Targeting S6K/NFκB/SQSTM1/Polθ signaling to suppress radiation resistance in prostate cancer.

In this study we have identified POLθ-S6K-p62 as a novel druggable regulator of radiation response in prostate cancer. Despite significant advances in delivery, radiotherapy continues to negatively affect treatment outcomes and quality of life due to resistance and late toxic effects to the surrounding normal tissues such as bladder and rectum. It is essential to develop new and effective strategies to achieve better control of tumor. We found that ribosomal protein S6K (RPS6KB1) is elevated in human prostate tumors, and contributes to resistance to radiation. As a downstream effector of mTOR signaling, S6K is known to be involved in growth regulation. However, the impact of S6K signaling on radiation response has not been fully explored. Here we show that loss of S6K led to formation of smaller tumors with less metastatic ability in mice. Mechanistically we found that S6K depletion reduced NFκB and SQSTM1 (p62) reporter activity and DNA polymerase θ (POLθ) that is involved in alternate end-joining repair. We further show that the natural compound berberine interacts with S6K in a in a hitherto unreported novel mode and that pharmacological inhibition of S6K with berberine reduces Polθ and downregulates p62 transcriptional activity via NFκB. Loss of S6K or pre-treatment with berberine improved response to radiation in prostate cancer cells and prevented radiation-mediated resurgence of PSA in animals implanted with prostate cancer cells. Notably, silencing POLQ in S6K overexpressing cells enhanced response to radiation suggesting S6K sensitizes prostate cancer cells to radiation via POLQ. Additionally, inhibition of autophagy with CQ potentiated growth inhibition induced by berberine plus radiation. These observations suggest that pharmacological inhibition of S6K with berberine not only downregulates NFκB/p62 signaling to disrupt autophagic flux but also decreases Polθ. Therefore, combination treatment with radiation and berberine inhibits autophagy and alternate end-joining DNA repair, two processes associated with radioresistance leading to increased radiation sensitivity.

Efficacy and Safety of Human Bone Marrow-Derived Mesenchymal Stem Cells according to Injection Route and Dose in a Chronic Kidney Disease Rat Model.

Background and Objectives: We compared the efficacy and safety of human bone marrow-derived mesenchymal stem cells (hBMSC), delivered at different doses and via different injection routes in an animal model of chronic kidney disease. Methods and Results: A total of ninety 12-week-old rats underwent 5/6 nephrectomy and randomized among nine groups: sham, renal artery control (RA-C), tail vein control (TV-C), renal artery low dose (RA-LD) (0.5×106 cells), renal artery moderate dose (RA-MD) (1.0×106 cells), renal artery high dose (RA-HD) (2.0×106 cells), tail vein low dose (TV-LD) (0.5×106 cells), tail vein moderate dose (TV-MD) (1.0×106 cells), and tail vein high dose (TV-HD) (2.0×106 cells). Renal function and mortality of rats were evaluated after hBMSC injection. Serum blood urea nitrogen was significantly lower in the TV-HD group at 2 weeks (p<0.01), 16 weeks (p<0.05), and 24 weeks (p<0.01) than in the TV-C group, as determined by one-way ANOVA. Serum creatinine was significantly lower in the TV-HD group at 24 weeks (p<0.05). At 8 weeks, creatinine clearance was significantly higher in the TV-MD and TV-HD groups (p<0.01, p<0.05) than in the TV-C group. In the safety evaluation, we observed no significant difference among the groups. Conclusions: Our findings confirm the efficacy and safety of high dose (2×106 cells) injection of hBMSC via the tail vein.

