Efficacy and safety of combined targeted therapy and immunotherapy versus targeted monotherapy in unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Cancer therapy has evolved from non-specific cytotoxic agents to a selective, mechanism-based approach that includes targeted agents and immunotherapy. Although the response to targeted therapies for unresectable hepatocellular carcinoma (HCC) is acceptable with the improved survival, the high tumor recurrence rate and drug-related side effects continue to be problematic. Given that immune checkpoint inhibitor alone are not robust enough to improve survival in unresectable HCC, growing evidence supports the combination of targeted therapy and immunotherapy with synergistic effect. METHODS: Online databases including PubMed, EMBASE, Cochrane Library, and Web of Science were searched for the studies that compared targeted monotherapy with the combination therapy of targeted drug and checkpoint inhibitors in unresectable HCC patients. Eligibility criteria were the presence of at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors (version 1.1) for unresectable HCC patients, an Eastern Cooperative Oncology Group performance status of 0-2, and a Child-Pugh score ≤ 7. Outcome measurements include overall survival (OS), progression-free survival (PFS), and treatment-related adverse event (TRAE). RESULTS: Three phase II/III randomized controlled trials were included in this study. The pooled results showed that combination therapy significantly improved survival than targeted monotherapy, in terms of OS (hazard ratio (HR) = 0.67; 95% confidence interval [CI]: 0.50-0.91) and PFS (HR = 0.58; 95% CI: 0.51-0.67), respectively. In the incidence of grade 3-5 TRAEs, the combination therapy was significantly higher than targeted monotherapy (odds ratio = 1.98; 95% CI: 1.13-3.48). CONCLUSION: For unresectable HCC, combined targeted drug and immunotherapy significantly improved survival compared with targeted monotherapy. However, the incidences of AEs of combinational therapy were higher than targeted monotherapy.

Effectiveness of tutor shadowing on faculty development in problem-based learning.

BACKGROUND: To enhance tutors' teaching skills, tutor shadowing for novice tutors of problem-based learning (PBL) in addition to conventional faculty development (FD) was applied. This study aimed to develop a tutoring-skill scale (TS-scale) and evaluate the effect of shadowing on PBL tutors. METHODS: This study employed a before-and-after study design with three phases. In phase 1, a TS-scale was elaborated. A validity examination was performed in phase 2. Phase 3 was a study of the effectiveness using a TS-scale survey of novice PBL tutors before and after the FD course. The FD course for novice PBL tutors included an FD workshop and PBL shadowing activities. RESULTS: A TS-scale with a 32-item questionnaire of self-rated confidence for PBL tutors was identified in phase 1. In phase 2, 7 experienced specialists in medical education were invited to evaluate the content validity of the scale. The item content validity index (I-CVI) ranged from 0.86 to 1, and the scale-CVI (S-CVI) was 0.95. A total of 85 novice PBL tutors completed the TS-scale before the FD course, yielding a Cronbach's alpha of 0.98. An exploratory factor analysis with varimax rotation was performed. The twenty-four items with significant loadings greater than 0.5 were incorporated into a new TS-scale and were grouped into three factors: student contact, medical expertise, and teaching expertise. In phase 3, 76 novice PBL tutors completed the 24-item TS-scale before (pretest) and after (posttest) the FD course. Their self-rated confidence improved significantly across the three factors after the FD course. The pretest and posttest scores did not differ according to the tutors' gender, the grades they taught, or their specialty background. CONCLUSIONS: Novice PBL tutors benefit from FD that incorporates tutor shadowing in the 3 key domains of tutoring competencies. The TS-scale developed in this study can be applied in future research on FD design.

Moving from tangibility toward digitalization: investigating team dynamics and facilitator support among medical students in conventional and digital small-group tutorials.

