Enhancement of Bone Tissue Regeneration with Multi-Functional Nanoparticles by Coordination of Immune, Osteogenic, and Angiogenic Responses.

Inorganic nanoparticles are promising materials for bone tissue engineering due to their chemical resemblance to the native bone structure. However, most studies are unable to capture the entirety of the defective environment, providing limited bone regenerative abilities. Hence, this study aims to develop a multifunctional nanoparticle to collectively control the defective bone niche, including immune, angiogenic, and osteogenic systems. The nanoparticles, self-assembled by biomimetic mineralization and tannic acid (TA)-mediated metal-polyphenol network (MPN), are released sustainably after the incorporation within a gelatin cryogel. The released nanoparticles display a reduction in M1 macrophages by means of reactive oxygen species (ROS) elimination. Consequently, osteoclast maturation is also reduced, which is observed by the minimal formation of multinucleated cells (0.4%). Furthermore, the proportion of M2 macrophages, osteogenic differentiation, and angiogenic potential are consistently increased by the effects of magnesium from the nanoparticles. This orchestrated control of multiple systems influences the in vivo vascularized bone regeneration in which 80% of the critical-sized bone defect is regenerated with new bones with mature lamellar structure and arteriole-scale micro-vessels. Altogether, this study emphasizes the importance of the coordinated modulation of immune, osteogenic, and angiogenic systems at the bone defect site for robust bone regeneration.

Cell-homing and immunomodulatory composite hydrogels for effective wound healing with neovascularization.

Wound healing in cases of excessive inflammation poses a significant challenge due to compromised neovascularization. Here, we propose a multi-functional composite hydrogel engineered to overcome such conditions through recruitment and activation of macrophages with adapted degradation of the hydrogel. The composite hydrogel (G-TSrP) is created by combining gelatin methacryloyl (GelMA) and nanoparticles (TSrP) composed of tannic acid (TA) and Sr2+. These nanoparticles are prepared using a one-step mineralization process assisted by metal-phenolic network formation. G-TSrP exhibits the ability to eliminate reactive oxygen species and direct polarization of macrophages toward M2 phenotype. It has been observed that the liberation of TA and Sr2+ from G-TSrP actively facilitate the recruitment and up-regulation of the expression of extracellular matrix remodeling genes of macrophages, and thereby, coordinate in vivo adapted degradation of the G-TSrP. Most significantly, G-TSrP accelerates angiogenesis despite the TA's inhibitory properties, which are counteracted by the released Sr2+. Moreover, G-TSrP enhances wound closure under inflammation and promotes normal tissue formation with strong vessel growth. Genetic analysis confirms macrophage-mediated wound healing by the composite hydrogel. Collectively, these findings pave the way for the development of biomaterials that promote wound healing by creating regenerative environment.

Engineering pre-vascularized 3D tissue and rapid vascular integration with host blood vessels via co-cultured spheroids-laden hydrogel.

Recent advances in regenerative medicine and tissue engineering have enabled the biofabrication of three-dimensional (3D) tissue analogues with the potential for use in transplants and disease modeling. However, the practical use of these biomimetic tissues has been hindered by the challenge posed by reconstructing anatomical-scale micro-vasculature tissues. In this study, we suggest that co-cultured spheroids within hydrogels hold promise for regenerating highly vascularized and innervated tissues, bothin vitroandin vivo. Human adipose-derived stem cells (hADSCs) and human umbilical vein cells (HUVECs) were prepared as spheroids, which were encapsulated in gelatin methacryloyl hydrogels to fabricate a 3D pre-vascularized tissue. The vasculogenic responses, extracellular matrix production, and remodeling depending on parameters like co-culture ratio, hydrogel strength, and pre-vascularization time forin vivointegration with native vessels were then delicately characterized. The co-cultured spheroids with 3:1 ratio (hADSCs/HUVECs) within the hydrogel and with a pliable storage modulus showed the greatest vasculogenic potential, and ultimately formedin vitroarteriole-scale vasculature with a longitudinal lumen structure and a complex vascular network after long-term culturing. Importantly, the pre-vascularized tissue also showed anastomotic vascular integration with host blood vessels after transplantation, and successful vascularization that was positive for both CD31 and alpha-smooth muscle actin covering 18.6 ± 3.6µm2of the luminal area. The described co-cultured spheroids-laden hydrogel can therefore serve as effective platform for engineering 3D vascularized complex tissues.

