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PURPOSE The objective of this study was to determine whether pretreatment neutrophil-to-lymphocyte ratio (NLR) could predict survival outcomes and liver toxicity in hepatocellular carcinoma (HCC) patients treated with stereotactic ablative radiation therapy (SABR). METHODS AND MATERIALS In this retrospective study we collected pretreatment NLR of HCC patients treated with SABR between December 2007 and August 2018 and determined its association with overall survival (OS), progression-free survival, and radiation-related liver toxicity defined as an increase in the Child-Turcotte-Pugh score by ≥2 within 3 months after SABR in the absence of disease progression. RESULTS A total of 153 patients with a median follow-up of 13.3 months were included. Receiver operating characteristic curve analysis found that an NLR ≥2.4 was optimum (area under the curve, 0.762; 95% confidence interval [CI], 0.682-0.841, P < .001) for predicting poor 1-year OS (38.2% vs 83.6%, P < .001). Multivariable analysis demonstrated that NLR was significantly associated with OS, both as a continuous (P = .006) and a binary variable (NLR set at 2.4; P = .003). Multiple tumors (P = .003), macrovascular invasion (P = .024), extrahepatic spread (P = .002), and albumin-bilirubin score (P = .020) were also significant predictors of OS. Elevated NLR independently prognosticated poor progression-free survival (P = .016). Liver toxicity was seen in 22 evaluable patients (15.4%). Receiver operating characteristic curve analysis found NLR ≥4.0 was optimum at predicting liver toxicity (31.4% vs 10.2%, P = .005). A higher NLR (P = .049) and albumin-bilirubin score (P = .002) were independent risk factors for liver toxicity. CONCLUSIONS NLR is an objective and ubiquitous inflammatory marker that can predict OS and liver toxicity in HCC patients undergoing SABR. NLR could be a useful biomarker for patient risk stratification and therapeutic decision-making.

Background Few studies have focused on DNA methylation in endometrial cancer. The aim of our study is identify its role in endometrial cancer prognosis. Methods A publicly available dataset was retrieved from The Cancer Genome Atlas. For validation of expression alteration due to methylation, RNA sequencing data were obtained from other independent cohorts. MethSurv was used to search for candidate CpG probes, which were then filtered by least absolute shrinkage and selection operator Cox regression and multivariate Cox regression analyses to identify final set of CpG probes for overall survival. A methylation-based risk model was developed and receiver operating characteristic analysis with area under curve was used for evaluation. Patients were divided into high- and low-risk groups using an optimal cut-off point. Comprehensive bioinformatic analyses were conducted to identify hub genes, key transcription factors, and enriched cancer-related pathways. Kaplan–Meier curve was used for survival analysis. Results A 5-CpG signature score was established. Its predictive value for 5-year overall survival was high, with area under curve of 0.828, 0.835 and 0.816 for the training, testing and entire cohorts. cg27487839 and cg12885678 had strong correlation with their gene expression, XKR6 and PTPRN2, and lower PTPRN2 expression was associated with poorer survival in both The Cancer Genome Atlas and the validation datasets. Low-risk group was associated with significantly better survival. Low-risk group harboured more mutations in hub genes and key transcription factors, and mutations in SP1 and MECP2 represented favourable outcome. Conclusion We developed a methylation-based prognostic stratification system for endometrial cancer. Low-risk group was associated with better survival and harboured more mutations in the key regulatory genes.

