It is suggested that blue®m mouthwash positively influences tissue healing reducing pain and the postsurgical inflammatory process; however, randomized clinical trials should be done to prove this clinical observation.The aim of this case series was to evaluate the effects of blue®m mouthwash on oral surgical wounds. Eleven patients underwent bilateral preprosthetic surgery and were instructed to apply the product only to the right side of the surgery. In this way, the right side corresponds to the test side and the left side (place without applying any type of solution) to the control side. After seven days of using the product (3 times a day), the following parameters were evaluated by means of a visual analogue scale: pain, changes in taste, and acceptance by the patient. Then, the level of tissue inflammation was assessed, by the number of pixels, using ImageJ® software. The main results show that the blue®m mouthwash was widely accepted by patients, reducing their pain. The number of inflammation pixels was lower on the test side ( Chlorhexidine (CHX) is considered the gold standard in the antiseptic treatment of the oral mucosa, due to its broad antibacterial spectrum , 2; it iA team of dental surgeons led by Dr. Peter Blijdorp in the Netherlands developed a product based on active oxygen (blue®m) with the intention of putting all the desirable properties of mouthwashes in just one product. blue®m mouthwash has in its composition sodium perborate, the enzyme glucose oxidase derived from honey, xylitol, and lactoferrin . ApplicaWound healing is an extremely complex process, which requires a variety of cells to increase its metabolic activity, resulting in oxygen demand . The appThe local use of active oxygen as support for wound healing and tissue regeneration may be a tendency to replace the use of CHX, but it inspires parsimony, due to the small number of clinical monitoring cases reported or clinical trials in the literature. It is hypothesized that the use of the mouthwash will improve healing thus reducing postoperative pain. Hence, the aim of this case series is to evaluate the effects of blue®m mouthwash (OOT) in postoperative oral surgery care.This study was approved by the Ethics and Research Committee on Human Beings at UNOESC under the number 2.031.509 CAAE: 65808817.3.0000.5367. Each patient received and signed an informed consent form and an image use term. The work was conducted in compliance with the Declaration of Helsinki.A sample of 14 patients of both sexes, aged between 54 and 74 years old, who underwent preprosthetic surgeries at Universidade do Oeste de Santa Catarina (UNOESC), Joaçaba, São Paulo, Brazil, was selected.The exclusion criteria involved patients that used drugs that could directly interfere with the tissue response, such as anticoagulants and antiplatelet agents, patients who have been on antibiotic or anti-inflammatory therapy in the past three months, diabetics, smokers, and individuals who have reported a history of hypersensitivity to any mouthwash. Also, irradiated patients, pregnant women, and patients who presented lesions such as candidiasis or lichen were considered exclusion criteria.The patients were submitted to preprosthetic surgery to remove hyperplasia of the maxillary posterior and anterior ridge. Infiltrative anesthesia was performed in the anterior border region using 4% articaine with epinephrine 1 : 100,000. Two parallel linear incisions were made, along the upper or lower alveolar ridge, extending along the excessive fibrous tissue over the ridge. The two incisions were found at the base (deepest region), forming a wedge of fibrous tissue. After making the incisions, the fibrous tissue was carefully removed with the aid of a Molt detacher. The continuous scalloped suture was performed with 4-0 silk thread. The surgeries were performed by different operators.After preprosthetic surgery, each patient was prescribed acetaminophen 750 mg and received 50 ml of the test antiseptic (blue®m mouthwash) together with 15 units of flexible rods with cotton tips. In the postoperative period, the patient was instructed to apply the solution over the entire length of the region, only on the right side up to the midline (below the nose), with the aid of flexible rods three times a day , for a week. The left side served as a control. Patients were instructed not to rinse their mouths with water or other mouthwashes and neither to eat for 30 minutes after applying the solution.The postoperative evaluation was performed 7 days after the surgery, at the time of suture removal . An intrThe photos of the healing surgical wound were analyzed using the ImageJ® program, developed by Wayne Rasband of the Research Services Branch, National Institute of Mental Health , which is a domain Java image processor and image analyzer software inspired in NIH Image for the Apple Macintosh. The repertoire of functions of this software can be expanded by means of several ready-made plugins, available on the Internet, or by developing new ones.Areas of inflammation (red), considered a less healed oral tissue, and areas of healthy tissue (pink), considered with a better healing tissue, were selected. A saturation pattern was set for all images to equalize the contrast by 0.5%. Through the threshold color plugin available on the Internet, the selection of colors given in pixel shapes was carried out. The area of interest was defined, whether covered with healthy tissue or granulation/inflammation. The number of red pixels  and pinkAll analyses were performed with a significance level of 0.05 using the Bioestat® Program version 5.3. Pain values (test side and control side) were compared using the ANOVA test. The healing images were subjected to the ANOVA test of paired samples.There were 14 patients in the study, 8 were women and 11 were men, and 81% of them were over 60 years old. Three were excluded: one because he was unable to attend the follow-up on the 7th day to remove the suture and for the photographic record and the other two because they had used antiseptic throughout the length of the surgery. Therefore, the study evaluated 11 patients.p < 0.05), as shown in Regarding the minimum pain measured by patients (categorized by pain intensity numbers 0 and 1), it was more often reported on the test side than on the control side . The mosThere were no patient-reported changes in taste, nor was there any adverse effect. Everyone replied that they would use the product again.p < 0.05) in relation to the number of red pixels (p > 0.05) when analyzed in relation to the number of pink pixels. More than 90% of the patients had a lower index of red pixels on the test side, while only 72% of patients presented with a lower index of red pixels on the control side.The control and test sides analyzed by the ImageJ® program showed statistical significance  that has a slow release of oxygen, with the hypothesis that, on the side that the product was applied, the patient would feel less pain and have a lesser inflammatory process. Our results showed that the hypothesis can be accepted. The mouthwash effects seem to reduce postoperative pain and inflammation.Some people have difficulty controlling plaque build-up by only conventional tooth cleaning. Oral surgery usually requires the use of chlorhexidine mouthwashes, in addition to conventional tooth cleaning, to avoid injuries, drop of sutures, or even patient's inability. Chlorhexidine is an effective chemical method of plaque control, used for the treatment of several periodontal conditions, such as gingivitis , 22. HowThis split-mouth model using test and control sides in the same patient was based on many intraoral studies in humans and also in animal studies. This methodological aspect was similar to that used by Laureano Filho et al.  and MarlDespite the presence of the product having reached a statistical difference, the pain intensities reported between the test and control sides should be more discrepant. One answer to this inconsistency would be the inappropriate choice of the method of collecting pain measurement in elderly patients. According to Gold and Roberto , the VisIt is known that there are many difficulties in performing clinical analysis of tissue healing. So, in this series of cases, we chose to use a methodology that was able to make the comparison between the test and control sides using an objective program (ImageJ®). This methodology had already been carried out in medical studies and is now beginning to be introduced in dentistry –33.The analysis of healing by ImageJ® revealed that sites treated with blue®m showed a higher frequency of less inflamed sites (fewer red pixels). However, there was no difference when analyzing the number of more healed sites (pink pixels). The work of Pansani et al.  clarifiePhotographic monitoring is used to monitor and illustrate the different degrees of severity of skin lesions. Benson et al.  used phoThe results of the present study prove to be promising. Therefore, studies on new mouthwash alternatives are necessary to reduce any harmful effect on oral tissues, especially during the postsurgical healing phase, aiding in healing and decreasing the morbidity of oral surgeries.Within the limits of this study, blue®m mouthwash seems to reduce postoperative pain as well as clinical signs of inflammation.


