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The use of natural killer (NK) cells is a promising approach in the field of cancer immunotherapy; however, combination treatments are required to enhance the effects of NK cell immunotherapy. In this study, we assessed the potential of irradiation and cisplatin as a chemoradiotherapy (CRT) regimen to augment the effects of NK cell immunotherapy in head and neck squamous cell carcinoma (HNSCC).NK cells were expanded using our recently established K562-OX40 ligand and membrane-bound interleukin (IL)-18 and IL-21 feeder cells in the presence of IL-2/IL-15 from peripheral blood of healthy donors.The results showed an increase in the purity of NK cells and expression of activation markers such as NKG2D and lymphocyte function-associated antigen 1 during the expansion process, which is positively correlated to the NK cell infiltration and overall survival in patients with HNSCC. CRT induced NK cell activation ligand (ULBP2) and adhesion molecules (ICAM-1, -2 and -3) on HNSCC, leading to enhanced cytotoxicity of NK cells against HNSCC.Our findings suggest that the NK cells have a potent anti-tumor effect in combination with CRT against HNSCC.

Purpose: This study aimed to determine the correlation between protein induced by vitamin K absence or antagonist-II (PIVKA-II) and stereotactic body radiotherapy (SBRT) in patients with hepatocellular carcinoma (HCC). Materials and Methods: Sixty-one patients received SBRT between 2015 and 2020 with a median dose of 48 Gy (range, 39 to 60 Gy) with a median of 4 fractions. Changes in tumor markers before and after SBRT were analyzed. Results: The median follow-up period was 31 months (range, 12 to 64 months). The estimated 2-year in-field failure-free survival, progression-free survival (PFS), and overall survival rates were 82.0%, 39.3%, and 96.7%, respectively. Patients with decreased PIVKA-II levels through SBRT had significantly few in-field failures (p = 0.005). Patients with PIVKA-II levels of ≤25 mAU/mL after SBRT had significantly long PFS (p = 0.004). Conclusion: PIVKA-II could be a useful surrogate marker for response or survival outcomes in patients with localized HCC receiving SBRT.

Purpose To evaluate the efficacy and toxicity of hypofractionated preoperative chemoradiotherapy (HPCRT) combined with oral capecitabine in patients with rectal cancer. Methods HPCRT was delivered by an intensity-modulated radiotherapy of either 33 Gy to the whole pelvis or 35 Gy in 10 fractions to the primary tumor and 33 Gy to the surrounding pelvis. Surgery was performed 4–8 weeks after HPCRT completion. Oral capecitabine was administered concurrently. Tumor response, toxicity, and survival were analyzed. Results Seventy-six patients were eligible for this study. Patients number of clinical stage I, II, III, and IVA were 5, 29, 36, and 6, respectively. Nine patients (11.8%) achieved a pathological complete response. Sphincter preservation was achieved in 23/32 (71.9%) and 44/44 (100%) of patients with a distal extent from anal verge of ≤ 5 cm and > 5 cm, respectively. Twenty-eight patients (36.8%) achieved T-downstaging, and 25 (32.9%) achieved N-downstaging. Five-year disease-free survival (DFS) was 73.6% and overall survival was 90.6%. In the multivariate analysis for DFS, significant prognostic factors were pathologic nodal stage and lymphovascular space invasion. Six patients with stage IVA underwent salvage treatments after HPCRT completion, and all survived to the final follow-up. Three patients experienced grade 3 postoperative complications. No grade 4 toxicities were observed. Conclusion HPCRT of 33 Gy or 35 Gy in 10 fractions showed similar results to those of long-course fractionation. This fractionation scheme could be beneficial for patients with early stage disease, locally advanced rectal cancer, simultaneous distant metastasis requiring early intervention, or for patients who wish to avoid multiple hospital visits.

In this study, the effect of Cl activation treatment on performance indicators of CdS/CdTe solar cells was investigated. We improved the performance of CdTe solar cells by applying a novel double treatment method that combines the CdCl2 dipping treatment and Freon (difluoro chloromethane) treatment methods that were previously studied. Conventional CdCl2 methanol dipping treatment (CdCl2 dipping treatment), Freon gas treatment that includes chlorine (Freon treatment), and CdCl2 dipping treatment + Freon treatment (double treatment) were performed, and the efficiencies, open circuit voltage (V OC ), and short circuit current (J SC ) for all three processes were observed. Although the efficiencies of the CdCl2 dipping treatment and Freon treatment were similar, there was a trade-off between the V OC and J SC in both processes. The double treatment sample shows an efficiency of 14.3%, which was higher than that of a single-treated sample. To investigate the characteristic change of each part of the solar cell, an equivalent circuit model in which the device was divided into a main junction and a back contact was used. In addition to electrical measurements, secondary ion mass spectroscopy (SIMS) and time of flight (TOF) analysis were performed. Through TOF measurement, drift mobility values for three treatment samples were calculated to be 1.1 cm 2/Vs, 1.8 cm 2/Vs, and 1.9 cm 2/Vs, respectively. With TOF measurement, it was proved that the double treatment had a significant influence on the efficiency of the sample.

