Bioprosthetic valves for tricuspid valve replacement (TVR) have become increasingly popular in recent years, but mechanical valves remain valuable, particularly for the patients who want to avoid reoperation for bioprostheses malfunction. The aim of this study was to review our 10-year experience in adult patients who underwent TVR with the St. Jude Medical (SJM) valve. From 2005 to 2015, 265 TVRs with SJM valves were performed at our institution. The mean age at operation was 44.1 ± 9.7 years, and 207 cases (78.1%) were female. The mean follow-up was 4.9 ± 2.7 years. Preoperative atrial fibrillation was present in 199 cases (75.1%) and ascites in 26 (9.8%). Of all cases, 88.7% were characterized as New York Heart Association class III or IV. The hospital mortality was 6.4%. There were 9 deaths (3.8%) during late follow-up. The overall survival rates were 89.2% ± 2.2% at 5 years and 86.6% ± 2.9% at 10 years. The linearized rates of valve thrombosis and bleeding events were 0.8%/patient-year and 1.5%/patient-year, respectively. Three cases (1.3%) were reoperated due to prosthetic valve thrombosis. There was no reoperation for sperivalvular leakage and structural failure. The freedom from reoperation was 98.6% ± 0.8% at 5 years and 98.6% ± 0.8% at 10 years. The SJM valve in the tricuspid position is a reliable mechanical prosthesis with a low rate of valve thrombosis and reoperation. It is a reasonable choice for the patients who require mechanical valve replacement in the tricuspid position. However, bioprostheses inevitably calcify and stenose, which may cause valve dysfunction. Therefore, the mechanical valve remains valuable in TVR, particularly for the patients who refuse to take on the risk of reoperation for bioprostheses malfunction.In recent years, an increasing number of patients undergoing tricuspid valve replacement (TVR) have received bioprostheses due to the great durability in the tricuspid position and to the advantage of freeing patients from anticoagulant medication4. It is characterized by favorable hemodynamic properties, and a low incidence of thromboembolism5. As a result of excellent durability, it is preferred in young patients. Although its good clinical performances in the mitral and aortic positions have been reported6, assessment for follow-up results in the tricuspid position is limited. With this background, we reviewed our 10-year experience of 265 TVRs with SJM valves at our institution.The St. Jude Medical (SJM) valve , a low-profile bileaflet mechanical valve constructed of pyrolytic carbon, has been widely used in patientsPreoperative and intraoperative characteristics of the study patients are presented in Table p < 0.001), larger preoperative left atrial diameter  and lower preoperative left ventricular ejection fraction . More patients in the moderate-severe PHT group received TVR concomitantly with other procedures (p < 0.001) and required a longer extracorporeal circulation time . However, the proportion of patients with a history of cardiac operation in the none-mild PHT group was significantly higher than the moderate-severe PHT group (p < 0.001).Compared with the none-mild pulmonary hypertension (PHT) group, the moderate-severe PHT group exhibited a greater prevalence of rheumatic valve disease (p = 0.090).The early postoperative results are presented in Table p = 0.078).There were 61 cases of early complications, including 22 low cardiac output syndrome, 17 respiratory infection, 10 re-exploration for excessive postoperative bleeding, 6 permanent pacemaker implant for atrioventricuiar block, 2 acute renal failure, 2 cerebral infarction, and 2 arrhythmia. These complications occurred in 24 TVRs (16.4%) of the none-mild PHT group and 30 (25.2%) of the moderate-severe PHT group, and the difference was not statistically significant (p = 0.027), presence of ascites (p = 0.025), extended ECC time (p = 0.005) and low LVEF (p = 0.027) were the independent predictors of prolonged ventilator support (Table Thirty-nine cases (14.7%) experienced prolonged postoperative ventilator support for more than 72 hours. Multivariate logistic analysis showed that the age  in the none-mild PHT group and 5 (5.0%) in the moderate-severe PHT group. The 5 years and 10 years survival rates were 93.7 ± 2.2% and 89.0 ± 4.0% for the none-mild PHT group, and 83.7% ± 3.9% and 83.7% ± 3.9% for the moderate-severe PHT group, respectively. Although the survival rates in the none-mild PHT group were higher than the moderate-severe PHT group, the difference was not statistically significant . Of them, 7 cases were associated with an irregular use of warfarin and unreasonable prolonging the intervals of international normalized ratio (INR) monitoring (more than 3 months). The other 2 cases were confirmed to have adequate anticoagulation with a therapeutic INR.Valve replacement was successfully performed in 3 cases. As no overt symptoms related to the tricuspid valve thrombosis were observed in the remaining 6 cases, they accepted conservative management which increased the target range of INR to 2.5–3.0. Echocardiographic monitoring showed complete resolution of the thrombus within 6 months follow-up and normally functioning mechanical leaflets in 2 cases. Freedom from valve thrombosis was 96.0% ± 1.4% at 5 years and 94.1% ± 2.3% at 10 years . Among them, 6 cases were gastrointestinal bleeding, 3 were cerebral bleeding , 3 were hematuria, 2 were leg hematomas, 2 were massive epistaxis, and 1 was retinal hemorrhage. Freedom from bleeding events was 91.8% ± 2.2% at 5 years and 87.5% ± 3.2% at 10 years Fig. . The linReoperation was performed for 3 cases (1.3%) due to prosthetic valve thrombosis. A new SJM valve was re-implanted in 1 case, and bioprostheses were implanted in the other 2. All of them survived at the end of follow-up. The intervals to reoperation were 2 months, 4 months, and 2.8 years, respectively. Freedom from reoperation was 98.6% ± 0.8% at 5 years and 98.6% ± 0.8% at 10 years. The linearized rate of reoperation was 0.3%/patient-year. Another case of perivalvular leakage was detected after follow-up of 6.5 years, but it was unnecessary to undergo reoperation. In addition, no case of structural failure was observed.7. A high hospital mortality rate associated with TVR was reported universally in previous studies, ranging from 10.0% to 27.6%10. The present result of 6.4% is relatively favorable compared with them. However, it is still higher than researches on mitral or aortic valve replacement6.TVR is uncommon in clinical practice and is reserved for few cases in which repair of the tricuspid valve is not feasible or efforts to repair it have failed12. The average age of our patients was 44.1 ± 9.7 years, while other studies were commonly more than 50 or even 60 years14. Second, recent advances in myocardial protection, surgical techniques and perioperative management may have had a positive effect15. Third, a low proportion of patients (13.6%) received previous open heart operations in this study16. Re-entry is technically challenging and is associated with a high risk of catastrophic hemorrhage and death.The reasons for such a favorable hospital mortality are varied and could be summarized as follows. First, a younger patient population is an important factor, as age was identified to be a strong predictor of hospital mortality17. We observed that the presence of ascites and low LVEF were independent predictors for more than 72 hours of ventilator support. Topilsky and colleagues8 reported the early results of 189 patients who had received TVR for severe tricuspid regurgitation, and they indicated that an acceptable hospital mortality can derive from a surgical correction before the onset of advanced heart failure symptoms. In recent years, our attitude toward the surgical correction of tricuspid valve disease tend to be more aggressive than ever in an aim to prevent or at least retard the progress of heart failure. Therefore, the lower hospital mortality found in this study is also related to the earlier intervention for tricuspid valve disease.Like other studies, the main cause of hospital mortality in this study was heart failure. Tricuspid valve disease is primarily asymptomatic and can be tolerated for a long period. Patients often arrive for surgery with a long history of heart disease. However, when the symptoms of right ventricular malfunction, such as peripheral edema and ascites, are manifested, the clinical condition of these patients is already into a rapidly-deteriorated stage18. Consistent with previously published studies11, we found that the main cause of late death was progressive heart failure and only 2 deaths occurred as a result of valve-related complications. Some authors19 have indicated that patient-related characteristics, such as heart failure and the presence of ascites, were independent predictors of long-term mortality, and the type of implanted prosthesis  in the tricuspid position did not affect the early and long-term results.The survival rate at 10 years in this study was 86.6% ± 2.9%, which is higher than that reported in other series, ranging from 59.9% to 84.3%12 reviewed 90 patients who underwent TVR with a mechanical valve or a bioprosthesis during 25 years of follow-up. Nine of 13 late deaths were associated with heart failure and only 1 patient died from cerebral hemorrhage. The late deaths were dominantly dependent from non-valve-related events. Chang and colleagues16 revealed a similar long-term mortality of bioprosthetic and mechanical valves, and indicated that the progression of heart failure is the most frequent cause of late death. These data demonstrate that late deaths are more attributed to patient-related characteristics than valve-related factors by the implanted prosthesis in the tricuspid position. Although the literatures have demonstrated the elevated pulmonary hypertension was an independent predictor for pathetic long-term outcomes20, not so in this study. The reason might be due to a higher previous open heart surgery rate in the none-mild PHT group than moderate-severe PHT group.Garatti and colleagues24. The present result of 0.8%/patient-year is comparable with or even lower than these reports. A higher prevalence of valve thrombosis in caged ball and tilting disc prostheses has been generally mentioned21.Valve thrombosis is considered the Achilles’ heel of mechanical valves in the tricuspid position. Its linearized rate ranges from 0.5% to 6.8%/patient-year according to other studies5. In the case of valve dysfunction for thrombosis, the bileaflet SJM valve may present hemodynamic advantages over the caged ball and tilting disc prostheses: one of the leaflets may still partially open and close to avoid catastrophic outcomes25. Nakano and colleagues23 observed that valve thrombosis occurred in only 1 out of 39 patients with the SJM valve in the tricuspid position over a 13.8-year follow-up. The result from Singh and colleagues25 is more promising because there was no thrombosis in 14 patients with 7 to 10 years of follow-up. However, in a retrospective study by Kawano and his colleagues24, 6 of 19 SJM valves after TVR were detected with valve thrombosis (2.9%/patient-years), and they emphasized that thrombosis was more likely to occur in valves of the tricuspid position. In our view, the higher thrombogenicity of the SJM valve may have been caused by the setting of a lower target INR (1.5–2.0). The irregular use of warfarin and the unreasonable prolonging of the intervals of INR monitoring were the major causes of valve thrombosis in this study. Therefore, the strict control of the anticoagulation intensity and the regular education of patients are important to avoid thrombotic complications16.The SJM valve was introduced as an alternative to last-generation mechanical valves with preeminent hemodynamics and low incidence of thromboembolism26. However, it seems to be a satisfactory result when compared with other mechanical valves in tricuspid valve position27. In China, after mechanical aortic valve replacement (AVR) and/or mitral valve replacement (MVR), low-intensity anticoagulation with a target INR less than 2.5  is recommended for decreasing the risk of bleeding28. Given the higher incidence of valve thrombosis in the tricuspid position, moderate-intensity anticoagulation (INR 2.0–3.0) is recommended in our hospital for patients who received TVR with a mechanical valve. The results of this study indicated that for Chinese TVR recipients, the target INR of 2.0–3.0 was concomitant with a low incidence of valve thrombosis and an acceptable occurrence of bleeding events, but further evaluations are required to confirm these findings.Bleeding was the main valve-related complication in this study. The present linearized rate of bleeding events was 1.5%/patient-year, which is higher than a previous series with SJM in other valve positions (0.3–1.0%/patient-year)25. In this study, 98.6% ± 0.8% of SJM valves were free from reoperation at 10 years. All reoperations were identified for valve thrombosis, rather than structural failure and perivalvular leakage. Similar to that of other studies25, excellent durability of the SJM valves was demonstrated in this study.Long-term durability is one of the creditable characteristics of the SJM valves. Structural failure due to the disruption of components of the prosthetic valve was not observed in this study or in other relevant studies15. However, the deficiencies for bioprostheses are late valve calcification, stenosis, and dysfunction. Nakano and colleagues18 detected the subclinical prosthetic dysfunction of bioprosthetic valves in 35% of patients who were followed up for