Randomized multicenter phase II trial of prophylactic irradiation of para-aortic lymph nodes in advanced cervical cancer according to tumor hypoxia: Korean Radiation Oncology Group (KROG 07-01) study.

We conducted a prospective phase II study on whether extended-field irradiation (EFI) confers survival benefits depending on hypoxic markers in locally advanced uterine cervical cancer (LAUCC). RNA-seq was performed to identify immune and hypoxic gene signatures. A total of 288 patients were randomized to either EFI or pelvic radiotherapy (PRT). All patients completed chemoradiotherapy. Overall, significantly higher 5-year para-aortic recurrence free survival (PARFS) rate occurred in EFI (97.6%) than in PRT group (87.2%), with marginal tendency to improve disease-free survival (DFS; 78% vs 70%, P = .066). Subgroup analyses were performed based on carbonic anhydrase 9 (CA9)-only positive, CA9/hypoxia-inducible factor (HIF) double positive and CA9 negative. In the CA9-only positive, EFI successfully increased 5-year PARFS (100% vs 76.4%, P = .010), resulting in significantly improved long-term DFS (85.7% vs 54.7%, P = .023) compared to the PRT, while there was no such benefit of EFI in the CA9/HIFs double positive. RNA-seq analysis identified distinct immunehigh subgroup with negative correlation with hypoxia gene signatures (R = -.37, P < .01), which showed a higher 5-year DFS than the immunelow (P = .032). Hypoxia-related genes were upregulated in the CA9/HIFs double positive compared to CA9 negative (P < .05). Only 17.4% of patients in CA9-negative group showed immunelow signatures, while 40.0% of patients in the double-positive group exhibited immunelow signatures. In conclusion, EFI improved PARFS significantly in all patients, but therapeutic efficacy of EFI in terms of improved DFS was solely observed in CA9-only positive LAUCC, and not in CA9/HIFs double-positive subgroup. RNA-seq analysis suggested that hypoxia-induced immunosuppression may be related to treatment resistance in LAUCC.

Orally administered collagen peptide protects against UVB-induced skin aging through the absorption of dipeptide forms, Gly-Pro and Pro-Hyp.

Collagen hydrolysate is a well-known nutritional supplement for the improvement of healthy skin. Here, collagen peptide NS (CPNS) from fish scale was prepared, and its physicochemical properties were investigated. Gly-Pro was revealed as a representative low molecular weight peptide of CPNS, by performing prep-HPLC and LC-MS/MS. CPNS treatment attenuated matrix metalloproteinase-1 production and increased the synthesis of type 1 procollagen in HDF cells. After orally administering CPNS to rats, the plasma concentrations of Gly-Pro and Pro-Hyp increased dramatically. To examine the protective effects of CPNS against ultraviolet B (UVB)-induced photoaging in vivo, the dorsal skins of hairless mice were exposed to UVB and supplemented with CPNS for 12 weeks. The CPNS consumption significantly attenuated UVB-induced wrinkle formation, transepidermal water loss, and epidermis thickness, and increased skin hydration. Collectively, these results suggest that bioactive peptides of CPNS, Gly-Pro and Pro-Hyp, exert beneficial effects on skin health.

Monte Carlo simulation study of an in vivo four-dimensional tracking system with a diverging collimator for monitoring radiation source (Ir-192) location during brachytherapy: proof of concept and feasibility.

Introduction: The aim of this study was to demonstrate the potential of an in vivo four-dimensional (4D) tracking system to accurately localize the radiation source, Iridium-192 (Ir-192) in high-dose rate brachytherapy. Methods: To achieve time-dependent 3D positioning of the Ir-192 source, we devised a 4D tracking system employing multiple compact detectors. During the system's design phase, we conducted comprehensive optimization and analytical evaluations of the diverging collimator employed for detection purposes. Subsequently, we executed 3D reconstruction and positioning procedures based on the 2D images obtained by six detectors, each equipped with an optimized diverging collimator. All simulations for designing and evaluating the 4D tracking system were performed using the open-source GATE (v9.1) Monte Carlo platform based on the GEANT4 (v10.7) toolkit. In addition, to evaluate the accuracy of the proposed 4D tracking system, we conducted simulations and 3D positioning using a solid phantom and patient data. Finally, the error between the reconstructed position coordinates determined by the tracking system and the original coordinates of the Ir-192 radiation source was analyzed. Results: The parameters for the optimized diverging collimator were a septal thickness of 0.3 mm and a collimator height of 30 mm. A tracking system comprising 6 compact detectors was designed and implemented utilizing this collimator. Analysis of the accuracy of the proposed Ir-192 source tracking system found that the average of the absolute values of the error between the 3D reconstructed and original positions for the simulation with the solid phantom were 0.440 mm for the x coordinate, 0.423 mm for the y coordinate, and 0.764 mm for the z coordinate, and the average Euclidean distance was 1.146 mm. Finally, in a simulation based on data from a patient who underwent brachytherapy, the average Euclidean distance between the original and reconstructed source position was 0.586 mm. Discussion: These results indicated that the newly designed in vivo 4D tracking system for monitoring the Ir-192 source during brachytherapy could determine the 3D position of the radiation source in real time during treatment. We conclude that the proposed positioning system has the potential to make brachytherapy more accurate and reliable.