Composite Spheroid-Laden Bilayer Hydrogel for Engineering Three-Dimensional Osteochondral Tissue.

A combination of hydrogels and stem cell spheroids has been used to engineer three-dimensional (3D) osteochondral tissue, but precise zonal control directing cell fate within the hydrogel remains a challenge. In this study, we developed a composite spheroid-laden bilayer hydrogel to imitate osteochondral tissue by spatially controlled differentiation of human adipose-derived stem cells. Meticulous optimization of the spheroid-size and mechanical strength of gelatin methacryloyl (GelMA) hydrogel enables the cells to homogeneously sprout within the hydrogel. Moreover, fibers immobilizing transforming growth factor beta-1 (TGF-ß1) or bone morphogenetic protein-2 (BMP-2) were incorporated within the spheroids, which induced chondrogenic or osteogenic differentiation of cells in general media, respectively. The spheroids-filled GelMA solution was crosslinked to create the bilayer hydrogel, which demonstrated a strong interfacial adhesion between the two layers. The cell sprouting enhanced the adhesion of each hydrogel, demonstrated by increase in tensile strength from 4.8 ± 0.4 to 6.9 ± 1.2 MPa after 14 days of culture. Importantly, the spatially confined delivery of BMP-2 within the spheroids increased mineral deposition and more than threefold enhanced osteogenic genes of cells in the bone layer while the cells induced by TGF-ß1 signals were apparently differentiated into chondrocytes within the cartilage layer. The results suggest that our composite spheroid-laden hydrogel could be used for the biofabrication of osteochondral tissue, which can be applied to engineer other complex tissues by delivery of appropriate biomolecules.

Development of a composite hydrogel incorporating anti-inflammatory and osteoinductive nanoparticles for effective bone regeneration.

BACKGROUND: Bone tissue regeneration is regulated by complex events, including inflammation, osteoinduction, and remodeling. Therefore, to induce the complete restoration of defective bone tissue, biomaterials with the ability to regulate the collective bone regenerative system are beneficial. Although some studies conclude that reducing reactive oxygen species created a favorable environment for bone regeneration by controlling inflammation, biomaterials that can simultaneously promote osteogenesis and regulate inflammation have not been developed. Herein, we describe the development of a multi-functional nanoparticle and its hydrogel composite with osteoinductive, anti-inflammatory, and osteoclast-maturation regulatory functions for enhanced bone regeneration. METHODS: Tannic acid-mineral nanoparticles (TMP) were prepared by self-assembly of tannic acid in an ion-rich simulated body fluid containing Ca2+ and PO43-. Particles with a diameter of 443 ± 91 nm were selected for their stable spherical morphology and minimal tendency to aggregate. The particles were homogeneously embedded within a gelatin-based cryogel (TMP/Gel) to be used in further experiments. The osteoinductive properties, anti-inflammatory and osteoclast-maturation regulatory functions in vitro were tested by culturing corresponding cells on either TMP/Gel or a gelatin-based cryogel without the particles (Gel). For in vivo analyses, a murine calvarial defect model was used. Statistical analyses were carried out using a Graphpad Prism 7 software (San Diego, CA, USA) to perform one-way analysis of variance ANOVA with Tukey's honest significant difference test and a Student's t-test (for two variables) (P < 0.05). RESULTS: Excellent biocompatibility and radical scavenging abilities were exhibited by the TMP/Gel. The expression of osteogenic mRNA is significantly increased in human adipose-derived stem cells seeded on the TMP/Gel compared to those without the particles. Furthermore, RAW264.7 cells seeded on the TMP/Gel displayed significantly lower-than-normal levels of pro-inflammatory and osteoclastogenic genes. Finally, the in vivo results indicated that, compared with the cryogel with no anti-inflammatory effect, the TMP/Gel significantly enhanced both the quality and quantity of newly formed bone, demonstrating the importance of combining anti-inflammation with osteoinduction. CONCLUSION: Collectively, these findings suggest our nanoparticle-hydrogel composite could be an effective tool to regulate complex events within the bone healing process.

