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Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, PD-L1-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented.KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1:1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary end point was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population.Between May 5, 2016, and May 28, 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cutoff (November 30, 2020) was 45.1 months (interquartile range, 39.0-48.8). Median OS was 17.2 months (95% confidence interval [CI], 11.7-22.9) with pembrolizumab and 15.3 months (95% CI, 10.9-18.1) with chemotherapy (hazard ratio, 0.90 [95% CI, 0.67-1.19; P = 0.2262]). Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage).Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events.ClinicalTrials.gov, NCT02611960.

A meeting of experts was held in November 2021 to review and discuss available data on performance of Epstein-Barr virus (EBV)–based approaches to screen for early stage nasopharyngeal carcinoma (NPC) and methods for the investigation and management of screen-positive individuals. Serum EBV antibody and plasma EBV DNA testing methods were considered. Both approaches were found to have favorable performance characteristics and to be cost-effective in high-risk populations. In addition to endoscopy, use of magnetic resonance imaging (MRI) to investigate screen-positive individuals was found to increase the sensitivity of NPC detection with minimal impact on cost-effectiveness of the screening program.

Quantitative measurement of plasma Epstein-Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients.Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA.The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS.NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing.

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.

Additional detail of materials and methods used. Figure 1. Flow chart detailing dose escalation schema. Figure 2. MVA-EBNA1/LMP2 Vaccination does not alter broad subsets of immune cells. Figure 3. EBNA1 antibody response before and after MVA-EL vaccination. Table 1 MHC class I and II restricted epitope peptides in EBNA1 and LMP2 used as targets in ELIspot assays. Table 2 Summary of EBNA1- and LMP2-specific immune responses stimulated by vaccination of UK NPC patients.

Purpose: We hypothesized that axitinib is active with an improved safety profile in nasopharyngeal carcinoma (NPC).Experimental Design: We evaluated axitinib in preclinical models of NPC and studied its efficacy in a phase II clinical trial in recurrent or metastatic NPC patients who progressed after at least one line of prior platinum-based chemotherapy. We excluded patients with local recurrence or vascular invasion. Axitinib was started at 5 mg twice daily in continuous 4-week cycles. Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients achieving complete response, partial response, or stable disease by RECIST criteria for more than 3 months.Results: We recruited 40 patients, who received a median of 3 lines of prior chemotherapy. Axitinib was administered for a mean of 5.6 cycles, with 16 patients (40%) receiving ≥6 cycles. Of 37 patients evaluable for response, CBR was 78.4% (95% CI, 65.6%–91.2%) at 3 months and 43.2% (30.4%–56.1%) at 6 months. Grade 3/4 toxicities were uncommon, including hypertension (8%), diarrhea (5%), weight loss (5%), and pain (5%). All hemorrhagic events were grade 1 (15%) or grade 2 (3%). Elevated diastolic blood pressure during the first 3 months of axitinib treatment was significantly associated with improved overall survival (HR, 0.29; 95% CI, 0.13–0.64, P = 0.0012). Patient-reported fatigue symptom was associated with hypothyroidism (P = 0.039). Axitinib PK parameters (Cmax and AUC(0-t)) were significantly correlated with tumor response, toxicity, and serum thyroid-stimulating hormone changes.Conclusions: Axitinib achieved durable disease control with a favorable safety profile in heavily pretreated NPC patients. Clin Cancer Res; 24(5); 1030–7. ©2018 AACR.

Pharmacokinetic profile of axitinib.

Purpose: Epstein–Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses.Experimental Design: Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 107 and 5 × 108 plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations.Results: Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively.Conclusions: MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 108 pfu) is recommended for investigation in current phase IB and II trials. Clin Cancer Res; 20(19); 5009–22. ©2014 AACR.