Objective: This study aims to describe the angiographic imaging characteristics of superficial venous malformations and evaluate the treatment effectiveness of digital subtraction angiography (DSA)-guided foam sclerotherapy with polidocanol.Materials and Methods: This prospective study was conducted in 18 patients with venous malformation treated by DSA-guided sclerotherapy. Treatment outcomes were evaluated based on pain improvement and reduction in lesion size on magnetic resonance imaging (MRI) 6-months posttreatment.Results: A total 21 lesions and 46 sclerotherapy sessions were analyzed. MRI findings presented 8/21 lesions (38.1%) with excellent response, 9/21 (42.9%) with good response, and 3/21 (14.3%) with average response, while one patient (4.8%) showed no response. All patients experienced pain. A significant reduction (p<0.01) was observed in the pre- to posttreatment pain score . Over a follow-up period of 1–4 years, three out of four patients (75%) in the retrospective cohort experienced recurrence; one patient had an increased lesion size and pain score, while the other two patients only showed an increased lesion size. No severe complications were seen.Conclusion: DSA-guided sclerotherapy with polidocanol is a safe and effective procedure for reducing lesion size and pain in symptomatic patients with superficial venous malformations. Venous malformations result from an abnormal growth during the fetal period, and symptoms depend on the lesion size and location. The skin color of the lesions is determined by the depth of the lesions and ranges from colorless to purple. The progression of venous malformations usually involves a steady and slow increase in size over time. The morphology and size of venous malformations change with posture, and they can compress nearby organs, causing pain and limited movement. Venous malformations occur anywhere in the body but more commonly in soft tissues. Over the past decade, vein specialists globally have supported the use of ultrasound and magnetic resonance imaging (MRI) for the classification and diagnosis of venous malformations. While its indication and treatment effectiveness remain controversial, sclerotherapy is considered to be the most important treatment for venous malformations. Indications for treatment include the occurrence of symptoms affecting patient function and aesthetics.Venous malformations are common vascular anomalies defined by low-flow and abnormal veins lacking valves. Although various types of sclerosants exist, the most common is absolute alcohol. Ethibloc  is a low-cost and effective sclerosing agent. Polidocanol (Aetoxisclerol) is a surfactant with a mechanism of action similar to that of absolute alcohol but with lesser toxicity and associated pain. The effectiveness of sclerotherapy is assessed based on the lesion size and the symptoms for which treatment is indicated. Treatment success rates vary among studies. A Cochrane library meta-analysis revealed numerous flaws in studies investigating treatment effectiveness and indicated that there was insufficient evidence to accurately determine the optimum treatment method. However, many researchers believe that sclerotherapy should be the first-line treatment due to its effectiveness, safety, and low cost.Sclerotherapy is considered the first-line treatment for venous malformations. With the development of a classification for venous malformations by Puig et al. in 2003, there has been an increasing number of studies evaluating the effectiveness of sclerotherapy under digital subtraction angiography (DSA) guidance worldwide. However, to the best of our knowledge, there have been no reports of this treatment method in Vietnam. Therefore, this study aimed to describe the angiographic features of superficial venous malformations and evaluate the treatment effectiveness of DSA-guided sclerotherapy with polidocanol in Vietnam.Sclerotherapy-associated local complications such as necrotic ulceration of the skin or nerve damage have been reported; however, since polidocanol (Lauromacron 400) became the main sclerosant administered in the procedure, venous malformations are treated more frequently with reduced complications.This study was approved by the Ethical Committee of Bach Mai Hospital under the reference number 08/BMH. Between 2015 and 2020, 18 patients were treated with venous malformations using DSA-guided sclerotherapy at the Bach Mai Radiology Center, Hanoi, Vietnam.All patients were hospitalized because of clinical symptoms, such as swelling, pain, limited movement, aesthetics, dysphagia, and shortness of breath, and were diagnosed by ultrasound with a high-frequency flat probe (7–15 MHz). MRI contrast agents were administered to assess the size and extent of lesions. We inserted 18–22 G needles directly through the skin into the lesion. The contrast agent was injected with a short wire, and an angiogram was then performed. The morphology of the venous malformations and drainage veins were carefully observed on MRI by two vascular interventional radiologists and classified according to Puig’s classification: type I, isolated malformation without drainage vein; type II, malformation that drains into normal veins; type III, malformation that drains into dysplastic veins; and type IV, venous ectasia. We mixed polidocanol, air, and contrast (in some cases) and determined this ratio based on the feature of lesions . If the lesions were too big and the patient agreed, we used over 4-ml polidocanol, because it was less costly. In our study, there was only one patient using over 4-ml polidocanol/time.The foam sclerosant drug, polidocanol (4-ml polidocanol/time/person), was mixed according to the Tessari technique using tripods and two syringes and was then pumped into the venous malformation. The ratio of the gas and liquid sclerosant volume varies according to lesion features.After the sclerotherapy, patients were followed up for at least 2 h and discharged on the same day. They were followed up for late complications, and evaluation of treatment success was conducted at 1 month, 3 months, and 6 months posttreatment.Success of sclerotherapy treatment was assessed according to the following parameters: (1) lesion size on MRI (pre- and posttreatment), (2) pain score  pre- and posttreatment, and (3) recurrence: increased lesion size on MRI or increased VAS pain score.SPSS v.20.0 software was used to statistically analyze and describe the patient characteristics, including age, lesion location, symptoms, and number of injections required for sclerotherapy. Follow-up treatment success was evaluated based on the reduction in lesion size  and improvement in pain score. These were calculated by a descriptive statistical algorithm.A total of 18 patients  with venous malformations were enrolled. Their mean age was 26.5±12.9 years (range: 6–59 years). Posttreatment, 8/21 lesions (38.1%) showed an excellent response in lesion size reduction, 9/21 (42.9%) showed a good response, and 3/21 (14.3%) showed an average response, while only 1 (4.8%) did not respond to treatment  were associated with symptoms immediately after sclerotherapy, all of which involved chest tightness, while 2 cases had dry cough. No serious complications altering pulse, temperature, blood pressure, and respiration rate were noted. All patients posttreatment showed a nonserious local inflammatory response that appeared between day 1 and day 7. No other complications occurred posttreatment.No recurrence was observed in the prospective group of 14 patients. In the retrospective group of four patients, recurrence occurred in three patients 1–4 years posttreatment, two of whom showed an increase in the lesion size on MRI. One patient had an increase in both the lesion size and pain score.In this combined prospective and retrospective cohort study, we described the angiographic imaging characteristics of superficial venous malformations and evaluated the effectiveness of DSA-guided foam sclerotherapy with polidocanol for treating venous malformations. Our findings indicate that it is a safe and effective procedure for reducing the lesion size and pain in symptomatic patients with superficial venous malformation. Su et al. , and Li et al. .All included patients were mostly young with an average age of 26.5±12.9 years; females comprised ∼61.1% of the cohort and males ∼38.9%. This demographic is similar to that of previous studies such as Lee et al. , and Li et al., in which type II was the most common .We used Puig’s classification to divide venous malformations into four types. This classification is mainly based on the characteristics of the drainage veins. We found that type II was the most common (57.1%), followed by type IV (19%), type I (14.3%), and type III (9.5%), as shown in The total number of injections required during the sclerotherapy for all patients in the present study was 46, with a mean of 2.19±1.7 injections per lesion . The number of required injections in venous malformation types I and II was lower than that for types III and IV (p=0.03<0.05) with 95% confidence. This may be explained by the difference in drainage vein features according to the type of venous malformation. Types III and IV contain dysplastic drainage veins and ectasis veins; therefore, the flow through the drainage vein is often large, and the foam can easily pass through into the systemic circulation. In addition, the distribution of vessels in types III and IV malformations tends to be more pervasive than that in types I and II, making it difficult for the foam to spread, which explains why types III and IV required a greater number of injections.We used MRI to evaluate the improvement in lesion size posttreatment because it has advantages over ultrasound such as optimal spatial and time resolutions, allowing a more accurate size assessment. To allow for complete resolution of inflammation post sclerotherapy, we reexamined via MRI at 6 months posttreatment. It enables prognosis of the treatment response as well as potential complications. However, the effectiveness of sclerotherapy remains controversial. In the present study, the lesion size reduced posttreatment in 95.2% of cases; only one case, involving a venous malformation type IV on the back, failed to respond to treatment, and recurrence was recorded, with no significant response to sclerotherapy. In this particular case, we believe that previous surgical processes resulted in fibrosis scars, which separated the lesions into small parts that did not communicate with each other, making it difficult for the foam sclerosant to spread in the lesion. Furthermore, type IV has been previously shown to have a poorer response to treatment compared to types I and II.Puig’s classification of venous malformations is well recognized and widely utilized because of its practical value. Mimura et al. showed a significant improvement in the pain score from a pretreatment average of 6.6–2.4 posttreatment.All patients were admitted to our hospital due to complaints of pain. There was a significant improvement in the pain scores after 1 month, 3 months, 6 months, and >6 months posttreatment. The average pain score before and after treatment was 5.45 and 0.64, respectively, and this difference was statistically significant . These findings are consistent with other studies worldwide. Johnson et al. reported a significant improvement in swelling and pain in 85.7% of patients.In the present study, during the intervention period, four patients (19%) presented symptoms such as dry cough and chest tightness, which appeared immediately after termination of sclerotherapy foam pumping. However, these symptoms were mild and did not affect vital signs or self-healing. These symptoms are caused by reflux of foam sclerosant into the systemic circulation and occurred in type II or III cases (with drainage veins). We used Garo wire to close draining veins for the lesion in the extremities. With the lesions in the head or neck, we blocked the draining by hand. In our study, one of these patients had a venous malformation located under the left jaw, an area where it is difficult to block the drainage vein, containing a fast-flowing large drainage vein. Therefore, the foam sclerosant did not remain in the lesion; instead, it was refluxed into the systemic circulation through the drainage vein, resulting in complications and a lack of treatment response. The remaining lesions were located in the lower extremities and deep into the muscles. Therefore, we could not completely block the drainage vein using the foam, and a small flow persisted in the drainage vein. No serious complications were recorded after the intervention, consistent with the findings of previous studies worldwide.The evaluation of recurrence after intervention was based on either an increase in pain scale or lesion size on MRI. We have 3 of the 18 patients (16.7%) who experienced recurrence symptoms after 1–4 years of follow-up, among which 2 patients showed an increased lesion size, and 1 patient showed both an increase in both lesion size and pain score. Posttreatment recurrence is believed to be a natural trend of the vascular malformation because vascular endothelial cells originate in the early stages of the fetal period; therefore, the cell growth characteristics of this period are retained. In addition, the insufficient spread of the foam sclerosant was also a factor that contributed to posttreatment recurrence.Our study has several limitations, such as small sample size and short-term follow-up. Furthermore, all patients in our study were treated by sclerotherapy under DSA guidance. In other words, no cases were managed without using fluoroscopy to compare the results between the two techniques with or without using fluoroscopy. MRI is better, but it is difficult to evaluate the success during injection.In conclusion, sclerotherapy under DSA guidance with polidocanol is a safe method to reduce the lesion size and pain in patients with superficial venous malformations. Further studies are strongly recommended in the field with a larger sample size and long-term follow-up to ascertain conclusions drawn from this study.


