Long-term results of clover and edge-to-edge leaflet repair for complex tricuspid regurgitation.

BACKGROUND: Aim of the study was to report the long-term results of the clover and edge-to-edge repair for complex tricuspid regurgitation(TR). METHODS: This was a single-center observational study. A competing risks proportional-hazards regression model, following the Fine-Gray model, was performed to analyze the time to TR≥2+, considering death as a competing risk. RESULTS: Hundred forty-five consecutive patients (female 57%) with severe or moderately-severe tricuspid regurgitation due to leaflets prolapse/flail(115 pts), tethering(27 pts) or mixed(3 pts) lesions underwent clover(110 pts) or edge-to-edge repair(35 pts). TR etiology was degenerative in 75% of cases, post-traumatic in 8% and secondary to dilated cardiomyopathy in 17%. Ring(64%) or suture(31%) annuloplasty was performed in 95% of patients. Concomitant procedures (mainly mitral surgery) were performed in 80% of cases. Hospital death was 5.5%. Follow-up was 98% complete, median 15[14-17] years. The 16-years overall survival was 56±5%. Previous cardiac surgery(HR 2.83, 95%CI 1.15-6.93, P=0.023) and right ventricle dysfunction(HR 2.24, 95%CI 1.01-4.95, P= 0.046) were identified as predictors of death. The 16-years Cumulative incidence function(CIF) of cardiac death with non-cardiac death as competing risk was 19.6% and previous cardiac surgery(HR 3.44, 95%CI 1.23-9.65, P=0.019) was detected as the only predictor of the event. At 16-years, CIF of TR≥2+ with death as competing risk was 23.8%. Particularly, TR≥3+ was detected in 4 patients(3%). CONCLUSIONS: When tricuspid regurgitation could not be treated by annuloplasty alone, concomitant leaflet repair with the clover/edge-to-edge technique effectively restored valve competence with very satisfactory long-term results and low rate of moderate or greater TR recurrence.

Neochordae implantation versus leaflet resection in mitral valve posterior leaflet prolapse and dilated left ventricle: a propensity score matching comparison with long-term follow-up.

OBJECTIVES: Uncorrected severe mitral regurgitation (MR) due to posterior prolapse leads to left ventricular dilatation. At this stage, mitral valve repair becomes mandatory to avoid permanent myocardial injury. However, which technique among neochoardae implantation and leaflet resection provides the best results in this scenario remains unknown. METHODS: We selected 332 patients with left ventricular dilatation and severe degenerative MR due to posterior leaflet (PL) prolapse who underwent neochoardae implantation (85 patients) or PL resection (247 patients) at our institution between 2008 and 2020. A propensity score matching analysis was carried on to decrease the differences at baseline. RESULTS: Matching yielded 85 neochordae implantations and 85 PL resections. At 10 years, freedom from cardiac death and freedom from mitral valve reoperation were 92.6 ± 6.1% vs 97.8 ± 2.1% and 97.7 ± 2.2% vs 95 ± 3% in the neochordae group and in the PL resection group, respectively. The MR ≥2+ recurrence rate was 23.9 ± 10% in the neochordae group and 20.8 ± 5.8% in the PL resection group (P = 0.834) at 10 years. At the last follow-up, the neochordae group showed a higher reduction of left ventricular end-diastolic diameter (44 vs 48 mm; P = 0.001) and a better ejection fraction (60% vs 55%; P < 0.001) compared to PL resection group. CONCLUSIONS: In this subgroup of patients, both neochordae implantation and leaflet resection provide excellent durability of the repair in the long term. Neochordae implantation might have a better effect on dilated left ventricle.

TRI-SCORE: a single-centre validation study.