Background aims Tracking administered natural killer (NK) cells in vivo is critical for developing an effective NK cell-based immunotherapy against human hepatocellular carcinoma (HCC). Here the authors established a new molecular imaging using ex vivo-activated NK cells and investigated real-time biodistribution of administered NK cells during HCC progression. Methods Ex vivo-expanded NK cells from healthy donors were labeled with a near-infrared lipophilic cytoplasmic dye, and their proliferation, surface receptor expression and cytotoxicity activity were evaluated. Human HCC HepG2 cells were implanted into the livers of NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ (NSG) mice. The authors administered 1,1’-dioctadecyltetramethyl indotricarbocyanine iodide (DiR)-labeled NK cells intravenously to non-tumor-bearing and intrahepatic HCC tumor-bearing NSG mice. Fluorescent imaging was performed using a fluorescence-labeled organism bioimaging instrument. Single cell suspensions from the resected organs were analyzed using flow cytometry. Results The fluorescent DiR dye was nontoxic and did not affect the proliferation or surface receptor expression levels of the NK cells, even at high doses. The administered DiR-labeled NK cells immediately migrated to the lungs of the non-tumor-bearing NSG mice, with increased NK cell signals evident in the liver and spleen after 4 h. NK cells migrated to the intrahepatic tumor-bearing livers of both early- and late-stage HCC mice within 1 h of injection. In early-stage intrahepatic tumor-bearing mice, the fluorescence signal increased in the liver until 48 h post-injection and decreased 7 days after NK injection. In late-stage HCC, the NK cell fluorescence signal was the highest in the liver for 7 days after NK injection and persisted for 14 days. The purity of long-term persistent CD45+CD56+CD3− NK cells was highest in early- and late-stage HepG2-bearing liver compared with normal liver 2 weeks after NK injection, whereas highest purity was still observed in the lungs of non-tumor-bearing mice. In addition, Ki-67 expression was detected in migrated human NK cells in the liver and lung up to 72 h after administration. With HepG2 tumor progression, NK cells reduced the expression of NKp30 and NKG2D. Conclusions Administered NK cells were successfully tracked in vivo by labeling the NK cells with near-infrared DiR dye. Highly expanded, activated NK cells migrated rapidly to the tumor-bearing liver, where they persisted for 14 days after administration, with high purity of CD45+CD56+CD3− NK cells. Liver biodistribution and persistence of administered NK cells showed significantly different accumulation patterns during HCC progression.

Tumour hypoxia is an important factor for developing resistance to radiation therapy (RT) and present a bleak prognosis in cancer patients undergoing treatment for RT resistant hepatocellular carcinoma. Here, we present the synthesis of liposome-coated Mn3O4 (MGN) nanoparticles (Lipo-MGN) and investigation of their therapeutic potential with RT utilizing a HepG2 cancer model. According to in-vitro research, Lipo-MGN effectively produced oxygen in the presence of H2O2 and significantly reduced the expression of HIF-1 in human HepG2 cells that were under hypoxic conditions. Lipo-MGN reversed the radio-resistance brought on by hypoxia and increased cell damage. When Lipo-MGN and RT were administered together in a HepG2 xenograft mice model, the tumor growth was delayed more than with RT alone. As determined by histochemistry, liposome-MGN also inhibited tumor angiogenesis. According to these findings, Lipo-MGNs may increase the impact of RT by simultaneously focusing on angiogenesis and tumor hypoxia. Hypoxic, radioresistant HepG2 cancer may be treated with Lipo-MGN in clinical studies.

Canine natural killer (NK) cells are large, granular lymphocytes that are neither B lymphocytes nor T lymphocytes. However, it has been reported that canine NK cells share some of the phenotypic characteristics of T lymphocytes, such as CD3 and CD5. Studies are needed to assess the safety of canine NK cells for immunotherapy, especially because the safety of using allogeneic NK cells as an immunotherapy for dogs has yet to be shown. In this study, the safety of cultured canine NK cells was assessed using a xenogeneic mouse model of graft-versus-host disease (GVHD). Mice were injected with either canine peripheral blood mononuclear cells (PBMCs) or cultured NK cells for 2 or 3 weeks. Data were then collected on changes in mice body weights, disease severity scores, and survival rates. Histopathological and immunohistochemical evaluations were also performed. All mice injected with canine PBMCs died within 45 days after injection. Severe clinical signs were caused by GVHD. The histopathological and immunohistochemical evaluations showed that mice injected with canine PBMCs had multiple lesions, including necrosis in their lungs, livers, kidneys, and stomachs, and the injected cells were present around the lesions. By contrast, no mice injected with cultured NK cells without removing the CD3+TCR– cells exhibited any clinical abnormalities. Moreover, they all survived the 90-day experimental period without exhibiting any histopathological changes. Accordingly, the results of this study suggest that canine NK cells do not cause significant side effects such as GVHD and allogeneic NK cells can safely be used for cancer immunotherapy in dogs.

The internal target volume (ITV)-based IMRT method can be used to reduce the effect of respiratory tumor motion. In this study, the effect of tumor motion on the dosimetric accuracy during ITV-based IMRT was investigated. ITV-based IMRT plans for a total of ten cases of liver cancer were prepared in TomoTherapy (Tomo) and volumetric modulated arc therapy (VMAT). Delivery quality assurance (DQA) plans were created using Delta4 phantom for the verification of dosimetric accuracy of the established Tomo and VMAT plans. DQA measurements were performed in both the static mode and the Hexa-Motion mode by using the Delta4 Hexa-Motion system in Tomo and VMAT. In the static mode, the average gamma passing rate (GPR) using a 3% dose difference/3 mm distance-to-agreement criteria was 99.61% in Tomo and 99.35% in VMAT, which confirmed sufficient dosimetric accuracy in both IMRT methods. For the Hexa-Motion measurement, the average GRP result of 90.93% in Tomo was higher than the result of 82.58% obtained in VMAT. In addition, the difference in the GPR results between the static and the Hexa-motion modes in Tomo was 8.68%, which is approximately 8% less than the 16.77% difference in VMAT. This study verifies that the dosimetric error of ITV-based IMRT due to the tumor motion was larger in VMAT than in Tomo. Also, Tomo can be considered to be more suitable than the conventional LINAC-based VMAT method in terms of the dosimetric accuracy of ITV-based IMRT for the treatment of a moving tumor.

The postoperative hypofractionated intensity-modulated radiation therapy (POHIM-RT) trial is a phase II study to evaluate toxicity following hypofractionated intensity modulated radiation therapy (IMRT) for cervical cancer. This study describes the results of a benchmark procedure for RT quality assurance of the POHIM-RT trial. Six participating institutions were provided computed tomography for RT planning and an IMRT plan for a sample and were instructed to delineate volumes, create a treatment plan and quality assurance (QA) plan, and submit the results of all procedures. The inter-institutional agreements on RT volume and plan results were evaluated using the kappa value and dice similarity coefficients. The simultaneous truth and performance level estimation (STAPLE) method was employed to generate a consensus target volume. The treatment volumes, organs-at-risk volumes, and results of the RT plan and QA reported by the institutions were acceptable and adhered well to the protocol. In terms of clinical target volume (CTV) delineation, there were differences between the institutions, particularly in vaginal cuff and paracolpium subsites. Consensus CTV was generated from the collected CTVs with the STAPLE method. The participating institutions showed considerable agreement regarding volume, dose and QA results. To improve CTV agreement in CTV, we provided feedback with images of the consensus target volume and detailed written guidelines for specific subsites that were the most heterogeneous.