Are leukocyte-poor or multiple injections of platelet-rich plasma more effective than hyaluronic acid for knee osteoarthritis? A systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Platelet-rich plasma (PRP) has gained popularity as a treatment option for knee osteoarthritis; however, its efficacy remains controversial. The optimal leukocyte concentration and number of injections have not been well investigated. This study was, therefore, designed to provide clinical evidence on the leukocyte concentration and number of intra-articular injections of PRP via a meta-analysis of randomized controlled trials (RCTs). METHODS: The MEDLINE, Embase, Cochrane Library, CINAHL, and Scopus databases were searched and RCTs comparing PRP and hyaluronic acid (HA) for treating knee osteoarthritis were included. Clinical outcomes, including visual analog scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and adverse reactions, were evaluated. RESULTS: A total of 138 studies were screened, of which 21 level 1 RCTs (2086 knees; 1077 PRP and 1009 HA) were included. PRPs showed significant improvement in pain according to the VAS score compared to HA at 6 and 12 months, regardless of leukocyte concentration. Both single and multiple injections of PRP improved pain better than HA at 12 months. Regarding function, both single and multiple injections of leukocyte-poor PRP and leukocyte-rich PRP led to significantly better improvement in total WOMAC score compared with HA at 6 months. There was no significant difference in procedure-related knee pain or swelling between the PRP and HA groups. Leukocyte-rich PRP had a significantly higher odds ratio for procedure-related knee pain or swelling compared to HA (odds ratio, 3.3 [95% confidence interval, 1.1-10.2], P = .037). CONCLUSION: Based on evidence from Level 1 studies, intra-articular injection of PRP improves pain and function in patients with knee osteoarthritis for up to 12 months and is superior to HA, regardless of leukocyte concentration or number of injections. The findings of this study support the routine clinical use of intra-articular injections of PRP for the treatment of knee osteoarthritis, regardless of the type and frequency of PRP injection. LEVEL OF EVIDENCE: Meta-analysis of level I studies.

Unique approaches for testicular shielding during total-body irradiation for pediatric patients.

Total-body irradiation (TBI) has been used as a part of the conditioning regimen for patients undergoing hematopoietic stem cell transplantation for certain nonmalignant conditions such as sickle cell disease. Although effective, TBI can cause lasting side effects for pediatric patients. One of these potential side effects includes oligospermia or even permanent azoospermia. Although many investigators have studied ways to shield the testicles during the TBI for nonmalignant conditions, there is no set standard. We describe the technical aspects of effective techniques to shield the testicles of male pediatric patients undergoing TBI. We verified that our techniques reduced the testicular dose by approximately 80%-85% of the TBI prescription dose in four male pediatric patients, keeping the dose well below the documented doses that can cause permanent infertility and hypogonadism.

Cost Effectiveness of Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Patients with Knee Osteoarthritis.

OBJECTIVES: The aim of this study was to assess the cost effectiveness of allogeneic umbilical cord blood-derived mesenchymal stem cells with sodium hyaluronate (hUCB-MSC) compared with microfracture in patients with knee cartilage defects caused by osteoarthritis (OA) in South Korea. METHODS: A partitioned survival model approach was taken consisting of five mutually exclusive health states: excellent, good, fair, poor, and death over a 20-year time horizon. Utility values were obtained from a randomized clinical trial. Cost data were extracted from a database provided by the Health Insurance Review & Assessment Service, and the utilization of healthcare services was estimated from an expert panel of orthopedic surgeons using a structured questionnaire. The incremental cost-effectiveness ratio (ICER) in terms of quality-adjusted life-years (QALY) was calculated. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: In the base case, the incremental costs of US$14,410 for hUCB-MSC therapy along with its associated QALY gain of 0.857 resulted in an ICER of US$16,812 (₩18,790,773) per QALY (95% confidence interval [CI] US$13,408-US$20,828) when compared with microfracture treatment from a healthcare payer perspective. From a societal perspective, the ICER was US$268 (₩299,255) per QALY (95% CI -US$2915 to US$3784). When using a willingness-to-pay threshold of US$22,367/QALY, the probability of hUCB being cost effectiveness compared with microfracture was 99% from the healthcare payer perspective and 100% from the societal perspective. CONCLUSIONS: The study demonstrated that hUCB-MSC therapy was cost effective compared with microfracture when treating patients with knee OA. These findings should inform health policy decision makers about considerations for cost-effective therapy for treating knee OA to ultimately enhance population health.

Efficacy and Safety of Human Bone Marrow-Derived Mesenchymal Stem Cells according to Injection Route and Dose in a Chronic Kidney Disease Rat Model