Chih-Weim Hsiang,1 Wen-Yen Huang,2,3 Jen-Fu Yang,2 Po-Chien Shen,2 Yang-Hong Dai,2 Ying-Fu Wang,2 Chun-Shu Lin,2 Wei-Chou Chang,1 Cheng-Hsiang Lo2 1Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 2Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 3Institute of Clinical Medicine, National Yang-Ming University, Taipei, TaiwanCorrespondence: Cheng-Hsiang LoDepartment of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec 2, Cheng-Gong Road, Neihu, Taipei, 114, TaiwanTel +886-2-87927122Fax +886-2-66002357Email lsir183@yahoo.com.twPurpose: Immune response to antitumor therapies has been correlated with oncologic outcomes. This study aimed to determine whether dynamic changes in immune parameters could predict survival outcomes and assess their relationship with liver toxicity in hepatocellular carcinoma (HCC) patients treated with stereotactic body radiation therapy (SBRT).Methods: Data on pre- and post-SBRT (within 3 months) peripheral blood cell counts, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were retrospectively collected. Kinetic changes in these immune parameters and delta-NLR (dNLR) and delta-PLR (dPLR) in response to SBRT were evaluated. Overall survival (OS) and progression-free survival (PFS) were compared based on baseline NLR/PLR and dNLR/dPLR. Additionally, the association of these dynamic measures with liver toxicity was determined.Results: The study included 93 patients with a median 10.7-month follow-up. Significant increases in NLR (p< 0.001) and PLR (p=0.003) were observed after SBRT. In the multivariable analysis, elevated pre-SBRT NLR (p< 0.001) and dNLR (p=0.011) were predictive of worse OS. dNLR was not associated with PFS. Neither PLR nor dPLR was predictive of survival outcomes. Patients with Child–Turcotte–Pugh class B had higher dNLR and greater risk of liver toxicity than class A counterparts. Receiver operating characteristic curve analysis found that dNLR ≥ 1.9 was an optimal cut-off value for determining liver toxicity risk (35.1% vs 7.5%, p=0.002).Conclusion: Baseline NLR and dNLR can complementarily predict OS in HCC patients treated with SBRT. Elevated dNLR is associated with worse OS and development of liver toxicity, possibly through their relationship with baseline liver function. Dynamic changes in NLR should be monitored in HCC care.Keywords: hepatocellular carcinoma, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, stereotactic body radiotherapy, liver toxicity

For nasopharyngeal carcinoma (NPC), radiotherapy is the primary treatment. However, complications occur after radiation to the nasopharynx, which could potentially affect the flying safety. Four fighter pilots with NPC were reported. With early to locally advanced NPC, they received radiotherapy with or without concurrent chemotherapy. The prescribed radiation dose was 70 Gy to the primary tumor over the nasopharynx. Before treatment, all patients presented with various degrees of hearing loss on pure tone audiometry (main frequencies of 20–45 dB at 3–4.5 kHz for affected ears). After the full course of radiotherapy, tumor regression was noticed during months to years of follow-ups. The follow-up audiometry evaluation showed gradually recovered hearing function (average improvement of 5 dB at pretreatment frequencies) in all pilots. They then returned back to the flight line on annual waiver points. Here, we conclude that fighter pilots with NPC could successfully return to the flight line after radiotherapy. However, detailed physical examinations and confirmation of adaptation to flying condition are warranted.

Background This study aimed to compare the clinical outcomes of stereotactic ablative radiotherapy (SABR) and conventionally fractionated radiotherapy (CFRT) in hepatocellular carcinoma (HCC) patients with portal vein invasion (PVI). Methods HCC patients with PVI treated with radiotherapy from 2007 to 2016 were analysed. CFRT was administered at a median dose of 51.5 Gy (interquartile range, 45–54 Gy) with 1.8–3 Gy per fraction. SABR was administered at a median dose of 45 Gy (interquartile range, 40–48 Gy) with 6–12.5 Gy per fraction. Treatment efficacy, toxicity, and associated predictors were assessed. Results Among the 104 evaluable patients (45 in the SABR group and 59 in the CFRT group), the overall response rate (ORR, complete and partial response) was significantly higher in the SABR group than the CFRT group (62.2% vs. 33.8%, p = 0.003). The 1-year overall survival (OS) rate (34.9% vs. 15.3%, p = 0.012) and in-field progression-free survival (IFPS) rate (69.6% vs. 32.2%, p = 0.007) were also significantly higher in the SABR vs. CFRT group. All 3 rates remained higher in the SABR group after propensity score matching. Multivariable analysis identified SABR and a biologically effective dose ≥65 Gy as favourable predicators of OS. There was no difference between treatment groups in the incidence of radiation-induced liver disease or increase of Child-Pugh score ≥ 2 within 3 months of radiotherapy. Conclusions SABR was superior to CFRT in terms of ORR, OS, and IFPS. We suggest that SABR should be the preferred technique for HCC patients with PVI.

