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Purpose The purpose of this phase II trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, to preoperative chemoradiotherapy (CRT) with capecitabine confers a clinical benefit to patients with locally advanced rectal cancer (LARC).Materials and Methods Patients with LARC (defined by clinical stage T3/4 and/or lymph node positivity) received preoperative radiation (45-50.4 Gy in 25-28 daily fractions) with concomitant capecitabine (825 mg/m2 twice per day) and simvastatin (80 mg, daily). Curative surgery was planned 4-8 weeks after completion of the CRT regimen. The primary endpoint was pathologic complete response (pCR). The secondary endpoints included sphincter-sparing surgery, R0 resection, disease-free survival, overall survival, the pattern of failure, and toxicity.Results Between October 2014 and July 2017, 61 patients were enrolled; 53 patients completed CRT regimen and underwent total mesorectal excision. The pCR rate was 18.9% (n=10) by per-protocol analysis. Sphincter-sparing surgery was performed in 51 patients (96.2%). R0 resection was achieved in 51 patients (96.2%). One patient experienced grade 3 liver enzyme elevation. No patient experienced additional toxicity caused by simvastatin.Conclusion The combination of 80 mg simvastatin with CRT and capecitabine did not improve pCR in patients with LARC, although it did not increase toxicity.

We consider a nanoelectromechanical system composed of a carbon nanotube suspended between two normal leads and coupled to a superconducting scanning tunneling microscope (STM) tip via vacuum tunnel barrier. Treating the nanotube as a single-level quantum dot, it is shown that an applied voltage between the superconducting STM tip and normal leads gives rise to a pumping or a cooling of the mechanical subsystem depending on the direction of the electronic flow. It is also demonstrated that the transition between these two regimes is controlled by the strength of the tunnel coupling between the nanotube and superconducting STM tip and the relative position of the electronic level. Such phenomena are realized due to a specific electromechanical coupling that is fully governed by the quantum dynamics of the Cooper pairs. The amplitude of the self-sustained oscillations in the pumping regime is analyzed numerically, and the effective temperature of the mechanical subsystem in the cooling regime is obtained.

The aim of this study is to determine the optimal indications for preoperative pelvic radiotherapy (RT) in patients with metastatic rectal cancer who underwent curative-intent surgical resection and/or ablation.Between January 2000 and October 2019, 246 patients who met our inclusion criteria were enrolled. Preoperative RT was performed in 22 patients (8.9%). Lower margin below the peritoneal reflection (p0.001), mesorectal fascia (MRF) invasion (p = 0.02), and lateral pelvic lymph node (LPLN) involvement (p = 0.005) were more frequent in the preoperative RT group.During the median follow-up period of 13.3 months (interquartile range [IQR]: 6.0-36.3 months), local recurrence (LR) was identified in 60 patients (24.4%). It was the first site of recurrence in 45 of them (18.3%). Among them, three patients were in the preoperative RT group. On multivariable analysis, lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, carcinoembryonic antigen (CEA) level ≥ 10 ng/mL before treatment, and preoperative RT were significant prognostic factors for LR-free survival (LRFS). In the patient group without any risk factors, the 2-year LRFS rate was 94.9% without preoperative RT. In the patient group with one or more risk factors, the 2-year LRFS was 64.4% without and 95.2% with preoperative RT.LR developed in about 25% of patients within 2 years. Preoperative RT should be considered, especially in patients with a risk factor for LR, including lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, or CEA ≥ 10 ng/mL before treatment.

Objective Hypofractionated radiotherapy has recently been applied to treat pulmonary metastases of hepatocellular carcinoma. However, there is no definite evidence on its safety and efficacy. We evaluate the clinical outcomes of hypofractionated radiotherapy for oligo pulmonary metastases of hepatocellular carcinoma in the multicenter and retrospective study. Methods From March 2011 to February 2018, 58 patients with fewer than five pulmonary metastases of hepatocellular carcinoma who underwent hypofractionated radiotherapy in nine tertiary university hospitals were analyzed retrospectively. The primary endpoint was the local control rate. The secondary endpoints were overall survival, progression-free survival, prognostic factors affecting the treatment outcomes and treatment-related side effects. Results The local tumor response rate including complete and partial response was 77.6% at 3 months after hypofractionated radiotherapy. The median survival and progression-free survival times were 20.9 and 5.3 months, respectively. The 1-year overall survival and progression-free survival rates were 65.5 and 22.4%, respectively. The good treatment response after hypofractionated radiotherapy (P = 0.001), the absence of intrahepatic tumor (P = 0.004) and Child-Pugh class A (P = 0.010) were revealed as significant prognostic factors for overall survival in the multivariate analysis. A progression-free interval of Conclusions The favorable local control rate and acceptable toxicity indicate the clinical usefulness of hypofractionated radiotherapy for hepatocellular carcinoma patients who have less than five pulmonary metastases.

