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Diagnostic boundaries between immune thrombocytopenia (ITP) and other thrombocytopenic states such as thrombocytopenic myelodysplastic syndromes, may be difficult to establish, and the detection of somatic mutations by next generation sequencing (NGS) may be of aid. Here we aimed at characterizing the prevalence and clinical significance of clonal hematopoiesis in ITP. In this multicentric retrospective observational study we enrolled 167 adult ITP patients, followed at 13 centers in Italy, UK, and USA. Patients underwent NGS evaluation after a median of 3.6 years from ITP onset and 83% had received at least one therapy line, median 2 (0-9) lines; 51 out of 167 patients had at least one mutation (30%). After exclusion of germline variants and polymorphisms, 18.5% (31/167) were defined as having clonal hemopoiesis. Most commonly mutated genes were TET2, DNMT3A, SRSF2, and ASXL1 (median VAF 29%); 19 of 31 subjects (68%) had high-risk variants, and 8 multiple mutations. Mutated patients were more frequently elderly males and showed a shorter time from first to second line therapy, particularly with TPO-RA. Additionally, clonal hematopoiesis was associated with increased thrombotic risk (26% vs 8% in NGS-negative cases, p=0.01), independently from TPO-RA exposure, though with an age effect. These data demonstrated the prevalence of clonal hematopoiesis in 18% of adult ITP patients, being associated with older age, relapsed/refractory disease, and high risk of thrombotic complications., (Copyright © 2024 American Society of Hematology.)

Objectives: To investigate pelvic organ prolapse (POP) after a novel abdominal prosthetic surgical technique - 'pelvic organ prolapse suspension' (POPS) - that has been proposed recently as an easily reproducible laparoscopic technique for the treatment of multicompartmental POP and rectal prolapse. This study also aimed to analyse treatment strategies of recurrent POP after POPS, reporting on anatomical, subjective and functional outcomes following recurrence surgery., Methods: Patients with a symptomatic prolapse relapse after POPS were collected and analysed prospectively at a single tertiary care institution. Each patient was offered a multidisciplinary clinical and radiological evaluation pre-operatively., Results: Twenty-five women with a median age of 59 [interquartile range (IQR) 49-73] years were enrolled in the study. Of these, 88 % were menopausal. All patients had high-grade (Pelvic Organ Prolapse Quantification System stage > 2) recurrent posterior vaginal wall-predominant prolapse after POPS. Multicompartmental prolapse was found in 64 % of patients. All women complained of vaginal bulging associated with obstructed defaecation syndrome (ODS) symptoms. Surgical treatment consisted of laparoscopic ventral rectopexy (VR) in all 25 cases (100 %), and concomitant sacral colpopexy (SCP) with previous mesh removal in 16 cases (64 %). No anatomical recurrences were observed after median follow-up of 12 (IQR 3-18) months. Overall subjective improvement after surgery was high in all patients (Patient Global Improvement Index ≤ 2)., Conclusions: Recurrent POP following POPS appears to predominantly involve the posterior vaginal wall, with associated ODS symptoms. A multidisciplinary approach is advisable for treatment of these patients. Minimally invasive VR alone or in combination with SCP seems to represent an effective treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Evans syndrome (ES) is rare and mostly treated on a "case-by-case" basis and no guidelines are available. With the aim of assessing disease awareness and current management of adult ES, a structured survey was administered to 64 clinicians from 50 Italian participating centers. Clinicians had to be involved in the management of autoimmune cytopenias and were enrolled into the ITP-NET initiative. The survey included domains on epidemiology, diagnosis, and therapy of ES and was designed to capture current practice and suggested work-up and management. Thirty clinicians who had followed a median of 5 patients (1-45)/15 years responded. The combination of AIHA plus ITP was more common than the ITP/AIHA with neutropenia (p < .001) and 25% of patients had an associated condition, including lymphoproliferative syndromes, autoimmune diseases, or primary immunodeficiencies. The agreement of clinicians for each diagnostic test is depicted (i.e., 100% for blood count and DAT; only 40% for anti-platelets and anti-neutrophils; 77% for bone marrow evaluation). Most clinicians reported that ES requires a specific approach compared to isolated autoimmune cytopenias, due to either a more complex pathogenesis and a higher risk of relapse and thrombotic and infectious complications. The heterogeneity of treatment choices among different physicians suggests the need for broader harmonization., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Literature is lacking strong evidence about comparisons of efficacy and quality of life-related outcomes between laparoscopic total and/or supracervical hysterectomy (LTH/LSCH) with laparoscopic sacrocolpopexy (LSC) and minimally invasive sacrohysteropexy (LSH)., Objective: To summarize and compare available data on this topic providing a useful clinical tool in the treatment decision process., Search Strategy: We performed a systematic research of PubMed (MEDLINE), Web of Science, and Gooogle Scholar., Selection Criteria: We included studies that compared at least one efficacy outcome (objective or subjective outcome) between LTH/LSCH with LSC and LSH. Data on surgery-related morbidities were also extracted where available., Data Collection and Analysis: A random-effect meta-analysis was conducted reporting pooled mean differences and odds ratios (OR) between groups using Review Manager V.7.9.0., Main Results: We included a total of nine observational studies. LTH/LSCH with LSH was associated with a significantly higher objective success (apical compartment OR 7.95; 95% confidence interval [CI] 2.23-28.33; I 2  = 0%; P = 0.001; anterior compartment OR 2.23; 95% CI 1.26-4.30; I 2  = 12%; P = 0.007) and subjective success (OR 3.19; 95% CI 1.42-7.17; I 2  = 39%; P = 0.005). No differences were found regarding intraoperative and postoperative complications, sexual dysfunction, and stress urinary incontinence rate after surgery. Hysteropexy showed shorter operative time and shorter hospital length with a pool mean difference of 27.37 min (95% CI 18.04-32.71; I 2  = 0%; P < 0.001) and 0.7 days (95% CI 0.24-1.17; I 2  = 75%; P = 0.003), respectively. Concurrent hysterectomy was not associated with a higher rate of mesh-related complications (P = 0.53). No major differences were found regarding recurrence and reoperation rate (P = 0.10 and P = 0.93, respectively)., Conclusions: LTH/LSCH with LSC has better objective and subjective outcomes in pelvic organ prolapse surgery than LSH alone, especially for apical and anterior compartments, and is not associated with higher postoperative sexual dysfunction and mesh-related complications. Adequate preoperative counseling is highly recommended in patients who desire uterine preservation., Prospero Registration Number: CRD42024537270., (© 2024 International Federation of Gynecology and Obstetrics.)