OBJECTIVES: The TRI-SCORE is a recently published risk score for predicting in-hospital mortality in patients undergoing isolated tricuspid valve surgery (ITVS). The aim of this study is to externally validate the ability of the TRI-SCORE in predicting in-hospital and long-term mortality following ITVS. METHODS: A retrospective review of our institutional database was carried out to identify all patients undergoing isolated tricuspid valve repair or replacement from March 1997 to March 2021. The TRI-SCORE was calculated for all patients. Discrimination of the TRI-SCORE was assessed using receiver operating characteristic curves. Accuracy of the models was tested calculating the Brier score. Finally, a COX regression was employed to evaluate the relationship between the TRI-SCORE value and long-term mortality. RESULTS: A total of 176 patients were identified and the median TRI-SCORE was 3 (1-5). The cut-off value identified for increased risk of isolated ITVS was 5. Regarding in-hospital outcomes, the TRI-SCORE showed high discrimination (area under the curve 0.82), and high accuracy (Brier score 0.054). This score showed also very good performance in predicting long-term mortality (at 10 years, hazard ratio: 1.47, 95% confidence interval [1.31-1.66], P < 0.001), with high discrimination (area under the curve >0.80 at 1-5 and 10 years) and high accuracy values (Brier score 0.179). CONCLUSIONS: This external validation confirms the good performance of the TRI-SCORE in predicting in-hospital mortality. Moreover, the score showed also very good performance in predicting the long-term mortality.

AI-SCoRE (artificial intelligence-SARS CoV2 risk evaluation): a fast, objective and fully automated platform to predict the outcome in COVID-19 patients.

PURPOSE: To develop and validate an effective and user-friendly AI platform based on a few unbiased clinical variables integrated with advanced CT automatic analysis for COVID-19 patients' risk stratification. MATERIAL AND METHODS: In total, 1575 consecutive COVID-19 adults admitted to 16 hospitals during wave 1 (February 16-April 29, 2020), submitted to chest CT within 72 h from admission, were retrospectively enrolled. In total, 107 variables were initially collected; 64 extracted from CT. The outcome was survival. A rigorous AI model selection framework was adopted for models selection and automatic CT data extraction. Model performances were compared in terms of AUC. A web-mobile interface was developed using Microsoft PowerApps environment. The platform was externally validated on 213 COVID-19 adults prospectively enrolled during wave 2 (October 14-December 31, 2020). RESULTS: The final cohort included 1125 patients (292 non-survivors, 26%) and 24 variables. Logistic showed the best performance on the complete set of variables (AUC = 0.839 ± 0.009) as in models including a limited set of 13 and 5 variables (AUC = 0.840 ± 0.0093 and AUC = 0.834 ± 0.007). For non-inferior performance, the 5 variables model (age, sex, saturation, well-aerated lung parenchyma and cardiothoracic vascular calcium) was selected as the final model and the extraction of CT-derived parameters was fully automatized. The fully automatic model showed AUC = 0.842 (95% CI: 0.816-0.867) on wave 1 and was used to build a 0-100 scale risk score (AI-SCoRE). The predictive performance was confirmed on wave 2 (AUC 0.808; 95% CI: 0.7402-0.8766). CONCLUSIONS: AI-SCoRE is an effective and reliable platform for automatic risk stratification of COVID-19 patients based on a few unbiased clinical data and CT automatic analysis.

Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial.

219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life.

Mobilization-based chemotherapy-free engraftment of gene-edited human hematopoietic stem cells.

Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) is proving successful to treat several genetic diseases. HSPCs are mobilized, harvested, genetically corrected ex vivo, and infused, after the administration of toxic myeloablative conditioning to deplete the bone marrow (BM) for the modified cells. We show that mobilizers create an opportunity for seamless engraftment of exogenous cells, which effectively outcompete those mobilized, to repopulate the depleted BM. The competitive advantage results from the rescue during ex vivo culture of a detrimental impact of mobilization on HSPCs and can be further enhanced by the transient overexpression of engraftment effectors exploiting optimized mRNA-based delivery. We show the therapeutic efficacy in a mouse model of hyper IgM syndrome and further developed it in human hematochimeric mice, showing its applicability and versatility when coupled with gene transfer and editing strategies. Overall, our findings provide a potentially valuable strategy paving the way to broader and safer use of HSPC-GT.

Role of anaesthesia in endoscopic and external dacryocystorhinostomy: A meta-analysis of 3282 cases.