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.

Periodically driven systems are ubiquitously found in both classical and quantum regimes. In the field of photonics, these Floquet systems have begun to provide insight into how time periodicity can extend the concept of spatially periodic photonic crystals and metamaterials to the time domain. However, despite the necessity arising from the presence of nonreciprocal coupling between states in a photonic Floquet medium, a unified non-Hermitian band structure description remains elusive. We experimentally reveal the unique Bloch-Floquet and non-Bloch band structures of a photonic Floquet medium emulated in the microwave regime with a one-dimensional array of time-periodically driven resonators. These non-Hermitian band structures are shown to be two measurable distinct subsets of complex eigenfrequency surfaces of the photonic Floquet medium defined in complex momentum space.

Proton beam therapy (PBT) is an effective treatment option for primary malignant liver disease. However, evidence regarding liver metastasis is insufficient. We aimed to investigate the efficacy and safety of hypofractionated high-dose PBT in the treatment of metastatic liver disease.From January 2019 to January 2021, patients with unresectable liver metastases were enrolled. For PBT, the dose schemes of 60 Gy relative biological effectiveness (GyRBE) in 5 fractions (fx) (biologically effective dose [BED] 132 GyE) or 70 GyRBE in 10 fx (BED 119 GyE) were used. Either a passive scattered beam or pencil beam scanning (PBS)-based intensity-modulated proton therapy (IMPT) was performed with proper respiratory management. The primary endpoint of the study was 6-month freedom from local progression (FFLP) rate; and the Kaplan-Meier method was used to calculate the FFLP and survival rates.Of the 49 liver metastases in 46 patients, the colorectum accounted for 60% of the primary cancer sites, followed by the gastrointestinal organs and pancreas/biliary tract. Forty patients presented only 1 liver metastasis, while the other 6 patients had 2 to 4 metastases. The Six-month FFLP rate was 95.2%. The 1-year FFLP rate in patients with3 cm liver metastasis was 87.4%, while that was 74.1% in patients with 3 cm group (p = 0.087). With regard to systemic treatment, the 1-year FFLP rate after PBT was better (94.1%) than that without systemic treatment (75.8%; p = 0.051). Regarding PBT-related toxicity, one patient developed a grade 2 gastric ulcer, while none of the patients developed grade ≥3 toxicities.Hypofractionated PBT with a BED 100 GyRBE for liver metastasis is safe and effective, given the high rate of 6-month FFLP without grade ≥3 treatment-related toxicities. However, further improvements are required for larger tumors and/or those without prior systemic therapy.

We analyze the effects of the strain-induced pseudo-magnetic fields (PMFs) originating from nanobubbles (NBs) to examine the possibility for a graphene quantum dot (QD) created by strain engineering. We study the electronic structures and quantum transport properties of graphene subjected to an NB, and report that the presence of PMFs facilitates a strong confinement of Dirac fermions. A circular geometry of the NB locally establishes the characteristic PMFs with $$C_{3}$$ symmetry, resulting in threefold localized states according to the given symmetry. We demonstrate the formation of a graphene QD induced by the NB via the conductance resonances calculated through the NB between opposite quantum Hall edge channels. Analyzing the scattering wavefunctions for the resonances, we confirm the existence of ground and excited states in the graphene QD. In addition, we show a possible valley-polarization in the graphene QD, as a consequence of quantum interference between symmetric and anti-symmetric valley-coupled modes.

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 [kep], and volume fraction of the extravascular extracellular matrix [ve] 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, kep, and ve of bone metastases changed significantly after RT. The percentage change in the ADC was closely related to local tumor progression.

Higher-order topological insulator is a newly discovered topological material, characterized by the topological corner states. In this work, we propose quantum oscillation that identifies the two-dimensional higher-order topological phase in twisted bilayer graphene systems. We use an instanton approach to argue that the tunneling of electrons between the topological corner states of the higher-order topological insulator generally causes the gate-tunable oscillation in the energy spectra. The oscillatory nodes signal the perfect suppression of the tunneling, which features the topological nature of the corner states. In the view of experimental realization, we propose the transport experiment that can readily observe the oscillation. Our work provides a feasible route to identify higher-order topological materials in twisted bilayer graphenes.

