTVs) overlapping with nasal cavity with material auto-assignment of lung (AXB_Lung) were compared to the values obtained when nasal cavity was reassigned to air (AXB_Air) under the dose-to-medium (Dm ) reporting mode of AXB. RESULTS: For dose calculated under AXB_Lung, the D98% , D2% , and Dmean of the PTV69.96 _Air Cavity (PTV of prescription dose 69.96 Gy overlapping with nasal cavity) were on average 16.1%, 1.6%, and 8.6% larger than that calculated under AXB_Air, respectively. Up to 19.5% difference in D98% , 3% difference in D2% , and 11.2% difference in Dmean were observed in the worst cases for PTV69.96 . Similar trend was observed for the PTV5940 _Air Cavity, in which the D98% , D2% , and Dmean calculated under AXB_Lung were on average 14.7%, 2.5%, and 10.2% larger than that calculated under AXB_Air, respectively. In the worst cases, the difference observed in D98% , D2% , and Dmean could be up to 17.7%, 4.5%, and 12.7%, respectively. CONCLUSIONS: Significant dose difference calculated by AXB between the material assignment of lung and air in nasal cavity for NPC cases might imply the possibility of underdosage to the PTVs that overlap with inhomogeneity. Therefore, attention should be put to ensure that accurate material assignment for dose calculation under AXB such that optimal dosage was given for tumor control.

Shift detection discrepancy between ExacTrac Dynamic system and cone-beam computed tomography.

Accurate detection of patient shift is essential during radiation therapy such that optimal dose is delivered to the tumor while minimizing radiation to surrounding normal tissues. The shift detectability of a newly developed optical surface and thermal tracking system, which was known as ExacTrac Dynamic (EXTD), was evaluated by comparing its performance with the image guidance under cone-beam computed tomography (CBCT). Anthropomorphic cranial and pelvis phantoms with internal bone-like structures and external heat pad were utilized to study the shift detection discrepancy between EXTD system and CBCT. Random displacements within the range of ± 2 cm for translations and ± 2 degrees for rotations were intentionally applied to the phantom. Positional shifts detected by optical surface and thermal tracking (EXTD_Thml), stereoscopic X-ray (EXTD_Xray), and CBCT were compared in 6 degrees of freedom. The translational difference between EXTD_Thml and CBCT was 0.57 ± 0.41 mm and 0.66 ± 0.40 mm for cranial and pelvis phantom, respectively, while it was 0.60 ± 0.43 mm and 0.76 ± 0.49 mm between EXTD_Xray and CBCT, respectively. For rotational movement, the difference between EXTD_Thml and CBCT was 0.19 ± 0.16° and 0.19 ± 0.22° for cranial and pelvis phantom, respectively, while it was 0.13 ± 0.18° and 0.65 ± 0.46° between EXTD_Xray and CBCT, respectively. This study demonstrated that the EXTD system with thermal mapping ability could offer comparable accuracy for shift detection with CBCT on both cranial and pelvis phantoms.

Sequencing-based counting and size profiling of plasma Epstein-Barr virus DNA enhance population screening of nasopharyngeal carcinoma.

Circulating tumor-derived DNA testing for cancer screening has recently been demonstrated in a prospective study on identification of nasopharyngeal carcinoma (NPC) among 20,174 asymptomatic individuals. Plasma EBV DNA, a marker for NPC, was detected using real-time PCR. While plasma EBV DNA was persistently detectable in 97.1% of the NPCs identified, ∼5% of the general population had transiently detectable plasma EBV DNA. We hypothesized that EBV DNA in plasma of subjects with or without NPC may have different molecular characteristics. We performed target-capture sequencing of plasma EBV DNA and identified differences in the abundance and size profiles of EBV DNA molecules within plasma of NPC and non-NPC subjects. NPC patients had significantly higher amounts of plasma EBV DNA, which showed longer fragment lengths. Cutoff values were established from an exploratory dataset and tested in a validation sample set. Adopting an algorithm that required a sample to concurrently pass cutoffs for EBV DNA counting and size measurements, NPCs were detected at a positive predictive value (PPV) of 19.6%. This represented superior performance compared with the PPV of 11.0% in the prospective screening study, which required participants with an initially detectable plasma EBV DNA result to be retested within 4 weeks. The observed differences in the molecular nature of EBV DNA molecules in plasma of subjects with or without NPC were successfully translated into a sequencing-based test that had a high PPV for NPC screening and achievable through single time-point testing.