Background: The NuvaRing®, a hormonal vaginal contraceptive device, has gained widespread usage due to its favourable efficacy and safety profiles. Exceedingly rare instances of unintended misplacement in the bladder have been reported. This study presents a review of the literature and the first video report illustrating the extraction of an intravesical NuvaRing®, discussing diagnostic and therapeutic approaches., Objective: To illustrate an effective method for intravesical NuvaRing® retrieval and raise awareness about this unusual complication., Materials and Methods: A 27-year-old patient with low urinary tract symptoms related to NuvaRing® misplacement underwent diagnostic procedures, including ultrasound and diagnostic cystoscopy. A cystoscopic extraction under general anaesthesia was performed., Main Outcome Measures: The effectiveness of pelvic ultrasound for diagnosing an intravesical foreign body, successful cystoscopic removal of NuvaRing® from the bladder, and symptom resolution were assessed., Results: The intravesical NuvaRing® was identified through pelvic ultrasound. During cystoscopy, the ring was detected inside the bladder. Multiple attempts with cystoscopic alligator graspers were made; the NuvaRing® was eventually extracted using transurethral Heiss forceps. The patient experienced minimal blood loss and was discharged the following day, reporting relief from symptoms., Conclusions: Unintentional NuvaRing® placement in the bladder is an extremely rare event that healthcare providers should consider when patients present with urinary symptoms and pelvic pain. Pelvic ultrasound is an efficient diagnostic tool, possibly averting the need for further imaging techniques. Cystoscopy remains the preferred method for diagnosis and treatment. This video report illustrates an effective technique for NuvaRing ® extraction, especially when appropriate graspers are unavailable. Adequate instruction on NuvaRing® insertion should always be emphasised.

Objectives: Although sacral colpopexy is considered the gold standard for the treatment of advanced apical prolapse, several warnings and restrictions has been delivered to urogynecological surgeons in order to avoid the implants of prosthetics meshes. The purpose of this systematic review is to investigate the role of sacral colpopexy performed with autologous tissue in literature., Methods: a systematic review according to PRISMA guidelines was performed in June 2022 through the Medline, Web of Science and Scopus databases. Quality assessment of each article was performed according to Critical Appraisal tool of Oxford center for EBM, LoE according to SORT standards, ROBINS-I tool for methodological assessment in non-randomized trials. From 236 screened records, 7 articles were considered eligible for this systematic review., Results: Collected data showed objective cure rate ranging from 94.7% to 100% in medium term follow up. Subjective cure rate was specifically investigated in 2 studies with high satisfaction rates. Complication rate ranged from 0 to 36.8%, with 90.1% graded ≤2 according to Clavien-Dindo classification., Conclusions: sacral colpopexy with autologous fascia shows satisfying outcomes in terms of safety and efficacy and may be taken in account in particular clinical situations., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

•Data on caplacizumab use for thrombotic thrombocytopenic purpura (TTP) in Italy are missing.•Twenty-six Italian patients were treated with caplacizumab for an acute immune TTP episode.•Caplacizumab was effective in treating acute TTP in the Italian real-world clinical setting.•Two major bleeds leading to drug discontinuation were observed., (© 2023 The Author(s).)

Introduction: We present the preliminary report of the first 60 cases of robotic sacrocolpopexy (RSCP) performed with a minimally invasive approach by using the new HUGO RAS system (Medtronic) with the aim of assessing its feasibility, safety and efficacy., Methods: Results in terms of operative time, intraoperative blood loss, post-operative pain, length of hospitalisation, intra and post-operative complications were comparable to previously described laparoscopic and robotic techniques., Results: Urogynecological assessment at three months follow up showed surgical anatomic success in 96.7% of patients (<2 POP-Q stage), while subjective cure rate was 98.3%., Conclusions: This is the first series analyzing RSCP outcomes for POP using the new Hugo RAS system. Our results suggest effectiveness both in objective and subjective outcomes, with minimal intra and post-operative complications. Larger series as well as longer follow-up are needed to better define advantages and possible disadvantages of this novel system. Our work may represent the basis of future studies to confirm its safety, efficacy and feasibility, and may provide technical notes for other centres that wish to perform RSCP through this innovative system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer (ML) declared a shared affiliation with the authors (GP, LV, GC, DC, SM, AL, and GS) to the handling editor at the time of review., (© 2023 Panico, Vacca, Campagna, Caramazza, Mastrovito, Lombisani, Ercoli and Scambia.)

Background: Minimally invasive sacral colpopexy is considered the gold standard for surgical treatment of Pelvic Organ Prolapse (POP), combining high success rates with low recurrence risk in comparison to other techniques. This is the first case of robotic sacral colpopexy (RSCP) performed with the innovative Hugo™ RAS robotic system., Objectives: The aim of this article is to show the surgical steps of a nerve sparing RSCP performed with the new Hugo™ RAS robotic system (Medtronic), by also evaluating the feasibility of this technique using this novel Robotic System., Materials and Methods: A 50-year-old Caucasian woman with symptomatic pelvic organ prolapse (POP-Q): Aa: +2, Ba: +3, C: +4, D: +4, Bp: -2, Ap: -2 , TVL:10 GH: 3,5 BP:3 underwent RSCP as well as a subtotal hysterectomy with bilateral salpingo-oophorectomy, using the new surgical robot Hugo™ RAS in the Division of Urogynaecology and Pelvic Reconstructive Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy., Main Outcome Measures: Intraoperative data, docking specifics, objective and subjective outcomes at three months follow up., Results: Surgical procedure was carried out without intra-operative complications, operative time (OT) was 150 minutes, docking time was 9 minutes. No system errors or faults in the robotic arms were registered. Urogynaecological examination at three months follow up showed a complete resolution of the prolapse., Conclusion: RSCP using the Hugo™ RAS system seems to be a feasible and effective approach according to results in terms of operative time, cosmetic results, postoperative pain and length of hospitalisation. Large number of case reports as well as longer follow up are mandatory to better define its benefits, advantages, and costs.