Recent trends in radiotherapy use for major cancers in Korea.

BACKGROUND: Although the trend in radiotherapy in all cancer patients has been studied, changes in radiotherapy modalities for specific cancer types have not been reported. This study aimed to analyze radiotherapy patterns for major cancers in Korea in recent years. MATERIALS AND METHODS: We collected data from claims and reimbursement records of the Health and Insurance Review and Assessment Service from 2017 to 2020, according to initial diagnostic codes. The radiotherapy modalities for major cancers, such as lung, stomach, colorectal, breast and liver cancer, were analyzed. The radiotherapy modalities consisted of two-dimensional radiotherapy, three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, proton radiotherapy and stereotactic body radiotherapy. RESULTS: Overall, from 2017 to 2020, the use of two-dimensional radiotherapy and three-dimensional conformal radiotherapy decreased, and intensity-modulated radiotherapy increased. In 2017, three-dimensional conformal radiotherapy accounted for approximately half of the radiotherapy in patients for lung and colorectal cancer, which was replaced by intensity-modulated radiotherapy in 2020. In 2020, stereotactic body radiotherapy also accounted for a large proportion of radiotherapy used in liver cancer cases. Intensity-modulated radiotherapy was most used, followed by three-dimensional conformal radiotherapy and two-dimensional radiotherapy for breast cancer in 2020. Among major cancers, radiotherapy utilization for breast cancer is the highest. Compared with other cancers, the number of patients receiving radiotherapy for stomach cancer was low. CONCLUSION: The number of patients receiving radiotherapy for major cancers has increased. The use of advanced forms of radiotherapy, such as intensity-modulated radiotherapy, is rapidly increasing for major cancers. The rate of radiotherapy utilization was higher in major cancer patients than in all cancer patients.

Recent Trends of Medical Expenses Associated with Radiation Therapy in Korea Based on HIRA Big Data.

PURPOSE: We aimed to determine the trends in the use of radiotherapy (RT) and the expenses associated with it in South Korea. Materials and Methods: The statistical data of the claims and reimbursement records provided on the Health and Insurance Review and Assessment Service website were utilized. This included information such as the number of patients, fractions, medical expenses according to treatment codes, in/outpatient, sex, age, and regions of hospitals. We analyzed data from 2016 to 2020. RESULTS: With a growing RT infrastructure and an increase in the number of radiation oncologists, the expenses for RT were 605.5 million USD in 2020, which had increased 1.5 times from 394.7 million USD in 2016. This growth was mainly because of the increased usage of advanced RT techniques. Furthermore, the proportion of intensity-modulated radiation therapy (IMRT) expenses in the total expenses increased by 1.6 times from 48.8% in 2016 to 76.9% in 2020. Advanced techniques were used more commonly in older individuals or children. However, the proportion of IMRT expenses increased mostly in young women. Additionally, geographical differences in RT use and expense were observed, although the gap in the IMRT fractions decreased among the regions. CONCLUSION: Recent medical expenses associated with RT in Korea have increased in tandem with technological advances and changes in demographics.

Spatially arranged encapsulation of stem cell spheroids within hydrogels for the regulation of spheroid fusion and cell migration.

