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Abstract Eigenstate coalescence in non-Hermitian systems is widely observed in diverse scientific domains encompassing optics and open quantum systems. Recent investigations have revealed that adiabatic encircling of exceptional points (EPs) leads to a nontrivial Berry phase in addition to an exchange of eigenstates. Based on these phenomena, we propose in this work an exhaustive classification framework for EPs in non-Hermitian physical systems. In contrast to previous classifications that only incorporate the eigenstate exchange effect, our proposed classification gives rise to finer $${{\mathbb{Z}}}_{2}$$ Z 2 classifications depending on the presence of a π Berry phase after the encircling of the EPs. Moreover, by mapping arbitrary one-dimensional systems to the adiabatic encircling of EPs, we can classify one-dimensional non-Hermitian systems characterized by topological phase transitions involving EPs. Applying our exceptional classification to various multiband systems, we expect to enhance the understanding of topological phases in non-Hermitian systems.

Background and Aims: Nivolumab was the first immune checkpoint inhibitor approved for hepatocellular carcinoma (HCC). External beam radiation therapy (EBRT) is locally effective and may enhance the effectiveness of immunotherapy. This study investigated the efficacy and safety of concurrent nivolumab and EBRT in HCC with macrovascular invasion. Methods: In this phase II multicenter trial, patients with HCC and macrovascular invasion were concurrently treated with intravenous nivolumab (3 mg/kg every 2 weeks) and EBRT, followed by maintenance nivolumab until progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) and safety, and secondary endpoints were overall survival, time-to-progression, objective response rate, and disease control rate. Results: Between January 2020 and June 2021, 50 patients (male 84%, median age 62.5) were enrolled; 47 (94.0%) and 13 (26.0%) with portal (Vp1/2, n = 21; Vp3, n = 23; Vp4, n = 3) and hepatic vein invasion, respectively. Patients received EBRT (median dose: 50 [IQR 43–50] Gy) after the first nivolumab dose. The median number of nivolumab doses was 8.5. Median PFS was 5.6 (90% CI 3.6–9.9) months. Median overall survival and time-to-progression were 15.2 (90% CI 10.8–19.6) and 5.6 (90% CI 3.6–9.9) months, respectively. The objective response rate and disease control rate were 36.0% and 74.0%, respectively. The median duration of response was 9.9 months. Of 35 patients with follow-up data, 23 received subsequent systemic treatment, including atezolizumab-bevacizumab, sorafenib, lenvatinib, and regorafenib. Treatment-related any grade adverse events (AEs) and grade 3/4 AEs occurred in 40 (80.0%) and 6 (12.0%) patients, respectively. Common treatment-related AEs included pruritus (38.0%) and rash (16.0%), with no treatment-related deaths. Conclusion: Concurrent nivolumab therapy and EBRT showed encouraging PFS with acceptable safety in patients with advanced HCC and macrovascular invasion. Impact and implications: Immune checkpoint inhibitors, the standard care for advanced hepatocellular carcinoma (HCC), show relatively poor therapeutic effects in patients with advanced HCC and macrovascular invasion. In this investigator-initiated phase II study, we, for the first time, show that concurrent external beam radiation therapy with nivolumab, an immune checkpoint inhibitor, led to encouraging progression-free survival in patients with HCC and macrovascular invasion. The concurrent treatment was tolerable without significant safety concerns. Further randomized studies investigating the combination of immunotherapy and external beam radiation therapy are required. ClinicalTrials.gov identifier: NCT04611165

Background: To evaluate the efficacy and optimal timing of local treatment in patients with borderline resectable (BR) or locally advanced pancreatic cancer (LAPC) treated with upfront FOLFIRINOX. Method: Between 2015 and 2020, 258 patients with pancreatic ductal adenocarcinoma (PDAC) were analysed. Treatment outcomes were compared between systemic treatment group (ST) and multimodality treatment groups (MT) using Kaplan–Meier curves and log-rank test. The MT were stratified as follows: FOLFIRINOX + radiation therapy (RT) (MT1), FOLFIRINOX + surgical resection (MT2), and FOLFIRINOX + RT + surgical resection (MT3). Results: With median follow-up period of 18 months, the 2-year overall survival (OS) for the ST was 22.0%, and it was significantly worse than MT (MT1, 46.3%; MT2, 65.7% and MT3; 90.2%; P < .001). The 2-year locoregional progression free survival (LRPFS) and overall PFS in ST were 10.7% and 7.0%, which were also significantly lower than those of MT (2-year LRPFS: MT1, 31.8%; MT2, 45.3%; MT3, 81.0%; 2-year overall PFS: MT1, 23.3%; MT2, 35.0%; MT3, 66.3%; P < .001). In time-varying multivariate Cox proportional hazard model, local treatment contributed to better treatment outcomes, with adjusted hazard ratios of 0.568 (95% confidence interval [CI], 0.398-0.811), 0.490 (95% CI, 0.331-0.726), and 0.656 (95% CI, 0.458–0.940) for OS, LRPFS, and overall PFS, respectively. The time window of 11–17 months after FOLFIRINOX appeared to demonstrate the maximal efficacy of local treatments in OS. Conclusions: Adding local treatment in BR/LAPC patients treated with upfront FOLFIRINOX seemed to contribute in improved treatment outcomes, and it showed maximal efficacy in OS when applied 11-17 months after the initiation of FOLFIRINOX. We suggest that administration of sufficient period of upfront FOLFIRINOX may intensify the efficacy of local treatments, and well controlled prospective trials are expected.

Abstract Background This study aimed to compare the outcomes of proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) by a systematic review and meta‐analysis of the existing clinical evidence. Methods A systematic literature search was performed to identify studies comparing the clinical outcomes of PBT and CIRT. The included studies were required to report oncological outcomes (local control [LC], progression‐free survival [PFS], or overall survival [OS]) or adverse events. Results Eighteen articles comprising 1857 patients (947 treated with PBT and 910 treated with CIRT) were included in the analysis. The pooled analysis conducted for the overall population yielded average hazard ratios of 0.690 (95% confidence interval (CI), 0.493–0.967, p = 0.031) for LC, 0.952 (95% CI, 0.604–1.500, p = 0.590) for PFS, and 1.183 (0.872–1.607, p = 0.281) for OS with reference to CIRT. The subgroup analyses included patients treated in the head and neck, areas other than the head and neck, and patients with chordomas and chondrosarcomas. These analyses revealed no significant differences in most outcomes, except for LC in the subgroup of patients treated in areas other than the head and neck. Adverse event rates were comparable in both groups, with an odds ratio (OR) of 1.097 (95% CI, 0.744–1.616, p = 0.641). Meta‐regression analysis for possible heterogeneity did not demonstrate a significant association between treatment outcomes and the ratio of biologically effective doses between modalities. Conclusion This study highlighted the comparability of PBT and CIRT in terms of oncological outcomes and adverse events.

Background/Aim Patients with large (>5 cm) hepatocellular carcinoma (HCC) have limited treatment options, thus necessitating the identification of prognostic factors and the development of predictive tools. This study aimed to identify prognostic factors and to construct a nomogram to predict survival outcomes in patients with large HCC. Methods A cohort of 438 patients, who were diagnosed with large HCC at a tertiary hospital between 2015 and 2018, was analyzed. Cox proportional hazards models were used to identify key prognosticators of overall survival (OS), and an independent set of prognostic factors was used to develop a nomogram. The discrimination and calibration abilities of the nomogram were assessed and internal validation was performed using cross-validation and bootstrapping methods. Results During a median follow-up of 9.3 months, the median OS was 9.9 months, and the 1-year OS rate was 43.9%. Multivariable Cox regression analysis revealed that performance status, modified albumin-bilirubin grade, tumor size, extent of portal vein tumor thrombosis, and initial treatment significantly affected OS. The newly developed nomogram incorporating these variables demonstrated favorable accuracy (Harrell’s concordance index, 0.807). Conclusions The newly developed nomogram facilitated the estimation of individual survival outcomes in patients with large HCC, providing an acceptable level of accuracy.