We propose a controllable qubit in a graphene nanobubble with emergent two-level systems induced by pseudo-magnetic fields. We found that double quantum dots can be created by the strain-induced pseudo-magnetic fields of a nanobubble, and that their quantum states can be manipulated by either local gate potentials or the pseudo-magnetic fields. Graphene qubits clearly exhibit an avoided crossing behavior via electrical detuning, with energy splittings of about a few meV. We also show a remarkable tunability of our device design that allows for the fine control of the Landau--Zener transition probability through strain engineering of the nanobubble, showing half-and-half splitting at the avoided crossing point. Further, we demonstrate that the two-level systems in the nanobubble exhibit Rabi oscillations near the avoided crossing point, resulting in very fast Rabi cycles of a few ps., 6pages, 5figures

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.

We investigated the combined effects of sarcopenia and inflammation on outcomes in patients with HCC treated with nivolumab. We reviewed 102 patients treated with nivolumab between 2017 and 2018. Sarcopenia was diagnosed when the L3 skeletal muscle indices were

One key to improve the performance of advanced optoelectronic devices and energy harvesting in graphene is to understand the predominant carrier scattering via optical phonons. Nevertheless, low li...

This study aimed to identify the risk factors for locoregional recurrence (LR) and determine possible candidates for postoperative concurrent chemoradiotherapy (CCRT) in pathologic T3N0 (pT3N0) rectal cancer patients with a negative resection margin after total mesorectal excision (TME). Data from 365 patients who had pT3N0 rectal cancer between 2003 and 2012 in the Samsung Medical Center were reviewed. All patients underwent upfront surgery without preoperative treatment. Postoperative management involved either no adjuvant therapy (n = 122), chemotherapy alone (n = 100), or CCRT (n = 143). The median follow-up duration was 71 months. The 5-year overall survival, disease-free survival, and LR-free survival (LRFS) rates were 95.9%, 86.9%, and 96.3%, respectively. When comparing the three groups (surgery alone [n = 122], chemotherapy alone [n = 100], and CCRT [n = 143]), there was no significant difference in LRFS among them (94.0%, 93.4%, and 99.2%, respectively; p = 0.20). However, when patients were stratified by risk factors (distance from anal verge ≤ 5 cm and distal resection margin [DRM] ≤ 2 cm), the 5-year LRFS improved by more than 10% by adding CCRT (98.9% with CCRT vs. 87.4% without CCRT, p = 0.006) in those with more than one risk factor. Postoperative CCRT did not affect the 5-year LRFS (100% with CCRT vs. 99.0% without CCRT, p = 0.66) in patients with no risk factors. Postoperative CCRT significantly decreased LR in patients with pT3N0 rectal cancer with a negative resection margin but having a distance from the anal verge ≤ 5 cm or DRM ≤ 2 cm.

PurposeThe purpose of this study was to investigate the role of carcinoembryonic antigen (CEA) levels in improving the performance of magnetic resonance imaging (MRI) for the prediction of pathologic response after the neoadjuvant chemoradiation (NCRT) for patients with rectalcancer.Materials and MethodsWe retrospectively reviewed the medical records of 524 rectal cancer patients who underwent NCRT and total mesorectal excision between January 2009 and December 2014. The performances of MRI with or without CEA parameters (initial CEA and CEA dynamics) for prediction of pathologic tumor response grade (pTRG) were compared by receiver-operating characteristic analysis with DeLong’s method. Cox regression was used to identify the independent factors associated to pTRG and disease-free survival (DFS) after NCRT.ResultsThe median follow-up was 64.0 months (range, 3.0 to 113.0 months). On multivariate analysis, poor tumor regression grade on MRI (mrTRG; p < 0.001), initial CEA (p < 0.001) and the mesorectal fascia involvement on MRI before NCRT (mrMFI; p=0.054) showed association with poor pTRG. The mrTRG plus CEA parameters showed significantly improved performances in the prediction of pTRG than mrTRG alone. All of mrTRG, mrMFI, and initial CEA were also identified as independent factors associated with DFS. The initial CEA further discriminated DFS in the subgroups with good mrTRG or that without mrMFI.ConclusionThe CEA parameters significantly improved the performance of MRI in the prediction of pTRG after NCRT for patients with rectal cancer. The DFS was further discriminated by initial CEA level in the groups with favorable MRI parameters.

