Drug Repurposing in Crohn's Disease Using Danish Real-World Data.

Aim: Drug repurposing, utilizing electronic healthcare records (EHRs), offers a promising alternative by repurposing existing drugs for new therapeutic indications, especially for patients lacking effective therapies. Intestinal fibrosis, a severe complication of Crohn's disease (CD), poses significant challenges, increasing morbidity and mortality without available pharmacological treatments. This article focuses on identifying medications associated with an elevated or reduced risk of fibrosis in CD patients through a population-wide real-world data and artificial intelligence (AI) approach. Methods: Patients aged 65 or older with a diagnosis of CD from 1996 to 2019 in the Danish EHRs were followed for up to 24 years. The primary outcome was the need of specific surgical procedures, namely proctocolectomy with ileostomy and ileocecal resection as proxies of intestinal fibrosis. The study explored drugs linked to an increased or reduced risk of the study outcome through machine-learning driven survival analysis. Results: Among the 9179 CD patients, 1029 (11.2%) underwent surgery, primarily men (58.5%), with a mean age of 76 years, 10 drugs were linked to an elevated risk of surgery for proctocolectomy with ileostomy and ileocecal resection. In contrast, 10 drugs were associated with a reduced risk of undergoing surgery for these conditions. Conclusion: This study focuses on repurposing existing drugs to prevent surgery related to intestinal fibrosis in CD patients, using Danish EHRs and advanced statistical methods. The findings offer valuable insights into potential treatments for this condition, addressing a critical unmet medical need. Further research and clinical trials are warranted to validate the effectiveness of these repurposed drugs in preventing surgery related to intestinal fibrosis in CD patients.

Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study.

OBJECTIVE: To study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism. DESIGN: Nationwide cohort study. SETTING: Denmark through national registries. PARTICIPANTS: All 15-49 year old women living in Denmark between 1996 and 2017 with no medical history of any venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility treatment (n=2 029 065). MAIN OUTCOME MEASURE: A first time discharge diagnosis of lower limb deep venous thrombosis or pulmonary embolism. RESULTS: Among 2.0 million women followed for 21.0 million person years, 8710 venous thromboembolic events occurred. Compared with non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of venous thromboembolism of 7.2 (95% confidence interval 6.0 to 8.5) in women not using hormonal contraception, 11.0 (9.6 to 12.6) in women using high risk hormonal contraception, 7.9 (5.9 to 10.6) in those using medium risk hormonal contraception, and 4.5 (2.6 to 8.1) in users of low/no risk hormonal contraception. The corresponding numbers of extra venous thromboembolic events per 100 000 women over the first week of NSAID treatment compared with non-use of NSAIDs were 4 (3 to 5) in women not using hormonal contraception, 23 (19 to 27) in women using high risk hormonal contraception, 11 (7 to 15) in those using medium risk hormonal contraception, and 3 (0 to 5) in users of low/no risk hormonal contraception. CONCLUSIONS: NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age. The number of extra venous thromboembolic events with NSAID use compared with non-use was significantly larger with concomitant use of high/medium risk hormonal contraception compared with concomitant use of low/no risk hormonal contraception. Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly.

Effectiveness and safety of P2Y12 inhibitors in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention: a nationwide registry-based study.

AIMS: To compare the effectiveness and safety of clopidogrel, ticagrelor, and prasugrel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: Nationwide, registry-based study of STEMI patients treated with primary PCI (2011-17) and subsequently with aspirin and a P2Y12 inhibitor. The effectiveness outcome was major adverse cardiovascular events (MACE) defined as a composite of recurrent myocardial infarction, repeat revascularization, stroke, or cardiovascular death at 12 months. The safety outcome was bleeding requiring hospitalization at 12 months. Multivariable logistic regression with average treatment effect modeling was used to calculate absolute and relative risks for outcomes standardized to the distributions of demographic characteristics of all included subjects. We included 10 832 patients; 1 697 were treated with clopidogrel, 7 508 with ticagrelor, and 1,627 with prasugrel. Median ages were 66, 63, and 59 years (P < 0.001). Standardized relative risks of MACE were 0.75 for ticagrelor vs. clopidogrel (95% confidence interval [CI], 0.64-0.83), 0.84 for prasugrel vs. clopidogrel (95% CI, 0.73-0.94), and 1.12 for prasugrel vs. ticagrelor (95% CI, 1.00-1.24). Standardized relative risks of bleeding were 0.77 for ticagrelor vs. clopidogrel (95% CI, 0.59-0.93), 0.89 for prasugrel vs. clopidogrel (95% CI, 0.64-1.15), and 1.17 for prasugrel vs. ticagrelor (95% CI, 0.89-1.45). CONCLUSION: Ticagrelor and prasugrel were associated with lower risks of MACE after STEMI than clopidogrel, and ticagrelor was associated with a marginal reduction compared with prasugrel. The risk of bleeding was lower with ticagrelor compared with clopidogrel, but did not significantly differ between ticagrelor and prasugrel.