Abstract Non-trivial linking invariant encodes robust information of topological matter. It has been recently shown that the linking and winding of complex eigenenergy strings can classify one-dimensional non-Hermitian topological matter. However, in higher dimensions, bundles of linked strings can emerge such that every string is mutually linked with all the other strings. To the best of our knowledge, a non-Hermitian Hopf bundle has not been experimentally clarified. Here, we attempt to explore the non-Hermitian Hopf bundle by visualizing the global linking structure of spinor strings in the momentum space of a two-dimensional electric circuit. By exploiting the flexibility of reconfigurable couplings between circuit nodes, we study the non-Hermitian topological phase transition by exploring the intricate structure of the Hopf bundle. Furthermore, we find that the higher-order skin effect in real space is accompanied by the linking of spinor strings in momentum space, revealing bulk-boundary correspondence between the two domains.

Abstract Universality class of wave chaos emerges in many areas of science, such as molecular dynamics, optics, and network theory. In this work, we generalize the wave chaos theory to cavity lattice systems by discovering the intrinsic coupling of the crystal momentum to the internal cavity dynamics. The cavity-momentum locking substitutes the role of the deformed boundary shape in the ordinary single microcavity problem, providing a new platform for the in situ study of microcavity light dynamics. The transmutation of wave chaos in periodic lattices leads to a phase space reconfiguration that induces a dynamical localization transition. The degenerate scar-mode spinors hybridize and non-trivially localize around regular islands in phase space. In addition, we find that the momentum coupling becomes maximal at the Brillouin zone boundary, so the intercavity chaotic modes coupling and wave confinement are significantly altered. Our work pioneers the study of intertwining wave chaos in periodic systems and provide useful applications in light dynamics control.

Abstract Pancreaticobiliary tract cancer has a poor prognosis with unmet needs in a new target treatment. Some studies have reported that an enhancement of T‐cell immunity is associated with a good prognosis. The aim of this study is to investigate the immunoprofile as a prognostic marker of pancreaticobiliary tract cancers. Unresectable pancreatic ductal adenocarcinoma (PDAC, n = 80) and biliary tract cancer (BTC, n = 74) diagnosed between January 2012 and December 2018 in Samsung Medical Center were analyzed. Expression levels of CD8, FOXP3, PD‐1, PD‐L1, and CXCL13 in PDAC and BTC tissue samples were examined with immunohistochemical staining, which was evaluated with various clinical factors. In PDAC, higher degree of PD‐L1 expression was significantly associated with shorter overall survival (OS) (p = 0.0095). On the other hand, higher infiltrations of PD‐1+ immune cells (p = 0.0002) and CD8+ T cells (p = 0.0067) were associated with longer OS. In BTC, higher FOXP3+ (p = 0.0343) and CD8+ (p = 0.0028) cell infiltrations were associated with better survival. Low infiltration of CD8+ (p = 0.0148), FOXP3+ (p = 0.0208), PD‐1+ (p = 0.0318) cells in PDAC, and FOXP3+ cells (p = 0.005) in BTC were considerably related to metastasis. In a combined evaluation of clinical factors and immunoprofiles, univariate analysis revealed that operation after chemotherapy (p

we realize a photonic analog of the moiré superlattice in the strong coupling regime. The cascades of robust topological flat bands occur at large twist-angles.

Abstract Background The present study aimed to investigate the dosimetric impact of metal stent for photon and proton treatment plans in hepatocellular carcinoma. Methods With computed tomography data of a water-equivalent solid phantom, dose perturbation caused by a metal stent included in the photon and proton treatment of hepatocellular carcinoma was evaluated by comparing Eclipse and RayStation treatment planning system (TPS) to a Monte Carlo (MC) based dose calculator. Photon and proton plans were created with anterior–posterior/posterior-anterior (AP/PA) fields using a 6 MV beam and AP/PA fields of a wobbling beam using 150 MeV and a 10 cm ridge filter. The difference in dose distributions and dosimetric parameters were compared depending on the stent's positions (the bile duct (GB) and intestinal tract (GI)) and angles (0°, 45°, and 90°). Additionally, the dose variation in the target volume including the stent was comparatively evaluated through dose volume histogram (DVH) analysis. And the comparison of clinical cases was carried out in the same way. Results Percentage differences in the dosimetric parameters calculated by MC ranged from − 7.0 to 3.9% for the photon plan and − 33.7 to 4.3% for the proton plan, depending on the angle at which the GB and GI stents were placed, compared to those without the stent. The maximum difference was observed at the minimum dose (Dmin), which was observed in both photon and proton plans in the GB and GI stents deployed at a 90° incidence angle. The parameter differences were greater in the proton plan than in photon plan. The target volume showed various dose variations depending on positions and angles of stent for both beams. Compared with no-stent, the doses within the target volume containing the GI and GB stents for the photon beam were overestimated in the high-dose area at 0°, nearly equal within 1% at 45°, and underestimated at 90°. These doses to the proton beam were underestimated at all angles, and the amount of underdose to the target volume increased with an increase in the stent angle. However, the difference was significantly greater with the proton plan than the photon plan. Conclusions Dose perturbations within the target volume due to the presence of the metal stent were not observed in the TPS calculations for photon and proton beams, but MC was used to confirm that there are dose variations within the target volume. The MC results found that delivery of the treatment beam avoiding the stent was the best method to prevent target volume underdose.

Abstract We study a nanoelectromechanical system consisting of a Cooper pair box qubit performing nanomechanical vibrations between two bulk superconductors. We demonstrate that a bias voltage applied to the superconductors may generate states represented by entanglement between qubit states and quantum ’cat states’, i.e. a superposition of the coherent states of the nanomechanical oscillator. We characterize the formation and development of such states in terms of the corresponding Wigner function and entropy of entanglement. Also, we propose an experimentally feasible detection scheme for the effect, in which the average current that attains the specific features created by the entanglement is measured.

Introduction: We aimed to investigate whether concurrent use of intrahepatic external beam radiotherapy (EBRT) is a viable option for patients with advanced hepatocellular carcinoma (HCC) undergoing tyrosine kinase inhibitor (TKI) therapy. Methods: A total of 453 patients with Barcelona Clinic Liver Cancer-stage C (BCLC-C) HCC, who started first-line treatment with TKI with intrahepatic EBRT (TKI + RT, n = 97) or TKI without intrahepatic EBRT (TKI, n = 356) were analyzed. The overall survival (OS) and progression-free survival (PFS) were compared in the overall cohort, patients who received at least 8 weeks of TKI treatment, and a propensity score-matched cohort. Results: OS and PFS was better in those treated with TKI + RT than TKI (8.6 vs. 4.4 months and 4.5 vs. 2.3 months, respectively, with p < 0.001). Of note, the TKI + RT group demonstrated significant longer time-to-intrahepatic tumor progression. In subgroup analysis, TKI + RT led to better OS than TKI in all subgroups and PFS was significantly improved in patients without extrahepatic metastasis, and those with portal vein invasion. There was no significant difference in treatment discontinuation due to adverse events between the TKI + RT and TKI groups (32.0% vs. 37.9%, p = 0.34). Furthermore, patients treated with TKI + RT showed better liver function preservation over time compared to TKI without intrahepatic EBRT. Comparable treatment outcomes were observed between patients who received at least 8 weeks of TKI treatment and the propensity-score matched cohort. Discussion/Conclusion: Concurrent intrahepatic EBRT targeting liver and/or macrovascular invasion can be a viable option to improve outcomes of BCLC-stage C patients receiving TKI therapy with an aim to control intrahepatic progression and preserving liver function.