Mesenchymal stem cell spheroids have been encapsulated in hydrogels for various applications because spheroids demonstrate higher cell activity than individual cells in suspension. However, there is limited information on the effect of distance between spheroids (inter-spheroid distance) on fusion or migration in a hydrogel. In this study, we developed temperature-responsive hydrogels with surface microwell patterns to culture adipose-derived stem cell (ASC) spheroids and deliver them into a Matrigel for the investigation of the effect of inter-spheroid distance on spheroid behavior. The ASC spheroids were encapsulated successfully in a Matrigel, denoted as sandwich culture, with a specific inter-spheroid distance ranging from 100 to 400 µm. Interestingly, ASCs migrated from the host spheroid and formed a bridge-like structure between spheroids, denoted as a cellular bridge, only when the inter-spheroid distance was 200 µm. Thus, we performed a sandwich culture of human umbilical vein endothelial cells (HUVECs) and ASCs in co-cultured spheroids in the Matrigel to create a homogeneous endothelial cell network in the hydrogel. The HUVECs sprouted through the ASC cellular bridge and directly interacted with the adjacent spheroid when the inter-spheroid distance was 200 µm. Similar results were obtained from an in vivo study. Thus, our study suggests the appropriate inter-spheroid distance for effective spheroid encapsulation in a hydrogel. STATEMENT OF SIGNIFICANCE: Recently, spheroid-based 3D tissue culture techniques such as spheroid encapsulation or 3D printing are being intensively investigated for various purposes. However, there is limited research regarding the effect of the inter-spheroid distance on spheroid communication. Here, we demonstrate a spatially arranged spheroid encapsulation method within a Matrigel by using a temperature-responsive hydrogel. Human adipose-derived stem cell spheroids are encapsulated with a precisely controlled inter-spheroid distance from 100 to 400 µm and show different tendencies in cell migration and spheroid fusion. Our results suggest that the inter-spheroid distance affects spheroid communication, and thus, the inter-spheroid distance needs to be considered carefully according to the purpose.

Directed Regeneration of Osteochondral Tissue by Hierarchical Assembly of Spatially Organized Composite Spheroids.

The use of engineered scaffolds or stem cells is investigated widely in the repair of injured musculoskeletal tissue. However, the combined regeneration of hierarchical osteochondral tissue remains a challenge due to delamination between cartilage and subchondral bone or difficulty in spatial control over differentiation of transplanted stem cells. Here, two types of composite spheroids are prepared using adipose-derived stem cells (hADSCs) and nanofibers coated with either transforming growth factor-ß3 or bone morphogenetic growth factor-2 for chondrogenesis or osteogenesis, respectively. Each type of spheroid is then cultured within a 3D-printed microchamber in a spatially arranged manner to recapitulate the bilayer structure of osteochondral tissue. The presence of inductive factors regionally modulates in vitro chondrogenic or osteogenic differentiation of hADSCs within the biphasic construct without dedifferentiation. Furthermore, hADSCs from each spheroid proliferate and sprout and successfully connect the two layers mimicking the osteochondral interface without apertures. In vivo transplantation of the biphasic construct onto a femoral trochlear groove defect in rabbit knee joint results in 21.2 ± 2.8% subchondral bone volume/total volume and a cartilage score of 25.0 ± 3.7. The present approach can be an effective therapeutic platform to engineer complex tissue.

Surface engineering of 3D-printed scaffolds with minerals and a pro-angiogenic factor for vascularized bone regeneration.

Scaffolds functionalized with biomolecules have been developed for bone regeneration but inducing the regeneration of complex structured bone with neovessels remains a challenge. For this study, we developed three-dimensional printed scaffolds with bioactive surfaces coated with minerals and platelet-derived growth factor. The minerals were homogeneously deposited on the surface of the scaffold using 0.01 M NaHCO3 with epigallocatechin gallate in simulated body fluid solution (M2). The M2 scaffold demonstrated enhanced mineral coating amount per scaffold with a greater compressive modulus than the others which used different concentration of NaHCO3. Then, we immobilized PDGF on the mineralized scaffold (M2/P), which enhanced the osteogenic differentiation of human adipose derived stem cells in vitro and promoted the secretion of pro-angiogenic factors. Cells cultured in M2/P showed remarkable ratio of osteocalcin- and osteopontin-positive nuclei, and M2/P-derived medium induced endothelial cells to form tubule structures. Finally, the implanted M2/P scaffolds onto mouse calvarial defects had regenerated bone in 80.8 ± 9.8% of the defect area with the arterioles were formed, after 8 weeks. In summary, our scaffold, which composed of minerals and pro-angiogenic growth factor, could be used therapeutically to improve the regeneration of bone with a highly vascularized structure. STATEMENT OF SIGNIFICANCE: Surface engineered scaffolds have been developed for bone regeneration but inducing the volumetric regeneration of bone with neovessels remains a challenge. In here, we developed 3D printed scaffolds with bioactive surfaces coated with bio-minerals and platelet-derived growth factors. We proved that the 0.01 M NaHCO3 with polyphenol in simulated body fluid solution enhanced the deposition of bio-minerals and even distribution on the surface of scaffold. The in vitro studies demonstrated that the attached cells on the bioactive surface showed the enhanced osteogenic differentiation and secretion of pro-angiogenic factors. Finally, the scaffold with bioactive surface not only improved the regenerated volume of bone tissues but also increased neovessel formation after in vivo implantation onto mouse calvarial defect.