Distal acquired lacrimal obstruction is a common adulthood pathology whose primary treatment is represented by EXT-DCR and END-DCR. When considering their influencing factors, the role of the type of anaesthesia applied during these surgeries has a major role. The aim of this study is to systematically analyse the influence of general and local/regional anaesthesia on the final success rates of EXT-DCR and END-DCR. Primary EXT-DCR and END-DCR articles published later than 2000 with at least 50 single clinician procedures were selected. Exclusion criteria included acute dacryocystitis, tumours, studies focussing on revision surgeries, surgeries with adjunctive procedures, not clearly demarcated surgeons, mixed cohort study of acquired and congenital disorders. This systematic review was conducted in accordance with MOOSE guidelines; where feasible, a meta-analysis of the collected results was conducted. As a result, 11,445 articles were selected of which 2741 were examined after screening, and 16 included after full text review (0.6% of the initial papers). Among all papers included, the number of EXT-DCR was not enough to provide a solid analysis of the effect of anaesthesia; conversely, a significant difference of success rate was noted between local anaesthesia + sedation (85.1%, IC 77.8%-90.4%), and general anaesthesia (90.8%, IC 88.8%-92.4%) in END-DCR (p = 0.048). In conclusion, END-DCR performed with general anaesthesia should be considered as the solution of choice; however, local anaesthesia, eventually associated with a sedation, can be used as an alternative in selected cases. No meaningful conclusions could be drawn for EXT-DCR, due to the lack of data.

Exocrine pancreas function is impaired in adult relatives of patients with type 1 diabetes.

AIMS: Alterations of the exocrine pancreas have been reported in type 1 diabetes, but their contribution to the pathogenesis of the disease is poorly understood. Here, we investigated markers of exocrine pancreas dysfunction in individuals at-risk of developing type 1 diabetes. METHODS: Serum P-amylase and lipase levels were assessed in samples obtained from healthy controls, patients with new onset type 1 diabetes, relatives participating to the TrialNet Pathway to Prevention who were, at blood collection, autoantibody negative or positive for a single autoantibody (low-risk individuals), and positive for multiple autoantibodies (high-risk individuals). Linear mixed models were adopted to estimate variation of pancreatic enzymes among the groups and to evaluate the influence of high-risk HLA genotypes and residual beta cell function on exocrine pancreas function. RESULTS: In adults, but not children, reduced levels of P-amylase and lipase were shown in at-risk individuals, including (for P-amylase levels only) those at low-risk, and in T1Dnew. Furthermore, while high-risk HLA genotypes negatively affected P-amylase levels in autoantibody negative adult individuals, fasting C-peptide levels did not correlate with pancreatic enzyme levels. CONCLUSIONS: Exocrine pancreas dysfunction precedes the onset of type 1 diabetes in adult at-risk individuals and may be unrelated to fasting C-peptide levels.

A prospective study on the efficacy of dupilumab in chronic rhinosinusitis with type 2 inflammation.

Objective: Treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) includes endoscopic sinus surgery and topic and/or systemic corticosteroids, which have only temporary effects. The development of biologic therapies has provided a new treatment paradigm for CRSwNP. Dupilumab is the only biological approved in Italy for CRSwNP, but its efficacy in a real-life context is still scarce. Methods: We carried out a monocentric prospective study at our institution with a 6-month follow-up on patients administered biweekly 300 mg dupilumab therapy for CRSwNP, prescribed according to EPOS 2020 criteria. Patients were evaluated at baseline and every 2 months. Results: Median values at baseline and 6 months were, respectively, 3/12 and 8/12 for the Brief Smell Identification Test (p = 0.005), 5/8 and 2/8 for the Nasal Polyp Score (p < 0.001), 10/20 and 6/20 for the Lund-Kennedy score (p < 0.001), 65/110 and 14/110 for the Sinonasal Outcome Test (p < 0.001), and 15/25 and 23/25 for the Asthma Control Test score (p = 0.009). Adverse events were mild, consisting mainly in discomfort at the site of injection. Four patients developed asymptomatic hypereosinophilia. The treatment was not discontinued in any patient. Conclusions: Dupilumab was confirmed to be an effective and safe treatment for CRSwNP, as previously seen in registrational studies.

MYD88 L265P mutation and interleukin-10 detection in cerebrospinal fluid are highly specific discriminating markers in patients with primary central nervous system lymphoma: results from a prospective study.