Background and Objectives@#We compared the efficacy and safety of human bone marrow-derived mesenchymal stem cells (hBMSC), delivered at different doses and via different injection routes in an animal model of chronic kidney disease. @*Methods@#and Results: A total of ninety 12-week-old rats underwent 5/6 nephrectomy and randomized among nine groups: sham, renal artery control (RA-C), tail vein control (TV-C), renal artery low dose (RA-LD) (0.5×10 6 cells), renal artery moderate dose (RA-MD) (1.0×10 6 cells), renal artery high dose (RA-HD) (2.0×10 6 cells), tail vein low dose (TV-LD) (0.5×10 6 cells), tail vein moderate dose (TV-MD) (1.0×10 6 cells), and tail vein high dose (TV-HD) (2.0×10 6 cells). Renal function and mortality of rats were evaluated after hBMSC injection. Serum blood urea nitrogen was significantly lower in the TV-HD group at 2 weeks (p＜0.01), 16 weeks (p＜0.05), and 24 weeks (p＜0.01) than in the TV-C group, as determined by one-way ANOVA. Serum creatinine was significantly lower in the TV-HD group at 24 weeks (p＜0.05). At 8 weeks, creatinine clearance was significantly higher in the TV-MD and TV-HD groups (p＜0.01, p＜0.05) than in the TV-C group. In the safety evaluation, we observed no significant difference among the groups. @*Conclusions@#Our findings confirm the efficacy and safety of high dose (2×10 6 cells) injection of hBMSC via the tail vein.

Identification of Cardiovascular Disease-Related Genes Based on the Co-Expression Network Analysis of Genome-Wide Blood Transcriptome.

Inference of co-expression network and identification of disease-related modules and gene sets can help us understand disease-related molecular pathophysiology. We aimed to identify a cardiovascular disease (CVD)-related transcriptomic signature, specifically, in peripheral blood tissue, based on differential expression (DE) and differential co-expression (DcoE) analyses. Publicly available blood sample datasets for coronary artery disease (CAD) and acute coronary syndrome (ACS) statuses were integrated to establish a co-expression network. A weighted gene co-expression network analysis was used to construct modules that include genes with highly correlated expression values. The DE criterion is a linear regression with module eigengenes for module-specific genes calculated from principal component analysis and disease status as the dependent and independent variables, respectively. The DcoE criterion is a paired t-test for intramodular connectivity between disease and matched control statuses. A total of 21 and 23 modules were established from CAD status- and ACS-related datasets, respectively, of which six modules per disease status (i.e., obstructive CAD and ACS) were selected based on the DE and DcoE criteria. For each module, gene-gene interactions with extremely high correlation coefficients were individually selected under the two conditions. Genes displaying a significant change in the number of edges (gene-gene interaction) were selected. A total of 6, 10, and 7 genes in each of the three modules were identified as potential CAD status-related genes, and 14 and 8 genes in each of the two modules were selected as ACS-related genes. Our study identified gene sets and genes that were dysregulated in CVD blood samples. These findings may contribute to the understanding of CVD pathophysiology.

The cost of elective nodal coverage in prostate cancer: Late quality of life outcomes and dosimetric analysis with 0, 45 or 54 Gy to the pelvis.

Purpose: Elective pelvic lymph node radiotherapy (PLNRT) in prostate cancer is often omitted from definitive (n = 267) and post prostatectomy (n = 160) radiotherapy (RT) due to concerns regarding toxicity and efficacy. Data comparing patient-reported outcome measures (PROMs) with or without PLNRT is limited. Our long-term supposition is that PLNRT, particularly to higher doses afforded by IMRT, will decrease pelvic failure rate in select patients. We aim to establish the impact of two different PLNRT doses on long term quality of life (QOL). Methods and materials: Prostate cancer patients (n = 428) recorded baseline scores using the Expanded Prostate Cancer Index Composite (EPIC), prior to definitive or post-prostatectomy RT. PLNRT, if given, was prescribed to 45 or 54 Gy at 1.8 Gy per fraction. New EPIC scores were recorded 20-36 months after radiotherapy. Absolute change in each domain subscale and summary score was recorded, along with if these changes met minimally important difference (MID) criteria. A separate multivariate analysis (MVA) was performed for each measure. Subsequent dosimetric analysis was performed. Results: Frequency of a MID decline was significantly greater with PLNRT to 54 Gy for urinary function, incontinence, and overall. No urinary decline was correlated with PLNRT to 45 Gy. PLNRT to 54 Gy was significant for decline in urinary function, bother, irritative, incontinence, and overall score in one or both MVA models while 45 Gy was not. Postoperative status was significant for decline in urinary function, incontinence, and overall. Amongst postoperative patients, there was significantly greater decline in urinary function score in the salvage setting. Neither 54 nor 45 Gy significantly affected bowel subscale or overall score decline. Conclusions: Using conventional fractionation, adding PLNRT to 54 Gy, but not 45 Gy, correlates with worse urinary QOL, with postoperative patients experiencing a steeper decline. PLNRT had no significant impact on bowel QOL with either dose.