Purpose We investigated whether adoptive cell therapy with ex vivo–activated natural killer (NK) cells enhances the therapeutic efficacy of local tumor radiation therapy (RT) using a human triple-negative breast cancer xenograft model. Methods and Materials NK cells from healthy donors were expanded ex vivo. MDA-MB-231/Luc-GFP cells were subcutaneously implanted into the thighs of NSG mice. The animals were divided into 4 experimental groups: control, RT, NK, and RT + NK. On day 17 after tumor implantation, tumors from the RT groups were irradiated. The ex vivo–expanded NK cells were intravenously administered twice, on days 17 and 19. Primary and secondary tumors were evaluated using long-term bioluminescence imaging, and histopathology was performed on resected tumor tissue specimens. Results The luciferase signals of the primary tumors in the RT + NK group were significantly lower than those of comparably sized primary tumors in the RT group. The long-term migration and infiltration of NK cells into the primary tumor sites were significantly higher in RT + NK than in NK mice. Moreover, lymphatic metastasis to the axillary lymph nodes and liver and lung metastases were highly suppressed in the RT + NK group, as demonstrated by BLI and p53 immunohistochemistry. The long-term survival of the RT + NK group was significantly higher than that of the RT or NK groups. Conclusions Reduction in tumor burden by combining RT and systemic NK cell therapy improved the suppression of primary tumor growth, with efficient NK cell migration and penetration into the primary tumor site. Administered NK cells were maintained in the primary tissue for a significantly longer time in RT + NK group compared with NK group. Both lymphatic spread and distant metastasis to the lungs and liver were effectively suppressed by the combined therapy.

Most two-dimensional (2D) detector arrays used for the verification of the intensity-modulated radiotherapy (IMRT) dose distribution comprise diode detectors or ion chamber detectors. These detectors show different sensitivities depending on the angle of incidence of the IMRT beam on the detector. In this study, the effect of the radiation beam’s angle of incidence onto the detector was analyzed in order to find an optimal 2D detector array setup position for delivery quality assurance in breast IMRT. For breast IMRT plans, comprising mostly tangential fields, the dose distribution produced with true composite beams was measured by arranging 2D detector array devices at various angles. The change in dosimetric accuracy was then assessed as a function of the radiation beam’s angle of incidence. A total of 72 dose distributions were measured and analyzed for 12 breast IMRT plans. Both the diode detector array and the ion chamber array showed a higher gamma passing ratio in the sagittal dose distribution measurement, where the beam’s angle of incidence was relatively larger. This study indicates that using a 2D detector array placed at a relatively large angle of incidence offers a more accurate verification of the IMRT dose distribution.

Purpose To investigate the differences in treatment outcomes between two radiation techniques, intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT). Materials and methods We retrospectively analyzed 160 (IMRT = 23, 3DCRT = 137) patients with stage I glottic cancer treated from January 2005 through December 2016. The IMRT was performed with TomoTherapy (16 patients), volumetric-modulated arc therapy (6 patients), and step-and-shoot technique (1 patient), respectively. The 3DCRT was performed with bilateral parallel opposing fields. The median follow-up duration was 30 months (range, 31 to 42 months) in the IMRT group and 65 months (range, 20 to 143 months) in the 3DCRT group. Results The 5-year overall survival and 3-year local control rates of the 160 patients were 95.7% and 91.4%, respectively. There was no significant difference in 3-year local control rates between the IMRT and 3DCRT groups (94.4% vs. 91.0%; p = 0.587). Thirteen of 137 patients in the 3DCRT group had recurrences. In the IMRT group, one patient had a recurrence at the true vocal cord. Patients treated with IMRT had less grade 2 skin reaction than the 3DCRT group, but this had no statistical significance (4.3% vs. 21.2%; p = 0.080). Conclusion IMRT had comparable outcomes with 3DCRT, and a trend of less acute skin reaction in stage I glottic cancer patients.

Purpose Glioblastoma (GBM) is the most aggressive type of brain tumor with heterogeneity and strong invasive ability. Treatment of GBM has not improved significantly despite the progress of immunotherapy and classical therapy. Epidermal growth factor receptor variant III (EGFRvIII), one of GBM-associated mutants, is regarded as an ideal therapeutic target in EGFRvIII-expressed GBM patients because it is a tumor-specific receptor expressed only in tumors. Flagellin B (FlaB) originated from Vibrio vulnificus is known as a strong adjuvant that enhance innate and adaptive immunity in various vaccine models. This study performed whether FlaB synergistically could enhance the anti-tumor effect of EGFRvIII peptide (PEGFRvIII). Methods EGFRvIII-GL261/Fluc cells were used for glioblastoma-bearing mouse brain model and cell-bearing mice were inoculated with PBS, FlaB alone, PEGFRvIII alone, and PEGFRvIII plus FlaB. Survival rate through tumor growth was investigated by MRI. T cell population was examined by flow cytometry analysis. Both cleaved caspase-3 and CD8+ lymphocytes were shown by immunohistochemistry (IHC) staining. Results The PEGFRvIII plus FlaB group showed delayed tumor growth and increased survival rate when compared to other treatment groups. As an evidence of apoptosis, cleaved caspase-3 expression and DNA disruption were more increased in the PEGFRvIII plus FlaB group than in other groups. In addition, the PEGFRvIII plus FlaB group showed more increased CD8+ T cells and decreased Treg cells than other treatment groups in the brain. Conclusion FlaB can enhance the anti-tumor effect of PEGFRvIII by increasing CD8+ T cell response in a mouse brain GBM model.