BACKGROUND: Small group tutorials (SGT) promotes self-directed learning and is widely used in medical education. The coronavirus pandemic (COVID-19) has accelerated the trend toward SGT digitalization, with unclear effect. We hypothesize that team dynamics and facilitator support influence SGT satisfaction in digital versus conventional SGT. METHODS: During the spring semester of year 2021, medical students (the second, third, and fourth year; n = 433) participating in conventional face-to-face and digital SGT curricula were enrolled. Participating students completed the collaborative learning attitude scale (including team dynamics, team acquaintance, and facilitator support dimensions) and teamwork satisfaction scale, previously validated for small-group collaborative learning, and chose preference between conventional or digital SGT in future curricula. Exploratory factor analysis (EFA) was performed to extract the essential structural factors of these scales. Paired t-tests were conducted to compare differences in different dimensions and satisfaction between the conventional and digital SGT settings. Two sets of multiple regression analyses were done; one with team satisfaction scale results and the other with preference for digital SGT as the dependent variable were used to evaluate determinants of these two variables. RESULTS: The EFA results revealed that the original collaborative learning attitude scale was concentrated on two dimensions: team dynamics and facilitator support. No significant differences were noted between the SGT settings for the two dimensions and teamwork satisfaction. Regression analyses showed that teamwork dynamics was independently correlated with teamwork satisfaction in both conventional and digital SGT. Facilitator support was positively correlated with teamwork satisfaction in conventional, but not digital SGT. Higher teamwork satisfaction was an important determinant of preference for digital SGT among medical students. CONCLUSIONS: Team dynamics were closely linked to teamwork satisfaction among medical students in both conventional and digital SGT, while the role of facilitator support became less obvious during digital SGT.

Targeting histone deacetylase 4/ubiquitin-conjugating enzyme 9 impairs DNA repair for radiosensitization of hepatocellular carcinoma cells in mice.

Several strategies to improve the efficacy of radiation therapy against hepatocellular carcinoma (HCC) have been investigated. One approach is to develop radiosensitizing compounds. Because histone deacetylase 4 (HDAC4) is highly expressed in liver cancer and known to regulate oncogenesis through chromatin structure remodeling and controlling protein access to DNA, we postulated that HDAC4 inhibition might enhance radiation's effect on HCC cells. HCC cell lines (Huh7 and PLC5) and an ectopic xenograft were pretreated with HDAC inhibitor or short hairpin RNA to knock down expression of HDAC4 and then irradiated (2.5-10.0 Gy). We evaluated cell survival by a clonogenic assay; apoptosis by Annexin V immunofluorescence; γH2AX, Rad51, and HDAC4 by immunofluorescence staining; HDAC4, Rad51, and ubiquitin-conjugating enzyme 9 (Ubc9) in HCC cell nuclei by cell fractionation and confocal microscopy; physical interaction between HDAC4/Rad51/Ubc9 by immunoprecipitation; and the downstream targets of HDAC4 knockdown by immunoblotting. Both HDAC4 knockdown and HDAC inhibitor enhanced radiation-induced cell death and reduced homologous recombination repair of DNA double-strand breaks and protein kinase B activation, leading to increased apoptosis. HDAC4 knockdown with or without an HDAC inhibitor significantly delayed tumor growth in a radiation-treated xenograft model. Radiation stimulated nuclear translocation of Rad51 in an HDAC4-dependent manner and the binding of Ubc9 directly to HDAC4, which led to Ubc9 acetylation. Moreover, these effects were accompanied by HDAC4/Ubc9/Rad51 complex dissociation through inhibiting nuclear translocation. Conclusion: HDAC4 signaling blockade enhances radiation-induced lethality in HCC cells and xenografts. These findings raise the possibility that HDAC4/Ubc9/Rad51 complex in DNA repair may be a target for radiosensitization of HCC. (Hepatology 2018;67:586-599).

The ratio of weight loss to planning target volume significantly impacts setup errors in nasopharyngeal cancer patients undergoing helical tomotherapy with daily megavoltage computed tomography.

BACKGROUND: Changes in head and neck anatomy during radiation therapy (RT) produce setup uncertainties of nasopharyngeal cancer (NPC) irradiation. We retrospectively analyzed image guidance data to identify clinical predictors of setup errors. PATIENTS AND METHODS: The data of 217 NPC patients undergoing definitive RT on a helical tomotherapy (HT) unit were analyzed. Factors including tumor stage, body mass index, weight loss, and planning target volume (PTV) were assessed as predictors of daily megavoltage computed tomography (MVCT) setup displacements, which were automatically registered using software. RESULTS: Mean daily setup displacements (in mm) were 1.2 ± 0.6, 1.8 ± 0.8, 3.4 ± 1.4 in the medial-lateral (ML), superior-inferior (SI), and anterior-posterior (AP) directions, respectively. Mean weight loss was 4.6 ± 3.3 kg (6.8 ± 4.9%). Patients with weight loss > 5% had significantly larger setup displacements in the AP (3.6 ± 1.5 vs. 2.9 ± 1.1 mm, p < 0.001) and SI (1.6 ± 0.7 vs. 1.9 ± 0.9 mm, p = 0.01) direction, but not in the ML direction (p = 0.279). The AP setup error increased 0.06 mm (y = 0.055x + 2.927, x: percentage of weight loss/PTV, y: AP displacement) per one percent increase in weight loss normalized to PTV. CONCLUSIONS: Patients with weight loss > 5% and smaller PTVs, possibly because of small body frame or neck girth, were more likely to have increased setup errors in the AP direction.