Rationale: Unlike traditional biopsy, liquid biopsy, which is a largely non-invasive diagnostic and monitoring tool, can be performed more frequently to better track tumors and mutations over time and to validate the efficiency of a cancer treatment. Circulating tumor cells (CTCs) are considered promising liquid biopsy biomarkers; however, their use in clinical settings is limited by high costs and a low throughput of standard platforms for CTC enumeration and analysis. In this study, we used a label-free, high-throughput method for CTC isolation directly from whole blood of patients using a standalone, clinical setting-friendly platform. Methods: A CTC-based liquid biopsy approach was used to examine the efficacy of therapy and emergent drug resistance via longitudinal monitoring of CTC counts, DNA mutations, and single-cell-level gene expression in a prospective cohort of 40 patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Results: The change ratio of the CTC counts was associated with tumor response, detected by CT scan, while the baseline CTC counts did not show association with progression-free survival or overall survival. We achieved a 100% concordance rate for the detection of EGFR mutation, including emergence of T790M, between tumor tissue and CTCs. More importantly, our data revealed the importance of the analysis of the epithelial/mesenchymal signature of individual pretreatment CTCs to predict drug responsiveness in patients. Conclusion: The fluid-assisted separation technology disc platform enables serial monitoring of CTC counts, DNA mutations, as well as unbiased molecular characterization of individual CTCs associated with tumor progression during targeted therapy.

External beam radiation therapy (EBRT) is commonly used as a palliative treatment for bone metastases of hepatocellular carcinoma (HCC). We planned a hybrid systematic review that meta-analyzed the efficacy and feasibility of EBRT and reviewed the literature to answer specific clinical questions. The PubMed, Medline, Embase, and Cochrane Library databases were searched through 1 December 2021. Primary endpoints were overall survival (OS) and response rate (RR). Secondary endpoints were comparative data, including treatment response and survival related to dose escalation, number of metastases, and fractionation scheme. Formal pooled analyses were performed on the primary endpoints, and the secondary endpoints were systematically reviewed. Complications were also reviewed. Nineteen studies involving 1613 patients with HCC and bone metastases were included. The median OS was 6 months (range: 3–13 months). The pooled one-year OS was 23.1% (95% confidence interval [CI]: 18.4–28.6); pooled pain RR was 81.5% (95% CI: 76.4–85.7) and of pain complete remission was 26.5% (95% CI: 21.7–32.0). Pain response might be related to dose escalation, considering the moderate consistency of results and plausibility, with a low-quality grade of evidence†. Considering the indeterminate results, we cannot suggest that dose escalation is correlated with OS. The oligometastasis status might be related to better OS, considering the high consistency of results and plausibility with low to moderate quality of evidence. Hypofractionated EBRT might yield comparable efficacy to conventional EBRT, with a low-quality grade of evidence. There were few complications of grade ≥3, except for hematologic complications, which ranged from 11.5to 34%. EBRT is an efficient and feasible palliative option. Clinical consideration of hematologic complications is necessary. Future studies are needed to increase the quality of evidence for actual clinical questions. †Reference to a system of the American Society for Radiation Oncology primary liver cancer clinical guidelines.

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., Comment: 6+16 pages+5 figures

PURPOSE We evaluated the role of oxaliplatin as adjuvant chemotherapy in patients with rectal cancer who received preoperative chemoradiotherapy (CRT) with fluoropyrimidine monotherapy and total mesorectal excision (TME). METHODS The ADORE trial (adjuvant oxaliplatin in rectal cancer) is a multicenter, randomized trial in patients with postoperative ypStage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after fluoropyrimidine-based preoperative CRT and TME. Patients were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (fluorouracil 380 mg/m2 and leucovorin 20 mg/m2) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil bolus 400 mg/m2 on day 1, fluorouracil infusion 2,400 mg/m2 for 46 hours). Stratification factors included ypStage and participating center. Primary end point was disease-free survival (DFS). RESULTS A total of 321 patients were enrolled between November 19, 2008, and June 12, 2012. Six-year DFS rates were 68.2% in the FOLFOX arm versus 56.8% in the FL arm, with a stratified hazard ratio of 0.63 (95% CI, 0.43 to 0.93; P = .018) by intention-to-treat analysis. In the subgroup analysis for DFS, FOLFOX was favorable versus FL in patients with ypStage III, ypN1b, ypN2, high-grade histology, minimally regressed tumor, and an absence of lymphovascular or perineural invasion. Six-year overall survival rate was 78.1% in the FOLFOX arm versus76.4% in the FL arm (hazard ratio, 0.73; 95% CI, 0.45 to 1.19; P = .21). In the subgroup analysis for OS, FOLFOX was favorable versus FL in patients with ypN2 and minimally regressed tumor. CONCLUSION Adjuvant FOLFOX improved DFS in patients with rectal cancer with ypStage II and III disease after preoperative CRT. Adjuvant FOLFOX may be considered on the basis of the postoperative pathologic stage in those who received preoperative CRT and TME.