Introduction: Bladder pain syndrome/interstitial cystitis (BPS/IC) is either Hunner lesion interstitial cystitis (HL IC) or non-Hunner lesion interstitial cystitis (N-HL IC), differing in the presence of HLs on cystoscopy. Cystoscopy is essential in diagnosing HL but are bladder biopsies useful in N-HL IC patients? Our objective was to assess bladder biopsy in patients with N-HL IC, evaluating whether the count of mast cells (MCs) and percentage of activated MCs could measure severity., Materials and Methods: This is a single-centre retrospective study., Inclusion Criteria: diagnosis of BPS/IC by ESSIC definition; absence of HLs. Each patient had three bladder biopsies., Statistical Analysis: χ2/Fischer's exact test; Wilcoxon signed-ranks test/Mann-Whitney U test. Statistical significance: p < 0.05., Results: We separated 48 women into Group 1 with <50% of MCs activated and Group 2 with >50%. We compared the results of the O'Leary-Sant questionnaire between the two groups and did not find any correlation between the severity of the pathology and either the MC count in the detrusor or the percentage of activated MCs in the lamina propria or detrusor., Discussion/conclusion: These findings cast doubt on the usefulness of bladder biopsy for the evaluation of severity in N-HL IC., (© 2022 S. Karger AG, Basel.)

Objectives: Laparoscopic uterosacral ligament suspension (LUSLS) of the vaginal apex for the treatment of pelvic organ prolapse (POP) has gained popularity. The aim of this systematic review is to investigate perioperative outcomes and complications, subjective and objective success rates and recurrence rates in women undergoing this surgical procedure., Study Design: A systematic literature search was performed in December 2021. The critical appraisal skills program (CASP) was used to assess the methodological quality of the selected studies. The Clavien-Dindo (CD) scale and the Satava scale were used to classify periprocedural complications. Continuous variables were described as means and standard deviations while categorical were expressed as percentages of the whole group. Statistical significance was set at p < 0.05., Results: 26 articles were selected and analysed, with a total population of 1401 patients. Anatomical and subjective success rates after LUSLS ranged from 79% and 100% and from 76.2% to 100% respectively. The re-operation rate varied from 2% to 4.5% in the largest cohorts. The overall complication rate was 13.6%, however grade III CD complications occurred only in 1% of patients. Ureteral complications were described in only 2 cases., Conclusions: LUSLS represent a safe and effective technique for vaginal apex resuspension in women with POP. Further larger prospective randomized studies are required to confirm these data., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering individually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Stress urinary incontinence (SUI) is usually treated with mid-urethral slings. The best approach is still debated and the relationship between slings and pelvic structures is not completely understood. The aim of this study is to identify any difference between trans-obturator tape (TOT) and single incision sling (minisling)., Methods: Patients submitted to TOT or minisling were included in the study. Q-tip and stress test, ICIQ-SF questionnaire, PGI-I validated score, and 2D/3D transvaginal ultrasound parameters were collected at 1- and 6-month follow-up. Correlations between ultrasound parameters and clinical outcomes, PGI-I and ICIq-SF, were performed., Results: 61 patients were included in the study. PGI-I score was significantly lower in the minisling group than in TOT group at 1-month (p = 0.016) and 6-month follow-up (p = 0.076). The median distance between the sling and the lumen of urethra was significantly higher and the angle between the branches of the sling was significantly narrower in the minisling group. There were significant differences in distances between the sling and the bladder neck at 1-month and 6-month follow-up. An inverse correlation between angle of the branches and the Q-tip test was observed (p = 0.059 Pearson's Rho - 0.578). PGI-I correlated also with angle of the branches (p = 0.009, Pearson's Rho 0.503)., Conclusion: Patients undergoing TOT or minisling are similarly satisfied but show differences at ultrasound exam at 1- and 6-month follow-up. Pelvic floor ultrasound could be used in a short-term follow-up to visualize the sling position and to plan the most appropriate follow-up strategy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: As Laparoscopic Sacrocolpopexy (LSCP) has proven to be the gold-standard for treating Pelvic Organ Prolapse, management of recurrence after its failure is a challenge with upcoming interest. In these patients, repeat LSCP might represent a suitable surgical choice., Study Design: We present a retrospective observational study analysing safety, feasibility and outcomes of Redo LSCP. Data of 20 patients with POP recurrence who underwent previous sacrocolpopexy were recruited, and all successfully underwent a repeat LSCP., Results: Median 24-months follow-up demonstrated a statistically significant improvement of objective and subjective outcome. No intra and postoperative complications were noted. Anatomical cure rate was 95%. Subjective cure rate was 100%, with a statistically significant POP symptoms resolution and improvement of voiding and storage symptoms. We compared perioperative data and outcome of Redo patients to a population who underwent LSCP for a first-time diagnosed POP. The findings demonstrated that surgery did not differ from standard procedure in terms of intra/postoperative complications, hospital stay, blood loss, except for operative time., Conclusions: Minimally invasive Redo LSCP appears to be a safe and effective procedure in treating recurrent and symptomatic Pelvic Organ Prolapse. Our series shows low recurrence rates, comparable to data from patients who underwent their primary surgery for POP., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Laparoscopic sacral colpopexy is the gold standard technique for apical prolapse correction but it is a technically challenging procedure with rare but severe morbidity. Laparoscopic high uterosacral ligament suspension could be a valid technically easier alternative using native tissue., Material and Methods: In the period from 2015 to 2018, 600 women were submitted to laparoscopic sacral colpopexy while 150 to laparoscopic high uterosacral ligament suspension in three Italian urogynecology referral centers. We enrolled women with apical prolapse stage ≥2 alone or multicompartment descensus. To reduce allocation bias, we performed a propensity matched analysis. Women undergoing laparoscopic high uterosacral ligament suspension surgery were matched 1:2 to women undergoing laparoscopic sacral colpopexy. The cumulative proportion of relapse-free women in time was analyzed by the Kaplan-Meier method. The primary objective of this multicenter case-control retrospective study was to compare the recurrence rate while the secondary objectives were to compare feasibility, safety, and efficacy of laparoscopic sacral colpopexy and laparoscopic high uterosacral ligament suspension in surgical treatment of pelvic organ prolapse., Results: Three hundred and nine women were enrolled (103 laparoscopic high uterosacral ligament suspension; 206 laparoscopic sacral colpopexy). Median operatory time was significantly shorter in the laparoscopic high uterosacral ligament suspension group ( P = 0.0001). No statistically significative difference was found in terms of estimated blood loss, admission time, intraoperative, and major early postoperative complications, postoperative pelvic pain, dyspareunia and de novo stress urinary incontinence. Surgical approach was the only independent risk factor for prolapse recurrence (RR = 6.013 [2.965-12.193], P = 0.0001). The objective cure rate was higher in the laparoscopic sacral colpopexy group (93.7 vs. 68%, 193/206 vs. 70/103, P = 0.0001) with a highly reduced risk of recurrence (RR = 5.430 [1.660-17.765]). Median follow up was 22 months., Conclusion: Both techniques are safe, feasible, and effective. Laparoscopic sacral colpopexy remains the best choice in treatment of multicompartment and advanced pelvic organ prolapse while laparoscopic high uterosacral ligament suspension could be appropriate for moderate and isolated apical prolapse when laparoscopic sacral colpopexy is not suitable for the patient or to prevent prolapse in women at high risk at the time of the hysterectomy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Campagna, Vacca, Panico, Vizzielli, Caramazza, Zaccoletti, Marturano, Granese, Arcieri, Cianci, Scambia and Ercoli.)