A Multicenter, Randomized, Double-Blinded, Parallel-Group, Placebo-Controlled Phase I/IIa Study to Evaluate the Efficacy and Safety of a Single Intra-Articular Injection of YYD302 in Patients with Knee Osteoarthritis.

This study was a phase I/IIa, multicenter, randomized, double-blinded, parallel, placebo-controlled clinical trial that aimed to assess the efficacy and safety of a single intra-articular injection of YYD302, a novel high-molecular-weight hyaluronic acid with divinyl sulfone cross-linking. Thirty adults with knee osteoarthritis were randomized to receive a single 2 mL intra-articular injection of YYD302 (test group 1), 3 mL of YYD302 (test group 2), or 3 mL of the placebo (placebo group). We compared the changes from the baseline in the weight-bearing pain of 100 mm using the Visual Analog Scale (VAS), the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Rheumatology-Osteoarthritis Research Society International (OMERACT-OASRSI) responder rates, and the use of rescue analgesics to assess the safety of this novel drug. A total of 26 subjects (10 in test group 1, 10 in test group 2, and 6 in the placebo group) were included in the full analysis set. At 12 weeks, only test groups 1 and 2 showed significant changes in the weight-bearing pain VAS scores (p = 0.0015 and p = 0.0085), symptoms, and average daily KOOS values compared to the baseline (p < 0.001, p = 0.0124, and p = 0.0018, p = 0.0426, respectively). While the rate and frequency of consuming the rescue drug continued to increase in the placebo group until 12 weeks, there was no change in the test groups. Our findings showed that YYD302, especially 2 mL of YYD302, reduced pain and improved knee joint function compared to the placebo.

Meniscus regeneration with injectable Pluronic/PMMA-reinforced fibrin hydrogels in a rabbit segmental meniscectomy model.

Injectable hydrogel systems are a facile approach to apply to the damaged meniscus in a minimally invasive way. We herein developed a clinically applicable and injectable semi-interpenetrated network (semi-IPN) hydrogel system based on fibrin (Fb), reinforced with Pluronic F127 (F127) and polymethyl methacrylate (PMMA), to improve the intrinsic weak mechanical properties. Through the dual-syringe device system, the hydrogel could form a gel state within about 50 s, and the increment of compressive modulus of Fb hydrogels was achieved by adding F127 from 3.0% (72.0 ± 4.3 kPa) to 10.0% (156.0 ± 9.8 kPa). The shear modulus was enhanced by adding PMMA microbeads (26.0 ± 1.1 kPa), which was higher than Fb (13.5 ± 0.5 kPa) and Fb/F127 (21.7 ± 0.8 kPa). Moreover, the addition of F127 and PMMA also delayed the rate of enzymatic biodegradation of Fb hydrogel. Finally, we confirmed that both Fb/F127 and Fb/F127/PMMA hydrogels showed accelerated tissue repair in the in vivo segmental defect of the rabbit meniscus model. In addition, the histological analysis showed that the quality of the regenerated tissues healed by Fb/F127 was particularly comparable to that of healthy tissue. The biomechanical strength of the regenerated tissues of Fb/F127 (3.50 ± 0.35 MPa) and Fb/F127/PMMA (3.59 ± 0.89 MPa) was much higher than that of Fb (0.82 ± 0.05 MPa) but inferior to that of healthy tissue (6.63 ± 1.12 MPa). These results suggest that the reinforcement of Fb hydrogel using FDA-approved synthetic biomaterials has great potential to be used clinically.

Intra-Articular Injection of a Novel DVS Cross-Linked Hyaluronic Acid Manufactured by Biological Fermentation (YYD302) in Patients With Knee Osteoarthritis: A Double-Blind, Randomized, Multicenter, Noninferiority Study.