more than 5 years after TVR. Chang and colleagues16 compared the long-term outcomes between two types of valves. Freedom from reoperation for mechanical valves at 15 years was 86.0% ± 6.2%, while that of bioprosthetic valves was only 55.1% ± 13.8%. The reoperation of TVR would bring about a high operative risk and hospital expense. As the patients in this study were characterized by a younger age and a lower income distribution, they refuse to take on the risk of reoperation for bioprostheses malfunction. Therefore, they more preferable to mechanical valves at present.Several studies have reported better durability of bioprostheses in a low-pressure chamber of the tricuspid position than in the aortic and mitral position29. In our opinion, more experiences in transcatheter tricuspid VIV and longer follow-up are needed before the expansion of bioprosthesis used in tricuspid position30. The technology of transcatheter tricuspid VIV may open a new clinical prospect in the near future for patients.In recent years, advances in the transcatheter valve-in-valve (VIV) technology is forcing more and more surgeons to implant bioprostheses, even in young patients. It is an attractive alternatives to redo conventional open heart surgery. However, most of the available studies are mainly focus on the treatment of dysfunctional aortic bioprosthesesThere are also limitations in this study that must be realized. First, it was a retrospective observational study performed in a single institution. However, to our knowledge, it is the largest number of patients undergoing TVR with SJM valve to be studied. Second, 85.7% of patients had concomitant MVR and/or AVR, early complications such as low cardiac output syndrome, respiratory infection, reoperation for bleeding might not have been directly related to mechanical TVR, rather may be due to valve replacement in either aortic or mitral valves. Third, for an average duration of 4.9 ± 2.7 years of this study, the long-term results still need to be further followed up.This study demonstrates the excellent mid-term results of SJM valve in the tricuspid position. The incidences of valve thrombosis and reoperation were low, and deaths were more attributed to the patient-related characteristics rather than valve-related complications. Therefore, the SJM valve is a reasonable choice for the patients who require mechanical valve replacement in the tricuspid position.From January 2005 to December 2015, 10202 cardiac valve replacements were performed in West China Hospital, Sichuan University. Of these operations, 5574 (54.6%) were MVR, 2666 (26.1%) were MVR and AVR, 1630 (16.0%) were AVR, and 332 (3.3%) were TVR either as an isolated procedure or combined with surgery on other valves. After patients with bioprostheses (42 cases), non-SJM mechanical valves  and younger than 18 years old (5 cases) were excluded, 265 cases of TVR with SJM valves were performed in 264 adult patients  TVRs were performed under cardiac arrest through median sternotomy in a conventional manner. The remaining 4 reoperative cases (1.5%) were performed while the heart was beating, and a right anterolateral thoracotomy was used to avoid retrosternal adhesions. Cardiopulmonary bypass and mild-moderate systemic hypothermia were initiated for all cases during the operations. The SJM valves were implanted with interrupted sutures. They were also used in other valve replacements, which were performed concomitantly with TVR. The prosthetic valve sizes of the SJM valves in TVR and MVR are shown in Fig. % TVRs we31. The patients were divided into the none-mild PHT (≤50 mm Hg) group and the moderate-severe PHT (>50 mm Hg) group according to the preoperative PHT condition. Both the preoperative and intraoperative data of the two groups are shown in Table The preoperative PHT was calculated through Doppler echocardiography by adding the systolic pressure gradient between the right ventricle and atrium to the right atrial pressure32. The events that occurred within this time were defined as early complication. Valve-related complications associated with the prosthetic valve in the tricuspid position, including valve thrombosis, bleeding events, prosthetic valve endocarditis, and perivalvular leakage, were included in the data analysis32Clinical follow-up was accomplished by a review of the medical records or telephone interviews with the patients themselves or their family members. The follow-up rate was 95.1% (252 of 265 cases), with an average duration of 4.9 ± 2.7 years ranging from 0 to 10.6 years. The cumulative follow-up was 1141.4 patient-years. Operative mortality was to be reported as all-cause mortality within 30 days of TVR or during the time of hospitalizationt-test. Categorical data were reported as rates and were analyzed with the Chi-squared test. Independent predictors for ventilator support time more than 72 hours were evaluated with a logistic regression model. Variables with p value < 0.20 in univariate analysis were incorporated into multivariate analysis. The rates of overall survival, freedom from valve-related complications and reoperations were estimated with the Kaplan-Meier method respectively, and the log-rank test was used for intergroup comparison. The incidences of valve-related complications were reported as linearized rates. A two-sided p < 0.05 was regarded as statistically significant. All data were analyzed with Statistical Package for Social Sciences .Continuous variables were described as mean ± standard deviation (SD) and were analyzed with the Student’s This study followed the tenets of Declaration of Helsinki and was approved by the ethics review board of West China Hospital, Sichuan University. A waiver of consent was received from them at the same time.Supplementary Figure S1


We hypothesized, that periprosthetic joint infection (PJI) accounts for the major proportion of first (primary) and repeated (secondary) Total Knee Arthroplasty revisions at our university referral arthroplasty center.One thousand one hundred forty-three revisions, performed between 2008 and 2016 were grouped into primary (55%) and secondary (45%) revisions. The rate of revision indications was calculated and indications were categorized by time after index operation. The odds ratios of the indications for primary versus secondary revision were calculated.In the primary revision group PJI accounted for 22.3%, instability for 20.0%, aseptic loosening for 14.9% and retropatellar arthrosis for 14.2%. PJI (25.6%) was the most common indication up to 1 year after implantation, retropatellar arthrosis (26.8%) 1–3 years and aseptic loosening (25.6%) more than 3 years after implantation.In the secondary revision group PJI accounted for 39.7%, aseptic loosening for 16.2% and instability for 13.2%. PJI was the most common indication at any time of revision with 43.8% up to one, 35.4% 1–3 years and 39.4% more the 3 years after index operation.p = 0.000) for PJI. For instability and retropatellar arthrosis the odds ratios were 0.60 times (p = 0.006) and 0.22 times (p = 0.000) lower.The odds ratios in repeated revision were 2.32 times higher (PJI is the most common indication for secondary TKA revision and within one year after primary TKA. Aseptical failures such as instability, retropatellar arthrosis and aseptical loosening are the predominant reasons for revision more than one year after primary TKA. Total knee arthroplasty (TKA) is the treatment of choice for symptomatic arthrosis. Patient satisfaction with TKA has improved from 81.2% between the years 1990 and 1999 to 85% between the years 2000 and 2012 . Recent That is why we hypothesized, that PJI accounts for the major proportion of primary and secondary revisions at our institution. Additionally, we hypothesized that, in contrast to primary revision, the frequency of PJI is not related to time of revision for secondary revision.This observational study was performed at the Department of Orthopaedic Surgery, University of Wuerzburg in Germany. Approval was waived by the University’s ethics committee .In August 2016, our department’s electronic data was scanned for all TKA revisions, that were performed since the introduction of our electronic database in December 2008. Only procedures involving an arthrotomy were considered a revision. The failure mechanism described by the operating surgeon as decisive for revision strategy was defined as indication for revision. Indications were categorized into polyethylene (PE)-wear, aseptic loosening, PJI, instability, periprosthetic fracture, malalignment, extensor mechanism deficiency, arthrofibrosis, retropatellar arthrosis and other.The authors acknowledge that diagnostic algorithms of the painful TKA are discussed controversial and are still under investigation –12. ThusPJI was evaluated in accordance with the guidelines of the Infection Disease Society of America . Two staInstability was assessed based on the patient’s history for example with swelling and giving way events. Additionally, coronal and sagittal instability was evaluated by clinical examination and on radiographs as described elsewhere . In caseArthrofibrosis was diagnosed by painful restriction of range of motion that was refractory to intensified physiotherapy, without any other underlying reason.For alignment evaluation, we routinely used the alignment parameters based on The Knee Society Total Knee Arthroplasty Roentgenographic Evaluation and Scoring System , 16. CT-One thousand one hundred forty-three revisions were identified. Revisions were performed in 36.4% in male and in 63.6% in female patients with a mean age of 67.9 years (21–93). First revisions after the primary TKA (index operation) were assigned to the primary revision group (55.0%). In case of any previous revision, which was not the primary implantation, this was regarded the index operation for the secondary revision group (45.0%).The mean duration from index operation to revision was 42.1 months (0–279). 55.5% of the primary revision cases and 38.9% of the secondary revision cases were transferred to our institution for further operation.To support a unification of the time to failure categorization we subdivided the time from index operation to revision in accordance with the recently published study by Thiele et al. into 1 year, 1–3 years and more than 3 years .Means were compared with the t-Test. Odds ratios for the indications were calculated depending on primary or secondary revision and tested for significant differences with the Pearson chi square test. Statistics were performed with SPSS 24 .In the primary revision group the major proportion 71.4%) of revisions was due to the four indications: PJI (22.3%), instability (20.0%), aseptic loosening (14.9%) and retropatellar arthrosis (14.2%) , followed by instability (19.0%) and retropatellar arthrosis (13.1%). 31.5% of TKAs failed 1–3 years after implantation. Of these 26.8% were due to retropatellar arthrosis, 24.7% due to instability and 20.7% due to PJI. 41.0% were revised more than three after index operation. 25.6% of these revisions were because of aseptic loosening, 20.2% because of PJI, 18.2% because of PE-wear and 17.4% because of instability. The complete distributions are shown in Fig. In the secondary revision group 68.1% of the revisions were due to three indications: PJI 39.7%), aseptic loosening (16.2%) and instability (13.2%) , followed by aseptic loosening (13.9%) and instability (11.3%). A comparable distribution was found for the 36.8% revisions between 1 and 3 years with 35.4, 15.9 and 14.8% and for the remaining 25.5% revision after more than 3 years with 39.4, 21.3 and 12.6%. The detailed distributions are depicted in Fig. 3.8%, folp < 0.000) for secondary revisions. However, the odds of being revised for instability or retropatellar arthrosis were significantly lower for secondary revisions (Table The odds of being revised for PJI were 2.5 times higher (ns Table .Table 1Op = 0.000) shorter in the secondary revision group (Table The mean duration to revision because of PJI and because of aseptic loosening was significantly (up Table .Table 2MWe found PJI to be the most common indication for both, primary and secondary TKA revision at a university referral arthroplasty center. This result is in accordance with the numbers published from the NIS for knee arthroplasty revisions, without discriminating primary from secondary revisions . The oddIn contrast to PJI, retropatellar arthrosis and instability are specific issues of primary TKA. In accordance with our results, instability is consistently reported a major failure mechanism after primary TKA , 5, 21. This study has limitations because of its retrospective design and the complexity of TKA revision.If the treatment of PJI failed and the patient was readmitted, the following revision was considered a new case. In this study with 345 primary and secondary revisions, about 10% were repeatedly revised for reinfection. Thus, the proportion of PJI might be biased by patient specific characteristics.Further, we did not investigate the proportion of resurfaced patellae before revision. These cases were not excluded from the analysis because the proportion of failures due to patellar arthrosis is clinically relevant and the discussion of the best treatment is still going on . The sigThe 14th NJR annual reported aseptical failure mechanisms the most frequent reasons for primary revision . The curPJI is the most common indication for secondary TKA revision and within one year after primary TKA. Aseptical failures such as instability, retropatellar arthrosis and aseptical loosening are the predominant reasons for revision more than one year after primary TKA.