Sonic Hedgehog inhibition as a strategy to augment radiosensitivity of hepatocellular carcinoma.

BACKGROUND AND AIM: Sonic Hedgehog (SHH) is a regulator in tumorigenesis of hepatocellular carcinoma (HCC). This study aimed to determine whether radiation-induced SHH signaling occurs in HCC and whether SHH inhibitor acts as a radiosensitizer. METHODS: The in vitro effects of combining SHH ligand (recombinant human SHH) or inhibitor (cyclopamine) with irradiation were evaluated in the human HCC cell lines, Huh-7 and PLC/PRF/5, and murine cell line BNL. Cell survival and apoptosis were measured using a colony formation assay, annexin-V staining, and poly (ADP-ribose) polymerase activation. Western blotting and immunofluorescence staining were used to detect protein expression. The in vivo response to radiotherapy and/or cyclopamine was tested in BALB/c mice bearing an orthotopic allogeneic tumor. RESULTS: Treatment of HCC cells with irradiation and SHH ligand had a protective effect on clonogenic cell survival. Treatment with irradiation and cyclopamine was a more potent inhibitor of cell proliferation than either modality alone. The antiproliferative activity of cyclopamine was attributable to apoptosis induction. Radiation dose-dependently upregulated the expression of Gli-1 (a transcription factor induced by SHH), and this effect was observed mainly in the nucleus. When combined with cyclopamine, irradiation inhibited Gli-1 and increased DNA double-strand breakage. Radiotherapy increased SHH and Gli-1 expression in allogeneic tumor. When compared with radiotherapy alone, cyclopamine with radiotherapy reduced the mean tumor size of orthotopic tumors by 67% (P < 0.05). CONCLUSION: Combining an SHH inhibitor with radiotherapy may enhance HCC cell and orthotopic tumor radiosensitivity.

High serum levels of vascular endothelial growth factor-A and transforming growth factor-ß1 before neoadjuvant chemoradiotherapy predict poor outcomes in patients with esophageal squamous cell carcinoma receiving combined modality therapy.

BACKGROUND AND PURPOSE: This study was aimed at using proximity ligation assay (PLA) followed by enzyme-linked immunosorbent assay (ELISA) to identify serum biomarkers that predict treatment response and survival for patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant concurrent chemoradiotherapy (CCRT) followed by esophagectomy. METHODS: Seventy-nine patients with ESCC receiving CCRT of taxane-based/5-fluorouracil-based chemotherapy and 40 Gy followed by surgery were enrolled. Serum samples were collected before and <1 month after CCRT. Fifteen biomarkers were analyzed using PLA. Biomarkers significantly correlating with pathological response/survival were verified by ELISA. Associations of the serum level of biomarkers and clinical factors with pathological response, disease-free survival (DFS), and overall survival (OS) were evaluated by analysis of variance and log-rank tests. RESULTS: Thirty patients had complete response (38 %), 37 had microscopic residual disease (47 %), and 12 had macroscopic residual disease (15 %). With a median follow-up of 52.8 months, the median DFS was 43 months. Among the 15 biomarkers screened by PLA, vascular endothelial growth factor (VEGF)-A and transforming growth factor (TGF)-ß1 were significantly associated with pathological response and/or DFS. These biomarkers were further analyzed by ELISA to confirm initial biomarker findings by PLA. After ELISA of these two markers, only VEGF-A levels were significantly correlated with pathological response. On multivariate analysis, patients with combined high pre-CCRT VEGF-A and TGF-ß1 levels (greater than or equal to the median), independent of pathological response, had significantly worse DFS (11 months vs. median not reached; p = 0.007) and OS (16 vs. 46 months; p = 0.07). CONCLUSIONS: Pre-CCRT serum VEGF-A and TGF-ß1 levels may be used to predict pathological response and survivals for ESCC patients receiving combined-modality therapy.

Neoadjuvant bevacizumab and chemoradiotherapy in locally advanced rectal cancer: early outcome and technical impact on toxicity.