Current status and comparison of national health insurance systems for advanced radiation technologies in Korea and Japan.

PURPOSE: This study aimed to compare the current status of the national health insurance system (HIS) for advanced radiation technologies in Korea and Japan. MATERIALS AND METHODS: The data of the two nations were compared according to the 2019 guidelines on the application and methods of medical care benefit from the Ministry of Health and Welfare of Korea and the 2020 medical fee points list set by the Ministry of Health, Labor and Welfare of Japan. RESULTS: Both countries have adopted the social insurance system and the general payment system which is fee-for-service for radiotherapy. However, for proton and carbon ion therapy, the Japanese system has adopted a bundled payment system. Copayment for radiotherapy is 5% in Korea and 30% (7-69 years old) in Japan, with a ceiling system. A noticeable difference is that additional charges for hypofractionation, tele-radiotherapy planning for an emergency, tumor motion-tracking, purchase price of an isotope purchase price, and image-guided radiotherapy are allowed for reimbursement in the Japanese system. There are some differences regarding the indication, qualification standards, and facility standards for intensity-modulated radiation therapy, stereotactic body radiation therapy, and proton therapy. CONCLUSION: Patterns of cancer incidence, use of radiotherapy and infrastructure, and national HIS are very similar between Korea and Japan. However, there are some differences in health insurance management systems for advanced radiation technologies.

3D printed micro-chambers carrying stem cell spheroids and pro-proliferative growth factors for bone tissue regeneration.

Three-dimensional (3D)-printed scaffolds have proved to be effective tools for delivering growth factors and cells in bone-tissue engineering. However, delivering spheroids that enhance cellular function remains challenging because the spheroids tend to suffer from low viability, which limits bone regenerationin vivo. Here, we describe a 3D-printed polycaprolactone micro-chamber that can deliver human adipose-derived stem cell spheroids. Anin vitroculture of cells from spheroids in the micro-chamber exhibited greater viability and proliferation compared with cells cultured without the chamber. We coated the surface of the chamber with 500 ng of platelet-derived growth factors (PDGFs), and immobilized 50 ng of bone morphogenetic protein 2 (BMP-2) on fragmented fibers, which were incorporated within the spheroids as a new platform for a dual-growth-factor delivery system. The PDGF detached from the chamber within 8 h and the remains were retained on the surface of chamber while the BMP-2 was entrapped by the spheroid.In vitroosteogenic differentiation of the cells from the spheroids in the micro-chamber with dual growth factors enhanced alkaline phosphatase and collagen type 1A expression by factors of 126.7 ± 19.6 and 89.7 ± 0.3, respectively, compared with expression in a micro-chamber with no growth factors.In vivotransplantation of the chambers with dual growth factors into mouse calvarial defects resulted in a 77.0 ± 15.9% of regenerated bone area, while the chamber without growth factors and a defect-only group achieved 7.6 ± 3.9% and 5.0 ± 1.9% of regenerated bone areas, respectively. These findings indicate that a spheroid-loaded micro-chamber supplied with dual growth factors can serve as an effective protein-delivery platform that increases stem-cell functioning and bone regeneration.

Comparison of radiotherapy infrastructure between Korea and Japan.