The aim of this study was to analyze the safety and effectiveness of stenting using partially covered self-expandable stents in palliation of dysphagia in patients with unresectable esophageal cancer.Retrospective analysis of hospital records of all patients who underwent esophageal stenting in the period 2008–2015 was performed. The study included patients with unresectable esophageal and esophagogastric cancer.p = 0.00001). During the follow-up, 55 (12.4%) patients experienced recurrent dysphagia due to tumor or granulation tissue overgrowth, and in 18 (4.1%) patients, migration of the stent occurred, for which an independent risk factor was adjuvant chemo- and/or radiation therapy (p = 0.001). Minor complications included chest pain (54.5%), delayed complete stent expansion (12.0%), feeling of a foreign body (25.3%), hiccup (1.6%), gastroesophageal reflux (45.6%) and post-discharge pneumonia (2.5%). A feeling of a foreign body in the esophagus was significantly more common after stenting of the cervical esophagus (p = 0.0001), and hiccup was more common after stenting of the esophagogastric junction (p = 0.02). Major complications included bleeding (1.3%), respiratory insufficiency (0.7%), esophageal perforation (0.9%) and irregular heartburn (2.3%). Overall procedure-related mortality was 0.4%. The median survival time was 117.8 days (range 2–732).There were 442 patients included. Mean age was 56 years (range 28–89), and 379 were males. In 40 (9.0%) patients, stenting was performed in the cervical, in 150 (39.3%)—in the middle thoracic, in 141 (31.9%)—in lower thoracic esophagus and in 111 (25.1%)—in the esophagogastric junction. Stenting resulted in significant alleviation of dysphagia grade (3.0 vs. 1.0, Stenting is an effective procedure in relieving dysphagia in patients with unresectable malignant esophageal stenosis and is associated with low rate of postoperative and long-term complications. Squamous cell carcinoma of the esophagus is the eighth most frequent cancer in the world, whereas carcinoma of esophagogastric junction (OGJ) is the tumor with the highest dynamics of incidence in the last two decades –4.It is estimated that in North America there are 5–10 cases of esophageal cancer per 100,000 inhabitants; however, depending on the geographical area, the incidence may increase up to 100/100,000, such as in Iran .Multimodal treatment consisting of preoperative chemoradiation therapy followed by complete resection and lymphadenectomy is a standard in therapeutic management. However, curative-intent treatment is possible in only 20–40% of patients. In a majority of them, palliative management is the only option, due to local advancement and/or distant metastases . In suchIn this study, we present one of the largest retrospective analyses with prospective follow-up of patients with esophageal cancer, who underwent esophageal stenting due to unresectability of the tumor or medical inoperability. The aim of this study was to evaluate the safety and efficacy of stenting in patients with esophageal squamous cell carcinoma and carcinoma of the esophagogastric junction, complications, re-interventions and survival after the treatment.This retrospective analysis of hospital records included data of a consecutive group of patients with advanced esophageal carcinoma, treated between 2008 and 2015 in Department of Thoracic Surgery, Jagiellonian University Collegium Medicum. Demographic and clinical data including age, sex, weight, dysphagia, dyspnea, chemotherapy/chemoradiation, technical success rate, stent migration, complications and survival were evaluated.The study included all patients treated in the period 2008–2015 for unresectable or medically inoperable esophageal or (OGJ) cancer, regardless of histological type.Preterminal condition, Karnofsky score ≤ 40%;Patients with mediastinal infiltration causing dysphagia in the course of lung cancer, lymphomas and other malignancies.Exclusion criteria included:0—no dysphagia;1—swallowing of a semiliquid diet;2—swallowing of a liquid diet;3—dysphagia to the liquids and saliva.Unresectability was determined on the basis of chest radiography, abdominal ultrasound, computed tomography (CT) of the chest and the upper abdomen, positron-emission tomography (PET) and endoscopy, with the endoscopic ultrasound (EUS) and endobronchial ultrasound (EBUS). Disease staging was based on the UICC classification . DysphagType 1—fistula to the mediastinum;Type 2—fistula to the trachea;Type 3—fistula to the bronchus;Type 4—fistula after stenting.Patients diagnosed with fistula in the course of esophageal or bronchogenic cancer were classified into four groups according to fistula location :Type 1—f0—less than 30% of tracheal or/and bronchial stenosis, no dyspnea;1—30–50% stenosis, dyspnea upon exercise;2—50–70% stenosis, dyspnea during daily activities;3—more than 70% stenosis, dyspnea while resting.Dyspnea severity was assessed with a four-grade scale :0—less tPatient performance status was assessed according to Karnofsky score .Esophageal stenting was performed under general anesthesia. Location of the stenosis was endoscopically identified, and in case of narrow stenosis, dilatation was performed with Savary–Gilliard dilators, up to the size of 10 Fr. After the dilatation, the neoplastic infiltration length was assessed using a small-diameter endoscope, then a guidewire was inserted and the esophageal stent was introduced over it. Deployment of the stent was performed under endoscopic control. Partially covered self-expandable metallic stents  were used.Airway compression or infiltration posing the risk of severe airway compromise after expansion of the esophageal stent.Double stenting was performed in patients with unresectable esophageal cancer involving the airway, with dysphagia and dyspnea;As a rule, airway stenting was performed before esophageal stenting. The double stenting procedure was performed under general anesthesia. The self-expandable Ultraflex stents  were used for stenting of fistulas to the trachea and silicone Y stents  in case of fistula located in the tracheal bifurcation and main bronchi. Stenting with the use of silicone Y stents was performed using the Freitag forceps according to the technique described elsewhere .Peri-, intra- and postoperative complications and any additional procedures were recorded. Complications after stenting were classified as minor or major. Minor complications were defined as those subsiding spontaneously or following pharmacological treatment only, potentially requiring endoscopy. All other, including life threatening or fatal, were defined as major complications.Postoperative complications were defined as early (occurring within ≤ 30 days following stenting) or late (occurring later than >  30 days following stenting).Following the procedure, patients received a liquid diet the same day. Routinely, on the first day after the procedure a follow-up chest radiogram was obtained and dyspnea and dysphagia scores were assessed. Patients received detailed instructions regarding nutrition at discharge from the hospital. Patients were followed up every 30 days thereafter. If the follow-up visit in the clinic was not feasible, patients were interviewed by phone. During the follow-up visit, the patients’ general condition, dysphagia and dyspnea were assessed.p < 0.05 was considered as statistically significant.Statistical analysis was performed using the STATISTICA 11 PL software package . The Mann–Whitney test was used to compare two samples. Kruskal–Wallis test was used to compare three or more attempts. In order to evaluate the changes over time , the Wilcoxon signed rank test was applied. To assess the significance of connections between data on nominal scale, the Fisher’s Chi-square test or Fisher’s exact test was used. The logistic regression model was used to find the risk factors for complications after stenting. If an important factor was found, odds ratio (OR) was calculated along with 95% confidence interval. Survival was calculated using Kaplan–Meier method. Gehena–Wilcoxon test was used to compare survival curves. 46 patients with lung cancer;2 patients with thyroid cancer;1 patient with colorectal cancer;1 patient with breast cancer;7 patients with lymphomas;45 due to the preterminal state or Karnofsky score ≤ 40%;14 patients who were lost from postoperative follow-up;48 patients stented before planned surgical resection.Between 2008 and 2015, 606 patients underwent esophageal stenting for malignant esophageal obstruction. The flowchart of the study is presented in Fig. The final analysis included homogenous group of 442 patients with esophageal or OEJ cancer, who underwent esophageal stenting procedure.Patients presented with body weight loss from 4 to 40 kg, dysphagia, cough and cachexia. The mean length of neoplastic infiltration in the esophagus was 5.9 cm (range 4–12 cm).28 (6.3%) and 30 (6.34%) patients with the tumor located between 18 and 21 cm from the incisors;12 (2.7%) and 18 (4.16%) patients with the tumor located between 22 and 25 cm from the incisors.In 40 (9.0%) patients, stenting of the upper segment of the esophagus was performed, including:In 150 (39.3%) patients, stenting was performed in the middle part of the esophagus, in 141 (31.9%)—in the lower thoracic part of the esophagus and in 111 (25.1%)—in the OGJ.Nineteen (4.3%) patients had primary fistula to the mediastinum or the airway. Fifteen (3.04%) patients with fistula developed after the stenting procedure. Adjuvant chemo- and radiation therapy was administered to 201 (45.5%) patients (Table Stenting procedure could not be performed in 3 (0.6%) patients due to complete obstruction of the esophagus. These patients underwent laparotomy and gastrostomy. Thus, the technical success rate was 99.4%.p = 0.00001).After stenting procedure, swallowing improvement was observed in all the patients. The mean dysphagia score improved from 3.0 (range 2–3) before stenting to 1 (range 1–2) after the stenting procedure (p = 0.004). In 209 (42.3%) patients, mild analgesia was required and the pain subsided within 2–4 days after the procedure, whereas in 33 (7.5%) patients long-term analgetic medication was needed.After esophageal stenting, 241 (54.5%) patients reported chest pain: in 28 (6.3%) patients with stent in the proximal esophagus, in 94 (21.2%)—in the middle part, in 78 (17.6%)—in the lower part and in 49 (11.0%)—in the EGJ. Pain occurred more frequently in patients with stents the proximal and middle part of the esophagus (Incomplete immediate stent