Segmental Ureterectomy Versus Radical Nephroureterectomy in Older Patients Treated for Upper Tract Urothelial Carcinoma.

INTRODUCTION: The world population is ageing and surgical procedures for older patients are associated with higher perioperative morbidity and mortality rates than in younger patients. Segmental ureterectomy (SU) has been proposed as an alternative to radical nephroureterectomy (RNU) for selected upper tract urothelial carcinomas (UTUC), to reduce post-operative morbidity, and preserve renal function. The aim of this study was to compare RNU and SU in terms of post-operative complications, functional outcomes, and overall survival (OS) in older patients treated for UTUC. MATERIALS AND METHODS: Data of patients aged 75 years or older and treated for UTUC were included. The primary outcome was to compare RNU versus SU according to post-operative complications, the estimated glomerular filtration rate (eGFR) variation, and OS. Complications were defined according to the Clavien-Dindo classification. eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Un-adjusted OS curves were plotted using the Kaplan-Meier method. RESULTS: Overall, 177 patients (150 RNU and 27 SU) were eligible for the analysis. Pre- and post-operative characteristics were similar between the 2 groups. RNU patients showed higher incidence of post-operative complications (34.0% vs. 7.4%, P = .011). The mean post-operative serum creatinine was lower in SU patients in comparison with the RNU ones (1.23 vs. 1.69 mg/dL, P = .046), but no differences were found in terms of eGFR variation (P = .258). At 3 years of follow-up, the OS was comparable between the two surgical techniques (P = .129). CONCLUSION: In older patients diagnosed with UTUC, SU could offer lower rates of post-operative complications without affecting survival.

Impact of MELD 30-allocation policy on liver transplant outcomes in Italy.

BACKGROUND & AIMS: In Italy, since August 2014, liver transplant (LT) candidates with model for end-stage liver disease (MELD) scores ≥30 receive national allocation priority. This multicenter cohort study aims to evaluate time on the waiting list, dropout rate, and graft survival before and after introducing the macro-area sharing policy. METHODS: A total of 4,238 patients registered from 2010 to 2018 were enrolled and categorized into an ERA-1 Group (n = 2,013; before August 2014) and an ERA-2 Group (n = 2,225; during and after August 2014). A Cox proportional hazards model was used to estimate the hazard ratio (HR) of receiving a LT or death between the two eras. The Fine-Gray model was used to estimate the HR for dropout from the waiting list and graft loss, considering death as a competing risk event. A Fine-Gray model was also used to estimate risk factors of graft loss. RESULTS: Patients with MELD ≥30 had a lower median time on the waiting list (4 vs.12 days, p <0.001) and a higher probability of being transplanted (HR 2.27; 95% CI 1.78-2.90; p = 0.001) in ERA-2 compared to ERA-1. The subgroup analysis on 3,515 LTs confirmed ERA-2 (odds ratio 0.56; 95% CI 0.46-0.68; p = 0.001) as a protective factor for better graft survival rate. The protective variables for lower dropouts on the waiting list were: ERA-2, high-volume centers, no competition centers, male recipients, and hepatocellular carcinoma. The protective variables for graft loss were high-volume center and ERA-2, while MELD ≥30 remained related to a higher risk of graft loss. CONCLUSIONS: The national MELD ≥30 priority allocation was associated with improved patient outcomes, although MELD ≥30 was associated with a higher risk of graft loss. Transplant center volumes and competition among centers may have a role in recipient prioritization and outcomes. CLINICAL TRIAL NUMBER: NCT04530240 LAY SUMMARY: Italy introduced a new policy in 2014 to give national allocation priority to patients with a model for end-stage liver disease (MELD) score ≥30 (i.e. very sick patients). This policy has led to more liver transplants, fewer dropouts, and shorter waiting times for patients with MELD ≥30. However, a higher risk of graft loss still burdens these cases. Transplant center volumes and competition among centers may have a role in recipient prioritization and outcomes.

The Relationship between Timing of Pretransplant Kidney Biopsy, Graft Loss, and Survival in Kidney Transplantation: An Italian Cohort Study.