BACKGROUND: Patterns of cancer incidence and radiotherapy use are similar in Korea and Japan, with differences in radiotherapy infrastructure. METHODS: The authors surveyed the megavoltage machines in 91 radiotherapy centers in Korea and published data in Japan. The number of megavoltage machines per center was used as an indicator of the fragmentation of radiotherapy services using four as the threshold, and the number of megavoltage machines per million people was compared. The practice pattern of intensity-modulated radiation therapy was analyzed. RESULTS: There were 91 centers in Korea and 825 in Japan. The number of megavoltage machines per center was 1.3 in Japan and 2.3 in Korea. Radiotherapy infrastructure showed fragmentation in Korea and hyperfragmentation in Japan. In Japan, 75% of radiotherapy centers operated with one megavoltage machine, whereas in Korea, 47% megavoltage machines per center was 3.2 in Seoul, while that in the non-capital area was 1.8, constituting a mixed pattern of centralization and fragmentation. In Japan, megavoltage machines per center in Tokyo, Kanagawa and Osaka, was 1.5, 1.3 and 1.2, respectively, indicating no concentration in the metropolis. The number of megavoltage machines per million in Korea was 4.0, whereas that in Seoul was 8.7, constituting capital concentration. In Japan, the number of megavoltage machines per million was 8.7, whereas in Tokyo, Kanagawa and Osaka, it was is 9.3, 6.3 and 9.0, showing uniform distribution. intensity-modulated radiation therapy utilization is increasing, accounting for 15% and 23% of radiotherapy patients in Japan and Korea, respectively. CONCLUSIONS: The fragmentation of radiotherapy services in Korea and Japan might affect radiotherapy quality.

Recent trends in intensity-modulated radiation therapy use in Korea.

PURPOSE: We aimed to analyze the trend in intensity-modulated radiation therapy (IMRT) use in Korea from 2011 to 2018. MATERIALS AND METHODS: We collected data from the Health and Insurance Review and Assessment Service (HIRA) big data based on the National Health Insurance Service claims and reimbursements records using primary treatment planning codes (HD 041) for IMRT from 2011 to 2018. We analyzed the changing patterns in clinical application to specific tumor sites and regional differences in IMRT utilization. RESULTS: The use of IMRT has exhibited an 18-fold steep rise from 1,921 patients in 2011 to 34,759 in 2018. With regard to IMRT in 2018, 70% of patients (24,248/34,759) were treated in metropolitan areas (Seoul, Incheon, and Gyeonggi Province). IMRT was most commonly used to treat breast, lung, and prostate cancers in 2018. Among these, the use of IMRT for breast cancer shows the most remarkable increase from 2016 when the National Health Insurance began to cover IMRT for all solid tumors. CONCLUSION: The use of IMRT is steadily increasing to treat cancer and is concentrated in metropolitan areas.

Patient-reported symptoms of radiation dermatitis during breast cancer radiotherapy: a pilot study.

PURPOSE: To find out which symptoms most frequently and severely affect breast cancer patients during radiotherapy and how patients manage the symptoms and unmet needs. METHODS: A cross-sectional survey was conducted with 111 patients who receive radiotherapy for breast cancer from January to April 2015 at Samsung Medical Center in Seoul, South Korea. Participants were asked about symptoms and discomfort due to radiotherapy, management methods for radiation dermatitis, unmet needs for radiation dermatitis care, and clinical and socio-demographic information. RESULTS: Of total, 108 out of 111 patients (97.3%) reported symptoms related to radiation dermatitis. Hyperpigmentation was the most commonly reported uncomfortable symptom followed by erythema. On average, patients reported 8.6 radiotherapy-induced skin problems (range, 0-11). Of total, 59 (53.2%) patients stated that they wanted care for radiation dermatitis, and 80.0, 59.4, and 51% of patients searched for information, used products, and visited the hospital to manage radiotherapy-related skin problems. Patients who experienced dryness, burning feelings, irritation, roughness, and hyperpigmentation were 11.73, 7.02, 5.10, 4.27, and 2.80 times more likely to have management needs than patients without those symptoms, respectively, adjusting age, current cycle of radiation therapy, chemotherapy, and type of surgery. CONCLUSIONS: Most of the breast cancer patients experience multiple symptoms associated with radiation dermatitis. Hyperpigmentation was the most common and uncomfortable symptom followed by erythema. Majority of patients wanted management for radiation dermatitis and patients who experienced dryness, burning feelings, irritation, roughness, and hyperpigmentation had higher needs for radiation dermatitis management.