Intensity-modulated radiotherapy (IMRT), an advanced RT technique, is a considerable treatment option for hepatocellular carcinoma (HCC). However, the distinguishing features of IMRT for HCC have not yet been clearly defined. A systematic review was performed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PubMed/MedLine, Embase, Cochrane Library, Web of Science, and KoreaMed were used to screen eligible studies focusing on treatment outcomes after IMRT for HCC until 18 April 2023. A total of 1755 HCC patients receiving IMRT among 29 studies from 2009 to 2023 were selected for the meta-analysis. The median proportion of Barcelona Clinic Liver Cancer stage C was 100% (range: 38–100%). Nineteen studies used combined treatment. Pooled rates of response and 1-year local control were 58% (95% confidence interval [CI], 50–65%) and 84% (95% CI, 70–94%), respectively. The median overall survival (OS) was 13 months (range: 5–45 months), and pooled 1- and 3-year OS rates were 59% (95% CI, 52–66%), and 23% (95% CI, 14–33%), respectively. Pooled rates of classic radiation-induced liver disease (RILD), nonclassic RILD, and hepatic toxicity ≥ grade 3 were 2%, 4%, and 4%, respectively. Although most patients had advanced-stage HCC and combined treatment was commonly used, IMRT for HCC showed similar survival to existing RT modalities and relatively low severe toxicity.

Abstract Background A limited number of studies have characterized genomic properties of hepatocellular carcinoma (HCC) patients in response to anti-PD-1 immunotherapy. Methods Herein, we performed comprehensive molecular characterization of immediate (D-42 to D-1) pre-treatment tumor biopsy specimens from 60 patients with sorafenib-failed HCC in a single-arm prospective phase II trial of pembrolizumab. Objective response rate was the primary efficacy endpoint. We used whole-exome sequencing, RNA sequencing, and correlative analysis. In addition, we performed single-cell RNA sequencing using peripheral blood mononuclear cells. Results The overall response rate of pembrolizumab in sorafenib-failed HCC patients was 10% ([6/60] 95% CI, 2.4–17.6). In a univariate analysis using clinicopathological features, female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were identified as contributing factors to pembrolizumab response. Somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that pembrolizumab responders demonstrated T cell receptor (TCR) signaling activation with expressions of MHC genes, indicating increased levels of T cell cytotoxicity. In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, patients with progressive disease showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways. Conclusions Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells during pembrolizumab treatment and down-regulation of neutrophil-associated markers, significantly benefited from pembrolizumab treatment. Trial registration NCT#03163992 (first posted: May 23, 2017)

Rectal cancer is the eighth most common malignancy worldwide. With the introduction of total mesorectal excision (TME) and neoadjuvant chemoradiation (NCRT), intrapelvic local control has been remarkably improved. However, lateral pelvic recurrence remains problematic, especially in patients with clinically suspicious lateral pelvic lymph node (LPLN). LPLN dissection has been applied for the management of LPLN metastasis, mainly in Japan and other Eastern countries, while the role of NCRT is more emphasized and LPLN dissection is performed in very limited cases in Western countries. However, the optimal management strategy for patients with rectal cancer with suspicious LPLN metastasis has not been determined. Herein, we review the latest studies on the optimal management of LPLN metastasis to suggest the most appropriate treatment policies according to current evidence and discuss future research directions.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, the sixth most common cancer, and the fourth leading cause of cancer related deaths worldwide. There are curative local treatment options for HCC, including liver transplantation, surgical resection, and radiofrequency ablation, all of which are applicable for a few patients. For advanced HCC, systemic treatments, such as target agents or immunotherapies, are recommended, however, with unsatisfactory efficacy. Therefore, radiation therapy (RT) has been used as an alternative or combination therapy. With the advances of RT technique in image guidance and accurate beam delivery, its applications have increased for the management of HCC. Proton beam therapy (PBT) is a highly advanced RT technique. Since proton beams have unique physical properties with a finite range in the distal direction, PBT has the potential to escalate the radiation dose without a significant increase in the risk of complications compared with X-ray therapy in the treatment of HCC. Various studies have reported favorable oncological outcomes and toxicity risks of PBT for HCC patients. In this review, we discuss the physical and biological properties, technical issues, current clinical data, and future perspectives on PBT for the treatment of HCC patients.

Abstract The objectives of this study were to assess changes in apparent diffusion coefficient (ADC) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) parameters after radiation therapy (RT) for bone metastases from hepatocellular carcinoma (HCC) and to evaluate their prognostic value. This prospective study was approved by the Institutional Review Board. Fourteen patients with HCC underwent RT (30 Gy in 10 fractions once daily) for bone metastases. The ADC and DCE-MRI parameters and the volume of the target lesions were measured before (baseline) and one month after RT (post-RT). The Wilcoxon signed-rank test was used to compare the parameters between the baseline and post-RT MRI. The parameters were compared between patients with or without disease progression in RT fields using the Mann–Whitney test. Intraclass correlation coefficients were used to evaluate the interobserver agreement. The medians of the ADC, rate constant [k ep], and volume fraction of the extravascular extracellular matrix [v e ] in the baseline and post-RT MRI were 0.67 (range 0.61–0.72) and 0.75 (range 0.63–1.43) (× 10–3 mm2/s) (P = 0.027), 836.33 (range 301.41–1082.32) and 335.80 (range 21.86–741.87) (× 10–3/min) (P = 0.002), and 161.54 (range 128.38–410.13) and 273.99 (range 181.39–1216.95) (× 10–3) (P = 0.027), respectively. The medians of the percent change in the ADC of post-RT MRI in patients with progressive disease and patients without progressive disease were − 1.35 (range − 6.16 to 6.79) and + 46.71 (range 7.71–112.81) (%) (P = 0.011), respectively. The interobserver agreements for all MRI parameters were excellent (intraclass correlation coefficients > 0.8). In conclusion, the ADC, k ep, and v e of bone metastases changed significantly after RT. The percentage change in the ADC was closely related to local tumor progression.

PurposeTo present the trends in radiotherapy for the management of hepatocellular carcinoma (HCC) at a single tertiary referral hospital in South Korea.Materials and MethodsWe retrospectively reviewed prospectively collected registry data of patients newly diagnosed with HCC between January 2005 and December 2017 at the Samsung Medical Center. Trends in radiotherapy, delivery techniques, tumor stage, and age were evaluated.ResultsDuring the study period, 9,132 patients were newly diagnosed with HCC at our institution. Of these, 2,445 patients (26.8%) received radiotherapy for all lesions, including extrahepatic metastases; 1,865 patients (20.4%) received radiotherapy for intrahepatic lesions alone, and 469 patients (5.1%) received radiotherapy as initial management. Although the proportion of patients receiving radiotherapy increased slightly over the study period (24.2% vs. 26.6%), the proportions of patients receiving radiotherapy for intrahepatic lesions (16.8% vs. 21.9%) and as initial management (0.1% vs. 12.5%) increased dramatically. The majority of patients treated between 2005 and 2008 received three-dimensional conformal radiotherapy (56.3%), whereas the majority of patients treated between 2018 and 2021 received proton beam therapy (43.6%). With the technical developments, the overall survival (OS) of patients who received radiotherapy as initial management increased significantly (5-year OS: from 5.4% to 30.1%), and the OS difference between patients who did and did not receive radiotherapy as initial management significantly decreased (ratio of restricted mean survival time: from 0.383 to 0.544).ConclusionThis registry-based, retrospective study indicated an increasing trend in the utilization of radiotherapy, adoption of advanced radiotherapy techniques, and OS improvements in patients with HCC.