Supplementary Methods

Radiotherapy (RT) is the standard-of-care for Epstein–Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), where the post-RT clearance of plasma EBV DNA is prognostic. Currently, it is not known whether the post-RT clearance of plasma EBV DNA is related to the presence of circulating T-cell subsets. Blood samples from NPC patients were used to assess the frequency of T-cell subsets relating to differentiation, co-signaling and chemotaxis. Patients with undetectable versus detectable plasma EBV DNA levels post-RT were categorized as clearers vs. non-clearers. Clearers had a lower frequency of PD1+CD8+ T cells as well as CXCR3+CD8+ T cells during RT compared to non-clearers. Clearers exclusively showed a temporal increase in chemo-attractant receptors CCR1, 4 and/or 5, expressing CD8+ T cells upon RT. The increase in CCR-expressing CD8+ T cells was accompanied by a drop in naïve CD8+ T cells and an increase in OX40+CD8+ T cells. Upon stratifying these patients based on clinical outcome, the dynamics of CCR-expressing CD8+ T cells were in concordance with the non-recurrence of NPC. In a second cohort, non-recurrence associated with higher quantities of circulating CCL14 and CCL15. Collectively, our findings relate plasma EBV DNA clearance post-RT to T-cell chemotaxis, which requires validation in larger cohorts.

To assess the effectiveness of partially hydrolyzed guar gum (PHGG) in improving constipation and reducing the use of laxatives among long term care facility (LTCF) residents.A single-center, prospective, randomized, placebo-controlled, single-blinded parallel-group trial from September 2021 to November 2021.Four LTCF in Hong Kong.Fifty-two LTCF residents with chronic constipation (mean age: 83.9±7.6 years, male 38%).5g PHGG mixed with 200ml water per day for 4 weeks was given to intervention group participants. Control group received 200ml water for 4 weeks. Participants continued their usual as-needed laxative (lactulose, senna or dulcolax) on their own initiative.Baseline measurements included age, gender, Charlson comorbidity index, Roackwood's Clinical Frailty Scale, body mass index and daily dietary fiber intake. Outcome measures were fecal characteristics assessed by Bristol Stool Form Scale, bowel opening frequency and laxative use frequency at baseline, first, second, third and fourth week of trial. Adverse events were measured. The study was registered on ClinicalTrial.gov; identifier: NCT05037565.There was no significant difference in bowel frequency and stool characteristics between the treatment group and control group. However, there was a significantly lower frequency of lactulose, senna, and total laxative use in the treatment group compared with controls in the third and fourth week. There was no significant difference in adverse effects between the two groups.This study showed that daily dietary fibre supplementation by using PHGG for 4 weeks in LTCF residents results in significantly less laxative use than placebo. It may be an effective way to reduce laxative dependence among older people living in LTCFs.

The purpose of this work was to study the radiobiological effect of using Acuros XB (AXB) vs Analytic Anisotropic Algorithm (AAA) on hepatocellular carcinoma (HCC) stereotactic body radiation therapy (SBRT). Seventy SBRT volumetric modulated arc therapy (VMAT) plans for HCC were calculated using AAA and AXB respectively with the same treatment parameters. Published tumor control probability (TCP) and normal tissue complication probability (NTCP) models were used to quantify the effect of dosimetric difference between AAA and AXB on TCP, NTCP and uncomplicated tumor control probability (UTCP). There was an average decrease of 2.5% in 6-month TCP. Normal liver has the largest average decrease in NTCP which was 59.7%. Bowels followed with 26.6% average decrease in NTCP. Duodenum, stomach and esophagus had 10.2%, 5.1%, and 4.3% average decrease in NTCP. There was an average decrease of 1.8% and up to 7.2% in 6-month UTCP. There was an overall decrease in TCP, NTCP, and UTCP for HCC SBRT plans calculated using AXB compared to AAA which could be clinically significant.