Introduction and Hypothesis: The choice of whether or not to preserve the uterus in the case of patients with urogenital prolapse who undergo sacral colpopexy is still debated. We compared objective and subjective outcomes of laparoscopic sacral hysteropexy (LSHP) and laparoscopic sacral colpopexy with concomitant supracervical hysterectomy (LSCP/SCH) in patients with symptomatic pelvic organ prolapse., Methods: This is a multicenter retrospective cohort study conducted at the Urogynecology Department of the Fondazione Policlinico Universitario A. Gemelli IRCCS of Rome and at the Diaconesses Croix Saint Simon Hospital of Paris. We collected data of 136 patients; 78 underwent LSHP and 58 underwent LSCP/SCH for pelvic organ prolapse between January 2016 and December 2017., Results: Patients of the two groups had similar preoperative characteristics. All patients completed 24-month follow-up evaluation. Overall, anatomical cure rate was 84.6% and 87.9% in the LSHP group and LSCP/SCH group, respectively, without statistically significant differences. In particular, in the LSHP group the anatomical success rate was 94.9%, 92.3% and 92.3% for the apical, anterior and posterior vaginal compartment whereas in the LSHP group LSCP/SCH was 100%, 91.4% and 94.8%, respectively. Subjective success rate was 89.7% among patients who underwent LSHP and 93.1% among women who underwent LSCP/SCH (p = 0.494). The median operative time (OT) was significantly shorter in LSHP. There were no significant differences between the groups in terms of estimated blood loss, conversion to laparotomy and intra- and postoperative complications. Patients' satisfaction was high in both groups without statistical differences., Conclusions: Both laparoscopic procedures are safe and effective in the treatment of pelvic organ prolapse. LSHP can be offered as an alternative in women who are strongly motivated to preserve the uterus in the absence of abnormal uterine findings., (© 2021. The International Urogynecological Association.)

Background: Marfan Syndrome (MS) is a dominantly inherited connective tissue disorder with consequences on the strength and resilience of connective tissues that may predispose to Pelvic Organ Prolapse (POP). Literature lacks studies investigating POP surgery in patients affected by MS that might help surgical management decisions., Objective: The objective of this paper is to describe the surgical procedure of laparoscopic sacral hysteropexy (LSHP) in a 37 years old woman affected by MS with symptomatic POP., Materials and Methods and Main Outcome Measures: We performed a nerve-sparing laparoscopic sacral hysteropexy without complications and looked for anatomical and subjective outcomes. The patient completed The Female Sexual Distress Scale (FSDS), Pelvic Floor Disability Index (PFDI-20), and Wexner questionnaires preoperatively and postoperatively., Results: The patient stated a complete resolution of all POP related symptoms and there was a total correction of the descensus. Furthermore, no perioperative and postoperative complications were noted., Conclusions: LSHP could be an effective and safe procedure for the treatment of POP in women affected by MS and this case report is the first to describe a reconstructive procedure in this category of patients., What Is New?: The literature lacks studies investigating POP surgery in women with MS, that might help surgeons, thus we present this case to describe surgical and functional outcomes in this patient category, underlying the higher risk of complications and relapses related to the weakness of connective tissue. This case report may represent the basis of future studies to confirm the safety, efficacy and feasibility of LSHP and sacral colpopexy in patients with MS.

Background: Abdominal lateral suspension with mesh represents an alternative treatment to suspend the vaginal apex., Objectives: The aim of this study was to summarize literature data regarding the anatomical and functional outcomes, and intra- and postoperative complications of this technique with minimally invasive approach (laparoscopic/robotic)., Search Strategy: Systematic literature search using MEDLINE/PubMed, SCOPUS, Web of Science., Data Collection and Analysis: Two authors extracted data on baseline characteristics (age, BMI, prior pelvic reconstructive surgery, preoperative POP stage), perioperative outcomes (operative time, estimated blood loss, intraoperative and postoperative complications, admission time), objective and subjective success rate, surgical failure, time of follow-up. Data were presented descriptively., Main Results: Thirteen studies were included in the review. The overall number of patients for our analysis was 1066. Patients referred for laparoscopic/robotic lateral suspension were most frequently postmenopausal, aged 50 to 65 years, BMI ≥ 25 kg/m2; 22.2% were already hysterectomized, while 17% had already a previous POP surgery. Operative time ranged from 78.4 ± 29.7 to 254 ± 45 min. The overall anatomic success was more than 90% in the apical compartment and more than 88% in the anterior compartment. Subjective cure rate varies from 78.4% to 100% in medium-term follow-up. Post-operative complication grade >= 3 according to Claiven-Dindo Scale was 1.03%. Mesh erosion rate varied between 0% and 13%., Conclusions: Results coming from our systematic review suggest safety, efficacy and feasibility of minimally invasive lateral suspension with optimal anatomical and functional outcomes. Well-designed, randomized, controlled trials are required to confirm this data., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: We compared surgical outcome of sacral colpopexy (SCP) performed with the most recent minimally invasive surgery such as 3-mm laparoscopy (Mini-LPS), percutaneous system (PSS), standard laparoscopy (LPS), and robotic surgery., Methods: This is a multicenter retrospective cohort study conducted at Urogynecological Department of the IRCCS A. Gemelli University Polyclinic Foundation in Rome and at the Gynecological Clinic of Maggiore della Carità Hospital in Novara, and of the Polyclinic of Abano. We collected data of 115 patients who underwent laparoscopic SCP for pelvic organ prolapse between June 2017 and June 2018 using PSS, Mini-LPS, standard LPS, and da Vinci Si., Results: Patients of all four groups had similar characteristics. The median operative time (OT) was significantly longer in robotic procedure compared to all other groups There were no significant differences between the four groups in terms of estimated blood loss, conversion to laparotomy, intraoperative complications and median postoperative ileus. Visual Analogue Scale (VAS) at 4 hours was significantly less for Mini-LPS compared to the other techniques. VAS at 24 hours was higher for robotic procedures than other techniques., Conclusions: Results rule out that minimize surgical invasiveness of laparoscopic techniques could bring improvements in SCP not only from a cosmetic point of view but also from a functional one without requiring longer OT and maintaining the same standard laparoscopic configuration. Even if robotic SCP is useful and safe because of its guarantee of efficiency, it cannot be considered the first choice for many women.