INTRODUCTION: Kidney biopsy is performed to assess if an extended criteria graft can be used for transplantation. It may be performed before or after cross-clamping during organ procurement. This study aims to evaluate whether the timing of biopsy may modify cold ischemia times (CIT) and/or graft outcomes. METHODS: Kidney transplants performed in our center from January 2007 to December 2017 were analyzed. Grafts with preimplantation kidney biopsy were included. Biopsies were performed during surgical back table (ex situ kidney biopsy [ESKB]) until 2012 and since then before the aortic cross-clamping (in situ kidney biopsy [ISKB]). To overcome biases owing to different distributions, a propensity score model was developed. The study population consists in 322 patients, 115 ESKB, and 207 ISKB. RESULTS: CIT was significantly lower for ISKB (730 min ISKB vs. 840 min ESKB, p value = 0.001). In both crude (OR 0.27; 95% confidence interval, 95% CI 0.12-0.60; p value = 0.002) and adjusted analyses (OR 0.37; 95% CI 0.14-0.94; p value = 0.039), ISKB was associated with a reduced odd of graft loss when compared to ESKB. DISCUSSION/CONCLUSION: Performing preimplantation kidney biopsy during the recovery, prior to the aortic cross-clamping, may be a strategy to reduce CIT and improve transplant outcomes.

Detecting deviations from the efficacy and safety results of single-arm trials using real-world data: The case of a CAR-T cell therapy in B-cell lymphoma.

PURPOSE: Personalized therapies are leading to an increasing number of marketing authorizations based on single-arm trials, which increases the demand for better post-authorization monitoring strategies. The aim of the present study was to estimate the power over time as data accrue in population-based registries for detecting deviations from the expected efficacy/safety of chimeric antigen receptor T cell (CAR-T) therapy approved for relapsed/refractory large B-cell lymphoma (RR-LBCL). METHODS: The number of real-world RR-LBCL patients was projected over time in a general population of 5, 15, and 25 million citizens using lymphoma registry data. For each scenario, we computed the power over time for detecting significant deviations in efficacy (1-year overall survival [1yOS]) when comparing to historical controls (SCHOLAR-1 study; 1yOS, 28%) and RR-LBCL patients treated with CAR-T cell therapy in a single-arm trial (ZUMA-1; 1yOS, 59%) as well as deviations in selected adverse events (grade ≥3 aphasia) from the ZUMA-1 trial. We assumed a 10% absolute deviation in 1yOS (efficacy) and a relative increase of 50% in grade ≥3 aphasia (safety). RESULTS: Assuming a general population of 5, 15, and 25 million, the accrual time needed to achieve 80% power for detecting a significant increase over the 1yOS reported in SCHOLAR-1 was 9, 4, and 3 years, respectively, while 80% power for detecting a significant decrease in 1yOS compared to ZUMA-1 required 10.5, 4.5, and 3 years of data accrual, respectively. However, corresponding estimates for aphasia were >20, 8, and 5 years, respectively. CONCLUSIONS: Projections of the statistical power for detecting important deviations in efficacy/safety from that reported in pivotal clinical trials(s) provide critical information about the expected performance of post-authorization monitoring programs.

Segmental ureterectomy vs. radical nephroureterectomy for ureteral carcinoma in patients with a preoperative glomerular filtration rate less than 90 ml/min/1.73 m2: A multicenter study.

OBJECTIVES: To compare segmental ureterectomy (SU) and radical nephroureterectomy (RNU) in terms of overall survival (OS) and impact on postoperative renal function in patients treated for upper tract urothelial carcinoma (UTUC) of the ureter with preoperatively reduced estimated glomerular filtration rate (eGFR). MATERIALS AND METHODS: We retrospectively collected the data of consecutive patients treated for UTUC, in 6 Italian tertiary referral centers, from 2003 to 2013, and analyzed those treated with RNU or SU for ureteral cancer and with a preoperative eGFR <90 ml/min/1.73m2. The primary outcome was to compare the postoperative eGFR variation and the OS according to the surgical technique chosen. RESULTS: Out of 521 patients with UTUC, 228 patients had preoperative reduced eGFR. Out of these patients, 93 had ureteral cancer and were included in the primary analyses - 67 (72.0%) treated with RNU and 26 (28.0%) with SU. Preoperative characteristics were similar in the 2 groups. The overall median follow-up period was 26.5 months. A nonsignificant postoperative eGFR decrease of 3.0 ml/min/1.73m2 was found overall (P = 0.094), with nonsignificant difference between the 2 groups (P = 0.735). A comparable 5-year OS was calculated for RNU and SU patients (P = 0.99). CONCLUSIONS: The type of surgery (SU vs. RNU) has a low impact on postoperative renal function and OS in patients with ureteral cancer and preoperative eGFR <90 ml/min/1.73m2. The indications for kidney sparing surgery for UTUC should be based on the surgical and oncological risks in these patients.