NPC-0501 trial on the value of changing chemoradiotherapy sequence, replacing 5-fluorouracil with capecitabine, and altering fractionation for patients with advanced nasopharyngeal carcinoma.

BACKGROUND: A current recommendation for the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy (RT) with concurrent cisplatin followed by adjuvant cisplatin and 5-fluorouracil (PF). This randomized NPC-0501 trial evaluated the therapeutic effect of changing to an induction-concurrent sequence or accelerated-fractionation sequence, and/or replacing 5-fluorouracil with capecitabine (X). METHODS: Patients with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC initially were randomly allocated to 1 of 6 treatment arms (6-arm full-randomization cohort). The protocol was amended in 2009 to permit centers to opt out of randomization regarding fractionation (3-arm chemotherapy cohort). RESULTS: A total of 803 patients were accrued (1 of whom was nonevaluable) from 2006 to 2012. Based on the overall comparisons, neither changing the chemotherapy sequence nor accelerated fractionation improved treatment outcome. However, secondary analyses demonstrated that when adjusted for RT parameters and other significant factors, the induction-concurrent sequence, especially the induction-PX regimen, achieved significant improvements in progression-free survival (PFS) and overall survival. Efficacy varied among different RT groups: although no impact was observed in the accelerated-fractionation group and the 3-arm chemotherapy cohort, a comparison of the induction-concurrent versus concurrent-adjuvant sequence in the conventional-fractionation group demonstrated a significant benefit in PFS (78% vs 62% at 5 years; P = .015) and a marginal benefit in overall survival (84% vs 72%; P = .042) after adjusting for multiple comparisons. Comparison of the induction-PX versus the adjuvant-PF regimen demonstrated better PFS (78% vs 62%; P = .027) without an increase in overall late toxicity. CONCLUSIONS: For patients irradiated using conventional fractionation, changing the chemotherapy sequence from a concurrent-adjuvant to an induction-concurrent sequence, particularly using induction cisplatin and capecitabine, potentially could improve efficacy without an adverse impact on late toxicity. However, further validation is needed for confirmation of these findings.

Nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is characterised by distinct geographical distribution and is particularly prevalent in east and southeast Asia. Epidemiological trends in the past decade have shown that its incidence has declined gradually but progressively, and mortality has been reduced substantially. These findings probably reflect lifestyle and environmental changes, enhanced understanding of the pathogenesis and risk factors, population screening, advancements in imaging techniques, and individualised comprehensive chemoradiotherapy strategies. In particular, plasma Epstein-Barr virus (EBV) DNA has been used for population screening, prognostication, predicting treatment response for therapeutic adaptation, and disease surveillance. Moreover, the widespread application of intensity-modulated radiotherapy and optimisation of chemotherapy strategies (induction, concurrent, adjuvant) have contributed to improved survival with reduced toxicities. Among the existing developments in novel therapeutics, immune checkpoint therapies have achieved breakthroughs for treating recurrent or metastatic disease and represent a promising future direction in nasopharyngeal carcinoma.

Analysis of Plasma Epstein-Barr Virus DNA to Screen for Nasopharyngeal Cancer.