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.

Purpose There is limited data on radiotherapy (RT) for hepatocellular carcinoma (HCC) in patients with Child-Pugh classification B (CP-B). This study aimed to evaluate the treatment outcomes of fractionated conformal RT in HCC patients with CP-B. Materials and Methods We retrospectively reviewed the data of HCC patients with CP-B treated with RT between 2009 and 2014 at 13 institutions in Korea. HCC was diagnosed by the Korea guideline of 2009, and modern RT techniques were applied. Fraction size was ≤ 5 Gy and the biologically effective dose (BED) ≥ 40 Gy10 (α/β = 10 Gy). A total of 184 patients were included in this study. Results Initial CP score was seven in 62.0% of patients, eight in 31.0%, and nine in 7.0%. Portal vein tumor thrombosis was present in 66.3% of patients. The BED ranged from 40.4 to 89.6 Gy10 (median, 56.0 Gy10). After RT completion, 48.4% of patients underwent additional treatment. The median overall survival (OS) was 9.4 months. The local progression-free survival and OS rates at 1 year were 58.9% and 39.8%, respectively. In the multivariate analysis, non-classic radiation-induced liver disease (RILD) (p < 0.001) and additional treatment (p < 0.001) were the most significant prognostic factors of OS. Among 132 evaluable patients without progressive disease, 19.7% experienced non-classic RILD. Normal liver volume was the most predictive dosimetric parameter of non-classic RILD. Conclusion Fractionated conformal RT showed favorable OS with a moderate risk non-classic RILD. The individual radiotherapy for CP-B could be cautiously applied weighing the survival benefits and the RILD risks.

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., Nivolumab‐related toxicities in advanced hepatocellular carcinoma were generally tolerable regardless of the history of radiotherapy. Previous and/or concurrent application of radiotherapy in the course of nivolumab treatment was related with longer progression‐free survival and overall survival.

Downregulation of MicroRNA-122 (miR-122) and its association with cancer progression have been reported in hepatocellular carcinoma (HCC) cell line models and a limited number of HCC samples. Recently, restoration of miR-122 expression by direct delivery of miR-122 yielded promising results in HCCs. However, the prognostic effect of miR-122 expression in human HCC samples is not fully understood. We investigated the expression level of miR-122 by quantitative real-time polymerase chain reaction in 289 curatively resected HCC samples and 20 normal liver samples and evaluated the prognostic effect of miR-122 expression. The relative quantification value of miR-122 was much lower in HCC samples than in normal liver tissues. During a median 119 months of follow-up for survival, the low miR-122 expression group showed shorter recurrence-free survival (RFS) (p = 0.033) and intrahepatic recurrence-free survival (IHRFS) (p = 0.014), and a trend of short distant metastasis-free survival (DMFS) (p = 0.149) than high expression group. On multivariate analysis, miR-122 expression was an independent prognostic factor for RFS, IHRFS and DMFS. Downregulation of miR-122 expression, frequently found in HCC samples, was an independent prognostic factor for RFS after curative resection. Emerging therapeutic approaches targeting miR-122 could be applicable in patients with miR-122 downregulated hepatocellular carcinoma.

Proton beam therapy (PBT) is one of the advances in radiotherapy techniques, which enables dose escalation with lower probability of radiation-induced liver or gastrointestinal injuries. However, the chest wall proximal to the tumor can be affected by high dose irradiation. Here, we report on a 58-year-old male patient who presented with huge hepatocellular carcinoma, received treatment with transarterial chemoembolization and PBT, and developed severe chest wall pain due to radiation-induced myositis. The patient’s symptoms were controlled by oral steroids. (J Liver Cancer 2019;19:136-142)