BackgroundThis study aimed to compare the clinical outcomes of patients with hepatocellular carcinoma (HCC) and macroscopic tumor thrombosis who were treated with lenvatinib with or without combined liver-directed radiotherapy (LRT).MethodsFrom the institutional registry, we enrolled 82 patients diagnosed with HCC involving macroscopic tumor thrombosis and treated with lenvatinib monotherapy (non-LRT group, n = 54, 65.9%) or lenvatinib in combination with LRT (LRT group, n = 28, 34.1%). Patients were classified into the LRT group if LRT was performed within 8 weeks of lenvatinib initiation.ResultsDuring the median follow-up period of 5.4 (range 1.4 to 17.5) months, there was no significant difference between the two groups in terms of overall adverse events. Although there was no statistical difference between the two groups in terms of overall response rate (32.1% vs. 20.4%, p = 0.15), a significantly higher treatment response was observed in the LRT group in terms of intrahepatic tumor response (67.9% vs. 20.4%, p < 0.001). In the LRT group, there was a slight difference in overall survival compared to the non-LRT group (64.1% in the LRT group vs. 37.7% in the non-LRT group at 12 months, hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.28–1.03; p = .06), although it did not reach a statistically significant level. However, progression-free survival (PFS, 67.2% in the LRT group vs. 35.0% in the non-LRT group at 6 months, HR 0.47; 95% CI 0.27–0.82; p = 0.008) and intrahepatic progression-free survival (IHPFS, 74.3% in the LRT group vs. 43.3% in the non-LRT group at 6 months, HR 0.45; 95% CI 0.25–0.81; p = 0.008) were significantly superior in the LRT group. This result was also reproduced in the multivariate analysis adjusted for α-fetoprotein, another significant prognostic factor in this study, and the well-known prognostic factors, namely the presence of main portal vein tumor thrombosis and albumin-bilirubin grade.ConclusionsThe combination of lenvatinib and LRT is relatively safe and effective in increasing the intrahepatic tumor response and improving PFS and IHPFS in patients with HCC and macroscopic tumor thrombosis.

Background/Aims The abscopal effect, a rare phenomenon induced by radiation, can be reinforced by immunotherapy. Although radiation therapy and immunotherapy are increasingly being utilized for the treatment of hepatocellular carcinoma (HCC), whether immunotherapy could boost the abscopal effect remains unclear. In this study, we aimed to elucidate the immunological mechanisms underlying the abscopal effect induced by the combination of irradiation and immunotherapy in a murine HCC model. Methods A syngeneic HCC mouse model was established by transplanting murine Hepa 1–6 HCC cells into both hind legs of immunocompetent C57BL/6 mice. The tumors on the right hind legs were irradiated, and abscopal effects were observed in the non-irradiated tumors on the left hind leg with or without the coadministration of anti-programmed cell death 1 (PD-1) antibodies. Flow cytometric analyses were performed to analyze the distributions of immune cells infiltrating both irradiated and non-irradiated tumors and the tumor-draining lymph nodes (TDLNs). Results Administration of 16 Gy in two fractions more effectively inhibited the growth of both irradiated and non-irradiated tumors with higher tumor infiltration of cytotoxic T cells than 8 Gy did in a single fraction. The higher dose also increased activated dendritic cells in TDLNs, which had higher expression of the programmed cell death ligand 1. Coadministration of anti-PD-1 antibodies significantly enhanced the abscopal effect and increased infiltration of activated cytotoxic T cells in both irradiated and non-irradiated tumors. Conclusions Our findings show that adding anti-PD-1 therapy to radiation enhanced the abscopal effect in a syngeneic murine model of HCC.

Abstract Although several studies have confirmed the clinical significance of the systemic inflammation markers in hepatocellular carcinoma (HCC), evaluating the clinical significance of each blood cell remains to be conducted. We aimed to evaluate the clinical importance of absolute counts of blood cells in the overall survival (OS) of patients with newly diagnosed HCC. We recruited patient cohorts from the prospective registry of newly diagnosed and previously untreated HCC at Samsung Medical Center, which included a training set of 6619 patients (2005–2013) and a validation set of 2084 patients (2014–2016). More than three-quarters of all patients had hepatitis B virus (HBV)-related HCC in both training and validation sets. The optimal cutoff values of the absolute counts of neutrophils, lymphocytes, monocytes, and platelets were 3917, 488, 1379, and 22,100, respectively, which correlated significantly with OS. The absolute blood cell counts categorized by each optimal cutoff value significantly correlated with liver function status determined by Child–Pugh class/albumin-bilirubin (ALBI) grade and the HCC burden determined by several staging systems/portal vein tumor thrombosis. Although the prognostic model based on these blood cells (ABC model) showed a lower prognostic ability than the Japan Integrated Staging or ALBI-T staging systems, it provided significant discrimination of survival in the subgroups of ALBI-T and showed the highest prognostic ability in the present study in the training and validation sets. Absolute counts of blood cells are independently associated with OS, though it is also significantly associated with liver function and tumor burden in newly diagnosed HCC.

Abstract Background This study aimed to investigate the clinical significance of previous and/or concurrent application of radiotherapy (RT) in the course of nivolumab treatment for advanced hepatocellular carcinoma (HCC). Methods Patients with advanced HCC who received nivolumab treatment between March 2017 and May 2018. were included. Nivolumab treatment was indicated in patients who did not respond to conventional therapy including locoregional therapy and/or sorafenib. RT was performed when necessary for curative/palliative purpose. Results Among the 76 HCC patients who received nivolumab, 54 (71.1%) had received RT for HCC before and/or during the treatment. The period from initial HCC diagnosis to nivolumab treatment was significantly longer (P = .007) and the rate of undergoing transarterial chemoembolization (TACE; P = .006) and sorafenib treatment (P = .007) was significantly higher in patients who received previous/concurrent RT than in those who did not. Nivolumab‐related toxicities were generally tolerable regardless of the history of RT. During the follow‐up, 39 (51.3%) patients died and 54 (71.1%) patients experienced disease progression according to the RECIST v1.1. Patients who had received previous/concurrent RT had a significantly longer progression‐free survival (PFS; P = .008) and overall survival (OS; P = .007) than those who did not receive RT; however, this trend was not observed in patients with a history of radiofrequency ablation or TACE (all P > .05). Conclusion Previous and/or concurrent application of RT in the course of nivolumab treatment was related with longer PFS and OS in advanced HCC patients. Nonetheless, further clinical studies are warranted to confirm our findings.

High-throughput mass-spectrometry-based quantitative proteomic analysis was performed using formalin-fixed, paraffin-embedded (FFPE) biopsy samples obtained before treatment from 13 patients with locally advanced rectal cancer (LARC), who were treated with concurrent chemoradiation therapy (CCRT) followed by surgery. Patients were divided into complete responder (CR) and non-complete responder (nCR) groups. Immunohistochemical (IHC) staining of 79 independent FFPE tissue samples was performed to validate the predictive ability of proteomic biomarker candidates. A total of 3637 proteins were identified, and the expression of 498 proteins was confirmed at significantly different levels (differentially expressed proteins—DEPs) between two groups. In Gene Ontology enrichment analyses, DEPs enriched in biological processes in the CR group included proteins linked to cytoskeletal organization, immune response processes, and vesicle-associated protein transport processes, whereas DEPs in the nCR group were associated with biosynthesis, transcription, and translation processes. Dual oxidase 2 (DUOX2) was selected as the most predictive biomarker in machine learning algorithm analysis. Further IHC validation ultimately confirmed DUOX2 as a potential biomarker for predicting the response of nCR to CCRT. In conclusion, this study suggests that the treatment response to RT may be affected by the pre-treatment tumor microenvironment. DUOX2 is a potential biomarker for the early prediction of nCR after CCRT.