PURPOSE To determine prognostic significance of lymphovascular invasion (LVI) in prostate cancer patients who underwent adjuvant or salvage postoperative radiotherapy (PORT) after radical prostatectomy (RP). MATERIALS AND METHODS A total of 168 patients with prostate cancer received PORT after RP, with a follow-up of ≥12 months. Biochemical failure after PORT was defined as prostate-specific antigen (PSA) ≥0.2 ng/mL after PORT or initiation of androgen deprivation therapy (ADT) for increasing PSA levels regardless of the value. We analyzed the clinical outcomes including survivals, failure patterns, and prognostic factors affecting the outcomes. RESULTS In total, 120 patients (71.4%) received salvage PORT after PSA levels were >0.2 ng/mL or owing to clinical failure. The 5-year biochemical failure-free survival (BCFFS), clinical failure-free survival (CFFS), distant metastasis-free survival (DMFS), overall survival, and cause-specific survival rates were 78.3%, 94.3%, 95.0%, 95.8%, and 97.3%, respectively, during a follow-up range of 12-157 months (median: 64 months) after PORT. On multivariate analysis, PSA level of ≤1.0 ng/mL at the time of receiving PORT predicted favorable BCFFS, CFFS, and DMFS. LVI predicted worse CFFS (p = 0.004) and DMFS (p = 0.015). Concurrent and/or adjuvant ADT resulted in favorable prognosis for BCFFS (p < 0.001) and CFFS (p = 0.017). CONCLUSION For patients with adverse pathologic findings, PORT should be initiated as early as possible after continence recovery after RP. Even after administering PORT, LVI was an unfavorable predictive factor, and further intensive adjuvant therapy should be considered for these patients.

Objectives. To investigate the prognostic factors and treatment outcomes of primary parotid carcinoma treated with surgery and postoperative radiotherapy (PORT).Methods. We reviewed retrospectively 57 patients with primary parotid carcinoma who were treated with surgery and PORT between 2005 and 2014. Superficial parotidectomy was performed in 19 patients, total parotidectomy in 10 patients, and total parotidectomy with lymph node dissection in 28 patients PORT on the tumor bed was performed in 41 patients, while PORT on tumor bed and ipsilateral cervical lymph nodes was performed in 16 patients.Results. With a median follow-up of 66 months, the 5-year overall survival, disease-free survival, locoregional control, and distant control rates were 77.0%, 60.2%, 77.6%, and 72.8%, respectively. The 5-year overall survival by stage was 100%, 100%, 80.0%, and 46.4% in stage I, II, III, and IV, respectively. Recurrences at primary lesions were found in seven patients, while at cervical nodes in six patients. Distant recurrences were developed in 12 patients. No patient with the low and intermediate histologic grade developed distant failure. As prognostic factors, the histologic grade for overall survival (P=0.005), pathological T-stage (P=0.009) and differentiation grade (P=0.009) for disease-free survival, pathological T-stage for locoregional control (P=0.007), and lympho-vascular invasion (P=0.023) for distant recurrence were significant on multivariate analysis.Conclusion. This study revealed that differentiation grade, histologic grade, pathological T-stage, and lympho-vascular invasion were significant independent prognostic factors on clinical outcomes.

Introduction To determine the prognostic significance of long-term adjuvant androgen deprivation therapy (A-ADT) over 1 year in achieving undetectable levels of prostate-specific antigen (PSA) less than 0.001 ng/mL in prostate cancer patients with high- or very high-risk prostate cancer who underwent radiotherapy (RT). Materials and methods A total of 197 patients with prostate cancer received RT, with a follow-up of ≥12 months. Biochemical failure was defined as PSA ≥nadir + 2 ng/mL after RT. We analyzed clinical outcomes, including survival, failure patterns, and prognostic factors affecting outcomes. Results Biochemical failure-free survival (BCFFS), clinical failure-free survival, distant metastasis-free survival, cancer-specific survival, and overall survival (OS) rates at 5 years were 91.1%, 95.4%, 96.9%, 99.5%, and 89.1%, respectively. Administration of long-term A-ADT significantly predicted favorable BCFFS (p = 0.027) and OS (p < 0.001) in multivariate analysis. Nadir PSA ≤0.001 ng/mL was an independent prognostic factor for BCFFS (p = 0.006) and OS (p = 0.021). The use of long-term A-ADT significantly affected nadir PSA ≤0.001 ng/mL (p < 0.001). The patients with A-ADT for 1 year or longer had better BCFFS or OS than those for less than 1 year or those without A-ADT (p < 0.001). The best prognosis was demonstrated in patients treated with long-term A-ADT and nadir PSA ≤0.001 ng/mL in BCFFS (p < 0.001). Conclusion The addition of long-term A-ADT over 1 year to RT demonstrated good treatment outcomes in patients with locally advanced prostate cancer. Achieving a nadir PSA value ≤0.001 ng/mL using combination therapy with RT and A-ADT is a powerful clinical predictor of treatment outcomes.

BACKGROUND: IBM Watson for Oncology (WFO) is a cognitive computing system helping physicians quickly identify key information in a patient’s medical record, surface relevant evidence, and explore treatment options. This study assessed the possibility of using WFO for clinical treatment in lung cancer patients. METHODS: We evaluated the level of agreement between WFO and multidisciplinary team (MDT) for lung cancer. From January to December 2018, newly diagnosed lung cancer cases in Chonnam National University Hwasun Hospital were retrospectively examined using WFO version 18.4 according to four treatment categories (surgery, radiotherapy, chemoradiotherapy, and palliative care). Treatment recommendations were considered concordant if the MDT recommendations were designated ‘recommended’ by WFO. Concordance between MDT and WFO was analyzed by Cohen’s kappa value. RESULTS: In total, 405 (male 340, female 65) cases with different histology (adenocarcinoma 157, squamous cell carcinoma 132, small cell carcinoma 94, others 22 cases) were enrolled. Concordance between MDT and WFO occurred in 92.4% (k=0.881, P

Surface-exposed calreticulin (ecto-CRT) is a well-known ‘eat-me’ signal exhibited by dying cells that contributes to their recognition and destruction by the immune system. We assessed the use of a CRT-specific binding peptide for imaging ecto-CRT during immunogenic cell death and its utility for the early prediction of treatment response. Methods: A synthetic CRT-specific peptide KLGFFKR (CRTpep) was labeled with fluorescein isothiocyanate or 18F and characteristics of ecto-CRT was evaluated in colon cancer cell line in vitro and in vivo. Results: In vitro flow cytometry, immunofluorescence staining, and in vivo micro positron emission tomography imaging results showed that CRTpep detected pre-apoptotic cells treated with immunogenic drugs or radiation, but not those treated with the non-immunogenic drug or a non-therapeutic dose of immunogenic drug. Conclusion: The present results indicate that the CRT-specific peptide would enable the prediction of therapeutic response, thereby facilitating early decisions regarding the continuation or discontinuation of immunogenic treatment.