BACKGROUND: Circulating cell-free Epstein-Barr virus (EBV) DNA is a biomarker for nasopharyngeal carcinoma. We conducted a prospective study to investigate whether EBV DNA in plasma samples would be useful to screen for early nasopharyngeal carcinoma in asymptomatic persons. METHODS: We analyzed EBV DNA in plasma specimens to screen participants who did not have symptoms of nasopharyngeal carcinoma. Participants with initially positive results were retested approximately 4 weeks later, and those with persistently positive EBV DNA in plasma underwent nasal endoscopic examination and magnetic resonance imaging (MRI). RESULTS: A total of 20,174 participants underwent screening. EBV DNA was detectable in plasma samples obtained from 1112 participants (5.5%), and 309 (1.5% of all participants and 27.8% of those who initially tested positive) had persistently positive results on the repeated sample. Among these 309 participants, 300 underwent endoscopic examination, and 275 underwent both endoscopic examination and MRI; of these participants, 34 had nasopharyngeal carcinoma. A significantly higher proportion of participants with nasopharyngeal carcinoma that was identified by screening had stage I or II disease than in a historical cohort (71% vs. 20%, P<0.001 by the chi-square test) and had superior 3-year progression-free survival (97% vs. 70%; hazard ratio, 0.10; 95% confidence interval, 0.05 to 0.18). Nine participants declined to undergo further testing, and 1 of them presented with advanced nasopharyngeal carcinoma 32 months after enrollment. Nasopharyngeal carcinoma developed in only 1 participant with negative EBV DNA in plasma samples within 1 year after testing. The sensitivity and specificity of EBV DNA in plasma samples in screening for nasopharyngeal carcinoma were 97.1% and 98.6%, respectively. CONCLUSIONS: Analysis of EBV DNA in plasma samples was useful in screening for early asymptomatic nasopharyngeal carcinoma. Nasopharyngeal carcinoma was detected significantly earlier and outcomes were better in participants who were identified by screening than in those in a historical cohort. (Funded by the Kadoorie Charitable Foundation and the Research Grants Council of the Hong Kong government; ClinicalTrials.gov number, NCT02063399 .).

The emerging data on choice of optimal therapy for locally advanced nasopharyngeal carcinoma.

PURPOSE OF REVIEW: We focus on the emerging data from randomized clinical trials for optimal integration of induction, concurrent, and/or adjuvant chemotherapy with intensity-modulated radiotherapy in locally advanced nasopharyngeal carcinoma (NPC), and the use of plasma Epstein-Barr virus (EBV) DNA for risk stratification. RECENT FINDINGS: Several phase 3 trials have shown that induction chemotherapy followed by concurrent chemoradiation (CRT) improved overall survival or disease-free survival when compared to CRT alone in stage III/IV NPC who is at high risk of distant metastases. The benefit of adjuvant chemotherapy following CRT when compared to CRT alone is uncertain. There are increasing clinical data supporting the use of plasma EBV DNA for risk stratification. There are growing clinical data supporting the integration of immune checkpoint inhibitors into the induction, concurrent, and/or adjuvant/maintenance phase of treatment in locally advanced NPC. SUMMARY: Concurrent chemoradiation remains the standard treatment backbone in locally advanced NPC. There is level 1 evidence for induction chemotherapy followed by CRT in stage III/IV NPC. There is increasing evidence against the indiscriminate use of adjuvant chemotherapy following CRT. With the increasing treatment intensification, future treatment algorithm in NPC should incorporate plasma EBV DNA and other biomarkers for risk stratification and treatment selection.

Sequencing Analysis of Plasma Epstein-Barr Virus DNA Reveals Nasopharyngeal Carcinoma-Associated Single Nucleotide Variant Profiles.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. Plasma EBV DNA is a validated screening tool for NPC. In screening, there are some individuals who do not have NPC but carry EBV DNA in plasma. Currently it is not known from screening if there may be any genotypic differences in EBV isolates from NPC and non-NPC subjects. Also, low concentrations of EBV DNA in plasma could pose challenge to such EBV genotypic analysis through plasma DNA sequencing. METHODS: In a training dataset comprised of plasma DNA sequencing data of NPC and non-NPC subjects, we studied the difference in the EBV single nucleotide variant (SNV) profiles between the two groups. The most differentiating SNVs across the EBV genome were identified. We proposed an NPC risk score to be derived from the genotypic patterns over these SNV sites. We subsequently analyzed the NPC risk scores in a testing set. RESULTS: A total of 661 significant SNVs across the EBV genome were identified from the training set. In the testing set, NPC plasma samples were shown to have high NPC risk scores, which suggested the presence of NPC-associated EBV SNV profiles. Among the non-NPC samples, there was a wide range of NPC risk scores. These results support the presence of diverse SNV profiles of EBV isolates from non-NPC subjects. CONCLUSION: EBV genotypic analysis is feasible through plasma DNA sequencing. The NPC risk score may be used to inform the cancer risk based on the EBV genome-wide SNV profile.