PURPOSE: This double-blind, randomized, Phase III clinical trial was conducted to assess the efficacy and safety of the novel divinyl sulfone cross-linked hyaluronate (YYD302) compared with the 1,4-butanediol diglycidyl ether cross-linked hyaluronate (Synovian) in patients with knee osteoarthritis. METHODS: A total of 184 patients with osteoarthritis (Kellgren-Lawrence grade I-III) were randomized to 1 of 2 study groups (YYD302 group, n = 95; Synovian group, n = 89). A single injection of YYD302 or Synovian was given to both groups, and 182 participants completed the study (YYD302 group, n = 95; Synovian group, n = 87). The primary end point was the change in weight-bearing pain (WBP) at 12 weeks after the primary single injection. Secondary end points included the Knee Injury and Osteoarthritis Outcome Score; the Western Ontario and McMaster Universities Osteoarthritis Index score; the Patient Global Assessment and Investigator Global Assessment; the range of motion, swelling, and tenderness of the target knee; OMERACT-OARSI responder rate; WBP responder rate (the proportion of patients achieving at least 20 mm or 40% decrease in WBP); and rate of rescue medicine use and its total consumption at weeks 2, 4, and 12. Based on the efficacy results at week 12, the responders were administered an additional single injection of the same study drug at week 24, and safety and efficacy were additionally assessed at week 36. FINDINGS: Mean changes of WBP at 12 weeks after the primary injection were -31.76 mm with YYD302 and -29.74 mm with Synovian, proving noninferiority of the YYD302 group to the Synovian group as the lower bound of the 95% CI (-4.3 to 8.3) was well above the predefined margin (-10 mm). At week 2, the Knee Injury and Osteoarthritis Outcome Score (total, pain, activities of daily living, and sports/recreation) and Western Ontario and McMaster Universities Osteoarthritis Index scores (total, stiffness) were significantly better in the YYD302 group than in the Synovian group. There were no significant differences between the groups in all other end points. Local overall adverse events (pain, heat, erythema, or swelling) at the injection site were observed in 48.4% of the YYD302 group and in 47.7% of the Synovian group. No serious reactions were reported. There was no statistically significant difference between the 2 groups regarding re-injected patients (YYD302 group, n = 54; Synovian group, n = 46) in any of the efficacy outcomes at week 36. IMPLICATIONS: The results of this study support that YYD302 is comparable to Synovian in terms of the efficacy and safety of the intra-articular injection treatment for osteoarthritis of the knee joint. Furthermore, YYD302 provided faster improvements in some efficacy assessments compared with Synovian. ClinicalTrials.gov identifier: NCT03561779.

A customizable aluminum compensator system for total body irradiation.

PURPOSE: To develop a simplified aluminum compensator system for total body irradiation (TBI) that is easy to assemble and modify in a short period of time for customized patient treatments. METHODS: The compensator is composed of a combination of 0.3 cm thick aluminum bars, two aluminum T-tracks, spacers, and metal bolts. The system is mounted onto a plexiglass block tray. The design consists of 11 fixed sectors spanning from the patient's head to feet. The outermost sectors utilize 7.6 cm wide aluminum bars, while the remaining sectors use 2.5 cm wide aluminum bars. There is a magnification factor of 5 from the compensator to the patient treatment plane. Each bar of aluminum is interconnected at each adjacent sector with a tongue and groove arrangement and fastened to the T-track using a metal washer, bolt, and nut. Inter-bar leakage of the compensator was tested using a water tank and diode. End-to-end measurements were performed with an ion chamber in a solid water phantom and also with a RANDO phantom using internal and external optically stimulated luminescent detectors (OSLDs). In-vivo patient measurements from the first 20 patients treated with this aluminum compensator were compared to those from 20 patients treated with our previously used lead compensator system. RESULTS: The compensator assembly time was reduced to 20-30 min compared to the 2-4 h it would take with the previous lead design. All end-to-end measurements were within 10% of that expected. The median absolute in-vivo error for the aluminum compensator was 3.7%, with 93.8% of measurements being within 10% of that expected. The median error for the lead compensator system was 5.3%, with 85.1% being within 10% of that expected. CONCLUSION: This design has become the standard compensator at our clinic. It allows for quick assembly and customization along with meeting the Task Group 29 recommendations for dose uniformity.

Efficacy and safety of a novel hemostatic material, BoneStat, compared with Ostene and Bone Wax in a rat calvarial defect model.