Irradiation enhances the adhesion between natural killer (NK) cells and target cells by up-regulating intercellular adhesion molecule-1 (ICAM-1) on target cells. Therefore, we investigated the effect of irradiation-induced ICAM-1 expression on human cancer cells on NK cell-mediated cytotoxicity.Expression levels of ICAM-1 on the target cell surface before and after irradiation of six human cancer cell lines (HL60, SKBR-3, T47D, HCT-116, U937 and U251) were analyzed by flow cytometry. Ex vivo expansion of NK cells from human peripheral blood mononuclear cells was performed by co-culture with irradiated K562 cells. The related adhesion molecule lymphocyte function-associated antigen 1 (LFA-1) on NK cells was analyzed by flow cytometry. An enzyme-linked immunosorbent assay was used to detect interferon-γ (IFN-γ), and WST-8 assays were performed to check NK cell cytotoxicity. Finally, blocking assays were performed using monoclonal antibodies against ICAM-1 or LFA-1.LFA-1 expression increased on NK cells after expansion (P 0.001). The expression of ICAM-1 was significantly upregulated by irradiation after 24 h in various cell lines, including HL60 (P 0.001), SKBR-3 (P 0.001), T47D (P 0.001) and U937 (P 0.001), although the level of expression depended on the cell line. ICAM-1 expression was extremely low before and after irradiation in U251 cells. NK cell-mediated cytotoxicity increased after irradiation of HL60 (P 0.001), SKBR-3 (P 0.001), T47D (P = 0.003), and U937 (P = 0.004) cells, in which ICAM-1 expression was significantly increased after irradiation. IFN-γ production by NK cells in response to HL60 (P 0.001) and T47D (P = 0.011) cells significantly increased after irradiation. NK cell-mediated cytotoxicity against irradiated SKBR-3 (P 0.001) and irradiated T47D cells (P = 0.035) significantly decreased after blocking of ICAM-1. Blocking of LFA-1 on NK cells resulted in reduced cytotoxicity against irradiated HL60 (P 0.001) and irradiated SKBR-3 (P 0.001).Irradiation upregulates ICAM-1 expression on the surface of human cancer cells and enhances activated NK cell-mediated cytotoxicity. Therefore, irradiation combined with NK cell therapy may improve the antitumor effects of NK cells.

Purpose This study evaluated outcomes of radiotherapy (RT) after chemotherapy in limited-stage head-and-neck diffuse large B-cell lymphoma (DLBCL). Materials and Methods Eighty patients who were treated for limited-stage head-and-neck DLBCL with CHOP (n = 43) or R-CHOP (n = 37), were analyzed. After chemotherapy, RT was administered to the extended field (n = 60) or the involved field (n = 16), or the involved site (n = 4). The median dose of RT ranged from 36 Gy in case of those with a complete response, to 45–60 Gy in those with a partial response. Results In all patients, the 5-year overall survival (OS) and disease-free survival (DFS) rates were 83.9% and 80.1%, respectively. In comparison with the CHOP regimen, the R-CHOP regimen showed a better 5-year DFS (86.5% vs. 73.9%, p = 0.027) and a lower rate of treatment failures (25.6% vs. 8.1%, p = 0.040). The volume (p = 0.047) and dose of RT (p < 0.001) were significantly reduced in patients treated with R-CHOP compared to that in those treated with CHOP. Conclusion The outcomes of RT after chemotherapy with R-CHOP were better than those of CHOP regimen for limited-stage head-and-neck DLBCL. In patients treated with R-CHOP, a reduced RT dose and volume might be feasible without increasing treatment failures.

Objective The aim of this multi-institutional study was to determine the prognostic impact of tumour parameters, such as tumour size (TS), tumour volume (TV), and marker expression, on survival during radiation therapy (RT) for cervical cancer patients. Methods A total of 231 patients with histologically confirmed cervical cancer, classified as Federation of Gynecology and Obstetrics (FIGO) Ib2-IVa, were enrolled in this study. Pre- and mid-RT pelvic magnetic resonance imaging (MRI) and squamous cell carcinoma antigen (SCC-ag) analysis were performed twice, during RT and just before brachytherapy. Results The median follow-up time was 27.8months (range, 2–116months). Multivariate analysis revealed that stage (odds ratio [OR], 2.936 and 95% confidence interval [CI], 1.119–7.707; P =0.029), tumour volume reduction rate (TVRR) (OR, 3.435 and 95% CI, 1.062–11.106; P =0.039), and SCC-ag reduction rate (SCCRR) (OR, 5.104 and 95% CI, 1.769–14.727; P =0.003) were independently associated with overall survival (OS), while pre-RT TS (OR, 2.148 and 95% CI, 1.221–3.810; P =0.009), mid-RT TV (OR, 3.106 and 95% CI, 1.685–5.724; P P =0.016) were associated with progression-free survival (PFS). Based on the prognostic factor analysis, patients with the highest prognostic risk score of 3 showed poorer overall survival and progression free survival than patients with lower prognostic risk scores. Conclusion We identified that tumour parameters such as TVRR, SCCRR, pre-RT TS, and mid-RT TV areindependent and strong prognostic parameters for patients with cervical cancer receiving RT. This scoring system-based prognostic factor analysis could be used to help develop optimized treatment plans for cervical cancer patients during RT.