Purpose To evaluate the quality of patient‐specific complicated treatment plans, including commercialized treatment planning systems (TPS) and commissioned beam data, we developed a process of quality assurance (QA) using a Monte Carlo (MC) platform. Specifically, we constructed an interface system that automatically converts treatment plan and dose matrix data in digital imaging and communications in medicine to an MC dose‐calculation engine. The clinical feasibility of the system was evaluated. Materials and Methods A dose‐calculation engine based on GATE v8.1 was embedded in our QA system and in a parallel computing system to significantly reduce the computation time. The QA system automatically converts parameters in volumetric‐modulated arc therapy (VMAT) plans to files for dose calculation using GATE. The system then calculates dose maps. Energies of 6 MV, 10 MV, 6 MV flattening filter free (FFF), and 10 MV FFF from a TrueBeam with HD120 were modeled and commissioned. To evaluate the beam models, percentage depth dose (PDD) values, MC calculation profiles, and measured beam data were compared at various depths (Dmax, 5 cm, 10 cm, and 20 cm), field sizes, and energies. To evaluate the feasibility of the QA system for clinical use, doses measured for clinical VMAT plans using films were compared to dose maps calculated using our MC‐based QA system. Results A LINAC QA system was analyzed by PDD and profile according to the secondary collimator and multileaf collimator (MLC). Values for MC calculations and TPS beam data obtained using CC13 ion chamber (IBA Dosimetry, Germany) were consistent within 1.0%. Clinical validation using a gamma index was performed for VMAT treatment plans using a solid water phantom and arbitrary patient data. The gamma evaluation results (with criteria of 3%/3 mm) were 98.1%, 99.1%, 99.2%, and 97.1% for energies of 6 MV, 10 MV, 6 MV FFF, and 10 MV FFF, respectively. Conclusions We constructed an MC‐based QA system for evaluating patient treatment plans and evaluated its feasibility in clinical practice. We observed robust agreement between dose calculations from our QA system and measurements for VMAT plans. Our QA system could be useful in other clinical settings, such as small‐field SRS procedures or analyses of secondary cancer risk, for which dose calculations using TPS are difficult to verify.

A thermally driven single-electron transistor with magnetic leads and a movable central island (a quantum dot) subject to an external magnetic field is considered. The possibility of a mechanical instability caused by magnetic exchange interactions between spin-polarized electrons in this system was studied by the density matrix method. We proved analytically that for noninteracting electrons in the dot there is no such mechanical instability. However, for finite strengths of the Coulomb correlations in the dot we numerically found critical magnetic fields separating regimes of mechanical instability and electron shuttling on the one hand and damped mechanical oscillations on the other. It was shown that thermally induced magnetic shuttling of spin-polarized electrons is a threshold phenomenon, and the dependence of the threshold bias temperature on model parameters was calculated.A thermally driven single-electron transistor with magnetic leads and a movable central island (a quantum dot) subject to an external magnetic field is considered. The possibility of a mechanical instability caused by magnetic exchange interactions between spin-polarized electrons in this system was studied by the density matrix method. We proved analytically that for noninteracting electrons in the dot there is no such mechanical instability. However, for finite strengths of the Coulomb correlations in the dot we numerically found critical magnetic fields separating regimes of mechanical instability and electron shuttling on the one hand and damped mechanical oscillations on the other. It was shown that thermally induced magnetic shuttling of spin-polarized electrons is a threshold phenomenon, and the dependence of the threshold bias temperature on model parameters was calculated.

Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. (Gut Liver 2019;13:227-299)

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and its incidence is rapidly increasing in North America and Western Europe as well as South-East Asia. Patients with advanced stage HCC have very poor outcomes; therefore, the discovery of new innovative approaches is urgently needed. Cancer immunotherapy has become a game-changer and revolutionized cancer treatment. A comprehensive understanding of tumor-immune interactions led to the development of immune checkpoint inhibitors (ICIs) as new therapeutic tools, which have been used with great success. Targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) reinvigorates anti-tumor immunity by restoring exhausted T cells. Despite their effectiveness in several types of cancer, of the many immune suppressive mechanisms limit the efficacy of ICI monotherapy. Radiation therapy (RT) is an essential local treatment modality for a broad range of malignancies, and it is currently gaining extensive attention as a promising combination partner with ICIs because of its ability to trigger immunogenic cell death. The efficacy of combination approaches using RT and ICIs has been well documented in numerous preclinical and clinical studies on various types of cancers but not HCC. The application of ICIs has now expanded to HCC, and RT is recognized as a promising modality in HCC. This review will highlight the current roles of PD-1 and CTLA-4 therapies and their combination with RT in the treatment of cancers, including HCC. In addition, this review will discuss the future perspectives of the combination of ICIs and RT in HCC treatment.