A first-year interim analysis of this two-year study suggested that intra-articular injections of highly purified, natural-origin polynucleotides and hyaluronic acid (HA) as a fixed combination (PNHA) might improve knee function and joint pain more effectively than HA alone in patients with knee osteoarthritis (OA). The purpose of the second-year analysis herein described was to verify whether the first-year interim outcomes persist over the whole two-year period.Randomised, double-blind, HA-controlled clinical trial in 100 knee OA patients  in a high-specialisation tertiary care setting. The hypothesised difference of efficacy between PNHA and HA for the original sample size estimate is 20%. Treatment cycle: three intra-articular knee injections of either PNHA or HA, at baseline and weekly for two weeks. Evaluations: Western Ontario and McMaster Universities (WOMAC) score and Knee Society Score (KSS) as, respectively, primary and secondary endpoints, evaluated at baseline and after 2, 6, 12, and 24 months; synovial fluid levels of mediators (at baseline and the end of the treatment cycle). Adverse effects investigated at each control visit. Statistical analysis: Kruskal-Wallis test for independent samples  after correction of means for age, Body Mass Index and Kellgren-Lawrence grade. If significant, pairwise post-hoc Sidak multiple comparisons.KSS total score and KSS pain item: significant improvement in both groups, with significantly more pain improvement in patients treated with PNHA (2-point reduction) than HA (1-point reduction). Both groups experienced significant long-term reductions in WOMAC total scores: significantly stronger in PNHA-treated patients after 24 months with a steady difference of 16% favouring PNHA in WOMAC pain subscore. No clinically significant adverse events in either group.The outcomes of the 2-year study confirmed that a short cycle of intra-articular treatment (3 weekly double-blind injections) with polynucleotides  in fixed combination with high molecular weight hyaluronic acid is more effective in improving knee function and pain in knee OA patients than HA alone. PNHA may be elective for viscosupplementation in knee OA patients with fastidious and resistant pain and worsening disease.NCT02417610.Registration, 15/04/2015.ClinicalTrials.gov database link: The debate about the actual value of hyaluronic acid (HA) as infiltrative therapy of knee osteoarthritis (OA) is far from over in evidence-based guidelines and consensus reports –3. HighlThe study aimed to verify over 2 years whether the association of PN-HPT™ and HA injections would reduce pain in patients affected by knee OA more than HA alone, and whether it is more effective in improving knee function and pain, in joints affected by OA, compared with HA alone, as suggested by the authors in their first-year interim report . The finRandomised, double-blind, single-centre, HA-controlled clinical trial in a high-specialisation tertiary care setting. A hundred knee OA patients, aged between 51 and 74 years, were initially screened between mid-September 2014 and mid-July 2015, and 98 randomised.The inclusion and exclusion criteria and the demographics of the screened knee OA patients are summarised in Table The assumptions initially leading to the sample size calculation and the technicalities adopted for creating the randomisation list and preserving the double-blindness of all those involved, patients, investigators, data collectors and outcome assessors, were exhaustively described in the first-year interim report .The main points about the sample size estimate are herein summarised. With the per cent WOMAC change at 12 months considered as the primary endpoint, the following formula gave an estimate of the needed sample size: Based on previous HA literature and exploratory unpublished PNHA minor studies, the basic assumption leading to the original sample size estimate was that standard deviations were 26.9% for PNHA-treated patients and 39.1% for HA-treated patients. Further assumptions were that standard deviations would be similar for the two populations to be enrolled. At the same time, the test would aim to detect a clinical efficacy difference between the two intrarticular treatments of at least 20% under the null hypothesis that the two treatments had similar WOMAC per cent variations. With the assumption of a false-positive  error of 0.05 and power to avoid false negatives of at least 0.80, a minimum clinically meaningful difference of 20% and a drop-out rate of 10%, the minimum estimated number of patients was 50 per group   , 46 in the PNPHA study group and 44 in the HA control group; all of them then progressed to [T6] (end of study). Seventy-nine patients completed the 2-year study. All the patients who had dropped out at the end of the first year did it for personal reasons .® and CONDROTIDE Plus®, Mastelli Srl, San Remo, Italy; indication “intra-articular treatment of degenerative chondral disorders”). The control HA product  is also a Class III CE 0373 commercially available medical device of HA (1200–1500 kDa), industrially obtained from bacterial fermentation and dosed at 40 mg in 2 mL. The formulation of both study products was as absorbable, viscoelastic sterile gels.The regulatory classification of the patented, proprietary fixed PNHA combination investigated in the 2-year study was as a Class-III CE-marked (0373) medical device: pre-filled, single-use, neutral glass 2-mL syringes dosed at 10 mg/mL of natural-origin PN-HPT™ and 10 mg/mL of a biotechnological sodium HA (molecular weight > 1500 kDa) for an overall syringe content of 40 mg in 2 mL of active principles. The European Union’s regulatory authorities and several extra-European countries registered the proprietary fixed PNHA combination . Samples of the synovial fluid  were collected and sent to the laboratory before the first infiltration [T0] and at the end of the treatment cycle [T2]   and the Descriptive data were tabulated as means ± standard deviations (SD) and graphically as boxplots. The general linear model for repeated measures or Kruskal-Wallis test for independent samples (nonparametric one-way ANOVA test) was applied, after correction of means for age, BMI and KL grade , to asseRegarding the synovial fluid analyses , the t-test for paired samples (one-sample t-test) was used to compare between experimental times within groups and the unpaired t-test (two-sample t-test) for comparisons between groups. The Pearson test for linear relationships between two continuous variables was used to investigate the correlations between the synovial markers, both among them and between them, and the KSS or WOMAC scores at [T0] and at the end of treatment—[T2] for SF and [T3] for KSS and WOMAC scores. Further statistical details are available in Ref. ClinicalTrials.gov database of privately and publicly funded clinical studies conducted worldwide .The Institutional Review Board of Istituto Ortopedico Rizzoli reviewed all study materials for ethical problems, and the principles of the Declaration of Helsinki were always respected. The study was registered in the p = 0.54), Kellgren–Lawrence grade (p = 0.13), gender (p = 0.84), BMI (p = 1), weight (p = 0.86), and height (p = 0.67).Figure p = 0.029; partial eta squared = 0.07); divarication of pain curves was both precocious,  and [T5] (p = 0.046), and an almost significant difference at [T6] (p = 0.059). The other WOMAC items did not show differences between the two groups, with the partial exception of “walking on a flat surface”, which was always tendentially easier for patients in the PNHA group and significantly so at [T5] and [T6]  and T (p = 0.0p = 0.02 at [T3] and p = 0.001 at both [T4] and [T5]). The 2-year study confirmed the tendency towards a long-term pain benefit for PNHA-treated patients at the last [T6] assessment , with 87% of patients of the PNHA treatment group (34 out of 39) and 66% of the HA group reporting an improvement of joint pain  were also in the expected range in all patients. The total white cell count was always within the non-inflammatory range of less than 2000 cell/mmAs already discussed in the first-year report, looking for some short-term correlation between symptoms and the synovial fluid levels of soluble factors related to joint gave no significant results . MMP1 anNeither infiltrative treatment was associated with short-term complications or long-term side effects of any clinical significance.The final two-year outcomes of this randomised, double-blind study confirm the preliminary outcomes of the previous 1-year interim report—the intra-articular co-administration of a fixed combination of PN-HPT™ and HA is associated with significant benefits for the knee joint pain, the primary study endpoint, and functional disabilities compared with HA alone . The finHighly purified, natural-origin PN-HPT™ — linear chains of polynucleotides from trout gonads — release nucleosides, nucleotides, and nitrogen bases by enzymatic cleavage in the synovial space and have shown long-term moisturising and viscoelastic properties in clinical studies in knee OA –6. PN-HPThe more rapid reduction of WOMAC pain scores, the primary endpoint of the study, in PNHA-treated patients compared with the HA group is likely to mirror the synergic short-term viscoelastic contribution of PN-HPT™ to the investigated fixed formulation. Such viscoelastic synergy also likely explains the steady long-term reduction of knee pain, substantial at [T4] and [T5] (months 6 and 12) compared with HA-treated patients, but extending over the whole two-year study period. Without that synergy in the HA treatment group, pain significantly decreased only at the second and fourth months of follow-up ([T3] and [T4]), but not after 12 ([T5]) and 24 months ([T6]). Of course, using a low-molecular-weight HA in controls, which may have low elastoviscosity and require frequent infiltrations, might have acted as a confounding factor tht deserves remark . The benThe PN-HPT™ viscoelastic contribution might have helped to improve knee OA symptoms more effectively and possibly earlier than HA in patients with high-grade chondropathy, as shown in previous observations , 6. MoreA retrospective stratification of OA severity supports the former observation about the comparative pain benefits progressively increasing in grade-1, grade-2 and grade-3 OA patients. However, the observation is limited to pain, meaning caution is warranted.The one-year interim report discussed the rationale for assaying intra-articular factors related to joint damage to cast some light on the still debated association between pain and synovial fluid markers , 16–18. As a final consideration, the authors acknowledge some weak points of their study: for instance, a three-edged, parallel-group study — placebo, PN-HPT™, PNHA — would have been more discriminating and informative. The primary study purpose was to identify a role, if any, and possibly a therapeutic niche for PNHA in the current HA-dominated landscape, and this justified the two-group design, according to the authors. The authors feel the study fulfilled this limited goal; other considerations, including pharmacoeconomics, will have to wait for future studies. The low mean clinical severity of enrolled patients  is possibly another weak point. Incorporating more grade-3 patients would have been likely more discriminating in a study of such ambition.A third point liable to criticism: why falling back to traditional radiology instead of evaluating cartilage trophism with a rapid magnetic resonance imaging technique like 3 T MRI? The reason was simple: even in an excellence centre, the risk of overburdened MRI resources was steadily substantial over the study years. A fourth methodological weak point is the lack of confidently effective methods to assess and control compliance. Investigators went to great lengths to discuss with all patients in the treatment groups how compliance is crucial. However, the lack of in-depth compliance controls, based on mechanical timed counters, might have introduced bias.Summarising, as shown by the two-year evolution of the primary endpoint, the WOMAC pain score, the study demonstrated a steady, long-term improvement of OA-related knee pain in PNHA-treated patients. The pain benefit vs HA was significant at all assessment times and greater in patients with a high KL degree of basal OA severity. It most probably correlated with the viscoelastic mechanical synergy between PN-HPT™ and HA due to the lack of any real correlation between symptom evolution and synovial soluble markers of joint damage. Conversely, WOMAC pain control was somewhat unsteady in many patients of the HA treatment group, worsening after six months and one year of follow-up, and, at least tendentially, even after two years. Although some secondary endpoints did not show significant differences, KSS pain control was more rapid, already after two months after the end of the treatment cycle, in PNHA-treated patients.The two-year, double-blind study outcomes confirmed natural-origin, highly purified polynucleotides (PN-HPT™) as agents with long-acting viscosupplementation and persistent protective activity in chondrocytes, and a valuable complement to HA for the relief of pain and functional symptoms in knee OA. The suggested PNHA therapeutic range is 2 to 4 mL, but even the lowest dose used in the trial (2 mL) led to favourable results. The indirect PN-HPT™ supporting activity on connective tissues suggested by in-vitro studies, including on chondrocytes and the joint cartilage, might be especially of value as the basis of the likely in-vivo synergy between the two viscoelastic agents.