This study compared the local control and overall survival (OS) between stereotactic body radiation therapy (SBRT) and transarterial chemoembolization (TACE) in medium-sized (3-8 cm) hepatocellular carcinoma (HCC).From January 2008 to October 2017, 188 patients with medium-sized HCC underwent either TACE (n = 142) or SBRT (n = 46). We adjusted for imbalances in treatment assignment using propensity score matching. Infield control (IFC) and OS were analyzed retrospectively.The median follow-up time was 17.1 months for all patients and 26.6 months for surviving patients. The 3-year IFC was 63.0% for the TACE group and 73.3% for the SBRT group. Multivariable analysis identified the independent predictors for IFC as treatment modality (SBRT vs TACE), sex (female vs male), and recurrence status (recurrence vs new diagnosis). The 3-year OS was 22.9% for the TACE group and 47.4% for the SBRT group. Multivariable analysis identified the independent predictors of OS as number of tumors, treatment modality (SBRT vs TACE), albumin-bilirubin grade, tumor volume, Eastern Cooperative Oncology Group status, and recurrence status. Propensity score matching analysis revealed that the SBRT group had better IFC (3-year IFC of 77.5% vs 55.6%; P = .007) and OS (3-year OS of 55.0% vs 13.0%; P.001) than the TACE group. For recurrent HCC, the SBRT group exhibited superior IFC (3-year IFC of 75% vs 57.5%; P = .022) and OS (3-year OS of 58.3% vs 5.9%; P.001) compared with the TACE group. However, there was no difference in IFC or OS between TACE and SBRT for patients with newly diagnosed HCC.SBRT has better IFC and OS rates than TACE in patients with medium-sized HCC, particularly for recurrent cases, which warrants prospective randomized controlled trials of TACE and SBRT.

Background Genomic profiles of specific gene sets have been established to guide personalized treatment and prognosis for patients with breast cancer (BC). However, epigenomic information has not yet been applied in a clinical setting. ST14 encodes matriptase, a proteinase that is widely expressed in BC with reported prognostic value. Methods In this present study, we evaluated the effect of ST14 DNA methylation (DNAm) on overall survival (OS) of patients with BC as a representative example to promote the use of the epigenome in clinical decisions. We analyzed publicly available genomic and epigenomic data from 1361 BC patients. Methylation was characterized by the β-value from CpG probes based on sequencing with the Illumina Human 450 K platform. Results A high mean DNAm (β > 0.6779) across 34 CpG probes for ST14, as the gene-associated methylation (GAM) pattern, was associated with a longer OS after adjusting age, stage, histology and molecular features in Cox model (p value XBP1 expression level and higher proportion of hormone-positive BC (p value Conclusions Here we show the potential role of ST14 DNAm in BC prognosis and warrant further study.

Background: Stereotactic body radiotherapy (SBRT) is an emerging modality for hepatocellular carcinoma (HCC). However, there is scant information about its safety and effectiveness in the neoadjuvant setting prior to liver transplantation (LT). We present the clinical outcome and pathologic assessment of SBRT followed by LT for patients with advanced HCC.Methods: This retrospective study included HCC patients treated with neoadjuvant SBRT prior to LT between 2009 and 2018. Radiographic response and adverse effects, including radiation-induced liver disease (RILD), were evaluated. Pathologic response was assessed by the percentage of tumor necrosis relative to the total tumor volume. Overall survival (OS) and recurrence-free survival (RFS) were calculated using the Kaplan–Meier method.Results: Fourteen patients underwent SBRT for a total of 25 HCC lesions, followed by LT. The median tumor size was 4.45 cm in diameter, and the median prescribed dose was 45 Gy in 5 fractions. SBRT provided significant AFP reduction, 100% infield control, and a 62.5% response rate. The maximum detected toxicity included grade 3 thrombocytopenia and two grade 3–4 hyperbilirubinemia. One patient developed non-classic RILD. Patients were bridged to LT with a median time of 8.4 months after SBRT, and 23.1% of them achieved a complete pathologic response. The median OS and RFS were 37.8 and 18.3 months from the time of LT, respectively.Conclusions: SBRT provides favorable tumor control and acceptable adverse effects for patients awaiting LT. Further prospective studies to test SBRT as a bridging therapy for LT are feasible.

Background : Stereotactic body radiotherapy (SBRT) is an effective but less focused alternative for treatment of hepatocellular carcinoma (HCC). To date, a personalized model for predicting therapeutic response is lacking. This study aimed to review current knowledge and to propose a radiomics-based machine-learning (ML) strategy for local response (LR) prediction. Methods : We searched the literature for studies conducted between January 1993 and August 2019 that used > 100 patients. Additionally, 172 HCC patients in our hospital were retrospectively analyzed between January 2007 and December 2016. In the radiomic analysis, 41 treated tumors were contoured and 46 radiomic features were extracted. Results : The 1-year local control was 85.4% in our patient cohort, comparable with current results (87-99%). The Support Vector Machine (SVM) classifier, based on computed tomography (CT) scans in the A phase processed by equal probability (Ep) quantization with 8 gray levels, showed the highest mean F1 score (0.7995) for favorable LR within 1 year (W1R), at the end of follow-up (EndR), and condition of in-field failure-free (IFFF). The area under the curve (AUC) for this model was 92.1%, 96.3%, and 99.2% for W1R, EndR, and IFFF, respectively. Conclusions : SBRT has high 1-year local control and our study sets the basis for constructing predictive models for HCC patients receiving SBRT.