Patient-specific quality assurance using machine log files analysis for stereotactic body radiation therapy (SBRT).

An in-house trajectory log analysis program (LOGQA) was developed to evaluate the delivery accuracy of volumetric-modulated arc therapy (VMAT) for stereotactic body radiation therapy (SBRT). Methods have been established in LOGQA to provide analysis on dose indices, gantry angles, and multi-leaf collimator (MLC) positions. Between March 2019 and May 2020, 120 VMAT SBRT plans of various treatment sites using flattening filter-free (FFF) mode were evaluated using both LOGQA and phantom measurements. Gantry angles, dose indices, and MLC positions were extracted from log and compared with each plan. Integrated transient fluence map (ITFM) was reconstructed from log to examine the deviation of delivered fluence against the planned one. Average correlation coefficient of dose index versus gantry angle and ITFM for all patients were 1.0000, indicating that the delivered beam parameters were in good agreement with planned values. Maximum deviation of gantry angles and monitor units (MU) of all patients were less than 0.2 degree and 0.03 % respectively. Regarding MLC positions, maximum and root-mean-square (RMS) deviations from planned values were less than 0.6 mm and 0.3 mm respectively, indicating that MLC positions during delivery followed planned values in precise manner. Results of LOGQA were consistent with measurement, where all gamma-index passing rates were larger than 95 %, with 2 %/2 mm criteria. Three types of intentional errors were introduced to patient plan for software validation. LOGQA was found to recognize the introduced errors of MLC positions, gantry angles, and dose indices with magnitudes of 1 mm, 1 degree, and 5 %, respectively, which were masked in phantom measurement. LOGQA was demonstrated to have the potential to reduce or even replace patient-specific QA measurements for SBRT plan delivery provided that the frequency and amount of measurement-based machine-specific QA can be increased to ensure the log files record real values of machine parameters.

Distinguishing early-stage nasopharyngeal carcinoma from benign hyperplasia using intravoxel incoherent motion diffusion-weighted MRI.

OBJECTIVES: MRI can detect early-stage nasopharyngeal carcinoma (NPC), but the detection is more challenging in early-stage NPCs because they must be distinguished from benign hyperplasia in the nasopharynx. This study aimed to determine whether intravoxel incoherent motion diffusion-weighted imaging (IVIM DWI) MRI could distinguish between these two entities. METHODS: Thirty-four subjects with early-stage NPC and 30 subjects with benign hyperplasia prospectively underwent IVIM DWI. The mean pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f) and apparent diffusion coefficient (ADC) values were calculated for all subjects and compared between the 2 groups using Student's t test. Receiver operating characteristics with the area under the curve (AUC) was used to identify the optimal threshold for all significant parameters, and the corresponding diagnostic performance was calculated. A p value of < 0.05 was considered statistically significant. RESULTS: Compared with benign hyperplasia, early-stage NPC exhibited a significantly lower D mean (0.64 ± 0.06 vs 0.87 ± 0.11 × 10-3 mm2/s), ADC0-1000 mean (0.77 ± 0.08 vs 1.00 ± 0.13 × 10-3 mm2/s), ADC300-1000 (0.63 ± 0.05 vs 0.86 ± 0.10 × 10-3 mm2/s) and a higher D* mean (32.66 ± 4.79 vs 21.96 ± 5.21 × 10-3 mm2/s) (all p < 0.001). No significant difference in the f mean was observed between the two groups (p = 0.216). The D and ADC300-1000 mean had the highest AUC of 0.985 and 0.988, respectively, and the D mean of < 0.75 × 10-3 mm2/s yielded the highest sensitivity, specificity and accuracy (100%, 93.3% and 96.9%, respectively) in distinguishing early-stage NPC from benign hyperplasia. CONCLUSION: DWI has potential to distinguish early-stage NPC from benign hyperplasia and D and ADC300-1000 mean were the most promising parameters. KEY POINTS: • Diffusion-weighted imaging has potential to distinguish early-stage nasopharyngeal carcinoma from benign hyperplasia in the nasopharynx. • The pure diffusion coefficient, pseudo-diffusion coefficient from intravoxel incoherent motion model and apparent diffusion coefficient from conventional diffusion-weighted imaging were significant parameters for distinguishing these two entities in the nasopharynx. • The pure diffusion coefficient, followed by apparent diffusion coefficient, may be the most promising parameters to be used in screening studies to help detect early-stage nasopharyngeal carcinoma.