The mean exposure time was 8.5 ± 7.7 months (range: 1–36 months). Only 52.5% of the abusers reported the physician of the relevant exposure history at the first time of visiting the doctor. The main clinical type was mixed (49.2%). The most common clinical manifestation was distal limb numbness (80.3%). The most frequent outcome was peripheral neuropathy (59%) and subacute combined degeneration (36%). Serum homocysteine level was elevated in 67.5% (27/40) of the patients, while 44.4% (20/45) showed reduced vitamin B12. Note that 61% (22/36) showed abnormal signals in the posterior or lateral funiculus of the spinal cord, and 97% (31/32) of the patients showed peripheral nerve damage by electromyography. In all cases, symptoms were alleviated after halting N2O abuse can lead to nervous system damage, especially peripheral nerve and spinal cord damage. A full understanding of its clinical epidemiological characteristics is helpful for clinicians to make a timely and clear diagnosis.N 2O mainly leads to nervous system damage by affecting the metabolism of vitamin B12, which is seriously harmful to the health of some teenagers. There are certain rules and characteristics in the clinical and epidemiological characteristics. A full understanding of these characteristics is helpful for clinicians to make timely and accurate diagnosis and treatment.Long‐term abuse of N In recent years, an increasing number of young people have been abusing N2O in their pursuit of stimulation, with a concomitant increase in the incidence of related neurologic diseases and irreversible nerve damage. However, the risks associated with N2O abuse—which include subacute combined lesions of spinal cord, toxic encephalopathy, peripheral neuropathy, and mental disorders—are not fully recognized by society and clinicians. Previous studies have focused on the pathogenesis and clinical characteristics of diseases caused by N2O abuse, and there have been few epidemiologic investigations despite the importance of data from such studies for the development and implementation of effective interventions by health authorities .Between January 2017 and December 2020, 71 patients who were abusing N2.22O abuse. The inclusion criteria used to select patients for this study were as follows: (1) a clear history of N2O inhalation over the course of the disease; (2) clinical manifestations and signs of nervous system damage after N2O abuse that could not be attributed to other nervous system diseases; and (3) complete baseline data were available. The exclusion criteria were as follows: (1) a history of neurologic and mental illness before exposure to N2O and (2) use of other addictive drugs during the period of N2O abuse.At present, there is no unified diagnostic standard for N2.32O was collected: household registration, sex, age, education level, occupation, exposure time, first visit, final diagnosis, and classification. Additionally, the main clinical symptoms and signs were as follows; laboratory , imaging, and neuroelectrophysiologic findings; and treatments and related data were summarized and analyzed.Based on studies on methamphetamine‐related mental symptoms conducted in China .Quantitative data were presented as means and SD (x ± s). Qualitative data were described as counts or percentages, and intergroup comparisons were performed by the Fisher test. Non‐normally distributed data were expressed as medians and interquartile range (IQR). 33.12O treated at our hospital showed a generally increasing trend from January 2017 to June 2020, although it decreased thereafter  had a bachelor's degree or higher education level. Most of the patients  were self‐employed or unemployed, and the rest had stable occupations. Most of the patients (78.7%) were unmarried.There were 54 patients (88.5%) who had local household registration and seven (11.5%) with nonlocal registration; 37 (60.7%) cases were from an urban area, whereas 24 (39.3%) were from a rural area.2O exposure ranged from 1 to 36 months (mean: 8.5 ± 7.7 months), and 35 patients (57.4%) had abused N2O for >6 months. The duration of hospitalization among inpatients ranged from 3 to 19 days (8.7 ± 3.5 days). Except for three cases in the emergency department, the patients were treated in the neurology department for the first time.The duration of N3.32O, we classified the patients based on a combination of criteria from previous reports and clinical data as follows  informed the physician of their history of exposure at the first visit. The exposure history of nearly half of the patients was revealed only after admission, and four cases were misdiagnosed as Guillain–Barré syndrome and received hormone or gamma globulin treatment (Table 3.42O were observed in our cohort. The top symptoms were numbness (80.3%) and limb weakness (65.6%), which was a decrease in distal muscle strength in most instances (Table Neurologic lesions caused by Nes Table . Other n3.53.5.1MTHFR) was detected in six cases . Five patients were positive for syphilis antibody; the syphilis titers of four patients were 1:2, 1:16, 1:32, and 1:32, respectively, and one patient has a positive result for the Treponema pallidum particle agglutination assay. Cerebrospinal fluid examination was performed in 11 patients, and elevated protein levels were detected in four, but there were no specific changes.Of the 45 patients who underwent serum vitamin B12 analysis, 44.4% (20/45) showed reduced vitamin B12. Of the 40 patients who underwent serum homocysteine (HCY) analysis, 27 (67.5%) had elevated levels. Hematologic examination revealed anemia in three patients  examination of the skull and cervicothoracic vertebrae. Among the 36 patients, abnormal spinal cord signal was found in 22 cases (61%) and typical spinal cord degeneration in 13 cases (36%), which showed long T2 signal at the proximal end of the spinal cord and inverted “V” shape on T2‐weighted images. In 20 cases (91%), there was an involvement of ≥3 spinal cord segments. Cranial MRI showed lacunar foci in four cases and cerebral atrophy in one case   had exposure time ≤6 months, six cases > 6 months; 14 cases had normal spinal cord MRI, 11 cases (78.57%) had exposure time > 6 months, three cases (27.27%) ≤6 months. There was a significant difference between the two groups (3.5.3Electromyography (EMG) was performed in 32 patients; 31 97%) showed peripheral nerve damage, and most had motor and sensory involvement , one had residual anxiety, and the others had no obvious sequelae. No relapse occurred in our cohort during the follow‐up.To halt N42O abuse were first reported in China in 2016, the number of cases has been increasing yearly. Long‐term abuse of N2O not only causes craniocerebral lesions, subacute combined degeneration (SCD), and peripheral neuropathy but also rare symptoms such as skin pigmentation, chest tightness, and auditory hallucinations. According to the 2014 Global Drug Survey report, N2O abuse is increasing globally  pandemic in China, parties and large‐scale activities such as festivals—venues that could encourage recreational N2O use .In our study population, 89.3% of the patients were registered locally and only a small number came from provinces and cities adjacent to Xuzhou. We also found that there was no significant difference in the number of patients from urban and rural areas. However, given the relatively small sample size in this study, it is possible that there is a difference in the rate of N2O abuse have the following demographic characteristics: (1) the overall age is younger, there are more men than women, and the average age of women is lower than that of men; (2) the proportion of unmarried patients is higher; (3) the overall level of education is not high; and (4) most of the patients have no stable occupation. In previous studies, the patients of N2O abuse were mainly adolescents  were visiting the neurology department for the first time but 47.5% of the abusers did not report the physician of the relevant exposure history at the first time of visiting the doctor. Most of these cases were initially diagnosed as peripheral neuropathy, five were admitted to the hospital with myelopathy, and four were misdiagnosed as Guillain–Barré syndrome and underwent related examination and treatment. In many cases, the history of exposure was unknown even after many outpatient visits, possibly because of the refusal of some patients to provide this information and a lack of awareness of symptoms on the part of clinicians.In cases of N2O abuse‐related disorder classification, peripheral nerve with spinal cord injury is the most common type of injury. Brain parenchyma lesions have been previously reported, but there were no cases with spinal cord or brain parenchyma involvement in our study  in vitamin B12, thereby inactivating and inducing the excretion of cobalamin from the body, which results in the inhibition of MS activity, accumulation of HCY, and decreased Met synthesis  decreases MTHFR activity  gene. In this study, MTHFR gene was detected in six patients. However, in view of the differences in nitrous oxide exposure time and intake, and the relatively small number of cases included in this study, it remains to be determined whether MTHFR gene polymorphism is related to the clinical severity and prognosis of N2O abuse cases.Human 2O exposure time of ≤6 months. Thus, while spinal cord MRI can be used as an auxiliary tool along with medical history, clinical features, and hematologic examination in the diagnosis and treatment of the patients who abuse N2O, it may not be suitable for evaluating N2O‐induced SCD and cannot predict clinical outcomes. Some of our patients also had abnormal signals in the cranial MRI including lacunar foci in four patients and brain atrophy in one patient, which may indicate white matter degeneration.SCD is a neurologic complication of vitamin B12 deficiency. Spinal cord MRI can reveal long or spotted abnormal signals in the posterior or lateral funiculus that are generally associated with the cervical and upper thoracic spinal cord and occasionally the lateral cord, but are rarely associated with the anterior funiculus, which may reflect how demyelination progresses in the dorsal spinal cord (Jain et al., 2O abusers. Demyelination with axonal damage has been described in previous studies (Bao et al., 2O abuse causes peripheral nerve damage in most of the cases.Peripheral nerve damage is common in N2O abuse; the main recommendations are to halt N2O intake and use vitamin B12 supplementation (Keddie et al., 2O abuse (Zhang et al., 2O exposure can lead to irreversible nerve damage or even sudden death (Layzer et al., 2O (Blair et al., 2O.There are no guidelines for the treatment of nervous system damage caused by N2O consumed by patients could not be calculated. Thirdly, not all patients underwent spinal MRI and EMG, which could have provided more detailed information on functional consequences of N2O abuse.This study had some limitations. First, as it was a retrospective study, some of the patients’ basic data as well as their prognosis were learned by telephone follow‐up, which may have introduced inaccuracies. Secondly, the specific amount of N2O abuse have certain clinical epidemiological characteristics. Long‐term abuse of N2O mainly leads to nervous system injury by affecting the metabolism of vitamin B12, and peripheral nerve and spinal cord injury is most common. Clinicians must understand the characteristics of neurological diseases related to N2O abuse, take the initiative to inquire about the history of exposure to suspicious patients, and improve the relevant examination in time.To sum up, patients with NThe authors declare no conflict of interest.Yueyue Li, Ruiguo Dong, Jing Dong, and Ran Xu conceived and designed the study. Yueyue Li, Jing Dong, Hongmei Ding, and Xin Wang acquired the data. Yueyue Li, Jing Dong, Ran Xu, Fanfan Feng, and Weihao Kan analyzed and interpreted the data. All authors contributed to the writing of the manuscript, read, and approved the final version.https://publons.com/publon/10.1002/brb3.2416The peer review history for this article is available at