Recurrence outcomes after omission of postoperative radiotherapy following breast-conserving surgery for ductal carcinoma in situ of the breast: a multicenter, retrospective study in Korea (KROG 16-02).

PURPOSE: To evaluate the loco-regional recurrence (LRR) rate after breast-conserving surgery without postoperative radiotherapy (RT) for ductal carcinoma in situ (DCIS) of the breast. METHODS: Between 2000 and 2010, 311 DCIS patients from 9 institutions were analyzed retrospectively. The median age was 47 (range, 20-82). The median tumor size was 7 mm (range, 0.01-76). Margin width was <1 cm in 85 patients (27.3%), and nuclear grade was high in 37 patients (11.9%). Two hundred and three patients (65.3%) received tamoxifen. RESULTS: With a median follow-up of 74 months (range, 5-189), there were 11 local recurrences (invasive carcinoma in 6 and DCIS in 5) and 1 regional recurrence. The 7-year LRR rate was 3.8%. On univariate analysis, age and margin width were significant risk factors influencing LRR (p = 0.017 and 0.014, respectively). When age and margin width were combined among 211 patients whose margin width were available, the 7-year LRR rates were as follows (p < 0.001): (1) 0% in patients with age >50 years and any margin width status (n = 64), (2) 1.2% in age ≤50 years and margin width ≥1 cm (n = 93), (3) 13.1% in age ≤50 years and margin width <1 cm (n = 54). CONCLUSIONS: The LRR rate was very low in selected DCIS patients treated with breast-conserving surgery without postoperative RT. However, adjuvant RT should be considered for those with age ≤50 years and margin width <1 cm.

Prognostic Impact of Elective Supraclavicular Nodal Irradiation for Patients with N1 Breast Cancer after Lumpectomy and Anthracycline Plus Taxane-Based Chemotherapy (KROG 1418): A Multicenter Case-Controlled Study.

PURPOSE: This study was conducted to evaluate the impact of supraclavicular lymph node radiotherapy (SCNRT) on N1 breast cancer patients receiving post-lumpectomy whole-breast irradiation (WBI) and anthracycline plus taxane-based (AT) chemotherapy. MATERIALS AND METHODS: We performed a case-control analysis to compare the outcomes of WBI and WBI plus SCNRT (WBI+SCNRT). Among 1,147 patients with N1 breast cancer who received post-lumpectomy radiotherapy and AT-based chemotherapy in 12 hospitals, 542 were selected after propensity score matching. Patterns of failure, disease-free survival (DFS), distant metastasis-free survival (DMFS), and treatment-related toxicity were compared between groups. RESULTS: A total of 41 patients (7.6%) were found to have recurrence. Supraclavicular lymph node (SCN) failure was detected in three patients, two in WBI and one in WBI+SCNRT. All SCN failures were found simultaneously with distant metastasis. There was no significant difference in patterns of failure or survival between groups. The 5-year DFS and DMFS for patients with WBI and WBI+SCNRT were 94.4% versus 92.6% (p=0.50) and 95.1% versus 94.5% (p=0.99), respectively. The rates of lymphedema and radiation pneumonitis were significantly higher in the WBI+SCNRT than in the WBI. CONCLUSION: We did not find a benefit of SCNRT for N1 breast cancer patients receiving AT-based chemotherapy.

Postmastectomy Radiotherapy in Patients with pT1-2N1 Breast Cancer Treated with Taxane-Based Chemotherapy: A Retrospective Multicenter Analysis (KROG 1418).