BACKGROUND: We aimed to evaluate early clinical and pathological results for treating locally advanced rectal cancer with bevacizumab and neoadjuvant concurrent chemoradiotherapy using the technique of prone-position volumetric modulated arc therapy and to compare the toxicity of volumetric modulated arc therapy with that of supine-position four-field box radiotherapy. METHODS: Twelve patients with stage IIA to IVA rectal adenocarcinoma, treated with neoadjuvant concurrent chemoradiotherapy (45 Gy in 25 fractions to the rectal tumor and pelvic lymphatics) and bevacizumab, were prospectively enrolled. Chemotherapy included FOLFOX (leucovorin, fluorouracil, and oxaliplatin) (n=11) and 5-fluorouracil (n=1). All patients received prone-position volumetric modulated arc therapy. A historical cohort treated with supine-position box radiotherapy, including six other patients treated with bevacizumab-based concurrent chemoradiotherapy in our hospital, was used for comparison. Setup errors, toxicities, and potential biomarkers were evaluated. RESULTS: All patients completed neoadjuvant concurrent chemoradiotherapy and underwent total mesorectal excision. Four (33.3%) patients had pathological complete response. Significantly more grade 2 or 3 diarrhea was associated with the supine-box technique (5/6 versus 2/12, P=0.01). The magnitude of setup errors was similar between the supine-box and prone volumetric modulated arc therapy techniques. The estimated 2-year survival and 2-year failure-free survival rates were 100% and 72.9% in the prone volumetric modulated arc therapy group and 66.7% and 66.7% in the supine box group, respectively. CONCLUSIONS: The early clinical outcome has been encouraging. Volumetric modulated arc therapy in prone-positioned patients was technically advantageous and reduced bowel toxicity.

Biomarker studies on radiotherapy to hepatocellular carcinoma.

Radiotherapy (RT) has been gradually integrated into the multimodality treatment for hepatocellular carcinoma (HCC). The various patterns of failure in HCC patients undergoing RT drive the need of effective biomarkers to guide treatment decisions. Limited numbers of biomarkers have been investigated in HCC, with even fewer of them for patients treated by RT. Serum or plasma biomarkers measured by enzyme-linked immunosorbent assay were the most common practice. Of particular interest are those biomarkers that are detectable early in the course of radiotherapy which correlated with ultimate clinical outcome. Functional magnetic resonance imaging (MRI) is increasingly used to evaluate the imaging pattern indicative of disease control following RT. Positron emission tomography shows that pre-RT standard uptake values associate with various types of recurrence after treatment. Proximity ligation assay (PLA) is evolving with the unique features of dual-probe identification, ligation and amplification to allow the small volume of serum/plasma samples for evaluating multiple biomarkers. We demonstrate the screening work of biomarkers by PLA with pre- and post-RT serum samples from HCC patients undergoing RT. Efforts are being made to search for the potential biomarkers for HCC patients treated by RT.

Safe Handling of Patient Gowns During the COVID-19 Pandemic: An Intelligent System for Patients With Cancer Undergoing Daily Radiotherapy.

BACKGROUND/AIM: Nosocomial infection is a substantial clinical, societal and economic burden, especially during the COVID-19 pandemic. Patients with cancer are required to change into patient gowns before receiving radiotherapy. To improve efficiency and infection control, we designed novel intelligent devices for both gown distribution and recycling. We conducted a pilot study to provide evidence for the device in healthcare quality improvement. MATERIALS AND METHODS: We designed and set up intelligent machines with an infrared sensor for patient gown distribution and recycling. The performance of these machines was assessed by questionnaire survey of patients' perceptions and handling by laundry personnel. RESULTS: We composed a questionnaire to measure patient/personnel satisfaction upon gown handling based on the existing data of our hospital. Two generations of patient gown distribution machines were introduced. One was the novel automated device for both gown distribution and recycling. The other one was the conventional wooden cabinets and/or hamper stands with foot pedals. Survey results showed that approximately 90% satisfaction was achieved with the automated machines. Overall satisfaction with the new soiled gown recycling machines was significantly higher than that with the conventional receptacles (p<0.01). CONCLUSION: The automated patient gown distribution machines safely and efficiently provide patients with suitable gowns. The automated patient gown recycling machine reduces contamination of the gown recycling area. Using these machines improves infection control in the hospital environment and effectively reduces the risk of nosocomial infection.

Topoisomerase I Inhibition Radiosensitizing Hepatocellular Carcinoma by RNF144A-mediated DNA-PKcs Ubiquitination and Natural Killer Cell Cytotoxicity.