expansion occurred in 53 (12.0%) patients. In all of them, the stent expanded fully without any intervention within 48 h.p = 0.0001). These symptoms subsided completely or partially within 3–7 days.Difficulties in swallowing, associated with the feeling of a foreign body, were reported by 112 (25.3%) patients, including 29 (6.6%) with a stent in the proximal esophagus, 30 (6.8%)—in the middle part, in 21 (4.8%)—in the lower part and in 29 (5.7%) of them after the stenting of OGJ. The feeling of a foreign body was present only in patients with stents in the proximal part of the esophagus (p = 0.02), requiring stent removal in 1 (0.2%) patient. In 3 patients with squamous cell carcinoma and in 4 with OGJ, carcinoma early migration of the stent occurred. Two hundred and two (45.6%) patients reported reflux symptoms, and they required treatment with proton-pump inhibitors. After discharge from the hospital, in 11 (2.5%) patients pneumonia occurred and they received outpatient treatment.Hiccup occurred in 7 (1.6%) patients after esophageal stenting: In 4 of them, it happened after stenting of the EGJ and required stent removal in 3 cases, and in 3 (0.7%) patients after stenting of the lower part of the thoracic esophagus  patients, and in 3 (0.7%) of them, transfusion of 2–4 units of packed red blood cells was necessary.Irregular heartburn occurred in 10 2.3%) patients (Table .3% patiep = 0.06) ]. There were no significant differences in the migration rates when SCC was compared with adenocarcinoma of the OGJ (p = 0.06).In 18 (4.1%) patients, migration of the stent occurred. It happened in the middle thoracic part of the esophagus in 3 (0.7%) the patients, in the lower part in 7 (1.6%) patients and in 8 (1.8%) patients in the OGJ (6) Table . AdjuvanIn 7 patients with squamous cell carcinoma and in 4 with OGJ carcinoma, late migration of the stent occurred.p = 0.54). In patients with stent obliteration by tumor or granulation tissue ingrowth, restoration of patency was performed with the use of argon plasma coagulation followed by re-stenting.Dysphagia associated with stent obliteration by the ingrowing granulation tissue occurred in 55 (12.4%) patients: in 46 (10.4%) at the proximal end of stent and in 9 (2.0%) patients at the distal end. In 2 (0.4%) patients, ingrowing tumor was observed. Development of granulation tissue was observed in the period from 27 to 103 days (mean 72 days) since stent implantation. In 5 (1.1%) patients, ingrowing granulation tissue was observed in the proximal part of the esophagus, in 16 (3.6%) patients in the middle part, in 19 (4.3%) patients in the lower part and in 16 (3.6%) patients in the EGJ ].Stent removal and re-stenting procedure were required in 28 (6.3%) and 31 (6.3%) patients, respectively. Forty-six (10.4%) patients with stent obstruction received CTH and/or RTH, which was a risk factor for stent obstruction [In 4 (0.9%) patients, esophageal stenting resulted in compression of the airway. In 2 (0.4%) of them, symptoms of dyspnea required additional stenting of the bronchial tree with Y stent; in the remaining 2 (0.4%) patients, compression of the bronchial tree < 30% of lumen occurred, without symptoms of dyspnea and not requiring additional stenting. These patients were subjected to follow-up (Table p = 0.06). Median survival time in patients with OAF was 74.5 days (range 41–432).The follow-up period ranged between 1 and 732 days. Median survival time was 117.8 days (range 2–732) , dyspnea score  and Karnofsky score  was achieved. There was no significant improvement in BMI . The median survival after stenting of the OAF was 74.5 days (range 41–432) days. The survival did not correlate with the use of chemotherapy or chemoradiation (p = 0.54).Esophago-airway fistula (OAF) was found in 34 (7.7%) patients Table . NineteeA primitive stent was used for the first time for intubation of the esophageal stenosis in 1885, and rapid development of stenting occurred together with the development of endoscopy . In the One of the most frequent complications of esophageal stenting is ingrowth or overgrowth of granulation tissue or tumor at the ends of the stent. In our study, the percentage of tissue overgrowth was 11.99%, with the applied stenting margin of 4 cm. These results are consistent with the literature data, showing its incidence of 4–47% (higher in cases of the use of non-covered stents) , 18. ResThe second most frequent complication is stent migration, which reportedly occurs in 0–20% cases –23. Our Although esophageal stenting is characterized by a very high technical success rate, it is associated with the risk of life-threatening complications. One of them is development of an OAF following the procedure. According to the literature, it occurs in up to 10% of patients after the stenting procedure. Ferreira et al. reported the occurrence of such fistulas in 7 out of 126 treated patients and Uitdehaag et al. in 2 out of 44 patients, after the application of SX Ella stents with anti-migration mechanism , 32. In Other most frequent severe complications include: hemorrhage, which occurs in 2–28%, perforations, perioperative mortality, which was estimated to be 0.5–7%, and a 30-day mortality that ranges from 7 to 18% , 32–37. Esophageal stenting may enable the introduction of chemotherapy or chemoradiation. Chemotherapy enables relief of dysphagia and full oral nutrition, so the European Society of Gastrointestinal Endoscopy recommends its administration , 39. TheGenerally, the use of partially covered self-expandable metallic stents in inoperable/unresectable esophageal cancer is safe and effective palliative procedure, with low rate of complications and perioperative mortality.


MKRN3 mutation in cases of familial iCPP.There have been recent advances in the understanding of the etiology of idiopathic central precocious puberty (iCPP) including new genetic associations. The aim of this clinical study was to determine the frequency of MKRN3 gene were evaluated in 19 participants from 10 families using next-generation sequencing analysis.Potential sequence variations in the maternally imprinted in silico analysis, consistent with the clinical findings.MKRN3 variation was found in only one of the 19 (5.3%) subjects. The male patient, who had a medical history of precocious puberty, had a heterozygous mutation, NM_005664.3:c.630_650delins GCTGGGC (p.P211Lfs*16). The father of this patient also had a history of precocious puberty and had the same mutation. p.P211Lfs*16 is a novel variant and it was identified as probably pathogenic by MKRN3 variants in our case series was much lower than reported elsewhere which suggests a need for further studies in Turkish iCPP patients.Given that MKRN3 mutation was detected in only one patient, with a paternal history of precocious puberty, this reinforces the importance of accurate family history taking. The detected incidence of  Since 2013, the underlying aetiology of some cases of familial idiopathic central precocious puberty (iCPP) has been elucidated.However, data on the incidence of these new aetiologies of familial iCPP in Turkish populations is scarce.This study showed a low rate of MKRN3 mutation in cases of familial idiopathic central precocious puberty (iCPP) in Turkey.This case series highlights the importance of always obtaining a good family history when investigating cases of iCPP as this may hasten diagnosis and help identify gene targets for investigation.KISS1 and KISSR1 genes and loss-of-function mutations in the makorin ring finger protein 3 (MKRN3) gene were shown to result in CPP  is defined as the development of secondary sex characteristics before eight years of age in girls and nine years of age in boys, due to early activation of the hypothalamic-pituitary-gonadal (HPG) axis ,2. Owingt in CPP ,5.MKRN3 gene product exerts an inhibitory effect on gonadotropin releasing hormone (GnRH) neurons. It has been proposed that the HPG axis is reactivated by loss-of-function mutations in the MKRN3 gene . All children included in the study had at least one first or second degree relative with documented iCPP.The Tanner and Marshall ,11 criteIn the girls luteinising hormone (LH), follicle-stimulating hormone (FSH) and 17β-estradiol (E2) were measured in a morning blood sample. A basal serum LH level ≥0.83 mIU/mL, with puberty precocious findings described above, was accepted as activation of the HPG axis . Cases wCongenital adrenal hyperplasia was excluded by 17-hydroxyprogesterone (17-OHP) <1.5 ng/mL in early morning samples and/or peak 17-OHP <10 ng/mL following an ACTH stimulation test. Cranial magnetic resonance imaging (MRI) was performed to exclude any organic lesion in all cases diagnosed with CPP.Standing height was measured to the nearest 0.1 cm with a Harpenden fixed stadiometer . Body weight was measured on a balance scale  to the nearest 0.1 kg. Height and weight standard deviation score (SDS) were calculated by comparison with Turkish national reference data (www.ceddcozum.com) . Adult hLH, FSH, and E2 levels were measured with an immunochemiluminometric assay using an Advia Centaur immunoanalyzer . Bone age (BA) was assessed according to the  Greulich and Pyle  Atlas meMKRN3 and flanking regions were amplified using polymerase chain reaction (PCR) primers, designed with PRIMER-Primer Designer v.2.0 software . Amplicon libraries were prepared with the NexteraXT kit (Illumina Inc.). Sequences were aligned to the hg19 genome with MiSeq Reporter software (Illumina Inc.). Detection of variants was performed with IGV 2.3 (Board Institute) software. In silico analysis, database search and literature evaluations were done by Varsome, Polyphen2, HGMD-Public, PubMed, Google search, Clinvar, EXAC and 1,000 Genome studies.Genomic DNA was isolated from ethylenediamine tetraacetic acid blood sample by Magnesia DNA isolation Kit . Sequencing study was done by NGS technology and it was performed using the MiSeq next generation sequencing platform . All coding exons of The data obtained were evaluated using the SPSS 16.0 software programme .The study included 19 patients with CPP from 10 families. In the familial CPP group, there were 17 girls and two boys  from 10 families. Clinical, anthropometric and biochemical data of the included patients and their parents are displayed in MKRN3 gene analysis was performed only in this patient’s father. We did not have the opportunity to study the genotype in his remaining family members. The patient with MKRN3 mutation presented with facial hair growth at 11 years and 7 months of age. Facial