Hemostasis has critical significance during surgical procedures. Bone Wax has traditionally been commonly used for bone hemostasis despite well-documented undesirable side effects: hindering osteogenesis and induction of inflammatory reactions with consequent increase in infection rates. A later developed formulation, Ostene, offers an alternative to Bone Wax with lesser undesired effects. In this study, BoneStat, a newly developed bone hemostatic formulation comprising water-soluble alkylene oxide co-polymers, was evaluated for water solubility, hemostatic efficacy, ease of handling, bone healing efficacy, and inflammatory reactions compared with Bone Wax and Ostene in a rat calvarial defect model. More than 95% of BoneStat was dissolved in water within 48 h, as was Ostene, but not Bone Wax. The time to hemostasis using BoneStat was significantly faster than with Ostene or Bone Wax. BoneStat also improved ease of handling compared to Ostene or BoneWax. BoneStat- and Ostene-treated groups constantly showed better bone healing than with Bone Wax. The BoneStat and Ostene groups presented no evidence of chronic inflammation reaction contrary to Bone Wax. These results suggest improved hemostasis, ease of handling, non-hindering bone healing, and unnoticeable chronic inflammatory reactions with BoneStat. Thus, Bonestat is a useful and reliable formulation for mechanical hemostasis.

Safety of autologous bone marrow-derived mesenchymal stem cells in erectile dysfunction: an open-label phase 1 clinical trial.

BACKGROUND AIMS: The efficacy of phosphodiesterase type 5 inhibitors (PDE5Is), which are commonly used to treat erectile dysfunction (ED), is not satisfactory in patients with denervation of the cavernous nerve due to pelvic surgeries and diabetes mellitus (DM). Pre-clinical studies using bone marrow-derived mesenchymal stem cells (BMSCs) to treat ED have shown promising results. The authors conducted a phase 1 clinical trial with autologous BMSCs in patients with ED due to radical prostatectomy or DM. METHODS: Ten patients (five with post-prostatectomy ED and five with DM-associated ED) who could not perform sexual activity despite taking the maximum dose of a PDE5I were enrolled. The brief clinical trial protocol was registered with the US National Institutes of Health on ClinicalTrials.gov (NCT02344849). The primary outcome was the safety of stem cell therapy, and the secondary outcome was the improvement of erectile function. RESULTS: Of the 13 patients screened, 10 were registered in the clinical trial and received autologous BMSCs and nine completed the clinical trial. One patient with post-prostatectomy ED experienced two treatment-emergent adverse events (TEAEs) (pyrexia and back pain), and two patients with DM-associated ED experienced a total of five TEAEs (one case each of viral upper respiratory tract infection, prostatitis and pruritus and two cases of hyperglycemia). Of these patients, one with DM-associated ED experienced two serious TEAEs (two instances of hyperglycemia). All TEAEs were considered not to be related to autologous BMSC therapy. In addition, no clinical significance was identified related to other safety measures, such as laboratory tests and vital signs. The mean International Index of Erectile Function score increased significantly at 1 month versus baseline (24.9 versus 18.1, P = 0.0222). CONCLUSIONS: This phase 1 clinical trial confirmed the safety and potential efficacy of autologous BMSC therapy in patients with ED. The authors' results need to be confirmed by a phase 2 clinical trial.

Adverse Reactions and Clinical Outcomes for Leukocyte-Poor Versus Leukocyte-Rich Platelet-Rich Plasma in Knee Osteoarthritis: A Systematic Review and Meta-analysis.

BACKGROUND: Platelet-rich plasma (PRP) has gained attention as a therapeutic option for knee osteoarthritis; however, its efficacy varies widely. Leukocytes in PRP raise the concern of aggravating proinflammatory activity. To date, PRP has rarely been investigated with regard to leukocyte concentration. PURPOSE: To provide clinical evidence of the intra-articular injection of PRPs containing different leukocyte concentrations. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: We systematically searched the MEDLINE, Embase, Cochrane Library, CINAHL, and Scopus databases. PRP was classified into leukocyte-poor (LP-PRP) and leukocyte-rich (LR-PRP). Clinical outcomes including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analog scale (VAS) for pain score, International Knee Documentation Committee (IKDC) subjective score, and adverse reactions were evaluated. The Methodological Index for Non-Randomized Studies criteria were used for quality assessment. RESULTS: Included were 32 studies with an evidence level between 1 and 4. Both LP-PRP and LR-PRP showed improvements above the minimal clinically important difference (MCID) in VAS pain score. No significant intergroup difference was seen at 3, 6, or 12 months of follow-up. Regarding function, both LP-PRP and LR-PRP showed improvements above the MCID in the WOMAC and IKDC scores, with no significant difference between the groups. Adverse reactions for pain were significantly higher in LR-PRP than in LP-PRP (odds ratio, 1.64; 95% confidence interval, 1.29-2.10; P = .01). After intra-articular PRP injection, LR-PRP showed a significantly higher rate of swelling than LP-PRP (odds ratio, 1.56; 95% confidence interval, 1.22-1.99; P = .02). The mean Methodological Index for Non-Randomized Studies score of the included studies was 18.6 (range, 10-24). CONCLUSION: Intra-articular PRP injection resulted in improvements above the MCID in terms of pain and function in patients with knee osteoarthritis up to 12 months. The risk of local adverse reactions appeared to be increased after LR-PRP compared with LP-PRP injection. The findings of this review can support the potential use of intra-articular PRP injection for the treatment of knee osteoarthritis. In clinical application, clinicians need to consider selecting a specific type of PRP for knee osteoarthritis.