Segmental resection of distal ureter with termino-terminal ureteric anastomosis vs bladder cuff removal and ureteric re-implantation for upper tract urothelial carcinoma: results of a multicentre study.

OBJECTIVES: To compare overall (OS), cancer-specific (CSS), recurrence-free survival (RFS) and postoperative renal function amongst patients with upper tract urothelial carcinoma (UTUC) of the distal (lower lumbar and pelvic) ureter, electively treated with segmental resection and termino-terminal anastomosis (TT) vs bladder cuff removal and ureteric re-implantation (RR). PATIENTS AND METHODS: A multicentre retrospective study, including 84 patients diagnosed with UTUC of the distal ureter and treated with TT or RR, is presented. The primary endpoint was to compare TT and RR in terms of OS, CSS and RFS. As a secondary outcome, we compared the postoperative creatinine values as an index of renal function in the two groups. RESULTS: Of 521 patients with UTUC, 65 (77.4%) and 19 (22.6%) patients underwent RR and TT, respectively. Pre- and postoperative characteristics were not statistically different between the two groups. The median follow-up period was 22.7 months. Patients treated with TT and those treated with RR did not have significantly different 5-year OS, CSS or RFS (73.7% vs 92.3%, P = 0.052; 94.7% vs 95.4%, P = 0.970: and 63.2% vs 53.9%, P = 0.489, respectively). No difference in postoperative creatinine variation emerged in association with the surgical technique (P = 0.411). CONCLUSION: Patients treated with TT or RR for UTUC showed comparable OS, CSS, RFS and postoperative renal function. Our data suggest that bladder cuff removal is not imperative in the treatment of distal ureteric UTUC, and TT can be a safe solution in selected cases.

Efficacy and safety of S-acyl glutathione 2% cream vs. placebo against UVB-induced erythema: a randomized, double-blinded clinical trial.

BACKGROUND: Reactive oxygen species have a major role in the UV-induced short- and long-term damage, thus the exogenous supplementation of antioxidant molecules may allow better skin protection. Despite glutathione has pivotal properties in the complex cytoplasmic antioxidant system, its supplementation is hampered by limited transmembrane absorption. Modification of glutathione pharmacokinetic properties via acetylation with long-chain polyunsaturated fatty acid may improve its passage through phospholipidic membranes. METHODS: This was a single center randomized double-blinded clinical trial, versus placebo, cross-sectional pairwise at time 0. The participants were 10 healthy volunteers with skin phototypes II or III and age ≥18 years interested in performing minimal erythema dose (MED) evaluation performed by photoallergology unit of Division of Dermatology at P. Palagi Hospital, in Florence. Each volunteer underwent UVB phototesting, treating four different areas with increasing UVB doses in four different conditions. One arm was treated as standard procedure (naïve arm), one applying linolenic-glutathione conjugate (Lin-GSH) cream 2% before irradiation (pre-Lin-GSH arm), one with placebo (placebo arm) and one applying Lin-GSH cream 2% (SoloSale Srl, Florence, Italy) after irradiation (post-Lin-GSH arm). The main endpoint was to evaluate efficacy of Lin-GSH cream 2% before UVB irradiation compared with placebo. A secondary endpoint was the evaluation of the same cream applied after irradiation compared to no treatment. Another secondary objective is the evaluation of safety in both conditions. Mean MED was evaluated at distinct conditions. Safety was evaluated reporting all grade 3-4 adverse events up to 30 days after treatment. All volunteers were treated in all four experimental conditions. The pre-Lin-GSH and placebo arms were applied in a double-blind condition for each volunteer. Neither the volunteer nor the investigator executing MED evaluation knew which arm was given Lin-GSH and which one placebo. RESULTS: Ten volunteers among 12 recruited for the study were correctly randomized and completed all study evaluations. Recruitment went from April 1st, 2016 to May 1st, 2016, up to adequate population number. Mean MED in pre-Lin-GSH arm was superior to mean MED in placebo arm (135±5.53 mJ/cm2 vs. 105±7.64 mJ/cm2, P=0.0003). No difference was observed among mean MED in post-Lin-GSH and naïve arms. No grade 3-4 adverse events were reported. CONCLUSIONS: Lin-GSH 2% cream seems a safe and effective in producing a significant increase in MED compared with placebo thanks to its antioxidant properties.