Background and Aims: Topoisomerase I (TOP1) participates the repair of DNA double-strand breaks (DSBs) upon radiation therapy (RT). RNF144A mediates ubiquitination of catalytic subunit of DNA protein kinase (DNA-PKcs), a critical factor in DSB repair. This study aimed to investigate the natural killer (NK) cell-mediated radiosensitization with TOP1 inhibition and the mechanism by DNA-PKcs/RNF144A. Methods: In vitro synergism with TOP1i or cocultured NK cells and RT were evaluated in human hepatocellular carcinoma (HCC) cell lines (Huh7/PLC5) by clonogenic survivals. Orthotopic xenografts were treated with Lipotecan and/or RT. Protein expression was analyzed by western blotting, immunoprecipitation, subcellular fractionation, and confocal microscopy. Results: Lipotecan/RT had a superior synergistic effect to RT on HCC cells. Combined RT/Lipotecan reduced the xenograft size by 7-fold than RT (p<0.05). Lipotecan caused more radiation-induced DNA damage and DNA-PKcs signaling. The expression of major histocompatibility complex class I-related chain A and B (MICA/B) on tumor cells is associated with the sensitivity to NK cell-mediated lysis. Cocultured NK and HCC cells with Lipotecan radiosensitized HCC cells/tissues with the expression of MICA/B. RNF144A increased more in Huh7 cells with combined RT/TOP1i, and reduced the prosurvival function of DNA-PKcs. The effect was reversed by inhibiting the ubiquitin/proteasome system. In comparison, RNF144A decreased through nuclear translocation with the cumulated DNA-PKcs and radio-resistance of PLC5 cells. Conclusions: TOP1i reinforces NK cell-activated anti-HCC effect of RT through RNF144A mediated DNA-PKcs ubiquitination. RNF144A provides a reason for differentiating radiosensitization effect between HCC cells.

Radiosensitization effect by HDAC inhibition improves NKG2D-dependent natural killer cytotoxicity in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Radiotherapy (RT) controls HCC unsatisfactorily and temporarily. Histone deacetylase inhibitor (HDACi) is a heterogeneous group of epigenetic therapeutics with promising anticancer effects and synergism in combination with RT. HDACi modulates natural killer (NK) cell ligand expression on tumor cells, and leads to immune evasion of cancer cells. Expressions of NK group 2D (NKG2D) ligands on cancer cells determine the cytotoxic effect by interacting with NKG2D receptor on NK cells. However, the role of NKG2D signaling in HCC upon combined RT and HDACi remains unclear. Method: In vitro co-culture system with NK cells was tested for human and murine HCC cell lines. Pan-HDACi (panobinostat) and specific HDAC4 knockdown (HDAC4-KD) were used for HDAC inhibition. Clonogenic assay and flow cytometry examined HCC cell survival and NKG2D ligand expression, respectively. Syngeneic mouse model was used to validate the radiosensitizing effect in vivo. Results: Combined RT and HDACi/HDAC4-KD significantly enhanced NK cell-related cytotoxicity and increased NKG2D ligands, MICA/MICB expressions in human and RAE-1/H60 expressions in murine HCC cells. Delayed tumor growth in vivo by the combinational treatment of RT and HDACi/HDAC4-KD was shown with the associated NKG2D ligand expressions. However, NKG2D receptor did not significantly change among tumors. Conclusion: Radiosensitizing effect with combined RT and HDAC inhibition increased the expression of NKG2D ligands in HCC cells and enhanced their susceptibility to NK cell-mediated cytotoxicity. These findings imply the potential use of combined RT/HDACi and NK cell-directed immunotherapy.

Practically acquired and modified cone-beam computed tomography images for accurate dose calculation in head and neck cancer.