Is it worth to perform initial non-operative treatment for patients with acute ACL injury?: a prospective cohort prognostic study.

PURPOSE: To evaluate the result of implementing an initial non-operative treatment program for an acute ACL injury and to find if the timing of initiating the non-operative treatment is significant. METHODS: This study included a prospective cohort of 85 consecutive patients with acute ACL injury who were treated according to the above strategy for the initial 3 months with 1-year follow-up. Clinical evaluations were made by Lysholm score, Tegner activity score, Lachman test (LT), pivot-shit test (PST), and the side to side difference (SSD) by KT-2000 arthrometer. The results were analyzed according to the timing of initiating the non-operative treatment. RESULTS: Initially, 84% of the patients showed LT and PST ≤ grade 1, and 16% with ≥grade 2. At 1-year follow-up, 77 patients (91%) with LT and PST ≤ grade 1 did not receive reconstruction as copers and 8 patients with LT or PST ≥ grade 2 required reconstruction (six patients received the operation and two refused). The patients with LT and PST ≤ grade 1 showed average Lysholm score 91.2, average SSD 2.5 mm, and mean Tegner score decreased from 6.9 (pre-injury) to 6.2. Patients who started the non-operative treatment within 2 weeks after injury revealed superior rates of grade 0 or 1 instability than those who commenced the treatment later than 2 weeks after injury (P = 0.043). CONCLUSIONS: Implementing a non-operative treatment with brace in acute phase of ACL injury appears to be an effective and viable option to achieve a reasonable clinical outcome. We recommend earlier initiation of the non-operative treatment to obtain a better result in patients with acute ACL injury.

Primary Mediastinal B Cell Lymphoma in the Positron-Emission Tomography Era Executive Summary of the American Radium Society Appropriate Use Criteria.

PURPOSE: Primary mediastinal B cell lymphoma (PMBCL) is a highly curable subtype of non-Hodgkin lymphoma that is diagnosed predominantly in adolescents and young adults. Consequently, long-term treatment-related morbidity is critical to consider when devising treatment strategies that include different chemoimmunotherapy strategies with or without radiation therapy. Furthermore, adaptive approaches using the end-of-chemotherapy (EOC) positron emission tomography (PET)/computed tomography (CT) scanning may help to determine which patients may benefit from additional therapies. We aimed to develop evidence-based guidelines for treating these patients. METHODS AND MATERIALS: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the PubMed database. The ARS expert committee, composed of radiation oncologists, hematologists, and pediatric oncologists, developed consensus guidelines using the modified Delphi framework. RESULTS: Nine studies met the full criteria for inclusion based on reporting outcomes on patients with primary mediastinal B cell lymphoma with EOC PET/CT response scored with the 5-point Deauville scale. These studies formed the evidence for these guidelines in managing patients with PMBCL according to the EOC PET response, including after a 5-point Deauville scale of 1 to 3, 4, or 5, and for patients with relapsed and refractory disease. The expert group also developed guidance on radiation simulation, treatment planning, and plan evaluation based on expert opinion. CONCLUSIONS: Various treatment approaches exist in the management of PMBCL, including different chemoimmunotherapy regimens, the use of consolidative radiation therapy, and adaptive approaches based on EOC PET/CT response. These guidelines can be used by practitioners to provide appropriate treatment according to different disease scenarios.

Injectable Fibrin/Polyethylene Oxide Semi-IPN Hydrogel for a Segmental Meniscal Defect Regeneration.