hair growth had appeared 1.5 years earlier. Family history revealed that facial hair growth had appeared at the same age in his father. The patient’s brother is unaffected and was found to be pre-pubertal in the examination performed at 10 years of age. The patient’s physical examination yielded the following findings: height, 156.5 cm [+1.27 standard deviation (SD)]; body weight, 44.6 kg (+0.3 SD); 15 mL testicular volume bilaterally; stage 5 pubarche; and axillary hair growth. The heights of mother and father were 167 (+0.6 SDS) and 159 cm (-2.4 SDS), respectively. The patient’s target height and predicted height were estimated to be 169.5 cm (-1 SDS) and 168.8 cm (-1.1 SDS), respectively. Routine biochemistry tests and complete blood count were normal. The hormone test results were as follows: LH, 5.4 mIU/mL; FSH, 13.7 mIU/mL; total testosterone: 393.3 ng/dL; 17OHP: 0.6 ng/mL; and dehydroepiandrosterone sulphate, 60.4 mcg/dL. BA 14 years. The same mutation was also detected in his father. The physical examination of the other boy with no mutation showed height 142.4 cm (1 SDS), weight 35.3 kg (0.6 SDS); 6 mL testicular volume bilaterally; stage 3 pubarche; and axillary hair growth. The heights of mother and father were 149 cm (-2.16 SDS) and 167 cm (-1.3 SDS), respectively. The patient’s target height and predicted height were estimated to be 164.5 cm (-1.65 SDS) and 174 cm (-0.4 SDS), respectively. The patient was followed-up without treatment due to slowly progressive puberty.Among the whole group, a novel heterozygous mutation, MRKN3:NM_005664.3:c.630_650delinsGCTGGGC (p.P211Lfs*16), was detected in only one boy with a paternal history of precocious puberty . A flow This mutation is a frame shift variant and causing production of a truncated protein with 226 amino acids while the wild type protein consists of 507 amino acids. Mutation taster predicts this variant as a disease-causing mutation, probably due to loss of function.MKRN3, is an intronless gene located on chromosome 15q11.2 in the Prader–Willi syndrome critical region   mutation. Simsek et al .  (37.5%)  detected (37.5%)  reportedek et al  reportedIn boys, there may be delay in recognising indicators of precocious puberty compared with those  in girls ,9,19,20.The small number of patients and the wide range of criteria which were used to diagnose CPP were the limitations of this study.MKRN3 mutation was detected in only one (5.3%) of 19 individuals from 10 families with familial CPP. Given the fact that the MKRN3 mutation was detected in only one patient with a paternal history of precocious puberty in our study, the importance of an accurate family history, which can reveal the paternal inheritance of familial iCPP due to a mutation in MKRN3, must be emphasized. Physicians should consider this type of inheritance in patients with iCPP thus facilitating targeted genetic analysis and providing an additional tool for the diagnosis of children with iCPP.


It is challenging to distinguish between primary ovarian mucinous tumors and metastatic mucinous neoplasms from the lower gastrointestinal tract, including appendiceal tumors. A combination of PAX8 and SATB2 immunohistochemical stains can be used as a diagnostic tool to distinguish between these cases.Immunostaining for SATB2, PAX8, CK7, CK20 and CDX2 was performed on 50 ovarian mucinous neoplasms (OMN) , 63 mucinous colorectal carcinoma (CRC), and 9 appendiceal mucinous neoplasms (AMN) [8 low grade appendiceal mucinous neoplasms (LAMN) and 1 adenocarcinoma]. PAX8 was positive in 32% of OMN and negative in all CRC and AMN cases. SATB2 was expressed in 2.0% of OMN, 77.8% of AMN, and 49.2% of CRC cases. CK7 was positive in 78.0% of OMN, 33.3% of AMN, and 9.5% of CRC cases. CK20 was expressed in 24.0% of OMN, 88.9% of OMN, and 87.3% of CRC cases. CDX2 was positive in 14.0% of OMN, 100% of AMN, and 90.5% of CRC cases. PAX8 can differentiate between OMN and AMN with high specificity but low sensitivity. CDX2 is the most sensitive marker for CRC and AMN, whereas SATB2 has better specificity. Primary ovarian mucinous neoplasms (POMNs) are among the ovarian epithelial tumors for which diagnosis with certainty remains difficult. The major challenge is to exclude metastatic mucinous tumors (MMTs) from extragenital sites, especially appendiceal origin, given the fact there is overlap between both tumors in regard to the morphological features and immunohistochemical expression –3. Many Among the most popular combinations are CK7, CK20, and CDX2. CK7 has been shown to be expressed in the majority of POMNs; however, CK7 is also expressed in MMTs, especially those of upper gastrointestinal origin with a lesser frequency for the lower gastrointestinal tumors (LGITs) –6. In coPAX8 has been shown to be positive in the majority of Müllerian epithelial tumors . The perSATB2  is a recently described transcription factor which is both sensitive and specific to colorectal epithelium , 14. SATIn this study, we sought to prove that the combination of PAX8 and SATB2 can be a sensitive and specific panel in discriminating POMNs from MMTs.We retrieved 122 cases of primary tumors, consisting of 50 ovarian, 63 colonic, and 9 appendiceal mucinous neoplasms, from the archives of King Abdullah University Hospital, obtained during the period of 2005 to 2015. All cases were reviewed by two pathologists (NA and ME) and one representative section was chosen from each case. All the procedures performed were approved by the ethical committee of Jordan University of Science and Technology  in accordance with the 1964 Declaration of Helsinki and its later amendments. Formal written informed consent was not required with a waiver by the IRB.Four µm sections were produced from paraffin blocks using a Dako autostainer—Plus . After the tissue was dewaxed, antigen retrieval was carried out in PT-link , using a high pH buffer for 20 min. Endogenous peroxidases activity was blocked by incubation with 2.5% hydrogen peroxide for 10 min. Slides were then washed with phosphate buffer saline (PBS) twice and then primary antibodies were applied as follows: PAX8  for 45 min at room temperature; SATB2  for 45 min at room temperature; CK7  for 30 min at room temperature; CK20  for 30 min at room temperature; and CDX2  for 30 min at room temperature. Slides were then washed twice with PBS and signal detection was carried out using the Envision Dual Link System HRP Kit, K8000 . Slides were then washed with distilled water and, finally, counterstained with Mayer’s Hematoxylin.Stains were evaluated by two independent pathologists; the results were considered “positive” if > 5% of the tumor cells expressed the marker, and “negative” if < 5% of the tumor cells expressed the marker .Analyses for dependent and independent variables were performed using SAS statistical software . Frequencies and percentages were used for categorical variables (immunostain result for each cancer). Sensitivity, specificity, and negative and positive predictive value measures of the primary ovarian mucinous neoplasms were computed using SAS functions and are shown in Tables Immunohistochemical expression data for ovarian, colonic, and appendiceal tumors are summarized in Tables We retrieved 50 primary ovarian mucinous tumors; 39 cases (78.0%) were mucinous cystadenomas, four (8.0%) were borderline tumors, and seven 14.0%) were mucinous cystadenocarcinoma. All patients were presented with ovarian mass. The clinicopathological features for patients with POMNs are summarized in Additional file 4.0% wereAll mucinous borderline tumors  were . Two cases were  and the other two were .All malignant mucinous cystadenocarcinomas  expressed CK7, and were negative for PAX8 and SATB2. Five out of seven cases (71.4%), were positive for CK20 and only two (2/7) were positive for CDX2 (28.6%).Mucinous cystadenomas showed more heterogeneous results, in which 71.8% (28/39) and 35.9% (14/39) were expressing CK7 and PAX8, respectively, while 10.3% (4/39) were positive for CK20 and CDX2. SATB2 was negative in all cases. Two of the mucinous cystadenomas were associated with teratoma; both were consistently negative for CK20, CDX2, and PAX8. One case was positive for SATB2, and one was positive for CK7 while the other was negative.We retrieved nine cases of primary AMNs; eight cases were LAMN and one case was adenocarcinoma. The clinicopathologic characteristics for patients with AMNs are summarized in Additional file All LAMN cases exhibited a similar immunoprofile , while the adenocarcinoma case co-expressed CDX2 and SATB2 with negativity for CK7, CK20 and PAX8.We retrieved 63 cases of primary mucinous colonic adenocarcinoma. The clinicopathologic characteristics for patients with colonic mucinous adenocarcinoma are summarized in Additional file Discriminating POMNs from MMTs is one of the problematic issues facing the pathologist in their practice and it is a crucial decision as respective management is totally different. Patients with POMNs have a better prognosis and usually do not require adjuvant chemotherapy –20, wherThe most popular panels used to discriminate POMNs from MMTs are CK7, CK20 and CDX2. CK7 was positive in 86% of POMNs, while 33% were positive for CK20 and CDX  showed tCDX2 is typically expressed in a strong diffuse pattern in colorectal and appendiceal adenocarcinomas, with sensitivity of 100% , in contSATB2 is expressed by lower gastrointestinal normal epithelium, as well as by primary and metastatic CRC , 14. In PAX8 is a sensitive and specific marker for tumors of Müllerian origin –12. ThisIn conclusion, the most sensitive marker for POMNS is CK7 (78.0%), whereas the most specific is PAX8 (100%). Regarding mucinous tumors arising from the colon and appendix, the most sensitive marker is CDX2 (91.7%), while the most specific is SATB2 (98.0%). Therefore, adding PAX8 and SATB2 to the panel of immunostains for differentiating mucinous tumors will be of great benefit. If the tumor is positive for PAX8, it is most likely to be of ovarian origin. On the other hand, positivity for SATB2 is most likely of colonic/appendiceal tumors.In the present study, we had a relatively small sample size, especially for AMNs and ovarian mucinous adenocarcinoma cases. We recommend the use of larger sample sizes in future research involving multiple institutions, instead of a single institution as in our study.Additional file 1: Table S1. Clinicopathologic characteristics of the ovarian mucinous neoplasms. Table S2. Clinicopathologic characteristics of colorectal and appendiceal mucinous tumors.