PURPOSE: The purpose of this study was to evaluate the impact of postmastectomy radiotherapy (PMRT) on loco-regional recurrence-free survival (LRRFS), disease-free survival (DFS), and overall survival (OS) in pT1-2N1 patients treated with taxane-based chemotherapy. MATERIALS AND METHODS: We retrospectively reviewed the medical data of pathological N1 patients who were treated with modified radical mastectomy and adjuvant taxane-based chemotherapy in 12 hospitals between January 2006 and December 2010. RESULTS: We identified 714 consecutive patients. The median follow-up duration was 69 months (range, 1 to 114 months) and the 5-year LRRFS, DFS, and OS rates were 97%, 94%, and 98%, respectively, in patients who received PMRT (PMRT [+]). The corresponding figures were 96%, 90%, and 96%, respectively, in patients who did not receive PMRT (PMRT [-]). PMRT had no significant impact on survival. Upon multivariable analysis, only the histological grade (HG) was statistically significant as a prognostic factor for LRRFS and DFS. In a subgroup analysis of HG 3 patients, PMRT (+) showed better DFS (p=0.081). CONCLUSION: PMRT had no significant impact on LRRFS, DFS, or OS in pT1-2N1 patients treated with taxane-based chemotherapy. PMRT showed a marginal benefit for DFS in HG 3 patients. Randomized studies are needed to confirm the benefit of PMRT in high risk patients, such as those with HG 3.

Parametrial Involvement on Magnetic Resonance Imaging Has No Effect on the Survival of Early-Stage Cervical Cancer Patients.

OBJECTIVES: Parametrial involvement (PMI) in patients with cervical cancer is known to be an unfavourable prognostic factor. The purpose of this study was to investigate the prognostic significance of PMI on magnetic resonance imaging (MRI) in patients with early-stage cervical cancer. METHODS: Three hundred three patients with stage IB or IIA cervical cancer treated by adjuvant radiotherapy or concurrent chemoradiotherapy following primary surgery from 2001 to 2011 were enrolled in this study. We reviewed preoperative MRI and pathologic findings and compared recurrence and survival of group defined according to PMI status. RESULTS: There were 73 patients (24.1%) with PMI based on MRI and 52 patients (17.2%) with PMI based on surgical pathology. The accuracy of MRI for detecting PMI was 77.2% (sensitivity, 53.8%; specificity, 82.1%). In all patients, pathology-based evidence of PMI had a negative effect on both 5-year disease-free survival (73.2% vs 85.3%, P = 0.048) and 5-year overall survival (76.6% vs 91.4%, P = 0.009), but PMI on MRI did not have a significant effect on survival. In subgroups defined according to PMI status on MRI and surgical pathology, subgroups with pathology-based evidence of PMI showed a trend of a lower survival rate, regardless of PMI on MRI, but without statistical significance. CONCLUSIONS: Unlike pathologic results, PMI on MRI was not associated with recurrence or survival in patients with early-stage cervical cancer.

Clinical outcomes in patients treated with radiotherapy after surgery for cervical cancer.

PURPOSE: The purpose of this study was to analyze clinical outcomes from cervical cancer and stratify patients into risk groups for prognostic factors for early-stage disease. MATERIALS AND METHODS: We retrospectively reviewed patients with stage IB or IIA cervical cancer treated with adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) following primary surgery at Samsung Medical Center from 2001 to 2011. Adjuvant RT was added for patients with intermediate-risk factors, and adjuvant CCRT was performed on high-risk patients after surgery. RESULTS: We reviewed 247 patients-149 in the high-risk group and 98 in intermediate-risk group. The median follow-up was 62 months. Loco-regional failure (LRF) alone occurred in 7 patients (2.8%), distant metastasis alone in 37 patients (15.0%) and LRF with DM in 4 patients (1.6%). The 5-year disease-free survival (DFS) and overall survival (OS) rates for both groups were 79.7% and 87.6%, respectively. In the high-risk group, the 5-year DFS and OS probabilities were 72.5% and 81.9%, respectively. Histologic type, pathologic tumor size, and the number of pelvic lymph node (PLN) metastasis were significant prognostic factors for DFS and OS. We suggest a scoring system (0-3) using these prognostic factors to predict poor prognosis in high-risk patients. Using this system, patients with higher scores have higher recurrence and lower survival rates. CONCLUSION: In the high-risk cervical-cancer group who received primary surgery and adjuvant CCRT, non-squamous type, large tumor size and the number of PLN metastasis were significant prognostic factors, and the number of these factors was associated with survival rates.