ImportanceParental astigmatism is a factor associated with risk for development of child astigmatism; however, the magnitude of the association has not been determined.ObjectiveTo determine the association between parental and child astigmatism.Design, Setting, and ParticipantsThis population-based, cross-sectional study included participants from familial trios, each comprising a child aged 6 to 8 years and both parents, recruited from the Hong Kong Children Eye Study. No restriction criteria were set on the children in terms of refractive status. Data were analyzed from February to June 2022.ExposuresCycloplegic autorefraction and autokeratometry were conducted on the children, whereas noncycloplegic autorefraction and autokeratometry were conducted on their parents. The children were categorized into 6 groups on the basis of the severity of astigmatism of both parents. Information on parental education, family income, and children’s outdoor and near work time were obtained by questionnaires.Main Outcomes and MeasuresThe primary outcome was the odds of child astigmatism among the 6 categories of children. Associations of factors with child astigmatism were evaluated by logistic regression analyses.ResultsA total of 17 124 participants from 5708 trios (2964 boys and 2754 girls) at a mean (SD) age of 7.32 (0.87) years, and 11 416 parents were examined. Astigmatism of 1.0 D or greater in both parents was associated with greater odds of refractive astigmatism (RA) (odds ratio [OR], 1.62; 95% CI, 1.15-2.26) and corneal astigmatism (CA) (OR, 1.94; 95% CI, 1.50-2.50) in the child. The respective ORs increased to 3.10 (95% CI, 1.34-7.21) and 4.31 (95% CI, 1.76-10.55) when both parents had astigmatism 2.0 D or greater. Higher parental astigmatism conferred higher risks for both RA and CA in children (P for trend Conclusions and RelevanceThe findings of this cross-sectional study suggest that parental astigmatism may confer an independent and dose-dependent association with child astigmatism. Children with parents with astigmatism should have early eye examinations for timely detection of astigmatism to facilitate age-appropriate vision correction and visual development.

Objective. To study the effects of magnetic field gradients on the dose deposition in an inhomogeneous medium and to present the benefits offered by magnetic-field-modulated radiotherapy (MagMRT) under multiple radiation beams. Approach. Monte Carlo simulations were performed using the Geant4 simulation toolkit with a 7 MV photon beam from an Elekta Unity system. A water cuboid embedded with material slabs of water, bone, lung or air was used to study the effects of MagMRT within inhomogeneous medium. Two cylindrical water phantoms, with and without a toroidal lung insert embedded, were used to study the effects of MagMRT under single, opposing or four cardinal radiation beams. Optimized magnetic field variations in the form of a wavelet were used to induce dose modulation within the material slabs or at the iso-center of the phantoms. Main results. The magnitudes of the dose enhancement and reduction induced by the magnetic field gradients become more prominent in a medium of lower density. A maximum dose increase of 6.5% and a decrease of 4.8% were found inside bone, while an increase of 20.4% and a decrease of 13.9% were found in lung tissue. Under multiple radiation beams, the dose enhancement can be induced at the iso-center while the dose reduction occurs in regions around the tumor. For the case with four cardinal beams irradiating a homogeneous water cylinder, an 8.4% of dose enhancement and a 2.4% of dose reduction were found. When a toroidal lung insert was embedded, a maximum dose enhancement of 9.5% and a reduction of 17.0% were produced for anterior-posterior opposing fields. Significance. With an optimized magnetic field gradient, MagMRT can induce a dose boost to the target while producing a better sparing to the surrounding normal tissue, resulting in a sharper dose fall-off in all directions outside the target volume.

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.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 (DFor dose calculated under AXB_Lung, the DSignificant 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.

In this study, we use an abductory induction mechanism (AIM) polynomial network, with material properties provided as input, to generate a model that predicts tool geometry. The resulting model allows for the rapid and accurate design of suitable tool geometries while using different materials. Here, we report the results for the tool geometry predicted by our model obtained when different materials are used; the materials examined are NAK80, quenched SKD61, annealed SKD61, quenched S45C, annealed S45C, SUS316L, SUS304, and Ti-6Al-4 V. After cutting, the flatness of the material is measured using a tool microscope to determine its flank. Whether the abnormal cutting phenomenon is caused in the form of a springback or chipping caused by material rebound is also investigated. The results confirm that the tool belongs to a normal cutting phenomenon. The fitting state of the model is adjusted to ensure an appropriate fit. We also verified the prediction model for two untested materials: SCM440 and SUS420. The polynomial network model predicts that SCM440 has a normal relief angle of 6.25°, a tool wedge angle of 76.47°, a predicted normal ISS420 with a normal relief angle of 3.46°, and a tool wedge angle of 68.72°. The value of the flatness of the cutting edge is determined to be within 5 μm, indicating that the flank surface has normal friction phenomenon.

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.