A total of 505 individuals with LBP were included: of those, 72.7% received an NSAID prescription and 27.3% an opioid one (64% of subjects started with strong opioid). Compared to patients receiving an NSAID, those with opioid prescriptions were younger, reported the highest pain intensity  and were more likely to have asthma . Despite clinical guidelines, a large proportion of LBP patients started with strong opioid therapy. Asthma, younger age and pain intensity were predictors of opioid prescribing when compared to NSAIDs for LBP treatment. This study explores which patient characteristics could affect the likelihood of starting low back pain (LBP) treatment with opioid analgesics vs. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in an Italian primary care setting. Through the computerized medical records of 65 General Practitioners, non-malignant LBP subjects who received the first pain intensity measurement and an NSAID or opioid prescription, during 2015–2016, were identified. Patients with an opioid prescription 1-year before the first pain intensity measurement were excluded. A multivariable logistic regression model was used to determine predictive factors of opioid prescribing. Results were reported as Odds Ratios (ORs) with a 95% confidence interval (CI), with  Over the past decade, opioid prescribing for Chronic Non-Cancer Pain (CNCP) has increased in many countries despite limited supporting evidence, high costs, and often related serious health risks ,2. Low BTherefore, this study aims to explore which patient characteristics could affect the likelihood of starting LBP treatment with opioid analgesics vs. NSAIDs in an Italian primary care setting.An observational retrospective study was carried out with the cooperation of 65 GPs, , all belonging to the Italian National Health Service (NHS) and affiliated to the “Parmenide” medical association. All the participating GPs used the same software to record data during their daily practice and received formal periodic training for data entry. For the purpose of this study, data were retrieved using an anonymous encrypted patient code linking demographic details with medical diagnoses, drug prescriptions and date of death or censoring (transfer to another GP). All diagnoses were coded according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) and the Anatomical Therapeutic Chemical (ATC) classification, respectively.Individuals aged 18 years and over with a diagnosis of LBP or sciatica , who received the pain intensity measurement and an NSAID (ATC M01A) or opioid prescription , between February 1, 2015 and January 31, 2016, were included. The date of the first pain intensity measurement during the study period was defined as the index date. The 365 days prior to the index date were checked to exclude patients who had received an opioid prescription during that period. Moreover, since we aimed to investigate the treatment in LBP patients without a cancer diagnosis, individuals with a diagnosis of primary or metastatic cancer  at any time before the index date were excluded.Finally, subjects were divided into two mutually exclusive groups: (i) those receiving an NSAID prescription at the index date (NSAID group); (ii) those receiving an opioid prescription with or without NSAIDs (Opioid group).For each patient, the following variables were assessed at the index date: age groups , sex, pain intensity measurement and comorbidities. The pain intensity was measured by the GPs using the 11-point Numerical Rating Scale (NRS-11). Specifically, each patient was asked to express the intensity of their pain with a number ranging from 0 (no pain) to 10 (the worst possible pain). The following comorbidities assessed at the index date were included in the analysis: diabetes, hypertension, cardiovascular or cerebrovascular diseases, chronic obstructive pulmonary disease (COPD), asthma, gastrointestinal disorders, chronic renal disease, arthropathy, rheumatism, mental disorders, and depression.2 tests to compare categorical variables between the groups and the Student’s t test for independent samples to compare continuous variables between the groups. A multivariable logistic regression model was used to determine the independent predictive factors of opioid prescribing. The dependent variable was opioid vs. NSAID prescribing. Age group, sex, pain intensity (mild pain (NRS 1–4), moderate pain (NRS 5–7), severe pain (NRS 8–10)) and comorbidities were the independent factors assessed. Multicollinearity was assessed computing the Variance Inflation Factor (VIF). The results were reported as Odds Ratio (OR) with 95% confidence interval (CI) and a p-value < 0.05 was considered statistically significant. All analyses were conducted using the SPSS software .Categorical variables were summarized using frequencies and percentages; continuous variables were summarized using means and standard deviations since the distributions were symmetrical. For the univariate analysis, we used χp = 0.005) and reported higher NRS-11 . Regarding comorbidities, statistically significant differences between the two groups were found only for gastrointestinal disorders  and asthma .A final sample of 505 patients who met the inclusion criteria was identified: 367 (72.7%) in the NSAID group and 138 (27.3%) in the opioid group. p < 0.0001) received at least 1 prescription for an NSAID 1-year before the index date. In both groups, diclofenac was the most prescribed NSAID followed by ketoprofen, celecoxib, and ibuprofen , followed by codeine combinations (29.0%). Only a minority of patients received a tramadol (7.2%), tapentadol (5.8%), and fentanyl (0.7%) prescription .The demographic and clinical factors associated with the likelihood of receiving an opioid prescription are shown in Through an analysis of demographic and clinical conditions, as well as pain severity, our study explores the factors which lead GPs to initiate opioid treatment in patients with non-cancer LBP. Our findings show few factors associated with the higher likelihood of receiving opioid prescriptions when compared to NSAIDs drugs. As expected, we found that the increasing pain intensity was positively associated with opioid prescriptions. Patients with moderate or severe pain had a 2-fold increase in risk of receiving opioids compared to those with mild pain. However, this does not mean that pain intensity is the only factor that physicians should consider. In prescribing opioids for LBP, GPs appear to be influenced by factors unrelated to pain intensity. Interestingly, we found that the diagnosis of asthma was strongly associated with opioid prescriptions. Specifically, when compared with NSAIDs, the odds of receiving an opioid prescription were almost four-fold higher for patients with asthma after adjustment for all other variables. Our results suggest that GPs should have a higher index of suspicion for NSAID-exacerbated respiratory disease in subjects with asthma. A well-known distinct clinical syndrome could be induced by the increased leukotriene synthesis in response to Cyclo-Oxygenases (COX) inhibition by NSAIDs. Particularly, COX-1 may mediate bronchoconstriction and inflammatory changes in asthma pathophysiology ,12. ThisBased on the odds ratio by the multivariable analysis, age also appears to play a significant role. Older patients were significantly less likely to receive opioids and were more likely to receive NSAIDs. This could be related to the well-known increased responsiveness to the effects of opioids in the elderly and the polypharmacy-related potential risk of drug–drug interactions . This maIn our study, approximately 64% of patients in the opioid group started with a strong opioid. Although these patients might simply have failed to be managed with alternative therapies or did not tolerate drugs like NSAIDS, the current guidelines recommend strong opioid prescriptions only for unremitting cases and even for short-term use, stepping patients down to weaker opioids where appropriate or removal altogether if not effective ,16.Our results should be interpreted in the context of some limitations. First, we could not differentiate between acute, subacute, and chronic LBP as well as nociceptive, neuropathic, and mixed pain because data were not available in the database under analysis. Second, subjects treated with OTC (Over The Counter) oral analgesics, such as paracetamol and NSAIDs, may have been underestimated, since these drugs can be directly purchased by the patient; therefore, they were not tracked in the database under analysis. Finally, generalizations of the study’s findings should be made with caution, particularly because the participating GPs were all from a Southern Italian area, and therefore were not fully representative of the GP workforce across Italy.In conclusion, our study shows that asthma, younger age and pain intensity are the factors leading GPs to initiate opioid treatment in patients with non-cancer LBP. Moreover, despite clinical guidelines suggesting that opioids should not be considered an option for LBP unless recommended treatments fail and only if the potential benefits are expected to outweigh the risks, a large proportion of patients are starting treatment with a strong opioid.