Reliable biomarkers are needed to avoid diagnostic delay and its devastating effects in patients with primary central nervous system (CNS) lymphoma (PCNSL). We analysed the discriminating sensitivity and specificity of myeloid differentiation primary response (88) (MYD88) L265P mutation (mut-MYD88) and interleukin-10 (IL-10) in cerebrospinal fluid (CSF) of both patients with newly diagnosed (n = 36) and relapsed (n = 27) PCNSL and 162 controls (118 CNS disorders and 44 extra-CNS lymphomas). The concordance of MYD88 mutational status between tumour tissue and CSF sample and the source of ILs in PCNSL tissues were also investigated. Mut-MYD88 was assessed by TaqMan-based polymerase chain reaction. IL-6 and IL-10 messenger RNA (mRNA) was assessed on PCNSL biopsies using RNAscope technology. IL levels in CSF were assessed by enzyme-linked immunosorbent assay. Mut-MYD88 was detected in 15/17 (88%) PCNSL biopsies, with an 82% concordance in paired tissue-CSF samples. IL-10 mRNA was detected in lymphomatous B cells in most PCNSL; expression of IL-6 transcripts was negligible. In CSF samples, mut-MYD88 and high IL-10 levels were detected, respectively, in 72% and 88% of patients with newly diagnosed PCNSL and in 1% of controls; conversely, IL-6 showed a low discriminating sensitivity and specificity. Combined analysis of MYD88 and IL-10 exhibits a sensitivity and specificity to distinguish PCNSL of 94% and 98% respectively. Similar figures were recorded in patients with relapsed PCNSL. In conclusion, high detection rates of mut-MYD88 and IL-10 in CSF reflect, respectively, the MYD88 mutational status and synthesis of this IL in PCNSL tissue. These biomarkers exhibit a very high sensitivity and specificity in detecting PCNSL both at initial diagnosis and relapse. Implications of these findings in patients with lesions unsuitable for biopsy deserve to be investigated.

Influence of Surgical Techniques on Endoscopic Dacryocystorhinostomy: A Systematic Review and Meta-analysis.

OBJECTIVE: Endoscopic endonasal dacryocystorhinostomy (END-DCR) has increased as a valid alternative to the classic external approach to treat distal lacrimal obstruction. Different surgical varieties of the END-DCR approach have been proposed with no clear understanding of the best surgical technique. DATA SOURCE: A comprehensive research was performed in PubMed, Embase, SCOPUS, and Cochrane databases with a final search on March 2020. REVIEW METHODS: The aim of this search was to identify relevant END-DCR procedures performed with mechanical (Mecn-END-DCR) and powered (Pow-END-DCR) approaches to compare their functional success rate. In addition, the influence of mucosal flaps was evaluated. Articles were selected only if they were published later than 2000 and had at least 50 single-clinician surgical procedures performed. Excluded articles included acute infections, cancers, mixed cohort study, and revision cases. RESULTS: A total of 11,445 publications were identified and 2741 reviewed after screening; 15 articles were included after full-text review (0.6% of the initial articles reviewed). The mean success rate was 91.34% (95% CI, 87.1%-94.3%) for Pow-END-DCR and 89.5% (95% CI, 86.5%-91.9%) for Mecn-END-DCR with no significant difference between the surgical approaches (P = .43). For mucosal flaps performed during END-DCR, the mean success rate was 89% (95% CI, 86%-91%) if mucosal flaps were used and 92% (95% CI, 88%-95%) if they were not used, with no statistical difference present (P = .14). CONCLUSIONS: Our analyses suggest that there are no differences in outcomes between mechanical and powered approaches in END-DCR and that mucosal flap preservation is not essential to achieve a superior END-DCR outcome.