BACKGROUND: On-line cone-beam computed tomography (CBCT) may be used to reconstruct the dose for geometric changes of patients and tumors during radiotherapy course. This study is to establish a practical method to modify the CBCT for accurate dose calculation in head and neck cancer. PATIENTS AND METHODS: Fan-beam CT (FBCT) and Elekta's CBCT were used to acquire images. The CT numbers for different materials on CBCT were mathematically modified to match them with FBCT. Three phantoms were scanned by FBCT and CBCT for image uniformity, spatial resolution, and CT numbers, and to compare the dose distribution from orthogonal beams. A Rando phantom was scanned and planned with intensity-modulated radiation therapy (IMRT). Finally, two nasopharyngeal cancer patients treated with IMRT had their CBCT image sets calculated for dose comparison. RESULTS: With 360° acquisition of CBCT and high-resolution reconstruction, the uniformity of CT number distribution was improved and the otherwise large variations for background and high-density materials were reduced significantly. The dose difference between FBCT and CBCT was < 2% in phantoms. In the Rando phantom and the patients, the dose-volume histograms were similar. The corresponding isodose curves covering ≥ 90% of prescribed dose on FBCT and CBCT were close to each other (within 2 mm). Most dosimetric differences were from the setup errors related to the interval changes in body shape and tumor response. CONCLUSION: The specific CBCT acquisition, reconstruction, and CT number modification can generate accurate dose calculation for the potential use in adaptive radiotherapy.

Competing Risk Analysis of Outcomes of Unresectable Pancreatic Cancer Patients Undergoing Definitive Radiotherapy.

PURPOSE: We investigated potential factors, including clinicopathological features, treatment modalities, neutrophil-to-lymphocyte ratio (NLR), carbohydrate antigen (CA) 19-9 level, tumor responses correlating with overall survival (OS), local progression (LP), and distant metastases (DMs), in patients with locally advanced pancreatic cancer (LAPC) who received definitive radiotherapy (RT). METHODS: We retrospectively analyzed demographic characteristics; biologically effective doses (BED10, calculated with an α/ß of 10) of RT; and clinical outcomes of 57 unresectable LAPC (all pancreatic adenocarcinoma) patients receiving definitive RT using modern techniques with and without systemic therapy between January 2009 and March 2019 at our institution. We used Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 to evaluate the radiographic tumor response after RT. The association between prognostic factors and OS was assessed using the Kaplan-Meier analysis and a Cox regression model, whereas baseline characteristics and treatment details were collected for competing-risk regression of the association with LP and DM using the Fine-Gray model. RESULTS: A median BED10 of 67.1 Gy resulted in a disease control rate of 87.7%, and the median OS was 11.8 months after a median follow-up of 32.1 months. The 1-year OS rate, cumulative incidences of LP, and DM were 49.2%, 38.5%, and 62.9%, respectively. Multivariate analyses showed that pre-RT NLR ≥3.5 (adjusted hazard ratio [HR] = 8.245, p < 0.001), CA19-9 reduction rate ≥50% (adjusted HR = 0.261, p = 0.005), RT without concurrent chemoradiotherapy (adjusted HR = 5.903, p = 0.004), and administration of chemotherapy after RT (adjusted HR = 0.207, p = 0.03) were independent prognostic factors for OS. Positive lymph nodal metastases (adjusted subdistribution HR [sHR] = 3.712, p = 0.003) and higher tumor reduction after RT (adjusted sHR = 0.922, p < 0.001) were significant prognostic factors for LP, whereas BED10 ≥ 67.1 Gy (adjusted sHR = 0.297, p = 0.002), CA19-9 reduction rate ≥50% (adjusted sHR = 0.334, p = 0.023), and RT alone (adjusted sHR = 2.633, p = 0.047) were significant prognostic factors for DM. CONCLUSION: Our results indicate that pre-RT NLR and post-RT monitoring of CA19-9 and tumor size reduction can help identify whether patients belong to the good or poor prognostic group of LAPC. The incorporation of new systemic treatments during and after a higher BED10 RT dose for LAPC patients is warranted.

Multi-Institutional Retrospective Study of Radiotherapy for Hepatocellular Carcinoma in the Caudate Lobe.

Background: No studies evaluating the clinical outcomes of radiotherapy (RT) for hepatocellular carcinoma (HCC) in the caudate lobe have been available to date. The purpose of this study was to evaluate the effectiveness and safety of RT for HCC in the caudate lobe. Material and Methods: Seventy patients with HCC in the caudate lobe treated with RT from a multi-institutional database were included in this study. The median equivalent dose in 2 Gy (EQD2) was 80.0 Gy10 (range, 31.3-99.3), and freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) rates were evaluated. Results: The median time of follow-up was 47.9 months (range, 3.4-127), and the 5-year FFLP, PFS, and OS rates were 80.6% [95% confidence interval (CI), 70.8-91.8], 13.8% (95% CI, 7.5-25.4), and 51.3% (95% CI, 39.9-66.1), respectively. In the multivariate analysis, the radiation dose was significantly associated with the FFLP rate [hazard ratio (HR), 0.57 per 10 Gy10 increase, p = 0.001], and the status of FFLP was significantly associated with OS (HR, 2.694, p = 0.014). The overall rate of ≥grade 3 adverse events was 5.7% (4 of 70), and RT-related mortality was not observed. Conclusion: RT for HCC in the caudate lobe showed promising FFLP and OS rates with safe toxicity profiles. These findings suggest that RT may be a promising treatment option for HCC in the caudate lobe.