Background aims Few studies have examined the migration pattern of natural killer (NK) cells, especially after radiation treatment for cancer. We investigated whether irradiation can modulate the expression of chemokines in cancer cells and the migration of NK cells to irradiated tumor cells. Methods The expression of chemokine receptors (CXCR3, CXCR4 and CXCR6) on interleukin-2 (IL-2)/IL-15–activated NK cells was assessed using flow cytometry. Related chemokine ligands (CXCL11, CXCL12 and CXCL16) in human breast cancer cell lines (MCF7, SKBR3 and MDA-MB231) irradiated at various doses were assessed using reverse transcription–polymerase chain reaction (RT-PCR), fluorescence-activated cell sorting (FACS) and enzyme-linked immunosorbent assay (ELISA). The cell-free culture supernatant was collected 96 h after irradiation of breast cancer cell lines for migration and blocking assays. Results The activated NK cells expressed CXCR6. Expression of the CXCR6 ligand CXCL16 increased in a time- and dose-dependent manner in all analyzed cancer cell lines. CXCL16 expression was statistically significantly enhanced in all breast cancer cell lines on day 3 after 20 Gy irradiation. Activated NK cells migration correlated with CXCL16 concentration ( R 2 = 0.91; P 0.0001). Significantly enhanced migration of NK cells to irradiated cancer cells was observed for a dose of 20 Gy in MCF7 ( P = 0.043) and SKBR3 ( P = 0.043) cells, but not in MDA-MB231 ( P = 0.225) cells. A blocking assay using a CXCR6 antibody showed a significant decrease in the migration of activated NK cells in all cancer cell lines. Conclusions Our data indicate that irradiation induces CXCL16 chemokine expression in cancer cells and enhances the migration of activated NK cells expressing CXCR6 to irradiated breast cancer cells. These results suggest that radiation would improve the anti-tumor effect of NK cells through enhanced migration of NK cells to tumor site for the treatment of patients with breast cancer.

The optimal protocol for thoracic radiotherapy (TRT) in combination with chemotherapy in patients with limited-stage small-cell lung cancer (LS-SCLC) remains elusive. The present study aimed to evaluate radiation parameters in association with survival outcomes. A total of 101 patients with LS-SCLC who completed TRT at ≥45 Gy and concurrent chemotherapy were retrospectively reviewed. The median dose and duration of TRT were 50 Gy and 38 days, respectively. The median duration from the start of either therapy to the end of TRT (SER) was 60 days. The median survival for all patients was 26.9 months. The 3-year local control (LC), progression-free survival (PFS) and overall survival (OS) rates were 52.0, 29.5 and 37.6%, respectively, and the 5-year LC, PFS and OS rates were 50.1, 28.3 and 26.7%, respectively. Univariate analysis revealed that patient age, tumor stage, timing and dose of TRT, SER, prophylactic cranial irradiation (PCI), and tumor response were significantly associated with treatment outcomes. Multivariate analysis revealed that stage was the only significant prognostic factor for LC (P=0.011), PFS (P

We evaluated the durability of cadmium telluride (CdTe) solar cells upon proton beam irradiation as well as the possibility of achieving a dosimeter usable in proton beam therapy by applying 100 MeV of pencil beam scanning (PBS) irradiation. Specifically, a 100 MeV proton PBS beam was applied at irradiation doses of 0, 1012, 1013, 1014, and 1015 cm-2. According to the results, the remaining factors (defined as the ratio of the degraded value to the initial value) of open-circuit voltage (Voc), short-circuit current (Jsc), fill-factor (FF), and efficiency (ƞ) which are solar cell performance parameters, were approximately 89%, 44%, 69%, and 30%, respectively, compared to those of the reference cell (without irradiation) at the highest dose of 1×1015 cm-2. In particular, the conversion efficiency, which is the main factor, was approximately 70% of that of the reference cell even at a high fluence of 1×1014 cm-2. In addition, we observed the projected range of the hydrogen atoms based on the PBS beam energy using the Tool for Particle Simulation software and assessed the amount of fluence accumulated in a CdTe cell. As the energy increased, the fluence accumulated inside the cell tended to decrease owing to the characteristics of the Bragg peak of the proton. Thus, the radiation damage to the cell induced by the proton beam was reduced. The results of this study are expected to provide valuable reference information for research on dosimetry sensors composed of thin-film solar cells, serving as the basis for future application in proton beam therapy with CdTe solar cells.

Purpose: To investigate disease-free survival (DFS) and prognostic factors following the administration of postoperative (chemo)radiotherapy in patients with early-stage cervical cancers. Methods: The medical records of 1,069 patients from 10 participating institutions were reviewed. Statistically and clinically established factors were considered as candidates for constructing the prediction model. This model was validated, using bootstrapping to correct for optimistic bias. Results: The 5-year DFS rate was 81.1%, with a median follow-up period of 59.6 months. The statistically significant prognostic factors were as follows: pelvic lymph node metastasis, histologic type, parametrial invasion, lymphovascular space invasion, and tumor size. The nomogram for DFS was constructed, and it demonstrated a good discrimination performance, with an internally validated concordance index of 0.72. Conclusions: Our predictive model exhibited accurate predictions and may be useful in designing clinical trials to study if further chemotherapy can reduce the recurrence of disease in high-risk patients.

To investigate whether combined chemoradiotherapy (CTRT) confers a benefit for survival outcome over radiotherapy (RT) alone after primary surgery in patients with FIGO stage IIIC endometrial adenocarcinoma.We conducted a multicenter retrospective study of patients with surgical stage IIIC endometrial cancer from 1990 to 2011. Adjuvant RT alone was performed in 85 patients (40.3%) and adjuvant CTRT in 126 patients (59.7%). Disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazards model.Stage IIIC1 and stage IIIC2 accounted for 63% and 37%, respectively. FIGO IIIC2 had a higher recurrence rate than FIGO IIIC1 (38.5% vs. 29.3%, p=0.172). Five-year OS and DFS were lower in FIGO IIIC2 than FIGO IIIC1 (85.1% vs. 76.9%, p=0.417; 71.0% vs. 59.2%, p=0.108, respectively). Eighteen patients (13.5%) in stage IIIC1 developed PALN recurrence, whereas only one (3.3%) in stage IIIC2 had PALN recurrence (p=0.001). In multivariate analysis, predictors of DFS were parametrial invasion (HR, 3.49; 95% CI, 1.83-6.64; p0.001), higher grade (HR, 2.78; 95% CI, 1.31-5.89; p=0.008), and3 positive pelvic nodes (HR, 1.84; 95% CI, 1.11-3.05; p=0.019). Combined CTRT did not affect DFS or OS in IIIC1 and IIIC2 compared with RT alone.CTRT showed comparable survival outcome to RT alone. Half of relapses (46%) in stage IIIC1 occurred in PALN region, whereas relapse in stage IIIC2 primarily occurred in distant metastasis (90%). Future randomized studies are needed to determine which subgroup may be most likely to benefit from CCRT.