Objective:The aim of this study was to evaluate the relationship of anastomotic leakage, local recurrence, and overall survival in rectal cancer patients treated with preoperative chemoradiotherapy (CRT) and curative resection.Background:Little is known about the association between anastomotic leak

We performed a retrospective analysis to evaluate treatment outcomes and the risk of fatal hemorrhage by tumor regression when definitive concurrent chemo-radiotherapy (CCRT) was delivered to patients with non–small cell lung cancer (NSCLC) invading adjacent great vessels on radiological findings. We selected 37 unresectable NSCLC patients with adjacent great vessel invasion (GVI) by carefully reviewing each patient’s images. The criteria of definite GVI were as follows: irregular indentation at the tumor–vessel contact border, slit-like narrowing of adjacent great vessels by the tumor, presence of intra-luminal mass formation, tumors contacting >5 cm of adjacent great vessel and obliteration of the intervening fat plane between tumor and adjacent great vessel, and/or tumors contacting more than half of the circumference of the aortic wall. All of the patients completed the CCRT, of which the median dose was 66.0 Gy (range, 59.4–72.0 Gy) with 1.8 or 2.0 Gy per fraction. The 2-year overall survival (OS) rate for total patients was 48.2%. Early nodal staging (P = 0.006) and good performance status (P = 0.044) were identified as independent prognostic factors associated with better OS. There was no fatal complication related to the GVI, such as a sudden death or massive hemoptysis due to vascular rupture after CCRT. We concluded that definitive CCRT for NSCLC patients with GVI on radiological findings has a low risk of fatal complication and it can benefit long-term survival when treated with CCRT in patients with early nodal staging or good performance status.

We show that new functionality of spin-orbit-active electronic weak links can be achieved by their time-dependent mechanical deformation. As an illustration we use a simple model to calculate the electronic spin current generated by rotating a bent spin-orbit-active nanowire coupled to bulk metallic leads.We show that new functionality of spin-orbit-active electronic weak links can be achieved by their time-dependent mechanical deformation. As an illustration we use a simple model to calculate the electronic spin current generated by rotating a bent spin-orbit-active nanowire coupled to bulk metallic leads.

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.

We predict and analyze mechanical instability and corresponding self-sustained mechanical oscillations occurring in a nanoelectromechanical system composed of a metallic carbon nanotube (CNT) suspended between two superconducting leads and coupled to a scanning tunneling microscope (STM) tip. We show that such phenomena are realized in the presence of both the coherent Andreev tunneling between the CNT and superconducting leads, and an incoherent single electron tunneling between the voltage biased STM tip and CNT. Treating the CNT as a single-level quantum dot, we demonstrate that the mechanical instability is controlled by the Josephson phase difference, relative position of the electron energy level, and the direction of the charge flow. It is found numerically that the emergence of the self-sustained oscillations leads to a substantial suppression of DC electric current.

We have studied topological edge states in bowtie ladders with various edge truncations. The symmetric bowtie ladder, which comprises two trivial Su-Schrieffer-Heeger (SSH) lattices, exhibits an insulator-metal transition with trivial insulating states. On the other hand, the lattice can be transformed into an extended SSH lattice depending on the edge shapes with non-trivial insulating states in that the winding number is non-zero. The winding numbers are permutationally designated in the phase diagram depending on the choice of unit cell. The topological edge states are affected by the shape of the edge and the corresponding winding number. We also studied general bowtie ladder models with richer phase diagrams using the characteristics of the localization length of the edge states showing state bifurcation., Comment: 6 pages, 4 figures

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 (&minus, )-agelamide D from Agelas extract and investigated the mechanism underlying its radiosensitization. (&minus, )-Agelamide D enhanced radiation sensitivity of Hep3B cells with decreased clonogenic survival and increased apoptotic cell death. Furthermore, (&minus, )-agelamide D increased the expression of protein kinase RNA-like endoplasmic reticulum kinase/inositol-requiring enzyme 1&alpha, /activating transcription factor 4 (PERK/eIF2&alpha, /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 (&minus, )-agelamide D enhanced tumor growth inhibition by radiation without systemic toxicity. Immunohistochemistry results showed that (&minus, )-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 (&minus, )-agelamide D may enhance the efficacy of RT in HCC management.

One key to improve the performance of advanced optoelectronic devices and energy harvesting in graphene is to understand the predominant carrier scattering

We investigated the combined effects of sarcopenia and inflammation on outcomes in patients with HCC treated with nivolumab.We reviewed 102 patients treated with nivolumab between 2017 and 2018. Sarcopenia was diagnosed when the L3 skeletal muscle indices were 42 cmWith a median follow-up of 21.9 (interquartile range, 8.3-58.3) months, patients with sarcopenia showed shorter OS than those without sarcopenia (median, 2.9 vs. 7.5 months, respectively). Patients with either hNLR or sLP exhibited inferior survival than those without risk factor (median OS, 2.8 vs. 14.5 months; median PFS, 1.3 vs. 3.7 months, respectively). Among 70 patients treated with RT, benefit of RT was observed in patients with sarcopenia or those without hNLR/sLP (all p 0.05). After multivariable analysis, RT, hNLR/sLP, albumin-bilirubin (ALBI) grade, and alpha-fetoprotein were significantly associated with OS (all p 0.05), and hNLR/sLP was also associated with decreased PFS together with ALBI grade, alpha-fetoprotein, and RT (all p 0.05).The current study hypothetically demonstrated that the risk group stratified by hNLR/sLP outweighs the significance of sarcopenia in predicting outcomes after nivolumab. Furthermore, patients with sarcopenia might benefit from RT, especially those without risk factors of hNLR/sLP.