Background/Purpose: This study aimed to evaluate the clinical outcomes of stereotactic body proton beam therapy (SBPT) for pancreatic cancer. Methods: This retrospective study included 49 patients who underwent SBPT for pancreatic cancer between 2017 and 2020. Survival outcomes, bowel-related toxicities, and failure patterns were analysed. SBPT was performed after induction chemotherapy in 44 (89.8%) patients. The dose-fractionation scheme included 60 gray (Gy) relative biological effectiveness (RBE) in five fractions (n = 42, 85.7%) and 50 GyRBE in five fractions (n = 7, 14.3%). The median follow-up was 16.3 months (range, 1.8–45.0 months). Results: During follow-up, the best responses were complete response, partial response, and stable disease in four (8.2%), 13 (26.5%), and 31 (63.3%) patients, respectively. The 2-year overall survival, progression-free survival, and local control (LC) rates were 67.6%, 38.0%, and 73.0%, respectively. Grade ≥ 3 gastroduodenal (GD) toxicity occurred in three (6.1%) patients. Among them, one patient underwent endoscopic haemostasis. The other two patients received surgical management. They were followed up without disease progression for >30 months after SBPT. Overall, there was no significant dosimetric difference between the grade ≥ 2 and lower toxicity groups. Conclusions: SBPT provides relatively high LC rates with acceptable toxicities in pancreatic cancer.

Objectives: This analysis was performed to evaluate the incidence of vertebral compression fracture (VCF) and determine the contributing factors for VCF in patients undergoing single-fraction stereotactic body radiotherapy (SBRT) for spinal bone metastases (SBM). Methods: A retrospective review of medical records was conducted for patients undergoing SBRT for SBM at our institution between January 2010 and December 2018. Patients who had undergone neither pre-SBRT surgical excision nor post-SBRT prophylactic fixation were included. The effects of clinical and dosimetric parameters were analyzed with respect to VCF risk. The following dosimietric parameters of the planning target volume (PTV) were calculated: mean/minimum/maximum dose, radiation dose to 10–90% volume, and irradiated volume receiving more than 10–25 Gy (PTV_V10 – 25 Gy). Results: Among 163 patients (179 vertebrae), 21 (12.8%) experienced VCF. The 1-year and 2-year VCF rates were 12.1% and 13.2%, respectively. Among dosimetric parameters, PTV_V15 Gy was the most significant for VCF prediction. In a univariate analysis, breast or prostate primary, no vertebral body collapse, and PTV_V15 Gy ≤42 cm3 were significantly associated with a lower incidence rate of VCF. In a multivariate analysis, PTV_V15 Gy was the only significant factor for VCF risk. The 1-year VCF rate was 3.8% in patients with PTV_V15 Gy ≤42 cm3, while it was 22.1% in those with PTV_V15 Gy > 42 cm3 (p

Systemic inflammatory markers (SIMs) are known to be associated with carcinogenesis and prognosis of hepatocellular carcinoma (HCC). We evaluated the significance of SIMs in intrahepatic recurrence (IHR) of early-stage HCC after curative treatment. This study was performed using prospectively collected registry data of newly diagnosed, previously untreated HCC between 2005 and 2017 at a single institution. Inclusion criteria were patients with Barcelona Clinic Liver Cancer stage 0 or A, who underwent curative treatment. Pre-treatment and post-treatment values of platelet, neutrophil, lymphocyte, monocyte, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR) were analyzed with previously well-known risk factors of HCC to identify factors associated with IHR-free survival (IHRFS), early IHR, and late IHR. Of 4076 patients, 2142 patients (52.6%) experienced IHR, with early IHR in 1018 patients (25.0%) and late IHR in 1124 patients (27.6%). Pre-treatment platelet count and PLR and post-treatment worsening of NLR, PLR, and LMR were independently associated with IHRFS. Pre-treatment platelet count and post-treatment worsening of NLR, PLR, and LMR were significantly related to both early and late IHR. Pre-treatment values and post-treatment changes in SIMs were significant factors of IHR in early-stage HCC, independent of previously well-known risk factors of HCC.

Proton beam therapy (PBT) is a critical treatment modality for head and neck squamous cell carcinoma (HNSCC). However, not much is known about drug combinations that may improve the efficacy of PBT. This study aimed to test the feasibility of a three-dimensional (3D) tumor-spheroid-based high-throughput screening platform that could assess cellular sensitivity against PBT. Spheroids of two HNSCC cell lines—Fadu and Cal27—cultured with a mixture of Matrigel were arrayed on a 384-pillar/well plate, followed by exposure to graded doses of protons or targeted drugs including olaparib at various concentrations. Calcein staining of HNSCC spheroids revealed a dose-dependent decrease in cell viability for proton irradiation or multiple targeted drugs, and provided quantitative data that discriminated the sensitivity between the two HNSCC cell lines. The combined effect of protons and olaparib was assessed by calculating the combination index from the survival rates of 4 × 4 matrices, showing that Cal27 spheroids had greater synergy with olaparib than Fadu spheroids. In contrast, adavosertib did not synergize with protons in both spheroids. Taken together, we demonstrated that the 3D pillar/well array platform was a useful tool that provided rapid, quantitative data for evaluating sensitivity to PBT and drug combinations. Our results further supported that administration of the combination of PBT and olaparib may be an effective treatment strategy for HNSCC patients.

Abstract Although radiation therapy is an effective treatment modality in many cancers, there is an urgent need to develop therapeutic drugs capable of overcoming radioresistance or minimizing normal tissue toxicity. A wide variety of marine-derived bioactive compounds have been screened for anti-cancer drug discovery, but little is known regarding radiation therapy applications. In this study, six different extracts of marine sponges collected from the Micronesian sea were screened for anti-cancer and radiosensitizing activity. Two extracts derived from Agelas sponges collected off the coast of Kosrae and Chuuk, the Federated States of Micronesia significantly decreased clonogenic survival of hepatocellular carcinoma (HCC) cells after exposure to ionizing radiation (IR). The Agelas extracts augmented IR-induced apoptosis and accumulation of reactive oxygen species (ROS). Endoplasmic reticulum (ER) stress was increased via unfolded protein response stimulation, which induced autophagy. N-acetylcysteine, a ROS scavenger, diminished ER stress and autophagy induction effects. This result indicated that Agelas extracts may sensitize HCC cells to IR via ROS overproduction in vitro. Our findings suggest that the Agelas sp. may have potential utility in radiosensitizer development.

Layered materials have strikingly anisotropic mechanical properties. Here, the authors use Raman spectroscopy and first-principles calculations to unveil that MoS2, an archetypal layered material, possesses a coupling between in-plane uniaxial strain and interlayer shear, enabling derivation of an unexplored off-diagonal elastic constant.