Objective: Laparoscopic high uterosacral ligament suspension (l-HUSLS) is a laparoscopic-transposed vaginal technique for the treatment of pelvic organ prolapse. Nowadays data regarding quality of life and sexual functions in patients who underwent l-HUSLS for pelvic organ prolapse are few and generic with most of the study investigating the anatomical outcome. For these reasons, the aim of our study is to evaluate these subjective outcomes in women undergoing this surgical procedure with the support of validated questionnaires., Study Design: This is a retrospective study with the primary aim of analysing the quality of life, sexual function, patient satisfaction rates and anatomical outcome among patients who underwent l-HUSLS in our institution. The SPSS Version 26.0 for Windows (Statistical package for the social studies, Chicago, IL, USA) was used for the statistical analysis., Results: A total of 60 patients underwent l-HUSLS between 2016 and 2018. All patients had a high grade of apical prolapse. No intraoperative and major postoperative complications were registered. The median follow-up was 24 months (24-48). PGI-I score was 1-2 in 55 (91.6 %) women. We observed a significant improvement of EQ-5D index and VAS scores from the baseline to the 2 years follow-up: from 0.72 (0.67-1) to 0.91 (0.79-1) and from 50 (30-90) to 70 (50-100) respectively (p = 0.000). All women showed a statistically significant amelioration of FSDS and ICIQ-SF scores. Anatomical success rate after 24 months was 83.7 %., Conclusions: l-HUSLS appears to be a safe, feasible and effective treatment for advanced pelvic organ prolapse with high rates of patient self-reported cure., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The aim of this case report was to evaluate the feasibility, efficacy, and safety of nerve-sparing laparoscopic sacrocolpopexy (SCP) performed with a minimally invasive approach by using 2.9-mm Senhance ® surgical robotic system (Senhance ® , TRANSENTERIX Inc., USA). A 60-year-old Caucasian woman with symptomatic pelvic organ prolapse-Q (POP-Q) Aa: 2, Ba: 3, C: +4, Bp:2, Ap: 2, TVL:10 underwent subtotal hysterectomy with bilateral salpingo-oophorectomy, with nerve-sparing SCP performed using the Senhance surgical robotic system.. The urogynaecological assessment on the day of discharge and at the 3 month follow-up showed surgical anatomic success (<2 POP-Q stage). The patient was fully satisfied with the cosmetic result. This is the first case of SCP performed with this innovative system. SCP using "Senhance ®" is a feasible and effective approach with good results in terms of operative time, cosmesis, postoperative pain and length of hospitalisation., Competing Interests: Conflicts of Interest: none., (Copyright © 2020 Facts, Views & Vision.)

Background: Pelvic organ prolapse (POP) is a dynamic disorder that affects the entire pelvic diaphragm. POP may often involve multiple organs. Abdominal sacrocolpopexy is considered the gold standard to treat female anterior and apical prolapse. Abdominal ventral mesh rectopexy has gained increasing acceptance as an effective treatment for rectal prolapse. The aim of the present study was to assess the safety, feasibility and 1-year outcomes of laparoscopic sacrocolpopexy plus ventral rectopexy as a combined treatment of multicompartment POP., Methods: All female patients at our institution with anterior and apical prolapse with symptoms of obstructed defecation were examined by an urogynecologist and a colorectal surgeon, and were judged suitable for the study. Patients with Pelvic Organ Prolapse Quantification (POP-Q) system stage III and IV and concomitant rectal prolapse were treated by laparoscopic sacrocolpopexy plus ventral rectopexy. After surgery, 1- and 12-month follow-up was performed and the data were retrospectively analyzed. Patients' symptoms were evaluated using the Female Sexual Distress Scale (FSDS), Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ-12), and Wexner-Agachan constipation score., Results: A total of 98 patients underwent surgery. No intraoperative or postoperative morbidity occurred. At the time of follow-up, all women expressed great satisfaction with the surgical treatment: all the patients had at most POP-Q Stage 1 and 78.8% had a Patient Global Impression of Improvement (PGI-I) score < 3. Significant improvement of symptoms related to POP and to obstructed defecation syndrome, as shown by the FSDS, PISQ-12, and Wexner-Agachan constipation score, was observed in all patients at follow-up CONCLUSIONS: Laparoscopic sacrocolpopexy with ventral rectopexy is a feasible and safe procedure for the combined surgical management of anterior, apical, and posterior prolapse, and provides excellent objective and subjective outcomes.

Objective: Pelvic organ prolapse (POP) recurrence in transvaginal mesh surgery patients has become increasingly common, due to widespread mesh use before the FDA alert. The aim was to assess feasibility, effectiveness and safety of laparoscopic sacral colpopexy (LSCP) in recurrent POP after previous vaginal surgery with polypropylene mesh., Study Design: Medical records of 20 patients with ≥ stage 2 POP recurrence, who underwent LSCP from January 2015 to July 2018, were retrospectively analyzed in a monocentric observational study. We analyzed operative time, intraoperative complications - defined as bowel, bladder, ureteral, or vascular injuries, post-operative complications - assessed with Clavien-Dindo's classification, and postoperative patient satisfaction - evaluated with the Patient Global Impression of Improvement questionnaire. Pre- and postoperative data were compared using t-test., Results: All women presented apical prolapse recurrence regardless of mesh type implanted and most of them involved the posterior compartment. No perioperative complications or cases of mesh extrusion, de novo urinary stress, urge incontinence, dyspareunia were recorded. At 12-month follow-up the POP-Q examinations demonstrated a statistically significant improvement of all parameters with a complete resolution of bulge, voiding and storage symptoms in all patients., Conclusion: LSCP suggests safety, feasible and efficacy in the treatment of recurrent POP after prior transvaginal polypropylene mesh surgery. We suggest to conduct a prospective research with larger sample size to gain further insights., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: This study investigated perioperative and mid-term clinical outcomes after laparoscopic sacrocolpopexy (LSCP) with light titanium-coated polypropylene (TCP) mesh in a large group of patients affected by International Continence Society stage II-IV pelvic organ prolapse (POP)., Methods: This multicenter retrospective study included 217 patients treated with LSCP using TCP mesh. We aimed to (1) analyze the intra- and postoperative complication rates according to the ICS/IUGA Complication Classification Code guidelines, (2) evaluate the anatomical results and (3) assess postoperative patient satisfaction with the Patient Global Impression Improvement questionnaire. Nonparametric Wilcoxon signed-rank tests, χ2 test and Fisher's exact test were used where appropriate., Results: The intraoperative complications were two (0.9%) cases of hemorrhage, two (0.9%) cases of incidental cystotomy and four (1.8%) cases of incidental colpotomy. During the postoperative follow-up, we recorded mesh exposure in 3 (1.4%) out of 217 patients. These 3 patients were from a group of 22 women who underwent vaginal opening during surgery, while in the remaining 195 patients without incidental colpotomy, no mesh exposure was observed (13.6% vs. 0.0%, p < 0.001). No failure of the apical compartment was observed, while 3 (1.4%) out of 217 patients experienced isolated anterior recurrence, and 1 (0.4%) patient had isolated posterior recurrence. All patients reported PGI-I scores ≥ 3, and 209 patients (96.3%) had a PGI-I score ≥ 2., Conclusions: The use of light TCP mesh is safe and effective during LSCP for POP repair from both an anatomical and a functional point of view, posing a very low postoperative mesh-related complication risk.