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.

Background: Radiotherapy has gained increasing attention as an effective cytotoxic agent to improve therapeutic response to immunotherapy. However, synergic effect is seldom seen clinically and reliable biomarkers for optimal patient selection remains to be identified. Radiosensitivity index (RSI) is a well-known measure of tumor’s response to radiotherapy, which is derived from genomic data and system biology. Its association with the immune landscape in cancer is unclear. Methods: Genomic data from Merged Microarray-Acquired dataset (MMD) were established and the Cancer Genome Atlas (TCGA) were obtained. Based on rank-based regression model including 10 genes, RSI was calculated. A total of 12,832 primary tumors across 11 major cancer types were analyzed. RSI was stratified into RSI-Low and RSI-High by a cutpoint of 0.46. Gene set variance analysis was applied to measure the genomic pathway activity (18 genes for T-cell inflamed activity). Kaplan-Meier analysis was performed for survival analysis. Findings: We found that RSI was significantly associated with homologous DNA repair, cancer stemness and various cancer-specific molecular features. Tumors with low RSI were associated with significantly higher portion of M1 macrophage, relative to M2 macrophage, and higher IFNG expression. Additionally, dominant interferon-γ (IFN-γ) response was characterized by low RSI and potentially predicted better response to programmed cell death 1 (PD-1) blockade. Interpretation: RSI is strongly associated with immune response and efficacy to PD-1 blockade. IFN-γ dominant status could be estimated by RSI, providing an alternative selection strategy to identify suitable patients for combined radiotherapy and immunotherapy. Funding Statement: This study was supported by study project of Tri-Service General Hospital (TSGH-D109063). Declaration of Interests: The authors declare that they have no competing interests.

Matriptase plays important roles in epithelial integrity and function, which depend on its sorting to the basolateral surface of cells, where matriptase zymogen is converted to an active enzyme in order to act on its substrates. After activation, matriptase undergoes HAI-1-mediated inhibition, internalization, transcytosis, and secretion from the apical surface into the lumen. Matriptase is a mosaic protein with several distinct protein domains and motifs, which are a reflection of matriptase's complex cellular itinerary, life cycle, and the tight control of its enzymatic activity. While the molecular determinants for various matriptase regulatory events have been identified, the motif(s) required for translocation of human matriptase to the basolateral plasma membrane is unknown. The motif previously identified in rat matriptase is not conserved between the rodent and the primate. We, here, revisit the question for human matriptase through the use of a fusion protein containing a green fluorescent protein linked to the matriptase N-terminal fragment ending at Gly-149. A conserved seven amino acid motif EEGEVFL, which is similar to the monoleucine C-terminal to an acidic cluster motif involved in the basolateral targeting for some growth factors, has been shown to be required for matriptase translocation to the basolateral plasma membrane of polarized MDCK cells. Furthermore, time-lapse video microscopy showed that the motif appears to be required for entry into the correct transport vesicles, by which matriptase can undergo rapid trafficking and translocate to the plasma membrane. Our study reveals that the EEGEVFL motif is necessary, but may not be sufficient, for matriptase basolateral membrane targeting and serves as the basis for further research on its pathophysiological roles.

In early stage breast cancer, intraoperative radiation therapy (IORT) is a form of accelerated partial breast irradiation (APBI) that provides attractive therapeutic effects while shortening the overall treatment time and sparing the normal tissue radiation exposure. This technique has been used in Taiwan for several years in selected patients with breast cancer. However, some randomized trials pointed out that IORT is associated with higher rate of recurrence, therefore impeding its wider use as one of the standard managements in breast cancer. Also, despite its theoretical benefits for smaller tumor after surgery, the problem of recurrence warrants the necessity of strict and careful patient selection. The purpose of this article is to comprehensively review the updated consensus and current opinions on the use of IORT for early stage breast cancer.