Abstract Although efficacy of combined histone deacetylase (HDAC) inhibitors and conventional photon radiotherapy is being tested in clinical trials, their combined effect with proton beam radiotherapy has yet to be determined. Here, we compared combined effect of valproic acid (VPA), a class I and II HDAC inhibitor and antiepileptic drug with proton and photon irradiation in hepatocellular carcinoma (HCC) cells in vitro and in vivo. We found that VPA sensitized more Hep3B cells to proton than to photon irradiation. VPA prolonged proton-induced DNA damage and augmented proton-induced apoptosis. In addition, VPA further increased proton-induced production of intracellular reactive oxygen species and suppressed expression of nuclear factor erythroid-2-related factor 2 (NRF2), a key transcription factor regulating antioxidant response. Downregulation of NRF2 by siRNA transfection increased proton-induced apoptotic cell death, supporting NRF2 as a target of VPA in radiosensitization. In Hep3B tumor xenograft models, VPA significantly enhanced proton-induced tumor growth delay with increased apoptosis and decreased NRF2 expression in vivo. Collectively, our study highlights a proton radiosensitizing effect of VPA in HCC cells. As NRF2 is an emerging prognostic marker contributing to radioresistance in HCC, targeting NRF2 pathway may impact clinical outcome of proton beam radiotherapy.

Immunomodulation by radiotherapy (RT) is an emerging strategy for improving cancer immunotherapy. Nanomaterials have been employed as innovative tools for cancer therapy. This study aimed to investigate whether mesoporous silica nanoparticles (MSNs) enhance RT-mediated local tumor control and the abscopal effect by stimulating anti-cancer immunity. Hepa1-6 murine hepatocellular carcinoma syngeneic models and immunophenotyping with flow cytometry were used to evaluate the immune responses. When mice harboring bilateral tumors received 8 Gy of X-rays on a single tumor, the direct injection of MSNs into irradiated tumors enhanced the growth inhibition of irradiated and unirradiated contralateral tumors. MSNs enhanced RT-induced tumor infiltration of cytotoxic T cells on both sides and suppressed RT-enhanced infiltration of regulatory T cells. The administration of MSNs pre-incubated with irradiated cell-conditioned medium enhanced the anti-tumor effect of anti-PD1 compared to the as-synthesized MSNs. Intracellular uptake of MSNs activated JAWS II dendritic cells (DCs), which were consistently observed in DCs in tumor-draining lymph nodes (TDLNs). Our findings suggest that MSNs may capture tumor antigens released after RT, which is followed by DC maturation in TDLNs and infiltration of cytotoxic T cells in tumors, thereby leading to systemic tumor regression. Our results suggest that MSNs can be applied as an adjuvant for in situ cancer vaccines with RT.

Abstract We demonstrate mesoscopic transport through quantum states in quasi-1D lattices maintaining the combination of parity and time-reversal symmetries by controlling energy gain and loss. We investigate the phase diagram of the non-Hermitian system where transitions take place between unbroken and broken $${\mathscr{P}}{\mathscr{T}}$$ P T -symmetric phases via exceptional points. Quantum transport in the lattice is measured only in the unbroken phases in the energy band–but not in the broken phases. The broken phase allows for spontaneous symmetry-broken states where the cross-stitch lattice is separated into two identical single lattices corresponding to conditionally degenerate eigenstates. These degeneracies show a lift-up in the complex energy plane, caused by the non-Hermiticity with $${\mathscr{P}}{\mathscr{T}}$$ P T -symmetry.

Recent studies have highlighted the implications of genetic variations in the relative biological effectiveness (RBE) of proton beam irradiation over conventional X-ray irradiation. Proton beam radiotherapy is a reasonable radiotherapy option for hepatocellular carcinoma (HCC), but the impact of genetic difference on the HCC RBE remains unknown. Here, we determined proton RBE in human HCC cells by exposing them to various doses of either 6-MV X-rays or 230-MeV proton beams. Clonogenic survival assay revealed variable radiosensitivity of human HCC cell lines with survival fraction at 2 Gy ranging from 0.38 to 0.83 and variable proton RBEs with 37% survival fraction ranging from 1.00 to 1.48. HCC cells appeared more sensitive to proton irradiation than X-rays, with more persistent activation of DNA damage repair proteins over time. Depletion of a DNA damage repair gene, DNA-PKcs, by siRNA dramatically increased the sensitivity of HCC cells to proton beams with a decrease in colony survival and an increase in apoptosis. Our findings suggest that there are large variations in proton RBE in HCC cells despite the use of a constant RBE of 1.1 in the clinic and targeting DNA-PKcs in combination with proton beam therapy may be a promising regimen for treating HCC.

BackgroundGiven the complexity of managing hepatocellular carcinoma (HCC), a multidisciplinary approach (MDT) is recommended to optimize management of HCC patients. However, evidence suggesting that MDT improves patient outcome is limited.MethodsWe performed a retrospective cohort study of all patients newly-diagnosed with HCC between 2005 and 2013 (n = 6,619). The overall survival (OS) rates between the patients who were and were not managed via MDT were compared in the entire cohort (n = 6,619), and in the exactly matched cohort (n = 1,396).ResultsIn the entire cohort, the 5-year survival rate was significantly higher in the patients who were managed via MDT compared to that of the patients who were not (71.2% vs. 49.4%, P < 0.001), with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval [CI]; 0.41-0.53). In the exactly matched cohort, the 5-year survival rate was higher in patients who were managed via MDT (71.4% vs. 58.7%, P < 0.001; HR [95% CI] = 0.67 [0.56-0.80]). The survival benefit of MDT management was observed in most pre-defined subgroups, and was especially significant in patients with poor liver function (ALBI grade 2 or 3), intermediate or advanced tumor stage (BCLC stage B or C), or high alphafetoprotein levels (≥200 ng/ml).ConclusionMDT management was associated with improved overall survival in HCC patients, indicating that MDT management can be a valuable option to improve outcome of HCC patients. This warrants prospective evaluations.

Epigenetic modulation by histone deacetylase (HDAC) inhibitors is an attractive anti-cancer strategy for diverse hematological and solid cancers. Herein, we explored the relative effectiveness of the pan-HDAC inhibitor panobinostat in combination with proton over X-ray irradiation in HCC cells. Clonogenic survival assays revealed that radiosensitization of Huh7 and Hep3B cells by panobinostat was more evident when combined with protons than X-rays. Panobinostat increased G2/M arrest and production of intracellular reactive oxygen species, which was further enhanced by proton irradiation. Immunofluorescence staining of γH2AX showed that panobinostat enhanced proton-induced DNA damage. Panobinostat dose-dependently decreased expression of an anti-apoptotic protein, Mcl-1, concomitant with increasing acetylation of histone H4. The combination of panobinostat with proton irradiation enhanced apoptotic cell death to a greater extent than that with X-ray irradiation. Depletion of Mcl-1 by RNA interference enhanced proton-induced apoptosis and proton radiosensitization, suggesting a potential role of Mcl-1 in determining proton sensitivity. Together, our findings suggest that panobinostat may be a promising combination agent for proton beam therapy in HCC treatment.

We evaluated the effect of manganese ferrite nanoparticles (MFN) on radiosensitization and immunologic responses using the murine hepatoma cell line Hepa1-6 and the syngeneic mouse model. The clonogenic survival of Hepa1-6 cells was increased by hypoxia, while being restricted by ionizing radiation (IR) and/or MFN. Although MFN suppressed HIF-1α under hypoxia, the combination of IR and MFN enhanced apoptosis and DNA damage in Hepa1-6 cells. In the Hepa1-6 syngeneic mouse model, the combination of IR and MFN notably limited the tumor growth compared to the single treatment with IR or MFN, and also triggered more frequent apoptosis in tumor tissues than that observed under other conditions. Increased expression of PD-L1 after IR was not observed with MFN alone or the combination of IR and MFN in vitro and in vivo, and the percentage of tumor-infiltrating T cells and cytotoxic T cells increased with MFN, regardless of IR, in the Hepa1-6 syngeneic mouse model, while IR alone led to T cell depletion. MFN might have the potential to overcome radioresistance by alleviating hypoxia and strengthening antitumor immunity in the tumor microenvironment.