Optimizing External Beam Radiotherapy as per the Risk Group of Localized Prostate Cancer: A Nationwide Multi-Institutional Study (KROG 18-15).

PURPOSE: This nationwide multi-institutional study analyzed the patterns of care and outcomes of external beam radiotherapy (EBRT) in localized prostate cancer patients. We compared various risk classification tools and assessed the need for refinements in current radiotherapy (RT) schemes. METHODS AND MATERIALS: We included non-metastatic prostate cancer patients treated with primary EBRT from 2001 to 2015 in this study. Data of 1573 patients from 17 institutions were analyzed and re-grouped using a risk stratification tool with the highest predictive power for biochemical failure-free survival (BCFFS). We evaluated BCFFS, overall survival (OS), and toxicity rates. RESULTS: With a median follow-up of 75 months, 5- and 10-year BCFFS rates were 82% and 60%, and 5- and 10-year OS rates were 95% and 83%, respectively. NCCN risk classification revealed the highest predictive power (AUC = 0.556, 95% CI 0.524-0.588; p < 0.001). Gleason score, iPSA < 12 ng/mL, intensity-modulated RT (IMRT), and ≥179 Gy1.5 (EQD2, 77 Gy) were independently significant for BCFFS (all p < 0.05). IMRT and ≥179 Gy1.5 were significant factors in the high-risk group, whereas ≥170 Gy1.5 (EQD2, 72 Gy) was significant in the intermediate-risk group and no significant impact of dose was observed in the low-risk group. Both BCFFS and OS improved significantly when ≥179 Gy1.5 was delivered using IMRT and hypofractionation in the high-risk group without increasing toxicities. CONCLUSIONS: With NCCN risk classification, dose escalation with modern high-precision techniques might increase survivals in the high-risk group, but not in the low-risk group, although mature results of prospective studies are awaited.

Long-term results and PSA kinetics after robotic SBRT for prostate cancer: multicenter retrospective study in Korea (Korean radiation oncology group study 15-01).

BACKGROUND: To evaluate the treatment outcome and prostate-specific antigen (PSA) change after stereotactic body radiotherapy (SBRT) for localized prostate cancer. METHODS: Patients with localized prostate cancer treated with SBRT at three academic hospitals were enrolled. Treatment was delivered using Cyberknife with dose range from 35 to 37.5 Gy in 5 fractions. Biochemical failure (BCF) was assessed with Phoenix definition and toxicities were scored with Radiation Therapy Oncology Group (RTOG) toxicity criteria. The PSA kinetics were analyzed in patients who received no androgen deprivation therapy (ADT) and showed no recurrence. RESULTS: Of the total 88 patients, 14 patients (15.9%) received ADT. After median follow-up of 63.8 months, the 5-year BCF free survival (BCFFS) was 94.7%. Two patients experienced late grade ≥ 3 GI toxicities (2.2%). The median nadir PSA was 0.12 ng/mL (range, 0.00-2.62 ng/mL) and the median time to nadir was 44.8 months (range, 0.40-85.7 months). Patients who reached nadir before 24 months showed poorer BCFFS than the others. The rate of PSA decline was maximum in the first year after treatment and gradually decreased with time. The pattern of PSA change was significantly different according to the risk groups (p = 0.011) with the slope of - 0.139, - 0.161 and - 0.253 ng/mL/month in low-, intermediate- and high-risk groups, respectively. CONCLUSION: SBRT for localized prostate cancer showed favorable efficacy with minimal toxicities. The time to PSA nadir was significantly associated with treatment outcome. PSA revealed rapid initial decline and slower decrease with longer follow-up and the patterns of PSA changes were different according to the risk groups.

Tumor volume and uterine body invasion assessed by MRI for prediction of outcome in cervical carcinoma treated with concurrent chemotherapy and radiotherapy.

OBJECTIVE: The aim of this study was to evaluate the prognostic significance of primary tumor volume and uterine body invasion assessed by pre-treatment MRI for uterine cervical cancer patient treated with concurrent chemotherapy and radiotherapy. METHODS: A retrospective analysis of 106 patients with IB-IIIB cervical carcinoma was performed. Potential prognostic factors were stage, clinical tumor diameter, histology, age, pelvic lymph node, vaginal extension, parametrial invasion, tumor volume and uterine body invasion status. Multivariate analyses were performed to identify the prognostic factor for overall survival (OS) and disease-free survival (DFS). RESULTS: The 5-year OS, DFS rate were 59.7 and 56.6%. Using multivariate analyses, a large tumor volume (>/=30 ml; P = 0.012) and uterine body invasion (P = 0.020) and positive pelvic lymph node (LN) enlargement (P = 0.040) showed a significantly unfavorable influence on OS. Using these three factors, patients were divided into four subgroups: the OS rates of patients with risk 0 (volume <30 ml, no uterine body invasion, and negative LN), risk 1 (one of these three factors), risk 2 (two of these three factors) and risk 3 (volume >/=30 ml, uterine body invasion, and positive LN) were 96.3, 77.5, 53.0 and 14.8%, respectively (P < 0.0001). CONCLUSIONS: Tumor volume and uterine body invasion determined by MRI were significant prognostic factors for patients with cervical carcinoma. Pelvic lymph node enlargement diagnosed by CT also proved to be a significant prognostic factor in OS. Using these three parameters, we devised a practical and effective model to predict OS.