Flexible polymer nanopillar substrates were used to systematically demonstrate cell alignment and migration guided by the directional formation of focal adhesions. The polymer nanopillar substrates were constructed to various height specifications to provide an extensive variation of flexibility; a rectangular arrangement created spatial confinement between adjacent nanopillars, providing less spacing in the horizontal and vertical directions. Three polymer nanopillar substrates with the diameter of 400 nm and the heights of 400, 800, and 1200 nm were fabricated. Super-resolution localization imaging and protein pair–distance analysis of vinculin proteins revealed that Chinese hamster ovary (CHO) cells formed mature focal adhesions on 1200 nm high nanopillar substrates by bending adjacent nanopillars to link dot-like adhesions. The spacing confinement of the adjacent nanopillars enhanced the orthogonal directionality of the formation tendency of the mature focal adhesions. The directional formation of the mature focal adhesions also facilitated the organization of actin filaments in the horizontal and vertical directions. Moreover, 78% of the CHO cells were aligned in these two directions, in conformity with the flexibility and nanotopographical cues of the nanopillars. Biased cell migration was observed on the 1200 nm high nanopillar substrates.

Background Hepatobiliary cystadenocarcinoma is a rare epithelial malignant neoplasm of the liver or extrahepatic bile ducts. Early diagnosis of hepatobiliary cystadenocarcinoma is difficult because of its asymptomatic features and rarity. Moreover, the molecular pathogenesis of hepatobiliary cystadenocarcinoma remains unclear. Herein, we described a case of hepatobiliary cystadenocarcinoma in female with chronic hepatitis B and repeated hepatolithiasis. Case presentation A 65-year-old woman with medical history of latent hepatitis B virus infection, repeated choledocholisthiasis, and cholecystitis was admitted due to a heterogeneous cystic mass (5.6 cm × 4 cm) shown on abdominal ultrasonography during regular physical checkup. The patient complained about irregular bowel movements with intermittent diarrhea for two months before presentation. Computed tomography (CT) disclosed a multiloculated cystic lesion in the left hepatic lobe with the presence of intraductal stones and dilatation of intrahepatic ducts. Histological results obtained from left lobectomy specimens showed hepatobiliary cystadenocarcinoma without accompanied mesenchymal stroma. Conclusion Notably, hepatobiliary cystadenocarcinoma without mesenchymal stroma seldom occurs in women and is usually associated with poor prognosis. We present the rare findings in this patient and suggest that chronic inflammatory insults in the intrahepatic bile ducts might shed light on the cystadenocarcinogenesis.

Pethidine is an opioid that gains its popularity for the effective pain control through acting on the opioid-receptors. However, rapid pain relief sometimes brings about unfavourable side effects that largely limit its clinical utility. Common side effects include nausea, vomiting and hypotension. In patients with impaired renal and liver function, and those who need long-term pain control, pethidine may cause excitatory central nervous system (CNS) effects through its neurotoxic metabolite, norpethidine, resulting in irritability and seizure attack. On the contrary, though not clinically apparent, pethidine potentially causes inhibitory impacts on the CNS and impairs normal cerebellar and oculomotor function in the short term. In this case report, we highlight opioid's inhibitory side effects on the cerebellar structure that causes dysmetria, dysarthria, reduced smooth pursuit gain and decreased saccadic velocity.

The dual-color dynamic particle tracking approach that uses temporal focusing multiphoton fluorescence excitation and two-channel astigmatic imaging is utilized to track molecular trajectories in three dimensions to explore molecular interactions. Images of two fluorophores were obtained to extract their positions by optical sectioning excitation using a fast temporal focusing multiphoton excitation microscope (TFMPEM) and by the simultaneous collection of data in two channels. The presented pair of cylindrical lenses, which was used to adjust the astigmatism effect with the minimum shifting of the imaging plane, was more feasible and flexible than single cylindrical lens for aligning two separate detection channels in astigmatic imaging. The lateral and axial positioning resolutions were observed to be approximately 9-13 nm and 23-30 nm respectively, for the two fluorescence channels. The dynamic movement and binding behavior of clusters of GM-CSF receptors and JAK2 kinases in HeLa cells in the presence of GM-CSF ligands were observed. Therefore, the proposed dual-color tracking strategy is useful for the dynamic study of molecular interactions in living specimens with a fast frame rate, less photobleaching, better penetration depth, and minimum optical trapping force.