Radiation therapy (RT) is an effective local treatment for unresectable hepatocellular carcinoma (HCC), but there are currently no predictive biomarkers to guide treatment decision for RT or adjuvant systemic drugs to be combined with RT for HCC patients. Previously, we reported that extracts of the marine sponge Agelas sp. may contain a natural radiosensitizer for HCC treatment. In this study, we isolated (−)-agelamide D from Agelas extract and investigated the mechanism underlying its radiosensitization. (−)-Agelamide D enhanced radiation sensitivity of Hep3B cells with decreased clonogenic survival and increased apoptotic cell death. Furthermore, (−)-agelamide D increased the expression of protein kinase RNA-like endoplasmic reticulum kinase/inositol-requiring enzyme 1α/activating transcription factor 4 (PERK/eIF2α/ATF4), a key pathway of the unfolded protein response (UPR) in multiple HCC cell lines, and augmented radiation-induced UPR signaling. In vivo xenograft experiments confirmed that (−)-agelamide D enhanced tumor growth inhibition by radiation without systemic toxicity. Immunohistochemistry results showed that (−)-agelamide D further increased radiation-induced ATF4 expression and apoptotic cell death, which was consistent with our in vitro finding. Collectively, our results provide preclinical evidence that the use of UPR inducers such as (−)-agelamide D may enhance the efficacy of RT in HCC management.

We aimed to evaluate the biliary complications and efficacy of proton beam therapy (PBT) for hepatocellular carcinoma (HCC). We retrospectively analyzed 167 patients who received PBT with ≥ 75 GyRBE of biological effective dose with ?/β = 10 for primary HCC. The perihilar region was defined as a 1-cm area extending from the right, left, and common hepatic ducts, including the gallbladder and cystic duct. PBT-related biliary complications were defined as follows: significant elevation in bilirubin level to > 3.0 mg/dL; elevation to more than twice of the baseline level after the completion of PBT; or newly developed radiological biliary abnormalities, which were not caused by HCC progression, comorbidities, or other treatments. Eighty (47.9%) had perihilar HCC. PBT-related events occurred in seven (4.2%), three of whom had perihilar HCC. Radiologic biliary abnormalities developed in 12 patients (7.2%); however, no events were PBT-related. All patients who experienced PBT-related biliary complications had underlying liver cirrhosis. The albumin-bilirubin grade was identified as an independent factor associated with PBT-related biliary complications. PBT at the current dose showed a low rate of PBT-related biliary complications even for patients with perihilar HCC. PBT for HCC patients with risk factors requires attention to reduce PBT-related biliary complications.

We consider the role of nontriviality resulting from a non-Hermitian Hamiltonian without band topology that conserves twofold PT symmetry assembled by interconnections between a PT-symmetric lattice and its time-reversal partner. Twofold PT symmetry in the lattice produces additional surface exceptional points that play the role of new critical points, along with the bulk exceptional point. We show that there are two distinct regimes possessing symmetry-protected localized states of which localization lengths are robust against non-Hermiticity parameter. The states are demonstrated by numerical calculation of a quasi-one-dimensional ladder lattice and a two-dimensional bilayered square lattice.

Radiation dermatitis (RD) is one of the most common side effects of radiotherapy; its symptoms progress from erythema to dry and moist desquamation, leading to the deterioration of the patients’ quality of life. Active metabolites in brown seaweed, including phlorotannins (PTNs), show anti-inflammatory activities; however, their medical use is limited. Here, we investigated the effects of PTNs in a mouse model of RD in vivo. X-rays (36 Gy) were delivered in three fractions to the hind legs of BALB/c mice. Macroscopic RD scoring revealed that PTNs significantly mitigated RD compared with the vehicle control. Histopathological analyses of skin tissues revealed that PTNs decreased epidermal and dermal thickness compared with the vehicle control. Western blotting indicated that PTNs augmented nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway activation but attenuated radiation-induced NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and inflammasome activation, suggesting the mitigation of acute inflammation in irradiated mouse skin. PTNs also facilitated fast recovery, as indicated by increased aquaporin 3 expression and decreased γH2AX (histone family member X) expression. Our results indicate that topical PTN application may alleviate RD symptoms by suppressing oxidative stress and inflammatory signaling and by promoting the healing process. Therefore, PTNs may show great potential as cosmeceuticals for patients with cancer suffering from radiation-induced inflammatory side effects such as RD.

This study aimed to investigate the clinical significance of systemic inflammation markers (SIMs)—including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR)—in patients with newly diagnosed, previously untreated hepatocellular carcinoma (HCC). The present study was performed using prospectively collected registry data of newly diagnosed, previously untreated HCC from a single institution. The training set included 6619 patients from 2005 to 2013 and the validation set included 2084 patients from 2014 to 2016. The SIMs as continuous variables significantly affected the overall survival (OS), and the optimal cut-off value of NLR, PLR, and LMR was 3.0, 100.0, and 3.0, respectively. There were significant correlations between SIMs and the albumin-bilirubin grade/Child-Turcotte-Pugh class (indicative of liver function status) and the staging system/portal vein invasion (indicative of the tumor burden). The OS curves were well stratified according to the prognostic model of SIMs and validated using the bootstrap method (1000 times, C-index 0.6367, 95% confidence interval (CI) 0.6274–0.6459) and validation cohort (C-index 0.6810, 95% CI 0.6570–0.7049). SIMs showed significant prognostic ability for OS, independent of liver function and tumor extent, although these factors were significantly correlated with SIMs in patients with newly diagnosed, previously untreated HCC.

Background: The purpose of this study was to evaluate the clinical outcomes following postoperative chemotherapy (XP) versus chemoradiotherapy (XP-RT) according to mesenchymal subtype based on RNA sequencing in gastric cancer (GC) in a cohort of the Adjuvant chemoRadioTherapy In Stomach Tumor (ARTIST) trial. Methods: Of the 458 patients enrolled in the ARTIST trial, formalin-fixed, paraffin-embedded (FFPE) specimens were available from 106 (23.1%) patients for RNA analysis. The mesenchymal subtype was classified according to a previously reported 71-gene MSS/EMT signature using the NanoString assay. Results: Of the 106 patients analyzed (50 in XP arm, 56 in XP-RT arm), 36 (34.0%) patients were categorized as mesenchymal subtype by NanoString assay. Recurrence-free survival (RFS, p = 0.009, hazard ratio (HR) = 2.11, 95% confidence interval (CI): 1.21–3.70) and overall survival (OS, p = 0.003, HR = 2.28, 95% CI: 1.31–3.96) were significantly lower in the mesenchymal subtype than in the non-mesenchymal subtype. In terms of post-operative radiotherapy (RT), mesenchymal subtype was not an independent variable to predict RFS or OS regardless to the assigned arm (XP with or without RT) in this patient cohort. However, there was a trend in the adjuvant XP arm, which showed higher OS than the XP-RT arm for the mesenchymal subtype and lower OS than the XP-RT arm for the non-mesenchymal subtype. Conclusions: We could not determine any significant differences between the mesenchymal and non-mesenchymal subtypes with respect to the effects of adjuvant XP with or without RT in gastric cancer following curative surgery.