Targeting human epidermal growth factor receptor 2 enhances radiosensitivity and reduces the metastatic potential of Lewis lung carcinoma cells.

BACKGROUND: Sublethal radiation induces matrix metalloproteinase 9 (MMP-9)-mediated radioresistance in Lewis lung carcinoma (LLC) cells and their metastatic dissemination. We aim to determine if EGFR/HER2 activation associates with MMP-9-mediated radioresistance and invasiveness in irradiated LLC cells. METHODS: LLC cells were treated with erlotinib or afatinib followed by sublethal radiation. After irradiation, we examined the phosphorylation of EGFR/HER2 and MMP-9 expression. Colony formation assay determined if the kinase inhibitors sensitize LLC cells to radiation. Matrigel-coated Boyden chamber assay assessed cellular invasiveness. Resulting tumors of wild-type LLC cells or HER2 knock-down mutant cells were irradiated to induce pulmonary metastases. RESULTS: Afatinib more effectively sensitized LLC cells to radiation and decreased invasiveness by inhibiting phosphorylation of EGFR, HER2, Akt, ERK, and p38, and down-regulating MMP-9 when compared to erlotinib. Afatinib abolished radiation-induced lung metastases in vivo. Furthermore, LLC HER2 knock-down cells treated with radiation had growth inhibition. CONCLUSION: Dual inhibition of radiation-activated EGFR and HER2 signaling by afatinib suppressed the proliferation and invasion of irradiated LLC cells. Increased radiosensitivity and decreased metastatic dissemination were observed by pharmacological or genetic HER2 inhibition in vivo. These findings indicate that HER2 plays a pivotal role in enhancing radioresistance and reducing metastatic potential of LLC cells.

Development and Validation of a Nomogram for Patients with Nonmetastatic BCLC Stage C Hepatocellular Carcinoma after Stereotactic Body Radiotherapy.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an emerging treatment modality for hepatocellular carcinoma (HCC) with promising outcome. However, appropriate survival prediction models are scarce. This study aimed to develop a simple and clinically useful prognostic nomogram for patients with nondistant metastatic Barcelona Clinic Liver Cancer (BCLC) stage C HCC undergoing SBRT. METHODS: The data were based on a prospective multi-institutional registry enrolling 246 patients with nondistant metastatic BCLC stage C HCC treated with SBRT between January 1, 2008 and December 31, 2016. They were randomly divided into two subsets: 164 into the development cohort and 82 into the validation cohort. We identified and included prognostic factors for survival to derive a nomogram in the development cohort. The predictability of the nomogram was evaluated in the validation cohort. The area under the receiver operating characteristic curve (AUROC) and the calibration plot were used to evaluate the performance of the nomogram. RESULTS: The median survival was 13.5 months, with 1- and 2-year overall survival (OS) rates of 55.0 and 32.9%, respectively. Number of tumors, largest tumor size, macrovascular invasion, Child-Turcotte-Pugh class, and biologically effective dose were significantly associated with OS (p < 0.05). These predictors were included to develop a nomogram with an AUROC of 0.77 (0.73-0.87). The prediction model was well calibrated in the validation cohort. The OS for patients who were divided by their risk scores differed significantly (p < 0.001). CONCLUSIONS: The nomogram we generated had discriminatory and satisfactory predictability for OS among nonmetastatic BCLC stage C HCC patients treated with SBRT. It demands further validations with cross-country data to confirm its worldwide usefulness.

Using cone-beam computed tomography to evaluate the impact of bladder filling status on target position in prostate radiotherapy.