Prophylactic irradiation of para-aortic lymph nodes for patients with locally advanced cervical cancers with and without high CA9 expression (KROG 07-01): A randomized, open-label, multicenter, phase 2 trial.

BACKGROUND AND PURPOSE: The efficacy of prophylactic extended-field irradiation (EFI) plus concomitant cisplatin in patients with locally advanced uterine cervical cancer (LAUCC) is unknown, nor is it known whether tumor carbonic anhydrase IX (CA9) expression level, a hypoxia marker, influences survival outcome. MATERIAL AND METHODS: We recruited patients with UCC, FIGO stage IB1 with pelvic lymph node (LN) metastases to IVA with negative para-aortic LN on PET/CT. CA9 expression was examined and patients were randomized to either EFI or pelvic only radiotherapy (PRT) in each CA9 group. The primary outcomes were para-aortic recurrence-free survival (PARFS) and disease-free survival (DFS). RESULTS: Between 2006 and 2011, 79 patients with CA9-positive and 37 with CA9-negative tumors were enrolled, respectively. The median follow-up period was 69.2months (range 6.8-102.1). For CA9-positive patients, 5-year PARFS was 100% and 81.7% for those receiving EFI and PRT (p=0.007), respectively. DFS was 78.6% for EFI and 71.3% for PRT patients (p=0.353). For CA9-negative patients, 5y PARFS was 100% and 94.1% for EFI and PRT (p=0.317), respectively. DFS was 100% for EFI and 70.7% for PRT (p=0.018). CONCLUSION: EFI significantly reduced recurrences in PAN in patients with CA9-positive tumors, but survival outcome was not improved, due to high local recurrence and high distant metastases rates. This study indicates the necessity for new therapeutic strategies for LAUCC patients whose tumors show high CA9 expression.

High resolution LC-ESI-TOF-mass spectrometry method for fast separation, identification, and quantification of 12 isoflavones in soybeans and soybean products.

A high resolution LC-ESI-TOF-MS analytical method was established for the rapid isolation, identification, and quantification of 12 isoflavones in soybean and soybean products. Individual isoflavones were identified on the basis of the accurate mass data of their respective protonated mass ions, Na or K adduct ions, fragment ions, and isotope ion patterns. The protonated mass ions of isoflavones were extracted for their quantification in soybean products. Twelve different isoflavones in the soybean products were fully separated, identified and quantified within 12min separation time. The established LC-TOF/MS was an effective analytical method for the simultaneous characterization and quantification of isoflavones with exceptionally short analytical time, high selectivity, a high linearity (r(2)>0.992) in a wide range, low LOD and LOQ, high precision, inter-and intra-day repeatability, and no significant matrix effect. Furthermore, it requires simple sample preparation procedure (solvent extraction, dilution, and syringe filtration).

Pretreatment tumor diameter/volume and pelvic lymph node status assessed by magnetic resonance imaging for uterine cervical carcinoma treated with concurrent chemotherapy and radiotherapy.

AIM: The aim is to evaluate the prognostic value of tumor diameter, volume and pelvic lymph node status assessed by magnetic resonance imaging (MRI) in patients with uterine cervical carcinoma patients treated with concurrent chemotherapy and radiotherapy. METHODS: Ninety-eight patients diagnosed with stage IB to IIIB cervical carcinoma were entered into the study. Tumor diameter was evaluated in T2-weighted image. The tumor volume was calculated by the equation (volume = width x length x height x pi/6) as an ellipsoid approximation. Univariate and multivariate analyses were performed to identify the prognostic factors for overall survival (OS), disease-free survival (DFS), pelvic control (PC) and distant metastasis-free survival (DMFS). RESULTS: The 5-year OS, DFS, PC and DMFS rate were 59.8%, 57.3%, 67.9% and 78.8%, respectively. Using univariate analyses, large MRI tumor diameter (4 cm), large tumor volume (30 mL), pelvic enlarged pelvic lymph nodes, large clinical diameter (4 cm) and International Federation of Gynecology and Obstetrics (FigO) stage showed a statistically significantly unfavorable influence on OS and DFS. In multivariate analyses, large tumor volume affected OS, DFS, PC and DMFS, and enlarged pelvic lymph nodes also affected OS. CONCLUSION: Tumor volume and enlarged pelvic lymph nodes determined by pretreatment MRI examinations were significant prognostic factors for patients with invasive cervical carcinoma treated with concurrent chemotherapy and radiotherapy.