Diffusivities of nonassociated aromatic compounds at infinite dilution in methanol and in cyclohexane were measured by the Taylor dispersion method. At constant temperatures, the diffusivity recipr...

The past three decades have borne witness to many advances in the understanding of the molecular biology and treatment of nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated cancer endemic to southern China, southeast Asia and north Africa. In this Review, we provide a comprehensive, interdisciplinary overview of key research findings regarding NPC pathogenesis, treatment, screening and biomarker development. We describe how technological advances have led to the advent of proton therapy and other contemporary radiotherapy approaches, and emphasize the relentless efforts to identify the optimal sequencing of chemotherapy with radiotherapy through decades of clinical trials. Basic research into the pathogenic role of EBV and the genomic, epigenomic and immune landscape of NPC has laid the foundations of translational research. The latter, in turn, has led to the development of new biomarkers and therapeutic targets and of improved approaches for individualizing immunotherapy and targeted therapies for patients with NPC. We provide historical context to illustrate the effect of these advances on treatment outcomes at present. We describe current preclinical and clinical challenges and controversies in the hope of providing insights for future investigation.

Background: This work was to establish an uncomplicated tumour control probability (UTCP) model using Hepatocellular Carcinoma Stereotactic Body Radiation Therapy (HCC SBRT) clinical data in our institution. The model was then used to analyze the treatment outcome of the current dose prescription method and to seek the opportunity for improvement.Methods: A tumour control probability (TCP) model was generated based on local clinical data using the maximum likelihood method. A UTCP model was then formed by combining the established TCP model with the normal tissue complication probability (NTCP) model based on the study by Dawson et al. The authors investigated the dependence of maximum achievable UTCP on tumor mean biological effective dose (BED) at various ratio between tumour mean biological effective dose (BED) and normal liver mean BED (T/N BED ratios). A new term uncomplicated tumour control efficiency (UTCE) was also introduced to analyze the outcome. A UTCE value of 1 implied that the theoretical maximum UTCP for the corresponding T/N BED ratio was achieved.Results: The UTCE of the HCC SBRT patients based on the current dose prescription method was found to be 0.90±0.08. It was found that the UTCE could be increased to 0.99±0.03 by using a new dose prescription scheme, for which the UTCP could be maximized while keeping the NTCP value smaller than 5 %. Conclusion: The treatment outcome of the current HCC SBRT in our institution was analyzed using a UTCP model established based on local clinical data. It was shown that there could be a potential to increase the prescription dose of HCC SBRT. A new dose prescription scheme was proposed to achieve better treatment outcome.

The durability of improved xerostomia with intensity-modulated radiotherapy (IMRT) in patients with early stage nasopharyngeal carcinoma (NPC) is uncertain. We conducted a long-term prospective assessment of participants treated with IMRT or two-dimensional radiotherapy (2DRT) in a prior randomized study.Parent study participants (IMRT, n = 28; 2DRT, n = 28) who were free of second malignancy or recurrence were eligible. Long-term radiotherapy-related toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) criteria. Long-term patient-reported outcomes were assessed by the six-item xerostomia (XQ) and two European Organisation for Research and Treatment of Cancer (EORTC) questionnaires (QLQ-C30, QLQ-HN35). Overall survival (OS), locoregional relapse-free survival (LRFS), distant relapse-free survival (DRFS), and the rate of symptomatic late complications (SLCs) were estimated for the entire cohort (n = 56).Totally, 21 (IMRT, n = 10; 2DRT, n = 11) patients gave consent and were assessed for an overall median follow-up of 15.5 years. There was significantly less RTOG ≥grade 2 xerostomia with IMRT versus 2DRT (20% vs. 90%; p = 0.001), but no significant difference in XQ scores. Patients in the IMRT arm reported lower mean scores for the "dry mouth" domain of EORTC QLQ-HN35 (p = 0.02) and showed trends toward better 15-year OS (81.5% vs. 53.8%, p = 0.06), LRFS (70.6% vs. 53.8%, p = 0.38), and DRFS (81.5% vs. 53.8%, p = 0.07). SLCs were more frequent in the 2DRT arm.The parotid-sparing effect of IMRT in NPC treatment is durable, with significantly less physician- and patient-scored xerostomia at 15 years. IMRT results in better long-term survival and fewer SLCs.