Improving the antitumor activity of R-CHOP with NGR-hTNF in primary CNS lymphoma: final results of a phase 2 trial.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment of diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system (CNS) (primary central nervous system lymphoma [PCNSL]) is an exception because of the low CNS bioavailability of related drugs. NGR-human tumor necrosis factor (NGR-hTNF) targets CD13+ vessels, enhances vascular permeability and CNS access of anticancer drugs, and provides the rationale for the treatment of PCNSL with R-CHOP. Herein, we report activity and safety of R-CHOP preceded by NGR-hTNF in patients with PCNSL relapsed/refractory to high-dose methotrexate-based chemotherapy enrolled in a phase 2 trial. Overall response rate (ORR) was the primary endpoint. A sample size of 28 patients was considered necessary to demonstrate improvement from 30% to 50% ORR. NGR-hTNF/R-CHOP would be declared active if ≥12 responses were recorded. Treatment was well tolerated; there were no cases of unexpected toxicities, dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with confirmed tumor response in 21 patients (75%; 95% confidence interval, 59%-91%), which was complete in 11. Seventeen of the 21 patients with response to treatment received consolidation (ASCT, WBRT, and/or lenalidomide maintenance). At a median follow-up of 21 (range, 14-31) months, 5 patients remained relapse-free and 6 were alive. The activity of NGR-hTNF/R-CHOP is in line with the expression of CD13 in both pericytes and endothelial cells of tumor vessels. High plasma levels of chromogranin A, an NGR-hTNF inhibitor, were associated with proton pump inhibitor use and a lower remission rate, suggesting that these drugs should be avoided during TNF-based therapy. Further research on this innovative approach to CNS lymphomas is warranted. The trial was registered as EudraCT: 2014-001532-11.

Impact of Post-Surgical Therapies on Endoscopic and External Dacryocystorhinostomy: Systematic Review and Meta-Analysis.

BACKGROUND: Epiphora is a common ophthalmologic sign that is most commonly caused by distal acquired lacrimal obstruction. Recent data have demonstrated that external dacryocystorhinostomy (EXT-DCR) and endoscopic endonasal dacryocystorhinostomy (END-DCR) can be considered the treatments of choice. However, different post-surgical medical therapies are available and are currently used to improve surgical outcomes, although no direct comparison has been performed. OBJECTIVE: To analyse the influence of post-surgical medical treatments on END-DCR and EXT-DCR outcomes. METHODS: A structured search was conducted using the U.S. National Library of Medicine (PubMed), EMBASE, SCOPUS, and Cochrane databases with a final search performed in May 2020. The research identified papers published later than 2000 with at least 50 single clinician procedures performed in EXT-DCR and END-DCR. Articles that studied acute infections, revision cases, mixed cohort studies of acquired and congenital obstruction, and tumour were excluded. The influence of systemic antibiotic/steroids, local application of mitomycin C, nasal/ocular antibiotic, nasal/ocular steroids and nasal decongestants was analysed. RESULTS: In total, 11,445 papers were selected, 2,741 of which were reviewed after screening, and 18 included after full text review (0.6% of the initial articles reviewed) which involved 3,590 procedures. Considering the low number of publications on EXT-DCR, statistical analysis of post-surgical therapy was not feasible. In END-DCR, the analyses were performed only for nasal steroids (p = 0.58), oral antibiotics (p = 0.45) and nasal decongestant (p = 0.27), which demonstrated no meaningful influence. Given the variable association between adjunctive medical therapies, pharmacologic molecular heterogeneity and modality/concentration of application, these results should be considered critically. Additionally, no differences were seen for application of silicone stenting, whereas, no statistical analysis was performed for mitomycin C. CONCLUSIONS: Given the high success rate of EXT-DCR and END-DCR and the heterogeneity of literature data, the effective influence of post-surgical medical therapy is difficult to identify. Future large prospective randomized studies could help in detecting the optimal adjunctive therapy for these surgeries.

Long-lasting efficacy and safety of lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for or failed autologous transplantation.