Purpose To evaluate treatment outcomes and determine prognostic factors in patients with esophageal cancer treated with esophagectomy after neoadjuvant chemoradiotherapy (NCRT). Materials and methods We retrospectively evaluated 39 patients with esophageal cancer who underwent concurrent chemoradiotherapy followed by esophagectomy between 2002 and 2012. Initial clinical stages of patients were stage IB in 1 patient (2.6%), stage II in 5 patients (12.9%), and stage III in 33 patients (84.6%). Results The median age of all the patients was 62 years, and the median follow-up period was 17 months. The 3-year overall survival (OS) rate was 33.6% in all the patients. The 3-year locoregional recurrence-free survival (LRFS) rate was 33.7%. In multivariate analysis with covariates of age, the Eastern Cooperative Oncology Group performance status, hypertension, diabetes mellitus, tumor length, clinical response, clinical stage, pathological response, pathological stage, lymphovascular invasion, surgical type, and radiotherapy to surgery interval, only pathological stage was an independent significant prognostic factor affecting both OS and LRFS. The complications in postoperative day 90 were pneumonia in 9 patients, anastomotic site leakage in 3 patients, and anastomotic site stricture in 2 patients. Postoperative 30-day mortality rate was 10.3% (4/39); the cause of death among these 4 patients was respiratory failure in 3 patients and myocardial infarction in one patient. Conclusion Only pathological stage was an independent prognostic factor for both OS and LRFS in patients with esophageal cancer treated with esophagectomy after NCRT. We could confirm the significant role of NCRT in downstaging the initial tumor bulk and thus resulting in better survival of patients who gained earlier pathological stage after NCRT.

Objective Radiotherapy (RT) has been advocated for gliomatosis cerebri (GC) to delay tumor progression. However, patients with GC may experience poor performance status without recurrence after RT. Herein, we reviewed the responses of patients with GC treated with RT. Materials and methods Seventeen patients with diffuse radiologic infiltration of more than two cerebral lobes and diagnosed as having grade II ( N = 12) or III ( N = 5) glioma were treated with a mean radiation dose of 51.8 Gy (range, 42–59.4 Gy). The mean radiation volume to a mean marginal dose of 42.8 Gy (range, 36–45 Gy) was 693.4 cc (range, 316.5–1279.6 cc), which was 45.3% of the mean whole brain volume. We reviewed the clinical prognostic factors related to progression-free survival (PFS) and overall survival (OS) in all patients and described characteristics of patients with poor performance (Eastern Cooperative Oncology Group performance scale 3–4) without recurrence. Results In all patients, the median PFS was 12.3 months, and oligodendroglial pathology ( p = 0.002) and non-enhanced tumor ( p = 0.002) were associated with an improved PFS. The median OS was 39.3 months, and young age and adjuvant chemotherapy were associated with improved OS ( p = 0.022 and 0.002, respectively). Based on multivariate analysis, adjuvant chemotherapy was significantly associated with a longer OS ( p = 0.012; hazard ratio = 0.099; 95% CI, 0.016–0.596). Five patients (29.4%) showed poor performance without recurrence. The median age of these 5 patients was 65 years (range, 60–75 years). The mean radiation volume to a mean marginal dose of 41 Gy (range, 36–45 Gy) was 539.9 cc (range, 255.5–983.1 cc). The pathologic diagnosis was grade II glioma in 2 patients and grade III in 3 patients. The median OS was 10.0 months (range, 8.2–45.9 months). Conclusions Some GC patients, especially the elderly, might have a poor performance status without recurrence after RT of a larger radiation field.

Backgrounds Stereotactic ablative radiotherapy (SABR) is one of the newly developed innovative radiotherapy and of which optimal dose prescription needs to be standardized. We aimed to investigate the dose-response relationship for patients with SABR. Methods Fifty-three patients with Stage I non-small cell lung cancer patients, who underwent SABR between November 2006 and January 2015, were evaluated retrospectively. Thirteen patients (24.5%), who refused the surgery were included and 40 patients (75.5%) were medically inoperable at diagnosis. The median age was 74 years. The median SABR dose was 50 Gy in 3-8 fractions and the median biologically effective dose (BED;α/β = 10) was 105.6 Gy (range: 60-160.53 Gy). Results The median follow-up was 37.1 months. The 1 and 3 year local control rates were 91.7% and 85.1%. The 3 year overall and progression-free survival rate were 63.3% and 47.5%, respectively, and freedom from progression was 62.2%. Local control rate and 3-year overall survival according to tumor size was 100% and 79.4% in T1 tumors in a while 61.8% and 45% in T2a tumors. The 3-year local and regional control by BED10 was 79.4% and 69.4% in ≤100 Gy vs. 89.1% and 100% in >100 Gy (P = 0.526, 0.004). Dyspnea more than Grade 3 was reported in six (11.3%) patients and Grade 1 chest pain was shown in five (9.4%) patients. Conclusions The excellent regional control was conferred with a prescription of more than BED10 of 100 Gy, which also might be needed to achieve better local tumor control in T2a patients with tolerable lung function.