BACKGROUND: Meniscal deficiency from meniscectomy is a common situation in clinical practices. Regeneration of the deficient meniscal portion, however, is still not feasible. PURPOSE: To develop an injectable hydrogel system consisting of fibrin (Fb) and polyethylene oxide (PEO) and to estimate its clinical potential for treating a segmental defect of the meniscus in a rabbit meniscal defect model. STUDY DESIGN: Controlled laboratory study. METHODS: The Fb/PEO hydrogel was fabricated by extruding 100 mg·mL-1 of fibrinogen solution and 2,500 U·mL-1 of thrombin solution containing 100 mg·mL-1 of PEO through a dual-syringe system. The hydrogels were characterized by rheological analysis and biodegradation tests. The meniscal defects of New Zealand White male rabbits were generated by removing 60% of the medial meniscus from the anterior side. The removed portion included the central portion. The Fb/PEO hydrogel was injected into the meniscal defect of the experimental knee through the joint space between the femoral condyle and tibial plateau at the anterior knee without a skin incision. The entire medial menisci from both knees of each rabbit were collected and photographed before placement in formalin for histological processing. Hematoxylin and eosin, safranin O, and immunohistochemical staining for type II collagen was performed. The biomechanical property of the regenerated meniscus was evaluated using a universal tensile machine. RESULTS: The Fb/PEO hydrogel was fabricated by an in situ gelation process, and the hydrogel displayed a semi-interpenetrating polymer network structure. We demonstrated that the mechanical properties of Fb-based hydrogels increased in a PEO-dependent manner. Furthermore, the addition of PEO delayed the biodegradation of the hydrogel. Our in vivo data demonstrated that, as compared with Fb hydrogel, Fb/PEO hydrogel injection into the meniscectomy model showed improved tissue regeneration. The regenerated meniscal tissue by Fb/PEO hydrogel showed enhanced tissue quality, which was supported by the histological and biomechanical properties. CONCLUSION: The Fb/PEO hydrogel had an effective tissue-regenerative ability through injection into the in vivo rabbit meniscal defect model. CLINICAL RELEVANCE: This injectable hydrogel system can promote meniscal repair and be readily utilized in clinical application.

Clinical Efficacy of Platelet-Rich Plasma Injection and Its Association With Growth Factors in the Treatment of Mild to Moderate Knee Osteoarthritis: A Randomized Double-Blind Controlled Clinical Trial As Compared With Hyaluronic Acid.

BACKGROUND: Although platelet-rich plasma (PRP) has potential as a regenerative treatment for knee osteoarthritis, its efficacy varies. Compositional differences among types of PRP could affect clinical outcomes, but the biological characterization of PRP is lacking. PURPOSE: To assess the efficacy of intra-articular PRP injection in knee osteoarthritis as compared with hyaluronic acid (HA) injection and to determine whether the clinical efficacy of PRP is associated with its biological characteristics. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 110 patients with symptomatic knee osteoarthritis received a single injection of leukocyte-rich PRP (1 commercial kit) or HA. Clinical data were assessed at baseline and at 6 weeks and 3 and 6 months after injection. The primary endpoint was an improvement in the International Knee Documentation Committee (IKDC) subjective score at 6 months, and the secondary endpoints were improvements in scores based on the Patient Global Assessment, the visual analog scale (VAS) for pain, the Western Ontario and McMaster Universities Osteoarthritis Index, and the Samsung Medical Center patellofemoral score. Cell counts and concentrations of growth factors and cytokines in the injected PRP were assessed to determine their association with clinical outcomes. RESULTS: PRP showed significantly improvement in IKDC subjective scores at 6 months (11.5 in the PRP group vs 6.3 in the HA group; P = .029). There were no significant differences between groups in other clinical outcomes. The Patient Global Assessment score at 6 months was better in the PRP group (P = .035). The proportion of patients who scored above the minimal clinically important difference (MCID) for VAS at 6 months was significantly higher in the PRP group (P = .044). Within the PRP group, the concentrations of platelet-derived growth factors were high in patients with a score above the MCID for VAS at 6 months. The incidence of adverse events did not differ between the groups (P > .05). CONCLUSION: PRP had better clinical efficacy than HA. High concentrations of growth factors were observed in patients who scored above the MCID for clinical outcomes in the PRP group. These findings indicate that concentration of growth factors needs to be taken into consideration for future investigations of PRP in knee osteoarthritis. REGISTRATION: NCT02211521 (ClinicalTrials.gov identifier).