We report final results of a phase II trial addressing efficacy and feasibility of lenalidomide maintenance in patients with chemosensitive relapse of diffuse large B-cell lymphoma (DLBCL) not eligible for or failed after autologous stem cell transplantation (ASCT). Patients with relapsed DLBCL who achieved at least a partial response to salvage chemoimmunotherapy were enrolled and treated with lenalidomide 25 mg/day for 21 of 28 days for 2 years or until progression or unacceptable toxicity. Primary endpoint was 1-year PFS. Forty-six of 48 enrolled patients were assessable. Most patients had IPI ≥2, advanced stage and extranodal disease before the salvage treatment that led to trial registration; 28 (61%) patients were older than 70 years. Lenalidomide was well tolerated. With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Three patients died of complications during maintenance and three died due to second cancers at 32 to 64 months. There were 13 SAEs recorded in 12 patients; all these patients but two recovered. Lenalidomide was interrupted due to toxicity in other 6 patients, and 25 patients required dose reduction (transient in 21). At 1 year from registration, 31 patients were progression free. After a median follow-up of 65 (range 39-124) months, 22 patients remain progression free, with a 5-year PFS of 48% ± 7%. The duration of response to lenalidomide was longer than response to prior treatment in 30 (65%) patients. Benefit was observed both in de novo and transformed DLBCL, germinal-center-B-cell and nongerminal-center-B-cell subtypes. Twenty-six patients are alive (5-year OS 62% ± 7%). With the limitations of a nonrandomized design, these long-term results suggest that lenalidomide maintenance might bring benefit to patients with chemosensitive relapse of DLBCL not eligible for or failed after ASCT. Lenalidomide was associated with durable disease control and was well tolerated in this elderly population. Further investigations on immunomodulatory drugs as maintenance in these high-risk patients are warranted.

Best treatments available for distal acquired lacrimal obstruction: A systematic review and meta-analysis.

BACKGROUND: Epiphora is a common clinical sign whose primary cause is post-canalicular lacrimal obstruction. Treatment is both surgical and non-surgical. In the literature, there is some evidence to suggest that some treatments are superior to others, but there are no direct comparative data in this regard. OBJECTIVE OF REVIEW: To analyse the success rates of all available treatments to resolve post-canalicular acquired lacrimal obstruction. TYPE OF REVIEW: Systematic review and meta-analysis. SEARCH STRATEGY: A literature search was conducted in the US National Library of Medicine (PubMed), EMBASE, SCOPUS and Cochrane databases with a final search performed in January 2020. EVALUATION METHOD: The search strategy identified articles published later than 2000 with at least 50 procedures performed both surgically (external dacryocystorhinostomy [EXT-DCR], endoscopic dacryocystorhinostomy [END-DCR] and transcanalicular laser dacryocystorhinostomy [TCL-DCR]) and non-surgically (balloon dacryoplasty [DCP], probing-stenting [SP] and polyurethane stent [PoS]). The primary outcome was functional success, defined as symptom resolution or less than MUNK 2 scale; in addition to this, the influence of adjunctive treatments, such as application of mitomycin C and post-procedural silicone stenting, was evaluated. RESULTS: In total, 14 958 papers were selected, 440 of which were reviewed after screening; 55 were included after full-text review, which involved 9337 procedures. Mean success rate was 48.9% (35.7%-62.3%) for DCP, 54.4% (41.8%-66.5%) for SP, 73.6% (59.7%-84%) for PoS, 80% (75.1%-84%) for TCL-DCR, 89.8% (83.3%-93.9%) for EXT-DCR and 89.5% (87.2%-91.5%) for END-DCR. Among all procedures, a difference was noted between DCP and END-DCR (P < .001), DCP and EXT-DCR (P < .001), SP and END-DCR (P < .001), SP and EXT-DCR (P < .001), END-DCR and PoS (P = .016), and END-DCR and TCL-DCR (P = .001); no differences were noted between END-DCR and EXT-DCR (P = 1.00), EXT-DCR and PoS (P = .121) and EXT-DCR and TCL-DCR (P = .223). Considering surgical procedures, no differences were seen if a silicone stenting was applied, whereas, due to heterogeneity of the literature data, no statistical analysis was feasible for application of mitomycin C. CONCLUSIONS: Our analyses suggest that, among all procedures available, END-DCR and EXT-DCR should be considered as treatments of choice to resolve distal acquired lacrimal obstruction.

Nationwide survey on the current practice of ventricular tachycardia ablation.