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) affords stem cell protection and links microbes to intestinal epithelial regeneration. We investigated whether NOD2 status is associated with crypt survival and intestinal epithelial regeneration independent of microbiota-derived molecules. To assess crypt survival, a clonogenic microcolony assay was performed with 15 Gy of X-ray irradiation. The fractional crypt survival rate (46.0 ± 15.5% vs. 24.7 ± 9.2%, p < 0.01) and fractional EdU-positive crypt survival rate (29.8 ± 14.5% vs. 9.79 ± 4.37%, p = 0.015) were significantly decreased in the NOD2−/− mice compared with the wild-type (WT) mice at 3.5 days after irradiation. To evaluate intestinal epithelial regeneration capability, organoid reconstitution assays were performed. Small bowel crypts of the WT and NOD2−/− mice were isolated and seeded into Matrigel for 3D culture. In the organoid reconstitution assays, the number of organoids formed did not differ between the NOD2−/− and WT mice. Organoid formation ability was also assessed after exposure to 5 Gy irradiation. Organoid formation ability was significantly decreased in the NOD2−/− mice compared with the WT ones after exposure to 5 Gy irradiation (33.2 ± 5.9 vs. 19.7 ± 8.8/well, p < 0.01). NOD2 supports crypt survival after potentially lethal irradiation damage and is associated with intestinal epithelial regeneration.

When radiotherapy is applied to the abdomen or pelvis, normal tissue toxicity in the gastrointestinal (GI) tract is considered a major dose-limiting factor. Proton beam therapy has a specific advantage in terms of reduced doses to normal tissues. This study investigated the fundamental differences between proton- and X-ray-induced intestinal injuries in mouse models. C57BL/6J mice were irradiated with 6-MV X-rays or 230-MeV protons and were sacrificed after 84 h. The number of surviving crypts per circumference of the jejunum was identified using Hematoxylin and Eosin staining. Diverse intestinal stem cell (ISC) populations and apoptotic cells were analyzed using immunohistochemistry (IHC) and a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay, respectively. The crypt microcolony assay revealed a radiation-dose-dependent decrease in the number of regenerative crypts in the mouse jejunum; proton irradiation was more effective than X-ray irradiation with a relative biological effectiveness of 1.14. The jejunum is the most sensitive to radiations, followed by the ileum and the colon. Both types of radiation therapy decreased the number of radiosensitive, active cycling ISC populations. However, a higher number of radioresistant, reserve ISC populations and Paneth cells were eradicated by proton irradiation than X-ray irradiation, as shown in the IHC analyses. The TUNEL assay revealed that proton irradiation was more effective in enhancing apoptotic cell death than X-ray irradiation. This study conducted a detailed analysis on the effects of proton irradiation versus X-ray irradiation on intestinal crypt regeneration in mouse models. Our findings revealed that proton irradiation has a direct effect on ISC populations, which may result in an increase in the risk of GI toxicity during proton beam therapy.

Tumor hypoxia is a major mechanism of resistance to radiation therapy (RT), which is associated with poor prognosis in affected cancer patients. Various approaches to treat hypoxic and radioresistant cancers, including pancreatic cancer, have shown limited success. Fucoidan, a polysaccharide from brown seaweed, has antitumor and antiangiogenesis activities. Here, we discuss the development of fucoidan-coated manganese dioxide nanoparticles (Fuco-MnO2-NPs) and testing of the therapeutic potential with RT using pancreatic cancer models. In vitro data showed that Fuco-MnO2-NPs generated oxygen efficiently in the presence of H2O2 and substantially suppressed HIF-1 expression under a hypoxic condition in human pancreatic cancer cells. Fuco-MnO2-NPs reversed hypoxia-induced radioresistance by decreasing clonogenic survival and increasing DNA damage and apoptotic cell death in response to RT. In a BxPC3 xenograft mouse model, the combination treatment with Fuco-MnO2-NPs and RT resulted in a greater tumor growth delay than RT alone. Fucoidan-coated NPs, but not naked ones, further suppressed tumor angiogenesis, as judged by immunohistochemistry data with diminished expression of phosphorylated vascular endothelial growth factor receptor 2 (VEGFR2) and CD31. These data suggest that Fuco-MnO2-NPs may potentiate the effects of RT via dual targeting of tumor hypoxia and angiogenesis, and they are of great clinical potential in the treatment of hypoxic, radioresistant pancreatic cancer.

Although the adrenal glands are not common sites of metastasis from hepatocellular carcinoma (HCC), this metastasis can be met in patients with advanced HCC in some clinical settings. However, the effectiveness of radiotherapy against such metastases is unclear. Therefore, we performed the present multi-institutional study to investigate tumor response, overall survival (OS), treatment-related toxicity, and prognostic factors after radiotherapy. We retrospectively reviewed 134 patients who completed a planned radiotherapy for their adrenal metastases. Complete response was noted in 6 (4.3%), partial response in 48 (34.0%), and stable disease in 78 patients (55.3%). The median OS was 12.8 months, and the 1-, 2-, and 5-year OS rates were 53.1%, 23.9%, and 9.3%, respectively. Grade 3 anorexia occurred in 2 patients, grade 3 diarrhea in 1, and grade 3 fatigue in 1. Multivariate analyses revealed that the following factors had significant effects on OS: controlled intrahepatic tumor; controlled extrahepatic metastasis; and Child-Pugh class A. Although patients with adrenal metastasis from HCC had poor OS, radiotherapy provided an objective response rate of 38.3% and disease stability of 93.6%, with minimal adverse events. Therefore, radiotherapy for these patients could represent a good treatment modality, especially for patients with controlled intrahepatic tumors, controlled extrahepatic metastasis, and good hepatic function.

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We realize a nanomechanical impact oscillator driven by a radiofrequency signal. The mechanical impact of the oscillator is demonstrated by increasing the amplitude of the external radiofrequency signals. Electron transport in the system is dramatically modified when the oscillator is strongly driven to undergo forced impacts with electrodes. We exploit this nonlinear kind of electron transport to observe the current response in the chaotic regime. Our model adopting the Sharvin conductance at the moment of impact provides a description of the rectified current via the impact oscillator in the linear regime, revealing a path towards chaos.

Purpose: For the treatment of locally advanced rectal cancer (LARC), research on primary lesions with mesorectal fascia (MRF) involvement is lacking. This study analyzed the clinical outcomes and efficacy of dose-escalated neoadjuvant concurrent chemoradiotherapy (NCRT) to patients with LARC involving MRF. Materials and Methods: We retrospectively reviewed 301 patients who were diagnosed with LARC involving MRF and underwent NCRT followed by total mesorectal excision (TME). Patients who received radiotherapy (RT) doses of =50.4 Gy were defined as the non-boost group, while =54.0 Gy as the boost group. Pathological tumor response and survival outcomes, including intrapelvic recurrence-free survival (IPRFS), distant metastases-free survival (DMFS) and overall survival (OS), were analyzed. Results: A total of 269 patients (89.4%) achieved a negative pathological circumferential resection margin and 104 (34.6%) had good pathological tumor regression grades. With a median follow-up of 32.4 months, IPRFS, DMFS, and OS rates at 5-years were 88.6%, 78.0%, and 91.2%, respectively. In the subgroup analysis by RT dose, the boost group included more advanced clinical stages of patients. For the non-boost group and boost group, 5-year IPRFS rates were 90.3% and 87.0% (p = 0.242), 5-year DMFS rates were 82.0% and 71.3% (p = 0.105), and 5-year OS rates were 93.0% and 80.6% (p = 0.439), respectively. Treatment related toxicity was comparable between the two groups (p = 0.211). Conclusion: Although this retrospective study failed to confirm the efficacy of dose-escalated NCRT, favorable IPRFS and pathological complete response was achieved with NCRT followed by TME. Further studies combining patient customized RT dose with systemic therapies are needed. [ABSTRACT FROM AUTHOR]