Locally advanced and recurrent/ metastatic (R/M) head and neck cancers have poor prognosis generally. Radiotherapy (RT) is known to have multiple immunomodulatory effects, and various immune checkpoint inhibitors (ICIs) have been shown to be efficacious in the R/M setting in recent years. Hence, it is logical to combine RT and ICIs to improve the outlook for such patients, especially in view of the promising pre-clinical data on this novel combination. In this review, we highlighted the key mechanisms underlying the immunostimulatory and immunoinhibitory effects of RT, with a view to suggesting strategies to overcome radioresistance. We also discussed how the unique immune landscapes of virus-induced cancers, namely Epstein-Barr virus-induced nasopharyngeal carcinoma and human papillomavirus-mediated oropharyngeal cancer, could be exploited with ICIs. The landmark clinical trials in both the locally advanced and R/M settings were reviewed, and these trials showed that the combination of RT and ICIs is generally well tolerated. The potential reasons behind the largely negative results of these studies were also explored, focusing on various parameters including dose fractionation, sequencing, irradiated volume and the use of predictive biomarkers.

Because of the requirements of automated processing, the cutting status of a tool should be monitored in real-time to find out the processing quality in advance and detect cutting abnormalities in time. Thus, we developed an application called APP for tool-life management and damage detection to help operators control the timing of tool replacement and avoid time-delays and loss after damage to the product. The proposed system consists of two sub-systems: an electronic system (to capture signals) and a software system (APP). The electronic system has an accelerometer, a signal capture card, a current sensor, and a temperature sensor. The software system has operating interfaces, data visualization, and early warning systems. The principal component analysis uses a linear combination with the largest variance. The eigenvalues and eigenvectors can be obtained by drawing a slope diagram of the number of principal components by eigenvalues. The point when the slope changes significantly can be used as the selected monitoring characteristic parameter. To reduce the manpower required for follow-up processing, the proposed system can be combined with different controllers to achieve customized parameter adjustment. Unmanned control can ensure processing efficiency and quality.

The heat generation in the machining process at the cutting zone has a negative effect to cutting edge. The research purpose is to increase heat transfer in the cutting zone by applying a high-pressure internal cooling system to an external turning tool DCLNR 2525M12 with hope to increase the tool life, and better surface roughness.The standard design ISO tool DCLNR2525M12 has been modified by adding an internal cooling system. This function has 2 types of coolant holes at different positions. The main hole leads to the rake face to increase heat transfer in the cutting zone at the primary shear zone and secondary shear zone, it also improved the chip breakability. The second hole leads to the flank face to increase heat transfer in the cutting zone of the tertiary shear zone.In this study, the shape of the coolant hole is varied to find out the influence of the different shapes of the coolant hole with the same total area. The shape of the coolant hole contains 5 variations to the rake face and 2 variations to the flank face. The two types of holes are combined to study the experiments into 2 groups. Then the samples are analyzed using ANSYS fluid flow (fluent) to find the best hole's combination to reduce heat in the cutting zone.Based on the results of ANSYS Fluid Flow (Fluent) simulation, found 1 sample reduce temperature more than another samples. The sample is SX, reducing the temperature 97.0oK at inlet 20 m/s.

With the development of machine tools trending toward high precision, intelligence, multi-axis, and high speed, the improvement of the processing performance and rigidity of the machine is considerably important. The objective of this study is to design of a high-speed five-axis moving-column machine tool and perform structural analysis and optimization. We study the static and dynamic characteristics of the five-axis machine tool, design and improve the mechanical structure, and optimize the structural configuration of the machine. The entire machine structure is further analyzed and enhanced to improve its static and dynamic characteristics, including static rigidity, modal, transient, and spectral response characteristics. The static and dynamic characteristics of the machine structure directly affect the machine processing performance, and further affect the work piece precision machined by the tool. Through this study, the design technology for speed, accuracy, and surface roughness of the machine tool are further improved.

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.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.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.