Introduction and Hypothesis: The present video shows a rare case of erosion through the full rectal wall into the rectum after a transperineal implant of a double-arm polypropylene kit., Methods: A 70-year-old woman underwent a transperineal implant of a double-arm polypropylene kit. One year after surgery, she developed bothersome symptoms in the posterior perineum including heaviness, pain and rectal bleeding during defecation. A clinical examination showed the presence of a part of the prothesis traversing the rectal cavity. A minimally invasive transanal approach was performed to remove the mesh and restore the rectal integrity., Results: This surgical technique demonstrates rectal mesh removal with a transanal approach., Conclusions: To our knowledge, this is a rare complication of rectal erosion of a posterior transperineal mesh kit. The aim of this video is to show a complete transanal approach to treating this serious complication avoiding the more invasive and traumatic abdominal procedure.

Introduction and Hypothesis: Uterovaginal prolapse treatment is a challenge for the urogynecologist. Surgical management for apical prolapse can be successful with native tissue and uterosacral ligament (USL) fixation. However, some complications have been described, especially with use of the vaginal approach. The aim of this video is to describe an alternative laparoscopic approach to a traditional vaginal procedure to reduce nerve injury and ureteral complications., Methods: A 75-year-old woman was referred to our unit for symptomatic stage III apical prolapse and underwent laparoscopic USL fixation, according to the technique described herein., Results: This surgical technique was successful in correcting apical prolapse., Conclusions: This video tutorial may be useful to urogynecologists for improving surgical technique, thus leading to a reduction in the risk of nerve and ureteral complications. The technique offers the possibility of a correct under-vision suture positioning. Laparoscopic USL fixation can be safely performed to treat apical prolapse.

Sequential use of the TPO-RAs romiplostim and eltrombopag in ITP patients failing either agent was retrospectively evaluated to assess efficacy and impact of clinical characteristics on outcome. Patients were grouped into 5 categories: efficacy issues: 1 st TPO-RA failure; loss of response; non-efficacy issues: platelet fluctuations; patient's preference; adverse event development. Either one TPO-RA sequence was analyzed at 3 month and at last follow-up. 106/546 patients on TPO-RA underwent switch and 65% achieved, regained or maintained a short- term response independent of switch sequence, gender or age; lower response rates were associated with lines of previous therapy; disease duration lowers probability to respond. Clinically, patients switched for efficacy issue did not differ from those switched for non-efficacy issues. Response was achieved/regained in 57.8% of patients switched for efficacy issues, the lowest response rates were observed in non-responders to 1 st TPO-RA; 80% of patients switched for non-efficacy issues maintained a response. Platelet fluctuation resolved in 44.4%. Of the 49 patients evaluable for long-term outcome, 27 were in response on therapy; 16 discontinued the TPO-RA for reasons other than efficacy, while only 6 were non responders. We confirm the efficacy of TPO-RA switch; once achieved, response to the 2 nd TPO-RA seems durable., (© 2017 Wiley Periodicals, Inc.)

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms with variable risk of evolution into post-PV and post-ET myelofibrosis, from now on referred to as secondary myelofibrosis (SMF). No specific tools have been defined for risk stratification in SMF. To develop a prognostic model for predicting survival, we studied 685 JAK2, CALR, and MPL annotated patients with SMF. Median survival of the whole cohort was 9.3 years (95% CI: 8-not reached-NR-). Through penalized Cox regressions we identified negative predictors of survival and according to beta risk coefficients we assigned 2 points to hemoglobin level <11 g/dl, to circulating blasts ⩾3%, and to CALR-unmutated genotype, 1 point to platelet count <150 × 10 9 /l and to constitutional symptoms, and 0.15 points to any year of age. Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) allocated SMF patients into four risk categories with different survival (P<0.0001): low (median survival NR; 133 patients), intermediate-1 (9.3 years, 95% CI: 8.1-NR; 245 patients), intermediate-2 (4.4 years, 95% CI: 3.2-7.9; 126 patients), and high risk (2 years, 95% CI: 1.7-3.9; 75 patients). Finally, we found that the MYSEC-PM represents the most appropriate tool for SMF decision-making to be used in clinical and trial settings.