Many different preventatives have showed efficacy in the treatment of migraine. National guidelines differ in their recommendations and patients’ characteristics are usually taken into account in their selection. In Spain, real life use of preventive therapies seems to be heterogeneous. We aimed to evaluate differences in clinical practice and adherence to national guidelines among Spanish neurologists.Observational descriptive study. A survey was conducted among neurologists ascribed to the Spanish Society of Neurology. Participants were differentiated in accordance with their dedication to headache disorders. We analysed socio-demographic parameters and evaluated 43 questions considering migraine management as well as therapeutic choices regarding migraine sub-types and finally, neurologists’ personal perception.One hundred fifty-five neurologists participated from 17 different regions, 43.4% of them female and 53.3% under 40 years of age. 34.9% confirmed headache disorders as their main interest.The first choice for preventive therapy in chronic migraine among participants was topiramate (57%) followed by amytriptiline (17.9%) and beta-blockers (14.6%). However in episodic migraine, the preferred options were beta-blockers (47.7%), topiramate (21.5%) and amytriptiline (13.4%). Regarding perceived efficacy, topiramate was considered the best option in chronic migraine (42.7%) followed by onabotulinumtoxinA (25.5%) and amitryptiline (22.4%). Where episodic migraine was concerned, surveyed neurologists perceived topiramate (43.7%) and beta-blockers (30.3%) as the best options. When we evaluated the duration of treatment use with a view to adequate therapeutic response, 43.5% of neurologists preferred 3 months duration and 39.5% were in favour of 6 months duration in episodic migraine. However, considering the preferred duration of treatment use in chronic migraine, 20.4% recommended 3 months, 42.1% preferred 6 months and 12.5% and 22.4% opted for 9 and 12 months respectively. When considering onabotulinumtoxinA therapy, the number of prior therapeutic failures was zero in 7.2% of neurologists, one in 5.9%, two in 44.1%, three in 30.9% and four or more in 11.9%. Following an initial treatment failure with onabotulinumtoxinA, 49% of subjects decided against a second treatment. The number of OnabotA procedures before considering it as ineffective was two in 18.9% of neurologists, three in 70.8% and four in 10.4%.The initial management of migraine among Spanish Neurologists is in line with most guidelines, where first choice preventative drugs are concerned. The Management of episodic migraine differed from chronic migraine, both in terms of neurologist preference and in their perceived efficacy.The online version of this article (10.1186/s10194-019-0971-6) contains supplementary material, which is available to authorized users. HeadachThe Spanish Headache Study Group guidelines  recommenDespite the high number of therapies available, some of them have not been properly studied and the evidence is based on experts’ opinions . The arrWe aimed to evaluate the preferences in the management of migraine with preventive therapies, the perceived efficacy and safety of the current therapies among Spanish Neurologists.We conducted an observational, transversal study. The studied population was the community of Spanish Neurologists ascribed to the Spanish Society of Neurology.The study included an anonymous survey mailed three times to all neurologist members of the Society. It included 8 questions about demography and 43 concerning preventative preferences and utilization.The survey analysis considered if the neurologist was a member of the Spanish Headache Study Group (SHSG) and those in whom headache disorders were their main area of interest. For analytic purposes, we categorized responders in two differentiated age groups: junior neurologists if they were under 40 years old (juniors) and senior neurologists if they were 40 years old or above (seniors in advance). In Spain most trainees complete their Neurology training at age 29 following 4 years of residency.Demographic variables were gender, age group, region of origin, main area of interest, adscription to the SHSG, and duration spent working in headache medicine.Eligibilty criteria of treatments included all those mentioned in the Official Guidelines of the Spanish Headache Study Group, namely: beta-blockers, amitriptiline, topiramate, valproic acid, zonisamide, lisinopril, candesartan, fluoxetine, venlafaxine, desvenlafaxine, lamotrigine, magnesium, flunarizine, riboflavine, pregabalin, onabotulinumtoxinA (onabotA) and anaesthetic blockade of greater occipital nerves (GON) . We analWe specifically evaluated which was the preferred beta-blocker and we included among the possible answers propranolol, nadolol, atenolol, bisoprolol, nebivolol and esmolol. We analyzed by separate onabotA management in terms of number of prior preventive failures, employed units per procedure and long-term management.Surveyed neurologists were asked about their preferred first and second choices in preventive therapy in chronic migraine (CM), episodic migraine with aura (EMWA), and in episodic migraine without aura (EMOA). We also gave special consideration to conditions such as depression or pregnancy.Participants were also questioned about their personal opinion regarding the most effective drugs in both Chronic and Episodic Migraine and which they thought were the best-tolerated drugs.The Scientific Committee of the Spanish Society of Neurology approved the study and all the participants agreed to participate voluntarily.We present data as number and percentage. Missing data was managed by complete case analysis. We employed SPSS v16.0 for the Statistical Analysis. For the comparison of qualitative variables, we used Chi  test. InWe received responses from 153 neurologists, among which 53 (34.9%) were ascribed to the Spanish Headache Study Group. The percentage of female participants was 43.4%. Age of participants was < 30 years in 11.8%, 30–39 in 41.4%, 40–49 in 16.4% and > 50 in 30.4%.The most frequent regions were Madrid, with 32 participants (21.1%) and Catalonia with 24 (15.8%). The time since they were focused on headache disorders was < 6 years in 35.4%, 6–10 years in 14.6%, 11–15 years in 14.6%, 16–20 in 10.4% and > 20 years in 25%.Topiramate was the first choice drug in 57% of responders, followed by amitriptyline 17.8%), beta-blockers (14.6%) and flunarizine (6%). The most frequent second choice drug were beta-blockers (25.7%) followed by topiramate (23.2%), amitriptyline (20.5%), onabotA (10.6%) and flunarizine (9.3%). Complete data on all possible drugs is shown in the Additional file 7.8%, betManagement of CM seemed to be different among general neurologists when compared with those focused on headache disorders, particularly concerning the first choice selection of topiramate , amitriptyline  and flunarizine .Comparison of juniors and seniors did not yield any significant differences.The preferred drugs were beta-blockers (47.7%), followed by topiramate 21.5%), amitriptyline (13.4%) and flunarizine (11.4%). The most frequent second choice was topiramate (44.6%), followed by beta-blockers (23.6%), amitriptyline (15.5%), flunarizine (9.5%) and zonisamide (4.1%). Further data is available in Additional file .5%, amitTopiramate was the first choice for 50.3% of participants, followed by beta-blockers (23.2%) amitriptyline (9.3%), flunarizine (6.6%) and lamotrigine (2.6%). The most frequent second choice was topiramate 31.8%), beta-blockers (25.7%), lamotrigine (10.1%), amitriptyline (9.5%), zonisamide (8.8%), flunarizine (6.8%) and valproic acid (6.1%). Full list of responses are available in the Additional file .8%, betaWe did not find significant differences between headache specialists and general neurologists concerning the preferred drug in episodic migraine treatment, neither with nor without aura.Between junior and seniors, there was a trend but results did not reach statistical significance, to use less topiramate among juniors  and flunarizine  and higher use of amitriptyline .Figure Management was described to be different when treating female patients in 76.3% of neurologists. The preferred option in case of pregnancy was beta-blockers in 57.7%, magnesium (17.3%), Greater Occipital Nerve blockades (16.3%), onabotA (3.8%), lamotrigine (2.9%) and others (2%). Valproic acid was avoided in female migraineurs by 90.1% of responders.In patients with depression, the preferred drugs were amitriptyline in 67.1%, venlafaxin in 15.3%, and topiramate in 11.3%.Topiramate was considered the most effective drug in the treatment of CM by 42.7% of responders, followed by onabotA in 25.2%, amiptriptyline (22.4%), beta-blockers (3.5%) and flunarizine (2.1%).The second most frequently considered drug was also topiramate in 34.3%, followed by amitriptyline 19.7%), beta-blockers (15.3%), onabotA (8%), venlafaxin (5.8%), valproic acid and zonisamide (5.1% each). Full list of responses can be consulted in Additional file 9.7%, betOnabotA was considered as the most effective drug more frequently among neurologists with special interest in headache disorders than in general neurologists . In the group of general neurologists, amitryptiline tended to be considered as the most effective drug in more cases than in headache specialists . We did not found statistically significant differences between junior and senior neurologists concerning preferences in terms of efficacy.The drug perceived as most effective in episodic migraine was topiramate (43.7%), followed by beta-blockers (30.3%), amitriptyline 14.8%) and flunarizine (8.5%). Beta-blockers were considered the second most effective option in 32.9% of the answers, followed by topiramate (28.6%), amitriptyline (17.1%) and flunarizine (11.4%). Full data about efficacy can be consulted in Additional file 4.8% and Preferences of neurologists with special interest of headache did not differed from general neurologists, only amitriptyline was described as less effective .We found differences in the perception of efficacy of topiramate and amitriptyline comparing senior and junior neurologists. Seniors considered topiramate as the most effective more often , whereas juniors considered amitriptyline as the most effective in more cases .The preferred beta-blocker among surveyed neurologists was propranolol (62.1%), followed by nadolol and nebivolol (15.85% each), atenolol (4.1%) and bisoprolol (2.1%).Drugs considered as best tolerated in a young patient without any comorbidity were betablockers (42.4%), followed by flunarizine 14.6%), onabotA (11.3%), topiramate and amitriptyline (9.3% each), and magnesium (4%). Full data about tolerability preferences can be seen in Additional file 4.6%, onaFigure Differing opinions emerged between headache specialists and general neurologists where the best-tolerated drugs were concerned, however these results were not statistically significant Fig. p = 0,24, Pearson test), in EMOA was r = 0,23  and in EMWA r = 0,23 ; whereas the correlation between considering it as the most effective and selecting it as first choice was higher, r = 0,46 in EMOA  and r = 0,43 in EMWA  and for CM was r = 0,31 .In the correlation analysis we found that the correlation between considering topiramate well tolerated and selecting it as first choice in CM was r = 0,95, (Participants described patients comorbidities as the most important factor when choosing a preventative (70.2%) followed by guidelines recommendations (13.9%), personal experience (11.3%) and patients’ preferences (4.6%).Regarding the management in primary care, 80.9% of the surveyed neurologists considered that the general practitioner should prescribe preventatives before referral to neurology office. The number of preventatives considered to fail before referring the patient was none in 4.6%, one in 13.8%, two in 56.6% and three or more in 25% for episodic migraine whereas in chronic migraine was none in 21.1%, one in 22.4%, two in 40.8% and three or more in 15.8%.Regarding the duration of preventive therapy until achieved therapeutic response, in