METHODS: We performed a nationwide survey on the current practice of ventricular tachycardia catheter ablation in Italy during the year 2016. RESULTS: Among 145 operators participating in the survey, 58 (40.0%) did not perform any ventricular tachycardia ablation in 2016. Among those performing ventricular tachycardia ablation, 9 operators (6.2%) performed only right ventricular endocardial catheter ablation, 52 (35.9%) performed endocardial catheter ablation both in the right and left ventricle (LV) and 26 (17.9%) performed both endocardial and epicardial LV catheter ablations. Seventy operators (89.7%) among the 78 performing LV and epicardial ablations treated patients with ischemic cardiomyopathy; ablations in the setting of other causes were less frequently performed. The following were considered as minimum requirements for ventricular tachycardia ablation: presence of a three-dimensional mapping system (120 operators, 82.8%), ICU in the hospital (118 operators, 81.4%), operator's training in high volume centers (93 operators, 64.1%). Twenty-eight operators (19.3%) performed catheter ablation in patients with electrical storm only after hemodynamic stabilization, 41 operators (28.3%) also during the acute phase and 9 operators (6.2%) never performed catheter ablation in electrical storm patients; the remaining 67 operators did not perform ventricular tachycardia ablation at all, or performed ablations only in the right ventricle. CONCLUSION: The present survey provides a snapshot of the current invasive treatment of ventricular tachycardia by catheter ablation. The procedure, especially in the setting of ischemic cardiomyopathy, is performed nationwide. Complex cases, including those with electrical storm, should be managed within a preestablished integrated network of regional referral centers able to transfer patients as soon as possible.

R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-α in primary CNS lymphoma.

Patients with primary central nervous system lymphoma (PCNSL) are treated with high-dose methotrexate-based chemotherapy, which requires hospitalization and extensive expertise to manage related toxicity. The use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor. Tumor necrosis factor-α coupled with NGR (NGR-hTNF), a peptide targeting CD13+ vessels, induces endothelial permeabilization and improves tumor access of cytostatics. We tested the hypothesis that NGR-hTNF can break the BBB, thereby improving penetration and activity of R-CHOP in patients with relapsed/refractory PCNSL (NCT03536039). Patients received six R-CHOP21 courses, alone at the first course and preceded by NGR-hTNF (0.8 µg/m2) afterward. This trial included 2 phases: an "explorative phase" addressing the effect of NGR-hTNF on drug pharmacokinetic parameters and on vessel permeability, assessed by dynamic contrast-enhanced magnetic resonance imaging and 99mTc-diethylene-triamine-pentacetic acid-single-photon emission computed tomography, and the expression of CD13 on tumor tissue; and an "expansion phase" with overall response rate as the primary end point, in which the 2-stage Simon Minimax design was used. At the first stage, if ≥4 responses were observed among 12 patients, the study accrual would have continued (sample size, 28). Herein, we report results of the explorative phase and the first-stage analysis (n = 12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral/peritumoral areas, without interfering with drug plasma/cerebrospinal fluid concentrations. The NGR-hTNF/R-CHOP combination was well tolerated: there were only 2 serious adverse events, and grade 4 toxicity was almost exclusively hematological, which were resolved without dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with 9 confirmed responses (75%; 95% confidence interval, 51-99), 8 of which were complete. In conclusion, NGR-hTNF/R-CHOP was safe in these heavily pretreated patients. NGR-hTNF enhanced vascular permeability specifically in tumoral/peritumoral areas, which resulted in fast and sustained responses.

Predictive Score for Identifying Survival and Recurrence Risk Profiles in Patients Undergoing Ventricular Tachycardia Ablation: The I-VT Score.

BACKGROUND: Several distinct risk factors for arrhythmia recurrence and mortality following ventricular tachycardia (VT) ablation have been described. The effect of concurrent risk factors has not been assessed so far; thus, it is not yet possible to estimate these risks for a patient with several comorbidities. The aim of the study was to identify specific risk groups for mortality and VT recurrence using the Survival Tree (ST) analysis method. METHODS: In 1251 patients 16 demographic, clinical and procedure-related variables were evaluated as potential prognostic factors using ST analysis using a recursive partitioning algorithm that searches for relationships among variables. Survival time and time to VT recurrence in groups derived from ST analysis were compared by a log-rank test. A random forest analysis was then run to extract a variable importance index and internally validate the ST models. RESULTS: Left ventricular ejection fraction, implantable cardioverter defibrillator/cardiac resynchronization device, previous ablation were, in hierarchical order, identified by ST analysis as best predictors of VT recurrence, while left ventricular ejection fraction, previous ablation, Electrical storm were identified as best predictors of mortality. Three groups with significantly different survival rates were identified. Among the high-risk group, 65.0% patients were survived and 52.1% patients were free from VT recurrence; within the medium- and low-risk groups, 84.0% and 97.2% patients survived, 72.4% and 88.4% were free from VT recurrence, respectively. CONCLUSIONS: Our study is the first to derive and validate a decisional model that provides estimates of VT recurrence and mortality with an effective classification tree. Preprocedure risk stratification could help optimize periprocedural and postprocedural care.