5-Azacytidine is an effective therapy in high risk MDS and oligoblastic AML. This "real life" analysis was made on 185 patients treated with 5-azacytidine in 10 centers afferent to REL ("Rete Ematologica Lombarda"), a network in Lombardia region. The aim was to assess the influence of disease and comorbidity risk assessments on the survival. The results confirm the utility of 5-azacitidine in prolonging OS regardless of advanced age and the presence of comorbidities. They also encourage an early treatment since patients with IPSS-R High risk MDS have better outcome with respect to Very High risk ones. According to the IPSS cytogenetic risk, there was no difference in the outcome between Intermediate and High risk patients. Nevertheless, a poorer cytogenetic risk, according to the IPSS-R cytogenetic stratification, negatively influenced the outcome., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Patients with MPNs are prone to develop arterial and venous thrombosis either at diagnosis or during follow-up; in particular splancnic vein is strongly associated with MPN. Conversely, presence of MPN is uncommon in patients with deep vein thrombosis of the lower extremities and with pulmonary embolism. Only few studies with conflicting results have evaluated the prevalence of an underlying MPN in patients with cerebral venous thrombosis (CVT), and limited evidence exists on the incidence of CVT in patients with established MPN., Methods: We assessed the frequency of MPNs in a series of 706 patients with cerebral vein thrombosis (CVT) and the frequency of CVT in a cohort of 2,143 MPNs patients., Results: Twenty-seven CVT patients (3.8%) were diagnosed with MPN: 9 before CVT (1.3%), 4 concomitantly (0.6%), and 14 after CVT (2.0%). Nine CVT cases (0.4%) were diagnosed in the MPN cohort, with a slightly higher frequency in PV (five of 735, 0.7%) than in ET (three of 964, 0.3%) and in PMF (one of 444, 0.2%)., Conclusion: Considering the analyses of these databases jointly, the results obtained suggest a weak association between CVT and MPNs and ultimately suggest that a thorough investigation looking for an underlying MPN may not be warranted in all the patients with CVT without overt myeloproliferative features., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Calreticulin (CALR) mutations were recently described in JAK2 and MPL unmutated primary myelofibrosis (PMF) and essential thrombocythemia. In the current study, we compared the clinical, cytogenetic and molecular features of patients with PMF with or without CALR, JAK2 or MPL mutations. Among 254 study patients, 147 (58%) harbored JAK2, 63 (25%) CALR and 21 (8.3%) MPL mutations; 22 (8.7%) patients were negative for all three mutations, whereas one patient expressed both JAK2 and CALR mutations. Study patients were also screened for ASXL1 (31%), EZH2 (6%), IDH (4%), SRSF2 (12%), SF3B1 (7%) and U2AF1 (16%) mutations. In univariate analysis, CALR mutations were associated with younger age (P<0.0001), higher platelet count (P<0.0001) and lower DIPSS-plus score (P=0.02). CALR-mutated patients were also less likely to be anemic, require transfusions or display leukocytosis. Spliceosome mutations were infrequent (P=0.0001) in CALR-mutated patients, but no other molecular or cytogenetic associations were evident. In multivariable analysis, CALR mutations had a favorable impact on survival that was independent of both DIPSS-plus risk and ASXL1 mutation status (P=0.001; HR 3.4 for triple-negative and 2.2 for JAK2-mutated). Triple-negative patients also displayed inferior LFS (P=0.003). The current study identifies 'CALR(-)ASXL1(+)' and 'triple-negative' as high-risk molecular signatures in PMF.

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms to be diagnosed according to the WHO classification. Molecular profiling must include the analysis of JAK2 (looking for the V617F point-mutation in PV and ET, screening exon 12 for mutations only in V617F-negative PV), CALR and MPL mutations (both in V617F-negative ET). The current risk stratification to predict thrombosis requires two parameters: age over 60 years and prior history of thrombosis. On the basis of these two risk factors patients can be stratified in low-risk and high-risk and receive a proper treatment. However, a modern stratification of thrombotic risk might consider "new" low-risk patients: conventional low-risk plus absence of leukocytosis from diagnosis onwards and a hematocrit level below 45% during the course of disease for PV; conventional low-risk plus absence of leukocytosis from diagnosis onwards, JAK2 negativity, CALR positivity, and absence of cardiovascular risk factors for ET., (Copyright © 2014. Published by Elsevier Ltd.)

The international prognostic scoring system (IPSS) provides reliable risk assessment in patients with primary myelofibrosis (PMF). Recent clinical trials in PMF patients with intermediate-2 or high IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available therapy (COMFORT-2). Because crossover was allowed in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynamic IPSS (DIPSS). By adopting ad hoc statistical analyses, we compared survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-2 with that of 350 patients of the DIPSS study. Subjects were properly matched, and both left-truncation and right-censoring were accounted in order to compare higher IPSS risks exclusively. Patients receiving ruxolitinib had longer survival (5 years, 95% confidence interval [CI]: 2.9-7.8 vs 3.5 years, 95% CI: 3.0-3.9) with a hazard ratio of 0.61 (95% CI: 0.41-0.91; P = .0148). This observation suggests that ruxolitinib may modify the natural history of PMF.

Indolent non-Hodgkin's lymphomas (iNHLs) include follicular lymphomas (FL), marginal-zone lymphoma, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and small lymphocytic lymphoma. First-line standard therapy in advanced, symptomatic iNHL consists of rituximab-based immunochemotherapy. The recent rediscovery of the 'old' chemotherapeutic agent bendamustine, an alkylating agent with a peculiar mechanism of action, has added a new effective and well-tolerated option to the therapeutic armamentarium in iNHL, increasing response rates and duration. However, patients invariably relapse and subsequent active and well-tolerated agents are needed. In recent years a large number of new targeted agents have been tested in preclinical and clinical experimentation in FL and indolent nonfollicular lymphoma (iNFL), including the new monoclonal antibodies binding CD20 or other surface antigens, immunoconjugates and bispecific antibodies. Moreover novel agents directed against intracellular processes such as proteasome inhibitors, mTOR inhibitors and agents that target the tumour microenvironment, notably the immunomodulatory agent lenalidomide, are under active clinical investigation. The development of these new drugs may change in the near future the approach to iNHL patients, leading to better tolerated and effective therapy regimens.

Myeloproliferative neoplasms include 3 diseases: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). PV and ET are dominated by a high risk of thrombosis and a late risk of clonal evolution into secondary MF and acute myeloid leukemia. Patients with PMF may encounter many complications associated with disease progression or with PMF evolution. This article defines factors that determine prognosis in these 3 diseases., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Diagnosis of essential thrombocythemia (ET) has been updated in the last World Health Organization (WHO) classification. We developed a prognostic model to predict survival at diagnosis, named IPSET (International Prognostic Score for ET), studying patients with WHO-defined ET. Age 60 years or older, leukocyte count ≥ 11 × 10(9)/L, and prior thrombosis significantly affected survival, by multivariable Cox regression. On the basis of the hazard ratio, we assigned 2 points to age and 1 each to leukocyte count and thrombosis. So, the IPSET model allocated 867 patients into 3 risk categories with significantly different survival: low (sum of points = 0; median survival not reached), intermediate (sum = 1-2; median survival 24.5 years), and high (sum = 3-4, median survival 13.8 years). The IPSET model was further validated in 2 independent cohorts including 132 WHO-defined ET and 234 Polycythemia Vera Study Group-defined ET patients. The IPSET model was able to predict the occurrence of thrombosis, and not to predict post-ET myelofibrosis. In conclusion, IPSET, based on age ≥ 60 years, leukocyte count ≥ 11 × 10(9)/L, and history of thrombosis allows prognostic assessment of WHO-defined ET and the validation process makes IPSET applicable in all patients phenotypically appearing as ET.

Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy. Therapy was well tolerated; discontinuation rates at 1, 2, and 3 years were 24%, 36%, and 46%, respectively. OS of 107 MDACC patients was significantly better (P = .005) than that of 310 matched (based on trial enrollment criteria) historical control patients, primarily because of highly significant difference in OS in the high-risk subgroup (P = .006). Furthermore, among MDACC patients, those with high-risk MF experienced the same OS as those with intermediate-2 risk. Patients with ≥ 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction (P < .0001). Comparison of discontinuation rates and reasons for stopping the therapy to those reported for other 51 patients in the phase 1/2 trial, and 155 ruxolitinib-treated patients in phase 3 COMFORT-I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including OS benefit.

Purpose of Review: Myeloproliferative neoplasms (MPNs) are diseases that carry the JAK2 (V617F) mutation in about 70% of the patients. The purpose of this review is to describe the recent advances in the therapy of MPNs with JAK2 inhibitors., Recent Findings: Many drugs are now under investigations targeting different pathways critical for MPN development, such as the JAK-STAT (JAK2 inhibitors: INCB018424 or ruxolitinib, TG101348 or SAR302503, CYT387, SB1518, CEP701 and LY2784544) and the PI3K/AKT/mTOR (everolimus) pathways, or act through remodeling of chromatin with a key role in epigenetics (givinostat, panobinostat and vorinostat). The most relevant effects were spleen size reduction and relief of constitutional symptoms., Summary: Patients who might benefit from JAK2 inhibitors in clinical practice are mostly those with splenomegaly or with constitutional symptoms. We should alert patients with lower hemoglobin levels that these therapies might, although temporarily, favor the need for red blood cell transfusions.

DIPSS-plus (the Dynamic International Prognostic Scoring System-plus) includes 8 risk factors for survival in primary myelofibrosis. In the present study of 884 karyotypically annotated patients with primary myelofibrosis, we sought to identify 1 or 2 parameters that can reliably predict death in the first 2 years of disease. After a median of 8.2 years from time of referral to the Mayo Clinic, 564 deaths (64% of patients in the study) had been recorded. Risk factors associated with > 80% 2-year mortality included monosomal karyotype, inv(3)/i(17q) abnormalities, or any 2 of the following: circulating blasts > 9%, leukocytes ≥ 40 × 10(9)/L, or other unfavorable karyotype. Patients with any 1 of these risk profiles (n = 52) displayed significantly shorter overall survival than those otherwise belonging to a high-risk category per DIPSS-plus (n = 298); respective median survivals were 9 and 23 months (hazard ratio 2.2, 95% confidence interval 1.6-3.1; P < .01). The present information complements DIPSS-plus in the selection of primary myelofibrosis patients for high-risk treatment approaches.

Most BCR-ABL1-negative myeloproliferative neoplasms (MPN) carry an activating JAK2 mutation. Approximately 96% of patients with polycythemia vera (PV) harbors the V617F mutation in JAK2 exon 14, whereas the minority of JAK2 (V617F)-negative subjects shows several mutations in exon 12. Other mutation events as MPL, TET2, LNK, EZH2 have been described in chronic phase, while NF1, IDH1, IDH2, ASX1, CBL and Ikaros in blast phase of MPN. The specific pathogenic implication of these mutations is under investigation, but they may have a role in refinement of diagnostic criteria and in development of new prognostic models. Several trials with targeted therapy (JAK inhibitors) are ongoing mostly involving patients with PMF, post-PV MF and post-essential thrombocythemia (ET) MF. Treatment with ruxolitinib and TG101348 has shown clinically significant benefits, particularly in improvement of splenomegaly and constitutional symptoms in MF patients. On the other hand, JAK inhibitors have not thus far shown disease-modifying activity therefore any other deduction on these new drugs seems premature.

Survival in cytogenetically high-risk patients with acute myeloid leukemia or myelodysplastic syndromes is significantly worse in the presence of a monosomal karyotype (MK). The objective of the present study was to determine whether the same held true for primary myelofibrosis. Among 793 primary myelofibrosis patients seen at our institution, 62 displayed an unfavorable karyotype by way of complex karyotype (n = 41) or sole trisomy 8 (n = 21). Seventeen (41%) of the 41 patients with complex karyotype were classified as having an MK. Median survival was 6, 24, and 20 months in patients with MK, complex karyotype without monosomies, and sole trisomy 8, respectively (P < .0001). The corresponding 2-year leukemic transformation rates were 29.4%, 8.3%, and 0 (P < .0001); hazard ratios (95% confidence intervals) were 6.9 (1.3-37.3) and 14.8 (1.7-130.8). The prognostic relevance of MK was not accounted for by the Dynamic International Prognostic Scoring System. We conclude that MK in primary myelofibrosis is associated with extremely poor overall and leukemia-free survival.

Purpose: Abnormal cytokine expression accompanies myelofibrosis and might be a therapeutic target for Janus-associated kinase (JAK) inhibitor drugs. This study describes the spectrum of plasma cytokine abnormalities in primary myelofibrosis (PMF) and examines their phenotypic correlates and prognostic significance., Patients and Methods: Patients included in this study were required to have archived plasma, bone marrow biopsy, and cytogenetic information available at the time of first referral to the Mayo Clinic. Multiplex biometric sandwich immunoassay was used to measure plasma levels of 30 cytokines., Results: In total, 127 PMF patients were studied; comparison with normal controls (n = 35) revealed significantly increased interleukin-1β (IL-1β), IL-1RA, IL-2R, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, tumor necrosis factor α (TNF-α), granulocyte colony-stimulating factor (G-CSF), interferon alfa (IFN-α), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, hepatocyte growth factor (HGF), IFN-γ-inducible protein 10 (IP-10), monokine induced by IFN-γ (MIG), monocyte chemotactic protein 1 (MCP-1), and vascular endothelial growth factor (VEGF) levels and decreased IFN-γ levels. In treatment-naive patients (n = 90), increased levels of IL-8 (P < .001), IL-2R (P < .001), IL-12 (P < .001), IL-15 (P = .001), and IP-10 (P = .003) were independently predictive of inferior survival. A similar multivariable analysis that included all 127 study patients confirmed the prognostic value of these five cytokines, and IL-8, IL-2R, IL-12, and IL-15 remained significant when risk stratification, according to the recently revised Dynamic International Prognostic Scoring System (DIPSS plus), was added to the multivariable model. Leukemia-free survival was predicted by IL-8, which was also the only cytokine associated with ≥ 1% circulating blasts. Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP-10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1β, and JAK2V617F. A two-cytokine (IL-8/IL-2R) -based risk categorization delineated prognostically different groups within specific DIPSS plus risk categories., Conclusion: This study signifies the presence of specific cytokine-phenotype associations in PMF and a prognostically relevant plasma cytokine signature that might prove useful as a laboratory tool for predicting and monitoring treatment response.