Purpose: To investigate the prognostic impact of sarcopenia on the survival of patients with locally advanced pancreatic cancer (LAPC) treated with concurrent chemoradiotherapy (CCRT). Methods: We retrospectively reviewed 299 patients diagnosed with LAPC and treated with definitive CCRT from 2000 to 2015. Skeletal muscle index (SMI) was measured using computed tomography scans and sarcopenia was defined as SMI 2/m2 for women and 2/m2 for men. The significance of sarcopenia for progression-free survival (PFS) and overall survival (OS) was evaluated. Results: Sarcopenia was present in 29 patients (9.7%). In multivariate analysis, sarcopenia was a significant factor for PFS ( p = 0.043). Although sarcopenia was not a significant factor for OS ( p = 0.121) in multivariate analysis, long-term survivors were observed only in the no sarcopenia group (OS at 60 months: 9.5% vs 0%, p < 0.001). Conclusion: In patients undergoing CCRT for LAPC, sarcopenia is an independent factor for adverse prognosis.

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&ndash, 3.70) and overall survival (OS, p = 0.003, HR = 2.28, 95% CI: 1.31&ndash, 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.

Purpose To evaluate and compare the feasibilities of magnetic resonance (MR) image-based planning using synthetic computed tomography (sCT) versus CT (pCT)-based planning in helical tomotherapy for prostate cancer. Materials and methods A retrospective evaluation was performed in 16 patients with prostate cancer who had been treated with helical tomotherapy. MR images were acquired using a dedicated therapy sequence; sCT images were generated using magnetic resonance for calculating attenuation (MRCAT). The three-dimensional dose distribution according to sCT was recalculated using a previously optimized plan and was compared with the doses calculated using pCT. Results The mean planning target volume doses calculated by sCT and pCT differed by 0.65% ± 1.11% (p = 0.03). Three-dimensional gamma analysis at a 2%/2 mm dose difference/distance to agreement yielded a pass rate of 0.976 (range, 0.658 to 0.986). Conclusion The dose distribution results obtained using tomotherapy from MR-only simulations were in good agreement with the dose distribution results from simulation CT, with mean dose differences of less than 1% for target volume and normal organs in patients with prostate cancer.

We have studied the rectified current in a geometrically symmetric nano-electromechanical shuttle with periodic kicks and sinusoidal ac bias voltages. The rectified current is exactly zero under the geometrical symmetry which is generated by the electrons transferred from source to drain electrodes through the movable shuttle. We investigate the nonzero rectified currents through the symmetric shuttle with regular motion of which the time-translational symmetry is broken. The motion of the shuttle, moreover, becomes chaotic with the same mechanism of the kicked rotor and generates the scattered current as increasing kick strength. We point out that the time-translational-symmetry breaking of the instantaneous current is an important role of manipulation of the rectified current., Comment: 6 pages, 5 figures

BackgroundStereotactic body radiation therapy is an emerging treatment option for patients with unresectable advanced hepatocellular carcinoma (HCC). Because liver parenchyma neighboring the tumor ...

Placement of dental implants initiates inflammatory foreign body response, in which macrophages play a central role and affect the subsequent tissue healing process such as bone formation. The purpose of this study was to fabricate phosphatidylserine (PS)-containing supported lipid bilayers (SLBs) on a titanium surface to regulate the polarization of macrophages, a critical factor that affects following tissue healing and regeneration. The fluorescent recovery after photobleaching images showed that the percentage of PS had a critical influence on the fluidity, and 20% PS had the highest fluidity. Furthermore, more expanded and elongated cells were observed in the SLB-coated groups. transforming growth factor-β1 and vascular endothelial growth factor, the key cytokine markers of M2 macrophage polarization, were increased in the SLB-coated groups, especially in the 20% PS group. Consistently, cells cultured on the SLB-coated titanium exhibited the distribution of CD206+ , which is a M2 macrophage specific maker. The results of this study demonstrated M2 polarization of macrophages on PS-SLB-coated titanium discs, which suggests the application of PS-SLB as an immune-regulating coating material to improve tissue reactions to dental implants. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2625-2633, 2018.