Effect of the number of removed lymph nodes on prostate cancer recurrence and survival: evidence from an observational study.

BACKGROUND: The aim of this article is to analyze the effect on biochemical recurrence and on overall survival of removing an extensive number of pelvic lymph nodes during prostate cancer surgery. The lack of evidence from randomized clinical trials to address this specific question has hampered the ability to determine the true effect of the number of nodes removed. RESULTS: Our analysis is based on a large observational study, and this can lead unadjusted estimates to be very sensitive to confounding bias due to the different prognosis of individuals. We assess the effect of the number of lymph nodes removed by means of an Inverse Probability Weighting adjustment based on a Poisson regression model, and by a Doubly-robust adjustment. CONCLUSIONS: Our findings suggest that a large number of nodes removed is associated with a significant improvement in time to biochemical recurrence. However, it appears to have no impact on overall survival.

Lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplantation: an open label, single-arm, multicentre phase 2 trial.

BACKGROUND: Patients with relapsed diffuse large B-cell lymphoma (DLBCL) not eligible for autologous stem cell transplantation (ASCT) or having relapse after ASCT have a low likelihood of cure. Single-drug maintenance after salvage therapy might be an attractive strategy to prolong survival in these patients. Lenalidomide is a suitable candidate for long-lasting maintenance as it is an oral drug, active against DLBCL that can be taken for years with an acceptable toxicity profile. We designed a study to investigate safety and efficacy of lenalidomide maintenance in patients with chemosensitive relapse of DLBCL not eligible for ASCT or having relapse after ASCT. METHODS: In this open-label, single group, multicentre phase 2 trial, we recruited HIV-negative adults with de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy from 12 oncology-haematology centres in Italy. All patients were given oral lenalidomide 25 mg per day for 21 of 28 days until lymphoma progression or unacceptable toxicity (severely compromises organ function, quality of life, or both). Primary endpoint was 1-year progression-free survival. The estimated sample size was 47 patients; maintenance was deemed efficacious if at least 19 patients were progression-free survivors at 1 year. All enrolled patients were included in primary analyses, with the exception of patients who post-hoc objectively did not meet the eligibility criteria (modified intention-to-treat). This study is registered with clinicaltrials.gov registry, number NCT00799513. FINDINGS: Between March 24, 2009, and Dec 22, 2015, we recruited 48 patients. 46 of 48 enrolled patients were assessable (two patients had unconfirmed diagnoses). 36 (78%) of 46 patients had de novo DLBCL and ten (22%) of 46 patients had transformed DLBCL. At a median follow-up of 25 months (IQR 12-56), 556 lenalidomide courses had been delivered, with an average mean of 12 courses (range 3-41) per patient; 19 patients were still in treatment at a median follow-up of 25 months. Lenalidomide was well tolerated; with the exception of neutropenia, grade 3-4 toxicities were uncommon. We recorded ten severe adverse events in nine patients due to febrile neutropenia (n=4), diarrhoea (n=2), melena, stroke, vomiting, and intestinal infarction; all but one patient recovered, and six of these patients continued with lenalidomide treatment. The exception was the only death due to toxicity (intestinal infarction). At 1 year from trial registration, 28 patients were progression free, which was much higher than the predetermined efficacy threshold. During the whole observation period, 21 events occurred: progressive lymphoma in 19 patients, death due to toxicity in one, death while off therapy in one, 1-year progression-free survival was 70% (95% CI 57-83). INTERPRETATION: With the limitations of a non-randomised design, this trial supports the use of lenalidomide maintenance in patients with chemo-sensitive relapse of DLBCL who are not eligible for ASCT or who had relapse after ASCT. These results warrant further investigation of immunomodulatory drugs as maintenance in high-risk patients with DLBCL. FUNDING: Celgene Corp.