The mean decrease in VAS score between baseline and one week follow up was 4.8 (95% CI 4.2–5.4). VAS decrease over time between one week and one year following radiofrequency ablation was similar, suggesting that pain relief was immediate and durable. Neither patients with 1–2 vertebral metastases, nor those with multiple lesions, showed radiological signs of local progression or recurrence of the tumor in the index vertebrae during a median follow up of 19 months (4–46 months) and 10 months (4–37 months), respectively. Conclusion: Treatment of spinal metastases with a navigational radiofrequency ablation device and vertebral augmentation can be used to obtain local tumor control with immediate and durable pain relief, providing effective treatment in the multimodality management of difficult-to-reach spinal metastases.Aims: The purpose of this study was to assess the effectiveness of a navigational radiofrequency ablation device with concurrent vertebral augmentation in the treatment of posterior vertebral body metastatic lesions, which are technically difficult to access. Primary outcomes of the study were evaluation of pain palliation and radiologic assessment of local tumor control. Materials and Methods: Thirty-five patients with 41 vertebral spinal metastases involving the posterior vertebral body underwent computed tomography-guided percutaneous targeted radiofrequency ablation, with a navigational radiofrequency ablation device, associated with vertebral augmentation. Twenty-one patients (60%) had 1 or 2 metastatic lesions (Group A) and fourteen (40%) patients had multiple (>2) vertebral lesions (Group B). Changes in pain severity were evaluated by visual analog scale (VAS). Metastatic lesions were evaluated in terms of radiological local control. Results: The procedure was technically successful in all the treated vertebrae. Among the symptomatic patients, the mean VAS score dropped from 5.7 (95% CI 4.9–6.5) before tRFA and to 0.9 (95% CI 0.4–1.3) after tRFA ( The incidence of bone metastases in patients with cancer is extremely high: 84% for prostate, 72% for breast, 60% for thyroid, 37% for kidney, 33% for pancreas, and 31% for lung ,6. SurgiPatients who underwent minimally invasive CT fluoroscopy-guided percutaneous tRFA and VA between November 2013 and March 2017 were identified. Patients were included in the study if they had vertebral lesions from T1 to L5, with evidence of osteolytic or mixed metastatic lesions in the posterior vertebral body , irrespective of whether pathologic fractures occurred. Patients with disruption of the posterior cortical wall were also included. Patients with metastases located in the spinal cord and/or nerve root compression were excluded.(1)Group A: patients with 1 or 2 vertebral lesions.(2)Group B: patients having more than 2 metastatic spine lesions.Patients were classified into two groups according to the number of metastases located in the spine: All patients were assessed prior to surgery with a CT scan or MRI and, in some cases, PET scan in order to study the metastatic vertebral lesion and to plan the percutaneous intervention. CT scan, MRI, or PET scan were performed at 1, 6, and 12 months post tRFA treatment to assess the local activity of the vertebral metastases and/or residual viable tumor, and/or recurrence/growth of the spinal metastases . Pain seUsing CT fluoroscopy guidance , the spine lesion was identified, measured, and marked to establish and validate the desired needle pathway. The procedures were performed according to the following steps: (i) anesthesia: conscious sedation with intravenous infusion of fentanyl citrate  followed by subcutaneous injection of lidocaine hydrochloride (2%) performed until the pedicle periosteal and the bone cortex. (ii) tRFA: under CT scan, a 10-G vertebroplasty needle was introduced and, coaxially to it, the bipolar tRFA electrode  was placed into the vertebral lesion to deliver the RF energy and ablate the metastases properly. The instrument has two thermocouples  which actively monitor the temperature of the tumor avoiding undesired burns around the lesion. (iii) Vertebral augmentation: using the same vertebroplasty needle, in order to minimize cement leakage risk, ultra-high viscosity bone cement was inserted through a controller under low-pressure injection  for optimal filling of the vertebral lesion .CT scan, MRI, or PET (in selected cases) were performed at 1, 6, and 12 months after tRFA-VA treatment to assess local activity of the vertebral metastases and/or residual viable tumor, as well as recurrence/growth of the spinal metastases. Tumor progression was defined as an increase of the size of metastasis on CT or MRI. Stable disease was considered as a stable metastasis diameter along with no contrast enhancement. Recurrence at follow-up imaging was defined as contrast enhancement or enlargement at the site of successfully treated lesion, and/or the occurrence of osteolytic lesions near the treated areas.p < 0.05 was considered significant. Changes over time in the VAS score were evaluated using a linear mixed-effect model to account for the correlation between VAS scores within the same patient. Changes in the VAS score before and one week after tRFA were modeled with a dummy variable, while scores from one week after tRFA onwards were modeled as a linear function of time. All statistical analyses were performed using R Statistical Software (version 3.3.3) and n = 16, 46%), followed by lung , colon , prostate , and kidney . None of the patients had signs of neurological deficits, nor required an open surgical stabilization. Twenty-one (60%) patients belonged to Group A  (p < 0.0001). With the numbers available, we found no difference in the VAS score over time from one week up to one year after tRFA and VA, suggesting that pain relief was immediate and durable. There was no difference in the VAS scores before and after surgery between the two groups of the study. Use of steroids and non-steroidal anti-inflammatory drugs taken by patients in both groups were reduced or completely suspended after the procedure. Patient characteristics and results are summarized in Forty-one vertebral metastases were treated in thirty-five patients  age 59 (56–70) years). Breast cancer was the most common type of primary tumor (lesions) , the remlesions) . In one lesions) . Two patlesions) . Considelesions) . The meaThe use of tRFA associated to vertebroplasy with VA has been gaining importance in the management of spine metastases ,13,14,17This study has some limitations, the main being its retrospective nature and the small sample size. Moreover, the overlapping with radiation therapy in some patients and the use of drugs for pain relief, may have influenced the VAS score. However, this study has some points of strengths, in that it supports the use of a navigation radiofrequency ablation device for the treatment of metastases located in the posterior part of the vertebrae. As we reported in Spinal metastases represent a complex clinical scenario in patients affected from cancer, especially in those with decreased life expectancy ,14,18. Tp < 0.0001), and no difference was observed in the VAS score over time from one week up to one year after tRFA and VA, suggesting that pain relief was immediate and durable. These findings were consistent to previous studies. In the multicentric study from Anchala and colleagues, significant (p < 0.01) decrease in the VAS scores at one week, one month, and six months was observed, although only 62% of the spinal lesions in the largest institution participating in the study was located in the posterior vertebral body [p < 0.0001) in their multicentric study involving almost 50 patients [One of the purposes of our work was to evaluate the role of tRFA with concurrent VA in the control of pain, using a dedicated navigational device. Cancer-induced bone pain recognizes multiple mechanisms, including disruption of bone homeostasis, release of neurochemicals that modulate pain, and microglia activation. Furthermore, instability of a vertebral body usually causes pain, which is poorly localized, and sometimes becomes intractable . It has ral body . Reyes epatients .The second purpose of the present study was to evaluate the metastatic lesions in terms of radiological local control after tRFA and VA treatment. Our results reinforce the concept that treating patients with a navigational radiofrequency device with the goal to achieve tumor control is feasible . Twenty-As described elsewhere, the goal of performing tRFA before vertebroplasty is to destroy tumor tissue, to reduce the intrametastatic pressure, and to thrombose intravertebral venous plexus . The purExternal-beam radiation therapy is another option to treat pain and achieve local control and represents the standard treatment for pain relief and local control of spinal metastases ,12,13. HIt is our thought that the goal of the tRFA in treating patients with metastatic spinal tumors should be not only the pain relief, but also the achievement of an oncological outcome in terms of stopping lesions from spreading into the rest of the vertebral body to avoid neurological damage. Our study indicates that percutaneous treatment of spinal metastases with tRFA and vertebroplasty can be used in a multimodality therapeutic approach. In addition, it may bridge the gaps reported for conventional treatment methods in vertebral metastases management. Radiation therapy, chemotherapy, “open” spinal surgeries, vertebroplasty, and “conservative” treatment are treatments that must be tailored for each patient, considering the nature of the tumor, life expectancy, pain, metastases at high risk of fracture, and compression of neurovascular structures .In conclusion, tRFA using a dedicated radiofrequency ablation device, with concurrent VA, can achieve satisfactory results in terms of pain palliation and local tumor control in patients with posterior vertebral body metastases. That approach may widen the field of application of termoablation in the management of spinal metastases. Further studies with larger cohorts are necessary to establish the optimal role of tRFA and vertebroplasty in association with radiotherapy in the multidisciplinary treatment of vertebral metastases.