PURPOSE: To assess bladder filling status and its impact on target position during daily intensity-modulated radiation therapy (IMRT) using cone-beam computed tomography (CBCT) in prostate cancer patients. PATIENTS AND METHODS: 23 patients with prostate cancer undergoing image-guided IMRT (78 Gy in 39 fractions) were included. On-board CBCT images were acquired daily and an endorectal balloon was placed daily. All patients were instructed to have a full bladder. The interfraction changes in bladder dimensions in left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were measured from CBCT images. Distances from the uppermost part of prostate to pubic bone (PP) and from the uppermost part of prostate to treatment isocenter (PI) were measured to determine changes in target position. Standard deviation (SD) in all fractions of each patient was used to compare the variations between patients. Bladder dimension change ratio and Z-score were used to normalize data between patients. RESULTS: A total of 867 CBCT images were evaluated. The average LR, AP, and SI bladder dimensions were 7.8 +/- 1.5 cm, 6.7 +/- 1.4 cm, and 5.6 +/- 1.7 cm, respectively. The average LR, AP, and SI bladder dimension change ratios were 0.88 +/- 0.17, 0.90 +/- 0.15, and 0.86 +/- 0.32, respectively. The SD was significantly greater in SI dimension than in LR (p < 0.001) and AP (p < 0.001) dimensions. The interfraction changes in the three bladder dimensions were significantly larger than those of target position, and did not correlate with target position changes. CONCLUSION: Though they were not negligible, changes in bladder filling status did not have a significant impact on target position.

Improved prognosis with induction chemotherapy in pathological complete responders after trimodality treatment for esophageal squamous cell carcinoma: Hypothesis generating for adjuvant treatment.

PURPOSE: To compare the locations of recurrences and survival outcomes in esophageal squamous cell carcinoma (ESCC) patients with pathological complete response (pCR) after neoadjuvant concurrent chemoradiotherapy (CCRT) with or without preceding induction chemotherapy (IC) followed by esophagectomy. METHODS: Among 276 patients with locally advanced ESCC undergoing trimodality treatment during 2004-2014, 94 (34.1%) with pCR were eligible. The cohort included 26 patients undergoing IC before CCRT (IC group), and 68 patients who did not receive IC (non-IC group). RESULTS: At a median follow-up of 51.4 months (95% confidence interval; 42.9-62.1), 19 patients experienced recurrences. There was a trend toward fewer distant failures in the IC group (0% vs.14.7%, p = 0.057), while locoregional recurrence was similar (7.7% vs. 7.4%). IC was associated with significantly improved survivals with the 5-year RFS and OS rates for the IC group of 85.1% and 90.5%, respectively, compared to of 46.2% and 48.1% for the non-IC group (p = 0.008 for RFS, and p = 0.015 for OS). By multivariable analyses, IC remained the only significant factor associated with survivals (HR:0.18 for RFS, p = 0.020 and HR:0.18 for OS, p = 0.025). The effect of IC in the whole cohort, irrespective of pathological response, was also assessed. Patients with non-pCR in the IC group had a trend toward worse survivals compared to the non-IC group CONCLUSIONS: In ESCC patients with pCR after trimodality treatment, IC was associated with favorable survivals. The benefits of IC might be a hypothesis generation for adjuvant treatment for patients with pCR.

Treatment outcomes of and prognostic factors for definitive radiotherapy with and without chemotherapy for Stage I/II nasal extranodal NK/T-cell lymphoma.

Treatment strategies for nasal extranodal NK/T-cell lymphoma (ENKTL), including sequential chemotherapy followed by radiotherapy (SCRT), concurrent chemoradiotherapy (CCRT), or radiotherapy alone (RT), remain varied. The purpose of this study was to assess the treatment outcome, the toxicity, and the potential prognostic factors for patients with early-stage nasal ENKTL treated using definitive RT (minimum of 50 Gy) with or without chemotherapy. From 1998 to 2014, 37 patients were included in the study. Eight patients were treated with RT alone, 1 with CCRT, and 28 with SCRT. Local regional control (LRC), progression-free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method. RT resulted in an overall response rate of 91.2%, with a complete response rate of 78.4%. After a median follow-up time of 36.8 months, the 3-year LRC, PFS and OS were 87.4%, 64.0% and 76.3%, respectively. Acute severe toxicity (Grade 3) of mucositis was observed in 6 (16.2%) of the 37 patients. In univariate analyses, extensive disease (Stage I/II with local invasiveness) and the presence of B symptoms were significantly associated with a poor PFS, whereas extensive disease was significantly associated with a poor OS. Multivariate analysis identified the presence of extensive disease as an independent predictor of PFS (P < 0.001) and OS (P = 0.015). High-dose RT with or without chemotherapy reported promising locoregional control and a favorable outcome for patients with early-stage nasal ENKTL without local invasiveness. Further investigation of new treatment strategies for patients with local invasiveness is warranted.