Association Between Serum Folate Level and Toxicity of Capecitabine During Treatment for Colorectal Cancer.

BACKGROUND: Folate level was proposed to be a predictor for fluoropyrimidine-related toxicity. We conducted a prospective study to determine the association between serum and red-cell folate and capecitabine-related toxicity in patients with colorectal cancers. MATERIALS AND METHODS: Eligibility criteria included diagnosis of colorectal cancers; eligible patients who were scheduled to undergo capecitabine monotherapy or capecitabine-oxaliplatin (CAPOX) for adjuvant or palliative purposes. Exclusion criteria included concomitant radiotherapy or chemotherapy other than capecitabine or CAPOX and creatinine clearance <30 mL/min. Fasting serum and red-cell folate were measured prior to chemotherapy. Capecitabine was administered at 2,500 mg/m2 per day (monotherapy) or 2,000 mg/m2 per day (CAPOX) for 14 days every 3 weeks. The toxicity of the first four cycles was documented by clinical investigators who were blinded to folate levels. RESULTS: A total of 144 patients were recruited, of whom 126 were eligible; 40 patients had capecitabine alone, and 86 patients received CAPOX. The rates of grade 2 and grade 3 toxicity were 63.5% and 14.3%, respectively. Nausea and vomiting were the most common grade ≥2 adverse event (47.7%), followed by hand-foot syndrome (25.4%), diarrhea (23.1%), and neutropenia (22.3%). Combination with oxaliplatin (odds ratio [OR], 2.77; p = .043) and serum folate (OR, 10.33; p = .002) were independent predictors of grade ≥2 toxicity. Red-cell folate was not predictive of toxicity. For every 10 nmol/L increment in serum folate, the risk of grade ≥2 toxicity increased by 9%. CONCLUSION: Serum folate level, but not red-cell folate, was associated with higher rate of grade ≥2 toxicity during capecitabine-based treatment. Excessive folate intake may be avoided before and during capecitabine-based chemotherapy. IMPLICATIONS FOR PRACTICE: This is the first prospective study to evaluate the association between serum folate level and capecitabine-related toxicity in patients with colon cancers. It shows that higher serum folate level is associated with increased risks of moderate to severe toxicity during capecitabine-based treatment. Excessive folate intake should be avoided before and during capecitabine-based chemotherapy.

Nasopharyngeal carcinoma: relationship between invasion of the prevertebral space and distant metastases.

PURPOSE: To identify primary sites of nasopharyngeal carcinoma (NPC) invasion on the staging head and neck magnetic resonance imaging (MRI) that correlate with distant metastases (DM). MATERIALS AND METHODS: Staging head and neck MRI examinations of 579 NPC patients were assessed for primary tumour invasion into 16 individual sites, primary stage (T) and nodal stage (N). Results were correlated with distant metastasis-free survival (DMFS) using the Cox regression, and the diagnostic performance of significant independent markers for DM was calculated. In addition, sites of primary tumour invasion were correlated also with involvement of the first echelon of ipsilateral nodes (FEN+) using logistic regression. RESULTS: Distant metastases were present in 128/579 NPC patients (22.1%) after intensity-modulated radiotherapy (IMRT)/chemo-IMRT and 5-year DMFS was 78.8%. Prevertebral space invasion (PVS+) and N stage, but not T stage, were independent prognostic markers of DMFS (p = 0.016, < 0.001, and 0.433, respectively). Compared to stage N3, PVS invasion had a higher sensitivity (28.1 vs. 68.8%), but lower specificity (90.5 vs. 47.4%) and accuracy (76.7 vs. 48.9%) for correlating patients with DM. PVS invasion, together with parapharyngeal fat space invasion (PPFS+), was also an independent predictive marker of FEN+. CONCLUSION: PVS was the only site of primary tumour invasion that independently correlated with DM, and together with PPFS + was an independent prognostic marker of FEN+, but the low specificity and accuracy of PVS invasion limits its use as a prognostic marker of DM.