Diffusion coefficients of pseudoplanar aromatic compounds at infinite dilution in acetone have been measured at different temperatures by the Taylor dispersion technique. The data of the polar solutes that can form hydrogen bonds with acetone are compared with those of the nonpolar ones incapable of hydrogen bonding to quantify the effects of hydrogen-bonded association on diffusion. The effects are further found to correlate strongly with the overall hydrogen-bonded acidity of the polar solutes containing proton-donating groups. For the nonpolar solutes in this study, the diffusivities at different temperatures can be expressed very well by the recently developed molecular-modified fractional Stokes-Einstein relation with only two constants. An innovative model for solute diffusion in liquid solutions, which is constructed by combining the molecular-hydrodynamic relation for nonpolar solutes with the overall hydrogen-bonded acidity scale for polar solutes, is introduced for representing the diffusivities of different types of disc-shaped molecules at various temperatures. An equation developed from this model is demonstrated to be capable of calculating a total of 191 diffusion data of both the hydrogen-bonded and the nonassociated aromatic solutes in acetone from 268.2 to 328.2 K to a standard deviation of 2.7%.

BI836880 is a humanized bispecific nanobody directed against angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF)-derived peptides, with selective and potent antiangiogenic and antineoplastic activities. It comprises of blocking domains that bind to Ang2 and VEGF and prevents Ang2- and VEGF-mediated signalling; thus, inhibits both angiogenesis and tumour cell proliferation. Tumor angiogenesis contributes to progression of nasopharyngeal cancer (NPC) and VEGF/receptor inhibitors agents have activity in NPC patients. In this study, the preclinical activity of a novel VEGF/Ang-2 bi-specific nanobody, BI836880, was evaluated in two NPC-PDX models - Xeno-2117 and Xeno-666. The effect of BI836880 on tumor growth was compared with the control, bevacizumab - an anti-VEGF antibody which has been evaluated in NPC patients. Tumor-bearing mice were randomized into three groups: vehicle control, 15mg/kg bevacizumab (b.i.w) and 15mg/kg BI836880 (b.i.w.). Drug was administered by intraperitoneal injection and the treatment duration was four weeks. Tumor sizes and body weights were monitored by caliper and balance, respectively. The results showed that BI836880 was very well tolerated in mice, with no signs of stress and loss of weight observed during the treatment. At day 14, the mean tumor volumes of BI836880, bevacizumab vs vehicle control was 264.5±36.0, 290.0±32.4 vs 697.38±88.4 mm3 in Xeno-666 (p In conclusion, BI836880 can inhibit NPC growth to an extent that is comparable to bevacizumab, further investigation in combination with cytotoxic or immunotherapeutic agents are warranted. Citation Format: Eric Chi Wong, Gigi Lam, Connie Wong, Rachel C. Lam, Kwok Wai Lo, Edwin Pun Hui, Anthony Tak Chan, Brigette B. Ma. Preclinical evaluation of VEGF Ang2 bispecific nanobody BI836880 in patient-derived xenograft models of nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 948.

Limiting mutual diffusivities of o- and m-isomers of methylaniline, nitroaniline, nitrophenol, and aminophenol were measured in acetone at 298.2 K by the Taylor dispersion method. The data reveal that all of the o-substituted solutes capable of intramolecular hydrogen bonding diffuse faster than their m-counterparts without such bonding. By taking into account of the small corrections for the differences in molecular shape and steric hindrance between the o- and m-isomers that can form solute-solvent complexes, the net effects of intramolecular hydrogen bonding were uncovered to render the o-isomers greater in diffusivity by 3-15% as compared to their m-isomers in this study. For aromatic amines and phenols diffusing in acetone, the overall effects of intermolecular hydrogen bonding on diffusivity were ascertained by comparing the available diffusivity data of the associated aromatic solutes with those of the nonassociated ones. The intermolecular effects that cause solutes to diffuse slower were found to vary from approximately 12-39% in the present work. The results indicate that both of the opposite intra- and intermolecular effects are significant. In addition, the quantified effects were analyzed to show that they are closely related to the nature and position of the functional groups contained in the aromatic solutes, including those that are unable to form hydrogen bonds with acetone. A relation that can correlate the diffusivities of the hydrogen-bonded aromatic amines and phenols in acetone with the overall acidities of the compounds is also presented.