Bilateral elbow extension range of motion (ROM) on upper limb neurodynamic test 1 (ULNT1), bilateral pressure pain thresholds (PPT) on the median nerve at elbow joint, C6 zygapophyseal joint and tibialis anterior, Visual analogue scale (VAS), body chart distribution of pain, active cervical ROM (CROM), Neck Disability Index (NDI), and Tampa Scale of Kinesiophobia (TSK-11) were measured at baseline as well as immediately, 15 days, and 1 month after treatment. Results: There were no statistically significant interactions (p > 0.05) between treatment and time for median nerve mechanosensitivity outcomes, pain intensity, symptom distribution, and PPT of the widespread pain assessment, as well as cervical function, and kinesiophobia. Conclusions: MNNM gave no additional benefit to CLG in patients with NP regarding pain intensity, symptom distribution, mechanosensitivity, functionality, and kinesiophobia. Only two treatment sessions and the short follow-up are important issues, therefore, justifying further studies to answer the research question with better methodology.Background: This study aimed to compare the effectiveness of cervical lateral glide (CLG) added to median nerve neural mobilization (MNNM) in patients with neck pain (NP). Methods: A single-blinded randomized controlled clinical trial was carried out in a Pain Management Unit from a Hospital. A total sample of 72 patients with NP was recruited from a hospital. Patients were randomized to receive isolated CLG ( Neck pain (NP) is a common disabling condition that is likely to affect most people at some time in their lives ,2,3. NP Neuropathic features might be present in 6.9% to 10% of patients with NP . Indeed,Regarding neural mobilization approaches for musculoskeletal conditions in patients with CBP ,16, mediTo our knowledge, the effectiveness of combining MNNM with CLG has not yet been determined in patients with NP. This study aimed to compare the effectiveness of CLG plus MNNM  on median nerve mechanosensitivity, intensity and distribution of NP, local/remote pressure pain threshold (PPT), cervical function, and kinesiophobia in patients with NP.The study protocol was conducted from April to June of 2017 as an interventional phase II, parallel, single-blind, randomized controlled clinical trial. The study was conducted at the Pain Management Unit from the Alcala de Henares Hospital (Spain) in accordance with the CONSORT statement .All of the procedures used in this trial were programmed according to the ethical principles of the Declaration of Helsinki . All sub® 4.2 version, Xunta de Galicia, Spain) and randomized printed cards contained in consecutively numbered opaque sealed envelopes kept in a locked drawer unit. A member of the research team who was not involved in the assessment and/or treatment procedures performed the randomization and maintenance of the list. Treatment and outcome assessments were performed in different rooms and at different time points.The randomization and allocation of the patients to the trial group were done using computer software  and the Tampa Scale of Kinesiophobia (TSK-11) measurements were not obtained at post-intervention. Sociodemographic data were also collected.®, Bolingbrook, IL, USA). UNLT1 Intra and inter-observer reliability is considered from good to excellent (ICC ≥ 0.98) . All outcomes for median nerve mechanosensitivity are presented in By two-way ANCOVA, we detected statistically significant differences only in the group factor for the contralateral median nerve PPTs . However, no differences were found in the group × time interaction for pain intensity, body pain distribution, and PPT. Post hoc analysis for pain intensity, body pain distribution, and PPT are shown in There were significant differences for time factor in the PPT for the homolateral C6 zygapophyseal joint PPT . However, no statistically significant differences were observed in the group × time interaction for the cervical function and kinesiophobia. Multiple comparisons for the active cervical ROM, disability, and kinesiophobia are presented in The ANCOVA analysis only found statistically significant differences in the time factor for kinesiophobia . In our study, we detected an improvement of greater magnitude in the lateral cervical glide group with an increase of 34.16% (0.96 kg/cm2) at 30 days of follow-up, while in the group in which lateral cervical glide was combined with the mobilization of the median nerve the percentage of improvement was just 15.94% (0.44 kg/cm2). Another more recent study [2) that remains 1 year after follow-up. Bialosky et al. [The amount of improvement obtained in this study is similar or slightly higher than those obtained in other studies. Vicenzino et al.  found thnt study  applied y et al. , on the y et al.  found coIn relation to neural mechanosensitivity evaluated by the neural tension test neural measured by the range of motion of the elbow extension, Coppieters et al.  found anIn relation to the NP intensity, although no differences were found between the groups, these presented an improvement of 27.67% (1.2 points) in the CLG + MNNM group and 31.49% (1.3 points) in the CLG group. These results are lower than those obtained by Rodríguez et al.  in whichAlthough there was an improvement in function, this was inferior to that reported in other studies. The improvement in rotation in the CLG group only reached improvements of 8.57% (4.96 degrees) and 5.57% (3.32 degrees) in the contralateral rotation. These data are contradictory to those found in several previous studies ,20,22, aFew studies have previously included the kinesiophobia variable. The two studies we could identify in which neural mobilization is applied used kinesiophobia as a confusion variable to test how it interfered with the improvement of pain in healthy subjects  or pain This study has some limitations. First, the lack of a control group and/or placebo group means that we cannot determine the effects of these non-specific interventions or test whether they are superior to the absence of treatment. Second, only kinesiophobia was measured, so we cannot determine the effects on other psychological factors. The third limitation is that only two treatment sessions were carried out. If more sessions had been applied, we could have found other effects. Another limitation is the short-term (30 days) follow-up of patients; therefore, we cannot know the effects in the medium and long term.Adding neural mobilization of the median nerve to the cervical lateral sliding technique is not superior to performing it alone in improving the mechanosensitivity of the median nerve, expanding pain, NP intensity, improving function, and kinesiophobia. Only two treatment sessions and the short follow-up are important issues, therefore justifying further studies to answer the research question with better methodology.


Plantar enthesophyte is a common degenerative disorder. Surgical and medical treatment options are associated with either poor outcome or high percentage of relapse. Observations have indicated a beneficial effect of radiation therapy. We therefore wanted to evaluate pain reduction using orthovolt or cobalt-based radiation treatment for painful plantar enthesophyte and determine long-term response as well as prognostic parameters in this condition.We identified a total of 102 consecutive patients treated for a total of 117 symptomatic heel spurs. 59 patients were treated with cobalt radiation, 31 patients with orthovolt therapy and 12 patients with both radiation systems. Primary outcome measure was pain reduction being scored using the modified Rowe Score prior therapy, at the end of each treatment series as well as after 6 weeks. Secondary outcome measure was long-term outcome, evaluated in patients with a follow-up period of longer than 3 years.p = 0.012) for response to treatment.Before radiation therapy, 61 patients (60.4%) had a score of 0, significant strong pain. At the time of completion of radiation treatment, 3 patients (2.7%) were pain-free (score of 30), whereas 8 patients (7.9%) had still severe pain (score 0). 6 weeks after radiation therapy, 33 patients (32.7%) were pain-free and 8 patients (7.9%) had severe pain (score 0), while at the time data of collection, 74 patients (73%) were free of pain and 1 patient (1%) had strong pain (score 0). Duration of pain before the start of radiation treatment was a significant prognostic factor (Radiotherapy of painful plantar enthesophyte is a highly effective therapy with little side effects providing long-term therapeutic response. The only significant prognostic parameter for response to treatment is the duration of pre-radiation therapy pain. Early integration of radiation therapy in the treatment seems to result in superior pain reduction. Plantar enthesophyte is a painful degenerative disorder evolving over a long time –4 and isPlantar enthesophyte, often described as heel spur, was first described by Plettner . He inveThe plantar enthesophyte develops as a reactive formation of bone due to mechanical stress with degenerative changes and microtraumas at the insertion of the tendons of the abductor hallucis and the brevis flexor digitorum muscles as well as the plantar aponeurosis and can therefore be identified as a result of a plantar fasciitis. Nevertheless, this term is misnomer, since the plantar fascia is an aponeurotic rather than a fascial layer. Plantar enthesophytes are located at the calcaneus where the plantar aponeurosis inserts at the medial tuber calcanei or at the insertion of the Achilles tendon in a dorsal position. Combinations of the two locations have also been described . Risk faThe majority of patients with plantar enthesophyte remain asymptomatic. If clinically apparent, typical symptoms are pressure pain at the medial part of the arch of the foot radiating to the calf and the sole of the foot. The pain is often described as burning or stinging, emerging while walking barefoot or after resting. Therefore, the diagnosis of plantar fasciitis is mostly a clinical one. Any further diagnostic approach should be tailored according to the clinical picture and includes foremost plain X-ray. Additional diagnostical regimen may include technetium bone scintigraphy  as well as MRI, though both techniques are rarely used.If symptoms are present, physical activity may improve them. Conservative or invasive therapeutic options have been implemented in the therapy of plantar enthesophytes. Primary treatment usually consists of conservative management including orthotics, local or systemic analgesics, corticosteroids , antiphlIn this retrospective study, we tried to clarify the following questions:Which parameters influence the clinical outcome (pain reduction) in the radiation treatment (RT) of plantar enthesophytes? We identified radiation parameters , type of radiation) as well as clinical parameters .60Co) and 31 with X-rays with an orthovoltage irradiation (300 kV). 12 patients were treated with both energies.During 2 years, 102 patients were treated for overall 117 plantar enthesophytes. 28 male (27.2%) und 74 female (71.8%) patients with a mean age of 51.5 years  were included in this study. 