BACKGROUND/AIM The inhibition of a disintegrin and metalloproteinase (ADAM) has the potential to become a novel approach for natural killer (NK) cell-based cancer immunotherapy. Thus, the aim of this study was to investigate the influence of ADAM10 and ADAM17 inhibitors on expanded NK cell to enhance antibody-dependent cellular cytotoxicity (ADCC) in breast cancer cell lines. MATERIALS AND METHODS NK cells were expanded in medium supplemented with an ADAM10 or ADAM17 inhibitor to prevent the shedding of soluble CD16/FcγRIII. The expression level of CD16 and production of interferon-gamma (IFN-γ) was detected by flow cytometry using specific antibodies. ADCC activity of expanded NK cells was estimated in trastuzumab treated breast cancer cell lines such as MCF-7, MDA-MB-231, SKBR3, and BT-474 cells. RESULTS The ADAM17 inhibitor increased the purity of expanded NK cells to 90% after 14 days at 5 and 10 μM in vitro (p=0.043). However, the expansion rate of NK cells was decreased at 10 μM of the ADAM 17 inhibitor (p=0.043). Inhibition of ADAM10 suppressed the expansion of NK cells, although the NK purity was increased at 1 μM of the inhibitor. The expression of CD16 was significantly increased at 1 and 5 μM of the ADAM17 inhibitor (p=0.046, 0.028, respectively) during the culturing period. Inhibition of ADAM10 reduced the expression of CD16 on NK cells. The cytotoxic activity of the ADAM17 inhibitor treated NK cells against MCF-7 (p=0.039) and BT-474 (p=0.027) cells was significantly elevated. The ADCC activity of NK cells treated with 5 μM of ADAM17 inhibitor was significantly increased against SKBR-3 and BT-474 (p=0.027). Inhibition of ADAM17 increased the production of IFN-γ in expanded NK cells. CONCLUSION The inhibition of ADAM17 enhanced the purity of expanded NK cells and the ADCC activity of these cells against trastuzumab treated breast cancer cell lines.

Definitive chemoradiotherapy (CRT) followed by brachytherapy is a standard treatment for locally advanced cervical cancer. During CRT, marked reduction of cervical tumor is often observed in magnetic resonance imaging (MRI). The primary aim of this study was to assess the association between tumor response in MRI using FIGO classification and clinical outcomes.Multi-institutional data were retrospectively reviewed to identify the significance of MR tumor response on tumor recurrence and patient survival. 225 patients with histologically confirmed squamous cell carcinoma of the cervix, staged as FIGO Ib2-IVa on initial pelvic MRI, were included. Post-CRT MRI was performed median 35days after the beginning of CRT and before brachytherapy. A median 54Gy of external radiation was given with weekly cisplatin during CRT.112 (49.7%) of the 225 patients showed a positive response in post-CRT MRI and were named the responsive arm. After a median follow-up time of 36.2months, the responsive arm had significantly lower para-aortic recurrence (7.5% vs. 12.4%; p=0.04) and distant metastasis (13.2% vs. 27.6%; p=0.03) rates than did the non-responsive arm. The responsive arm had significantly higher 3-year cause-specific survival rate (94.6% vs. 81.1%, p0.01) than did the non-responsive arm. In the multivariate analysis, tumor size (hazard ratio, 1.91 and 95% confidence interval, 1.07-3.43; p=0.028) and positive MR response (hazard ratio, 1.75 and 95% confidence interval, 1.06-2.27; p=0.045) were significant factors for recurrence-free survival CONCLUSION: Early tumor response evaluation with MRI using FIGO classification effectively predicted distant tumor metastasis and disease-specific survival in locally advanced cervical cancer.

Purpose To determine inter-observer variability in target volume definition of cervical cancer in radical and adjuvant radiotherapy (RT) settings. Methods Eight physicians contoured CTVs of 2 patients underwent definitive and postoperative RT. Each volume was analyzed using the individual/median volume ratio and generalized conformity index (CIgen). And center of mass (COM) of each contour was calculated. Expert agreement was quantified using an expectation maximization algorithm for Simultaneous Truth and Performance Level Estimation (STAPLE). Results For definitive RT, the individual/median volume ratio ranged from 0.51 to 1.41, and CIgen was 0.531. Mean 3-dimensional distances of average to each COM were 7.8 mm. For postoperative RT setting, corresponding values were 0.65-1.38, 0.563, and 5.3 mm. Kappa value of expert agreement was 0.65 and 0.67, respectively. STAPLE estimates of the sensitivity, specificity, and kappa measures of inter-physician agreement were 0.73, 0.98, and 0.65 for the definitive and 0.75, 0.98, and 0.67 for the adjuvant radiotherapy setting. The largest difference was observed in the superior-inferior direction, particularly in the upper vagina and the common iliac area. Conclusion As there was still some variability in target delineation, more detailed guidelines for target volume delineation and continuing education would help to reduce this uncertainty.

Based on per-field data, 3 dose-volume histogram (DVH) is designed to calculate 3-dimensional (3D) dose using patient-computed tomography (CT) for an intensity-modulated radiation therapy (IMRT) delivery quality assurance (DQA) process measured with diode detector arrays. In this study, the characteristics and suitability of 3DVH for an IMRT DQA process were evaluated by assessment of clinically applied results. The DQA plans were prepared with a 2D diode detector array (MapCHECK 2) for 20 IMRT patients (10 with head and neck cancer and 10 with prostate cancer), and the matching rate between the calculated dose and the measured dose was analyzed. The relative dose differences between the original IMRT plan and the recalculated plan by 3DVH were evaluated for tumor target and organs at risk (OARs). Confidence limits (CLs) were determined for quantification of the degree of agreement that should be expected in each DQA method. The individual CLs for DQA accuracy of 3D dosimetric evaluation in the tumor target and OARs were also calculated to evaluate the differences compared with conventional 2D-based DQA results. The matching rates were sufficient to validate the accuracy of IMRT DQA analyses and the calculated CL values were reasonable values considering the normal criteria of our institution. The 3DVH analysis generally had better matching rate than per-field measurement analysis and the CL values for OARs were better than those for the planning target volume (PTV). The usefulness of the 3DVH tool was verified for IMRT DQA from the point of view of dose evaluation in the corresponding patient's CT data. It also enables dosimetric evaluation in each important structure (PTV and OARs), which can promote more effective evaluation of DQA error in terms of tumor treatment and side effects.