Nasopharyngeal carcinoma.

Epidemiological trends during the past decade suggest that although incidence of nasopharyngeal carcinoma is gradually declining, even in endemic regions, mortality from the disease has fallen substantially. This finding is probably a result of a combination of lifestyle modification, population screening coupled with better imaging, advances in radiotherapy, and effective systemic agents. In particular, intensity-modulated radiotherapy has driven the improvement in tumour control and reduction in toxic effects in survivors. Clinical use of Epstein-Barr virus (EBV) as a surrogate biomarker in nasopharyngeal carcinoma continues to increase, with quantitative assessment of circulating EBV DNA used for population screening, prognostication, and disease surveillance. Randomised trials are investigating the role of EBV DNA in stratification of patients for treatment intensification and deintensification. Among the exciting developments in nasopharyngeal carcinoma, vascular endothelial growth factor inhibition and novel immunotherapies targeted at immune checkpoint and EBV-specific tumour antigens offer promising alternatives to patients with metastatic disease.

Systematic evaluation of circulating inflammatory markers for hepatocellular carcinoma.

BACKGROUNDS & AIMS: A number of circulating inflammatory factors are implicated in the pathogenesis and prognostication of hepatocellular carcinoma (HCC). We aim to evaluate the prognostication of multiple serum inflammatory factors simultaneously and develop an objective inflammatory score for HCC. METHODS: A prospective cohort of 555 patients with HCC with paired serum samples was accrued from 2009 to 2012. The blood levels of conventional inflammatory markers, namely C-reactive protein (CRP), albumin, neutrophils, lymphocytes and platelet, were determined, and 41 other exploratory markers were measured by a multiplex assay. The prognostication and interaction of markers were determined by univariate and multivarite analyses. RESULTS: The cohort was randomly divided into training cohort (n=139) and validation cohort (n=416). There were no differences in baseline characteristics between the two cohorts. In the training cohort, independent prognostic factors for overall survival included CRP (hazard ratio [HR] 1.107; P=.003), albumin (HR 0.953; P=.032) and interleukin-8 (HR=5.816; P<.001). We have modified the existing inflammation-based index (IBI) by adding serum interleukin-8 level. The modified IBI could stratify patients into four groups with distinct overall survival (P<.001). The results were also validated in the validation cohort. When compared with IBI and other conventional inflammatory markers, the modified IBI had better prognostic performance with higher c-index and homogeneity likelihood ratio chi-square. CONCLUSIONS: Among the conventional and exploratory circulating inflammatory markers, higher CRP, lower albumin and higher interleukin-8 were independent prognosticators. By combining these factors, a simple and accurate inflammatory index could be constructed.

Incorporating albumin-bilirubin grade into the cancer of the liver Italian program system for hepatocellular carcinoma.

BACKGROUND AND AIMS: The albumin-bilirubin (ALBI) grade is a recently emerging alternative of the Child-Pugh (CP) grade. The Cancer of the Liver Italian Program (CLIP) was demonstrated to be a useful prognostic model for hepatocellular carcinoma (HCC) in large prospective cohorts. We aimed to investigate the feasibility of substituting the CP grade by the ALBI grade in the CLIP system and compare the prognostic performance with other existing staging systems. METHODS: A large cohort of 1973 Chinese patients with HCC was recruited to evaluate the prognostic performance of CP-based CLIP (CP-CLIP) and ALBI-based CLIP (ALBI-CLIP) systems and nine other staging systems by homogeneity likelihood chi-square, c-index, and corrected Akaike information criterion. RESULTS: The ALBI-CLIP system provided comparable prognostic performance than the CP-CLIP system, which was indicated by homogeneity likelihood chi-squares (ALBI-CLIP 1186.35 vs CP-CLIP 1145.54), c-indices (ALBI-CLIP 0.789 vs CP-CLIP 0.785) and AICs (ALBI-CLIP 15 493.47 vs CP-CLIP 15 534.28). Among 11 staging systems, ALBI-CLIP and CP-CLIP systems were associated with the highest homogeneity chi-squares and c-indices, and the lowest corrected Akaike information criterion. Patients in ALBI-CLIP score 0-4 had better median survival than those in corresponding CP-CLIP score. CONCLUSIONS: The ALBI grade performs as well as the CP grade when integrating into the CLIP system. ALBI-CLIP and CP-CLIP systems are the most accurate prognostic models among 11 existing staging systems.