87 patients had a uni-lateral plantar enthesophytes  and 15 patients had bilateral plantar enthesophytes. The correct diagnoses were confirmed using X-ray by two radiologists. 59 patients were treated with cobalt radiation  given 2–3 times a week up to total dose of 3 or 6 Gy. In detail, patients being treated with cobalt radiation were irradiated 3 times a week with a dose/fraction of 0.5 or 1 Gy up to a total dose of 3 or 6 Gy, depending on their pain intensity. Higher doses of radiation were prescribed for patients with persistent and severe pain. They always received a total of 6 fractions. Orthovoltage irradiation was applied 2 to 3 times per week with a dose/fraction of 1 Gy and a total dose of 3 or 6 Gy, resulting in a total of 3 or 6 fractions which were applied. In addition, the therapeutic effect of local steroid injection was evaluated. In 12 patients both 60-cobalt and orthovoltage therapy were administered. One reason for it was the availability of the machine. 12 patients started with orthovoltage irradiation, but as the machine was unavailable cobalt irradiation (60Co) was prescribed.If only temporary or partial pain relief was obtained, a second course was offered to the patients. This was given after a median time gap of 5.4 (range 3–12) months after initial treatment.Pain and function were evaluated using a modified score of Rowe et al. . Table 1We statistically evaluated radiation-associated factors  and clinical parameters  possibly influencing the clinical outcome using Microsoft-Excel 2010 and SPSS-20.U and t-test. p-values less than or equal to 0.05 were considered statistically significant . With the Kruskal–Wallis test, we examined the influence of radiotherapy on pain relief in different groups. Normal distribution was assessed using the D’Agostino–Pearson and Kolmogorov–Smirnov test.Data were expressed at mean ± standard error of the mean (SEM). Statistical significance was assessed by Mann–Whitney In this retrospective analyses, we identified 102 consecutive patients treated in our institutions within 2 years. Table Prior to RT treatment, 100 patients (99%) presented with a Rowe S-Score between 0 and 30 (severe pain) and only 1 patient (1%) had a S-Score between 30 and 60 (mild pain) Fig. .The pretOn the last day of RT treatment, 21 patients (20.8%) achieved a S-Score between 0 and 30 (mild to no improvement), 26 patients (25.7%) a S-Score between 30 and 60 (mild pain improvement), 24 patients (23.7%) a S-Score between 60 and 90 (mild to moderate improvement) and 29 patients (28.7%) had a S-Score between 90 and 120 (good pain response). Only 1 patient (1%) achieved a complete pain response with a S-Score between 120 and 150.If patients were contacted directly or interviewed by telephone and completed the questionnaire retrospectively for 6 weeks after radiation, during follow-up (at least 3 years after radiation treatment) 53 patients (52.5%) had a S-Score of 0–30 (mild to no improvement of pain), 2 patients (2%) a S-Score between 30 and 60 (mild improvement of pain), 7 patients (6.9%) a S-Score of 60–90 (mild to moderate improvement of pain) and 6 patients (5.9%) had an S-Score of 90–120 (major improvement of pain). Overall, 33 patients (32.7%) had a complete pain remission with a S-Score of 120–150.At the time of data collection, the results of a telephone questionnaire were the following: 19 patients (18.8%) reported a S-Score of 0–30, 2 patients (2%) a S-Score between 60 and 90, 7 patients (6.9%) a S-Score of 90–120 and 73 patients (72.3%) had a S-Score of 120–150. No patient reported a S-Score of 60–40 and 14 patients (13.9%) experienced a S-Score of 0.As presented in Figs. p-value: on the last day of RT: 0.922, 6 weeks after RT: 0.865, at data collection: 0.949). Similarly, no significant differences following the Pearson correlation could be identified between the total dose (3 or 6 Gy) and the therapeutic results according to the Rowe Scores on the last day of irradiation , 6 weeks after completion of radiotherapy  and at data collection . Moreover, no significant influence of the total treatment time on any outcome was detected using the Pearson correlation: on the last day of radiotherapy , 6 weeks after irradiation  and at data collection .The long-term response was evaluated in 102 patients after a median follow-up period of 94.4 months (range 36–187 months). 16 patients received 2 irradiation series . Furthermore, the influence of different parameters  on the therapeutic response (pain reduction) of the irradiation of heel spurs was evaluated. There were no significant differences between the groups receiving different single doses at any time point  of the field size on the clinical outcome at 6 weeks after irradiation. This indicates a better effect of radiotherapy when an extended field was used, to irradiate the complete pain expansion on the heel. Nevertheless, this effect did not influence the early outcome on the last day of irradiation  and the late outcome at data collection . A pretreatment of patients with oral NSAIDs had a significant effect (p = 0.047) 6 weeks after completion of radiotherapy. While patients who did not receive NSAIDs (n = 23) had an average score of 65.22 (SD = 29.52), patients undergoing NSAID therapy (n = 32) achieved an average score of 51.25 (SD = 24.05). This indicates that pretreated patients who continued NSAID therapy experienced a lesser pain improvement than patients receiving radiotherapy without NSAIDs. This effect was not significant at long-term follow-up.Regarding the size of the radiation fields, there was a significant influence (p = 0.036). 31 patients without prior corticoid therapy had an average score of 34.19 (SD = 16.6) compared to 24 patients who had received corticoid injections reported an average score of 23.7 (SD = 20.6). This significant difference may indicate that patients receiving local infiltrations on the last day of radiotherapy experienced less pain reduction than patients without corticoid therapy. It could also be that these patients have a more persistent plantar enthesophyte and that there has been no improvement even after many pre-therapies. This significance was also observed 6 weeks after radiotherapy as well (p = 0.001), while it was not significantly different at long-term outcome (p ≥ 0.05).Though not performed via randomization, we analyzed any effect of local steroid injection on therapeutic outcome. We identified a significant lapse of pain reduction when local corticosteroid injection on the last day of radiotherapy was administered  and at long-term follow-up . Nevertheless, there was a significant influence of the patients’ age on the therapeutic results 6 weeks after radiotherapy . Higher age was significantly associated with improved outcome 6 weeks after irradiation.There was no significant impact of the age of the patients on the therapy outcome on the last day of radiotherapy . Patients receiving irradiation a few months after the onset of plantar enthesophyte pain benefited significantly more from radiotherapy and experienced a higher pain remission than patients with delayed irradiation.Using the Mann–Whitney In the present study, we have categorized pain into functional scores. The pain was subdivided into pain at rest, pain at motion and pressure pain. Overall, 33 patients (32.7%) reported a complete pain regression six weeks after RT. After a follow-up of 94.4 months (range: 36–187 months), 74 patients (73%) achieved a complete response. These results confirm the effectivity of this treatment approach. The analysis of functional scores revealed that 85.5% of the patients had none or only minor restrictions in daily activities and 89% had a normal gait pattern.Degenerative and inflammatory diseases of the musculoskeletal system make up 70% of all benign diseases treated by irradiation , 29–40. Low-dose radiation decreases the expression and activity of glutathione peroxidase (Gpx) and nuclear factor erythroid 2-related factor 2 (Nrf2) in endothelial cells. The adhesion of peripheral blood mononuclear cells is also reduced. Large et al. provided evidence for an anti-inflammatory effect in endothelial cells stimulated by inflammation after low-dose radiation (largest effect after irradiation using 0.5 Gy) .Historically, plantar enthesophytes were treated surgically in most symptomatic patients. Since surgery carries a high risk of recurrence, it is rarely performed today. Moreover, the treatment focus on symptomatic pain relief. Physiotherapy, footbed insert and medical treatment using NSAID is associated with a high therapeutic failure rate. Multiple studies in German-speaking countries reported the benefits of radiation treatment in the treatment of plantar enthesophytes in the past , 47–56.Table Despite comprehensive clinical results, the optimal radiation dose concept needs yet to be identified. In the pattern-of-care study by Micke and Seegenschmiedt , single Heyd et al. recently published a prospective, randomized study comparing the effect of 3 Gy (6 fractions of 0.5 Gy) vs. 6 Gy (6 fractions of 1 Gy). Both groups demonstrated a significant improvement of symptoms. A different effect of the applied radiation dose was not reported.p = 0.011). At the time of long-term follow-up, this effect could no longer be demonstrated. Comparable results had not been reported previously.Our study identified size of the radiation field as a significant factor for the treatment response 6 weeks after radiation (Previous treatments with NSAID or local steroid injections had a detrimental effect on the response to therapy. NSAID-pretreated patients had a reduced pain response at 6 weeks after RT and corticoid injections led to a worse response at the last day of RT and 6 weeks hereafter. We were unable to obtain any comparable data from the literature.Statistical analysis provided evidence that a short pretherapeutic pain duration , 54, 81 Acute and late side effects of radiation treatment have not been studied in the present population. Some authors describe an initial pain exacerbation probably due to a probably localized acidotic tissue reaction . In theoThis study is limited by the retrospective study design. Furthermore, the investigated cohorts were irradiated with different concepts and techniques, which strongly reduces the validity of this study.Furthermore, in consideration of the benign condition, the length of the follow-up is not sufficient for a conclusive evaluation concerning the role of radiotherapy. Nevertheless, this study represents real-life data from a large cohort of patients with high levels of pain from a disease that has not been sufficiently investigated by large prospective trials, providing results to help inform radiotherapy decision-making.In addition to conservative treatment using physiotherapy, lifestyle changes, oral medication and orthopedic devices, radiotherapy can be regarded as a treatment option for painful plantar enthesophyte. Low radiation doses lead to a significant long-term pain reduction in more than 60% of the treated patients. In accordance with previous publications , 54, 86,