EM 51% of responders affirmed to keep the treatment for 3 months or less whereas in CM 42,1% treated during 6 months and 34,9% during at least 9 months. Figure Polytherapy was only considered in selected cases in the first visit by 22.3% of the participants. When asked about management in their patients, the percentage of them treated with polytheraphy was estimated to be 0–10% by 14.5% of neurologists, 11–25% in 44.1%; 26–50% in 27.6%; 51–75% in 9.2% and > 76% in 4.6%.Regarding specific OnabotA questions, we asked about the number of failure (efficacy or tolerability) in oral preventatives before starting OnabotA. Response was none in 7.2% of neurologists, one in 5.9%, two in 44.1%, three in 30.9%, four in 9.9% and five or more in 2%. When asked whether they considered specifically the failure to any preventative, 51.4% mentioned topiramate, 4.9% amitriptyline, 4.2% beta-blockers and 36,6% said they did not consider any specific failure.When comparing between headache specialists and general neurologists, the former started OnabotA earlier than general neurologists (p:0.014) Fig. We did not find differences when comparing juniors and seniors and 54.3% affirmed to start OnabotA after two preventive failures and 83,9% after the failure of three preventive drugs (p:0.49).Concerning OnabotA dose, in the first procedure, 50.9% of responders injected 155 Units and 41.7% 150 U. Figure The number of OnabotA procedures before considering it as ineffective was two in 18.9% of neurologists, three in 70.8% and four in 10.4%.Only 66 participants  described to be assisted by a nurse in the OnabotA preparation. The percentage of clinicians that self-charged the medication was higher among headache specialists compared with general neurologists .Figure The main findings of our study were that topiramate was selected as the first choice drug in CM and EMWA and the second choice in EMOA, whilst beta-blockers were the drugs of choice in EMOA. These findings follow the Spanish Headache Study Group recommendations , but difAccording to European Medicines Agency  recommenThe percentage of responders that mentioned other drugs such as candesartan , lisinopOnly topiramate and OnabotA have proved their efficacy in randomized controlled trials in Chronic Migraine and only recently its efficacy has been directly compared . DespiteWe also consider of interest how beta-blockers were perceived, as they were considered as the second most effective option in EM, slightly after topiramate. However, in Chronic Migraine, the percentage of neurologists that considered them as the most effective option was significantly lower, only 3.5% them in comparison with 30.3% in EM. Only one study compared them directly and could not find statistically significant differences in Episodic Migraine patients .Another topic of discussion is the duration of the preventive treatment. Spanish guidelines recommend at least 6 months of treatment , but we Concerning the tolerability profile, most of the responders preferred beta-blockers but the preferred drugs were flunarizine, OnabotA, amitriptyline and topiramate. Some of these drugs have been associated with adverse events in up to 75 to 82,5% of the patients in the pivotal trials , 14.Despite the difference of administration, OnabotA was perceived as well tolerated by a high percentage of neurologists, in line with long-term studies show , and it Spanish experts recommendations for the use of OnabotA stated that the first procedure should be performed according to the PREEMPT paradigm, administering 155 Units and in case of lack of response, dose could be increased up to 195 Units in the first three procedures [To date, some factors have been associated with an increased efficacy to OnabotA in CM: use of higher OnabotA dose up to 195 units –19, a shThe fact that all currently available preventive drugs have been developed for other indications may be related to the presence of adverse events and poor compliance. The arrival of novel specific drugs such as anti-CGRP antibodies and gepants could dramatically change the clinical picture , 25. NevThe panorama will change in the coming years and some factors will be of striking importance, such as the availability of the therapies, its efficacy in real world setting and the diffusion among the majority of clinicians. We support the creation of new European Guidelines and the harmonization of the National Guidelines according to the current literature.Our study has some limitations. As an online survey, not all the members of the Headache Study Group responded to it and the answers might not represent the opinions of all the Headache Specialists. Among the 51 questions, some of them were subjective and we did not allowed more than two possible answers.Also, our results reflect only opinion among Spanish neurologists, with a public healthcare system different of those from many other European Countries. Finally, we did not analysed non-pharmacological therapies or comorbidities management, which should be considered for future studies.Our study states that the main criterion in the selection of treatments is the subjective perceived efficacy, topiramate being the drug considered as the most effective and therefore the first choice drug in CM and EMWA.Despite the availability of many novel therapies, most of the clinicians employed the classical drugs.Additional file 1:Table S1. First and second choices in chronic Migraine. Number represent percentage or the total responses. Table S2. First and second choices in episodic migraine without Aura. Numberrepresentspercentage of total responses. Table S3. First and second choices in episodic migraine with Aura. Numbers represents percentage of total responses. Table S4. Perception about efficacy of the different drugs in the treatment of chronic migraine. Numbers represent percentage of the answers. Table S5. Perception about efficacy of the different drugs in the treatment of episodic migraine. Numbers represent percentage of the answers. Table S6. Answers about the drugs considered as the best tolerated and second best tolerated. (DOCX 68 kb)


Cabazitaxel is a treatment of metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure. The FUJI cohort aimed to confirm the real-life overall and progression-free survival  and safety of cabazitaxel.Multicentre, non-interventional cohort of French mCRPC patients initiating cabazitaxel between 2013 and 2015, followed 18 months.Four hundred one patients were recruited in 42 centres. At inclusion, median age was 70, main metastatic sites were bones (87%), lymph nodes (42%) and visceral (20%). 18% had cabazitaxel in 2nd-line treatment, 39% in 3rd-line and 43% in 4th-line or beyond. All had prior docetaxel, and 82% prior abiraterone, enzalutamide or both. Median duration of cabazitaxel treatment was 3.4 months. Median OS from cabazitaxel initiation was 11.9 months [95% CI: 10.1–12.9]. In multivariate analyses, grade ≥ 3 adverse events, visceral metastases, polymedication, and >5 bone metastases were associated with a shorter OS. Main grade ≥ 3 adverse events were haematological with 8% febrile neutropenia.2, median OS, respectively, 13.4 and 14.5 months). There was no effect of treatment-line on survival. No unexpected adverse concerns were identified.Real-life survival with cabazitaxel in FUJI was shorter than in TROPIC  or PROSELICA (clinical trial 20 vs 25 mg/mwww.encepp.eu, as EUPAS10391. It has been approved as an ENCEPP SEAL study.It was registered with the European Medicines Agency EUPASS registry, available at  Around 10% of patients are diagnosed at a metastatic stage with usually a very poor prognosis.3 Androgen deprivation therapy (ADT) with anti-androgens or LH-RH derivatives has been shown to delay progression. However, over time most prostate cancers will acquire resistance to ADT. This is referred to as castration-resistant prostate cancer (CRPC). In addition, to the patients diagnosed at the metastatic stage most CRPC become metastatic (mCRPC).4Prostate cancer is the second most common cancer in men and the fifth most common cause of cancer death worldwide.5 with only mitoxantrone with prednisone being licensed for its palliative effect without survival benefit. In 2004, docetaxel in combination with prednisone was shown to improve overall survival (OS).6 Over the last decade, three additional treatments have been licensed for treatment of mCRPC following failure of docetaxel, the new generation taxane cabazitaxel7 and two androgen-receptor-targeted therapies, abiraterone acetate8 and enzalutamide,9 with similar results.10 The latter two agents have subsequently been licensed also for first-line treatment of mCRPC.Treatment options for mCRPC have long been limited,11 Cabazitaxel plus prednisone demonstrated a significant OS improvement compared to mitoxantrone plus prednisone . The recommended dose of cabazitaxel is 25 mg/m² administered as a one-hour intravenous infusion every three weeks in combination with oral prednisone or prednisolone 10 mg administered daily throughout treatment.Cabazitaxel was approved as second-line treatment based on the results of the TROPIC trial, which enrolled 755 mCRPC patients progressing during or after docetaxel treatment.2 (C20) versus 25 mg/m² (C25) in 1200 post docetaxel mCRPC patients. Median OS, time to PSA progression and PSA response rate were 14.5 months, 6.8 months and 42.9%, for C25, respectively, and 13.4 months, 5.7 months and 29.5% for C20.12Since then, the PROSELICA clinical trial has confirmed the non-inferiority of cabazitaxel 20 mg/mAt the time of the marketing authorisation of cabazitaxel in France in October 2011, the French Health Authorities requested a post-marketing study documenting the effectiveness and safety of cabazitaxel in everyday clinical practice. The FUJI study was designed to meet this request. The primary objective of FUJI was to evaluate OS in mCRPC patients treated by cabazitaxel in daily practice. Secondary objectives included PSA response, progression-free survival, profile of patients receiving cabazitaxel including analgesic use and safety of cabazitaxel.® in real life) is a French multicentre non-interventional cohort study of patients with mCRPC starting treatment with cabazitaxel between 1 September 2013 and 31 August 2015 and followed 18 months.FUJI  data were extracted from the hospital records during the eighteen-month period following the first administration of cabazitaxel, or until the patient died and entered into an electronic case report form by a dedicated clinical research assistant. All data collected were validated by the participating physician and included the following: date of first cabazitaxel administration, patient demographics, disease history including prior treatments, cabazitaxel treatment modalities, outcomes , date of death, analgesic use and adverse events (AEs) reported during cabazitaxel treatment. Adverse events were coded using the current MedDRA classification and their severity was coded according to the grading system of the National Cancer Institute’s Common Terminology for the Classification of Adverse Events (NCI-CTCAE v4.0). Adverse events requiring hospital admission were also identified.16 . PSA progression was defined as an increase in PSA of at least 25% and of at least 2 ng/ml compared to the lowest post-cabazitaxel treatment value (PSA nadir), confirmed by a 2nd PSA value at least 3 weeks later. Radiological progression was defined by RECIST criteria version 1.0 as per physician judgment.17 Clinical progression was based on pain/symptoms and analgesic consumption as per physician judgment.The primary end-point was OS over eighteen months, calculated from first cabazitaxel administration. Secondary end-points were PSA response (defined by a PSA decrease of at least 50% from baseline) and progression-free survival (PFS) defined as in TROPIC16 OS and PFS were estimated using Kaplan-Meier survival analysis. Cox proportional hazard models over the eighteen-month follow-up period were used to identify risk factors associated with death or progression. The variables entered into the Cox models are listed in supplementary data Table The target sample size (400 subjects) was chosen to estimate OS at eighteen months with a precision of 4.9%, considering a median OS in TROPIC trial of 15.1 months.