Viral co-infections and paraproteins in HIV: effect on development of hematological malignancies.

The role of viral co-infections and paraproteins in the development of hematological malignancies (HMs) in HIV remains unclear. Using our large database of HIV+ patients, we investigated whether co-infection and paraproteinemia increase the risk of HM. Data on demographics, hepatitis B (HBV) and hepatitis C virus (HCV) co-infections, paraproteinemia, HIV characteristics, and biopsy proven malignant hematological disorders for HIV+ patients were collected over a 10-year period in a large urban hospital setting. We identified 10,293 HIV+ patients who were followed for a median duration of 53 months. Of the 10,293 patients with HIV, 229 (2.2 %) were diagnosed with a HM. Over 85 % of patients in both groups were tested; no significant difference in the prevalence of chronic HBV or HCV was noted between the HM positive (n = 229) and HM negative (n = 9992) patients. The serum protein electrophoresis test was performed for 1371 of the 10,221 patients. HM positive patients, compared to HM negative, were more likely to be tested for paraproteins (OR 3.3, 95 % CI 2.5-4.4) and more likely to have a discrete paraprotein band (OR 3.3, 95 % CI 1.2-8.9). Discrete paraproteins exclusively correlated with the development of plasma cell malignancies. Faint or oligoclonal protein bands were seen in high grade B cell lymphomas but did not show a significant correlation with HM development. Chronic hepatitis B or C infections did not correlate with the development of HM in HIV; however, viral influence on host gene transformation may have been impacted by anti-viral therapy limiting the duration of high viremic states.

Applicability of albumin-bilirubin-based Japan integrated staging score in hepatitis B-associated hepatocellular carcinoma.

BACKGROUND AND AIM: The Japan Integrated Staging (JIS) for hepatocellular carcinoma (HCC) has been extensively studied in hepatitis virus C-endemic Japanese population but seldom evaluated outside Japan, while albumin-bilirubin (ALBI)-based JIS (ALBI-T) has never been externally validated. We evaluate the prognostic significance of the ALBI-T score among Chinese patients with hepatitis virus B (HBV)-related HCC, and to explore its potential therapeutic application in selecting patients for appropriate treatments in addition to the Barcelona Clinic Liver Cancer (BCLC) recommendation. METHODS: A cohort of 1222 HBV-associated HCC patients was evaluated to compare the prognostic performance of JIS and ALBI-T scores by homogeneity likelihood chi-square and corrected Akaike information criterion. In the subgroup analysis of each BCLC stage, Kaplan-Meier method and log-rank statistics were used to compare overall survival of patients undergoing different treatment options. RESULTS: The ALBI-T score showed better prognostic performance than the JIS score, which were indicated by homogeneity likelihood chi-squares (ALBI-T 580.12 vs JIS 536.35) and Akaike information criteria (ALBI-T 9836.57 vs JIS 9880.23). Treatment options significantly influenced prognosis among patients of the same BCLC stage. With the use of ALBI-T score 4 as the cutoff, the current study identified that a portion of patients (14.7%, 25.2% and 28.6% of BCLC stage B, C and D, respectively) undergoing unnecessary therapy without survival advantage. CONCLUSIONS: The ALBI-T score is applicable to Chinese patients with HBV-related HCC to provide reasonable prognostic information as well as potentially helping clinicians to avoid offering non-beneficial aggressive treatments.