® , according to a statistical analysis plan defined prior to data lock.All statistical analyses were performed with SASThe study was conducted in accordance with all relevant national legislation and guidelines for observational studies, with approval from the French national data-protection Agency (CNIL). The study protocol was submitted to and approved by the French health authorities as part of the post-marketing commitments of the manufacturer of cabazitaxel (Sanofi-Aventis). All patient data in the study database were anonymised. The study was registered with the EU PAS registry (ENCEPP/SDPP/10391).Overall, 261 hospital pharmacies that had dispensed cabazitaxel at least once between September 2013 and December 2014 were contacted and invited to participate in the study. Of these, 93 pharmacies (35.6% of those contacted) accepted to participate and provided contact details of 234 physicians who had prescribed cabazitaxel. One hundred twenty eight of these agreed to participate, and 79 had recruited patients into the study when the target patient sample size was met. When recruitment was stopped, 401 patients had been recruited, between September 2013 and August 2015, in 42 centres. The patient recruitment process is illustrated in Fig. n = 389; 97.0%) had associated comorbidities, notably cardiovascular (69.2%), digestive (46.0%), endocrine (44.5%), urogenital (39.3%), musculoskeletal (33.4%) and respiratory (30.1%) disorders.Patient characteristics are presented in Table n = 364, 90.8%) at a starting dose of 25 mg/m2 . Other administration schedules were: <25 mg/m² every 3 weeks , >25 mg/m² every 3 weeks , 12–17 mg/m² every 2 weeks . In 125 patients (31.2%), the dose was reduced over the course of treatment.Cabazitaxel was most often administered every three weeks (The median duration of cabazitaxel treatment was 3.4 months with a median of five cycles. Among patients who had discontinued cabazitaxel at 18 months (95%), the main reasons for discontinuation were disease progression or disease-related death (83.2%), or the occurrence of AEs (15.2%).The 18-month OS rate was 32.4% [95% CI: 27.8–37.1] with a median OS of 11.9 months [10.1–12.9]. The Kaplan-Meier survival curve is presented in Fig. In the pre-specified subgroup analyses, median OS from first cabazitaxel administration ranged from 9.9 months 6.6–12.9] for patients with one previous LET line, 12.1 months [8.5–15.0] for patients with two previous LET lines, 12.9 months [10.0–14.7] for patients with three previous LET lines and 11.7 months [8.1–13.5] for patients with four previous LET lines before cabazitaxel initiation  to 38.9% (PSA response) depending on the criterion used Table . HoweverPSA response was available for 258 patients 64.3%)  experienced at least one AE during cabazitaxel treatment AEs requiring hospitalisation occurred in 41.1% of patients; the first AE occurred during the first or second cabazitaxel administration for half of patients (52.1%). At least one AE of Grade ≥ 3 was observed for 55.4% of patients, and these required hospitalisation in 26.6%.There was no difference in the event rates for grade ≥ 3 AE according to the number of previous treatment lines, from 54.2% with just one previous line, to 45.8% with four or five treatment lines before cabazitaxel.Adverse events are presented by System-Organ Class (SOC) and Preferred Term (PT) in Table The most frequent grade ≥ 3 AEs were anaemia (26.9%), neutropenia (15.0%) including febrile (8%), leukopenia (9.5%), renal failure (7.2%), thrombocytopenia (5.2%) and septicaemia and septic shock (5.0%). Six cabazitaxel-related deaths occurred, five of which were related to sepsis or septic shock with febrile neutropenia. These patients had at least one G-CSF treatment before or during the cycle when febrile neutropenia occurred, except for one patient who had an infectious shock after the first cabazitaxel administration.Use of Level I analgesics was more common during cabazitaxel treatment (70.3% of patients) than before (44.9%) or after (58.6%). Of the patients who were taking analgesics at cabazitaxel initiation, 30.9% reduced their analgesic consumption during the follow-up period. Analgesic consumption increased in 41.2% of patients. After discontinuation of cabazitaxel, the frequency of analgesic use remained stable in 67%. These data are summarised in supplementary data Table The objective of this study was to evaluate the effectiveness and safety of cabazitaxel in the treatment of mCRPC patients in everyday clinical practice in France. In this heavily treated population , the rate of OS at 18 months after cabazitaxel initiation was 32.4%. The most frequent AEs reported were haematological reactions, with 8% febrile neutropenia.n = 401), the broad eligibility criteria that encompassed all mCRPC patients treated with cabazitaxel whatever the treatment line, and the requirement that participating physicians include all their patients treated with cabazitaxel during the study recruitment period. In addition, follow-up was complete, and the status of all patients could be assessed at eighteen months. These features ensured that outcome could be determined with precision and be representative of outcome of mCRPC patients treated with cabazitaxel in everyday oncology practice in France. Nonetheless, some selection bias may be inherent to the voluntary participation of pharmacists and investigators. Around half the hospital pharmacies and around half the identified prescribers refused to participate in the study, so it is not certain that management of patients in these centres that did not participate was comparable to that observed in this study. Nonetheless, a previous study evaluating the impact of prescriber participation found no difference in patient outcomes between participating and non-participating physicians.18The strengths of this study were the relatively large sample size (11 (15.1 months [14.1–16.3])) or in the PROSELICA trial .12 There are two potential explanations for these differences. First, patients included in FUJI were in general older and more fragile than those enrolled in the clinical trials, where severe eligibility criteria were applied. For example, patients with poor performance status (ECOG score > 2) or with severe haematological, hepatic, renal or cardiac comorbidities were excluded in clinical trials. In contrast, eligibility criteria in FUJI were broad and all mCRPC patients treated by each participating investigator over the study period were enrolled, whatever their health status and whatever the duration of treatment. Indeed, if TROPIC inclusion and exclusion criteria were applied to FUJI, only two of 401 patients (0.5%) would have been eligible. Also, in TROPIC, all patients received cabazitaxel in second-line after docetaxel. In contrast with TROPIC, at the time of FUJI abiraterone acetate and enzalutamide were both available and only 18% received cabazitaxel immediately after docetaxel, with a median OS of 9.9 months. A possible explanation for the shorter OS as compared to TROPIC (15.1 months) may be that such patients might have had aggressive clinical features thought unlikely to respond to new AR-targeted agents. A phase 2 randomised controlled trial has indeed shown that taxanes were more effective than novel AR-targeted agents  in poor-prognosis mCRPC patients.19 Another explanation may be that patients with a very compromised status and short expected survival are often not included in clinical trials, whereas they are part of real-life observational studies.The median OS was shorter here , were independent predictors of mortality.20 Korea21 and Germany22 before cabazitaxel was commercially available. In the study from the Netherlands, median OS was 8.7 months [IQR: 6.0–15.9], which is close to the value observed in the FUJI study and again shorter than that reported in TROPIC. On the other hand, the Korean study reported a longer median OS (16.5 months [95% CI: 12.1–20.9]), close to the value reported in TROPIC. The German study reported mean OS (13.9 months [range: 0.7–35.8]) rather than median OS and is thus not really comparable. The publications on the Italian23 and Spanish24 compassionate use programs did not present data on survival.Effectiveness data on cabazitaxel in everyday oncology practice have also been published from the compassionate use programs established in the Netherlands,11 and 39.7% (20 mg/m2) or 54.5% (25 mg/m2) in PROSELICA.12 In all studies, haematological AEs were the most common. Although anaemia was reported at a relatively similar frequency in both studies (90% in FUJI and 97% in TROPIC), the reporting frequency of neutropenia was much lower in FUJI (26.9%) than in TROPIC (94%) or PROSELICA (41.8% and 73.3%). This may be explained by less intensive biological monitoring in real-life practice than in TROPIC, in which neutrophils were systematically measured at nadir, 8–10 days after each administration of cabazitaxel and G-CSF more systematically given.25 The frequency of febrile neutropenia was identical in both studies (8%), compared to 2.1 and 9.6% for C20 and C25, respectively, in PROSELICA.12 Six cabazitaxel-related deaths due to sepsis or septic shock, with febrile neutropenia in five, were reported in the FUJI study (1.5%), emphasising the importance of using prophylactic G-CSF from cycle 1 as per EORTC guidelines and carefully monitoring neutrophil counts in patients receiving cabazitaxel. In the PROSELICA C20 and C25 treatment groups, 2.1% and 3.2% of patients, respectively, died within 30 days of the last dose of cabazitaxel as a result of AEs.12 The occurrence of AEs was not a major reason for stopping treatment with cabazitaxel, concerning only around one in eight patients. The safety profile of cabazitaxel in FUJI can also be compared with the safety data collected in the European compassionate use program for cabazitaxel, which enrolled 746 patients.26 The frequency of adverse event reporting was generally higher in the compassionate use program than in the FUJI study, except for neutropenia. The compassionate use program reported 17.0% of patients with Grade 3 neutropenia, 5.5% with febrile neutropenia, 1.3% with neutropenic sepsis and seven deaths related to neutropenia or its complications.The safety profile of cabazitaxel in FUJI was essentially similar to that observed in TROPIC or PROSELICA, and no unanticipated safety issues arose. The proportion of patients presenting AEs of severity Grade 3 or 4 was 55.4% in FUJI compared to 57.4% in TROPICn = 47) could not account for the large number of patients starting at the lower dose of 20 mg/m² (196 patients). The fact that patients were less fit than in TROPIC (only 0.5% satisfied inclusion/exclusion criteria of TROPIC), may have contributed to it. The PROSELICA Phase 3 clinical trial12 has also demonstrated that a lower starting dose of 20 mg/m² was non-inferior to the approved dose of 25 mg/m² with a lower incidence of AEs. Prescribers may have been aware of that study and anticipated its results.27Cabazitaxel was generally used as recommended in the prescribing information at the time of the study. The licensed indication  was respected in all patients. Although the recommended treatment regimen of one cycle every three weeks was followed by most patients (90.8%), the recommended starting dose of 25 mg/m² was used in only half of the patients. Although dose reductions are recommended in patients with hepatic failure, the number of patients with hepatic disease (In conclusion, this real-life cohort study of cabazitaxel in mCRPC patients in France demonstrates that median OS at 18-months is slightly lower in everyday oncology practice than what was reported in the pivotal clinical trial, due to the presence of features of poor prognosis at baseline and use of cabazitaxel in 3rd line or beyond in 82% of patients. There were no unexpected safety issues, with severe neutropenia being the most important risk to consider when prescribing cabazitaxel.supplemental material