Robot-Assisted Nephron-Sparing Surgery for Cystic Nephroma in a Pediatric Patient: A Case Report.

Cystic nephroma is a benign kidney tumor, which presents as a unilateral cystic mass without solid elements. We presented the first case of cystic nephroma treated with robotic nephron-sparing surgery in a pediatric patient. The procedure adopted was the robot-assisted simple enucleation of the lesion, without arterial clamping.

Intraoperative assessment of ureteral and graft reperfusion during robotic kidney transplantation with indocyanine green fluorescence videography.

BACKGROUND: The aim of this paper is to report the first preliminary experience with intraoperative indocyanine green (ICG) fluorescence videography (IFV) to assess graft and ureteral reperfusion during robot-assisted kidney transplantation (RAKT). METHODS: We prospectively collected data from consecutive patients undergoing RAKT and IFV from living-donors at our Institution between January 2017 and April 2018. RAKT was performed following the principles of the Vattikuti-Medanta technique. ICG was injected intravenously after vascular anastomoses to quantitate graft and ureteral fluorescence signal. The signal intensity within selected intraoperative snapshots was evaluated for renal parenchyma, ureter and vascular anastomoses. A systematic review of the English-language literature about the topic was performed according to the PRISMA statement recommendations. RESULTS: Six patients were included. Neither conversions to open surgery nor major intra- or postoperative complications were recorded. At a median follow-up of 12 months (IQR 8-13), median estimated glomerular filtration rate was 64.2 mL/min/1.73 m2 (IQR 45.3-98.4). Intraoperative quantitative assessment of ICG fluorescence was successful in all patients. Of the five studies selected by our review, mostly prospective studies, all including open KT series. Yet, most studies were limited by lack of quantitative measures of IFV fluorescence. CONCLUSIONS: IFV during RAKT is feasible and safe and provides a reliable assessment of graft reperfusion. Larger studies are needed to standardize the technique and to evaluate the association between fluorescence signal, ultrasound parameters and postoperative kidney function.

Pillars and Pitfalls of the New Pharmacovigilance Legislation: Consequences for the Identification of Adverse Drug Reactions Deriving From Abuse, Misuse, Overdose, Occupational Exposure, and Medication Errors.

Rationale: The aim of this study is to investigate if following the implementation of the Regulation EU/1235/2010 and the Directive 2010/84/EU there was an increase of individual case safety reports (ICSRs) deriving from a medication error, abuse, misuse, overdose, or occupational exposure. Other objectives are the identification of drugs mostly involved in such cases, to establish if the codification of aforementioned conditions is performed correctly and, whenever codification errors exist, to identify predictors of codification errors. Finally, we estimated the magnitude of these errors on signal detection activities. Methods: ICSRs sent through Campania Region (Italy) spontaneous reporting system from July 2nd 2012 to December 31th 2017 were used as data source. A multivariable logistic regression model was used to identify predictors of codification errors. Four measures of disproportionality were used to investigate the magnitude of codification errors on a known safety signal or rather the association between benzodiazepines derivatives and abuse. Results: In all, 358 (1.4%) out of 25610 ICSRs reported "non-normal use" of drugs, mainly as cases of abuse. Drugs mostly involved in abuse were "Benzodiazepines derivatives" (171/358; 47.8%). For medication errors instead, "Other antiseptics and disinfectants" (9/358; 2.5%). At the first quality control, 125 (34.9%) out of 358 ICSRs did not have a codification of "non-normal use" or codifications were performed wrongly. Codification errors included misclassification of abuse as overdose (10/125; 8.0%) and misclassification of medication error as overdose (7/125; 5.6%) or abuse (7/125; 5.6%). Compared to pharmaceutical companies, patients/citizens (as reporters) had a 24.88 higher odd (Reporting Odds Ratio 24.88, 95%CI 1.82-449.95; p-value: 0.02) of performing un-classification or misclassification of aforementioned codifications. Codification errors were associated with the underestimation of measure of disproportionality' estimates in the identification of the safety signal "Benzodiazepine derivatives /abuse". Conclusion: In conclusion, this study found that in Campania Region (southern Italy) there was an exponential increase of ICSR reporting "non-normal use," mainly as cases of abuse, with an improvable proportion of cases misclassified/unclassified. Moreover, this study found that ICSRs sent by patients/citizens were associated with an increased odd of un-classification or misclassification that had a relevant impact on signal detection activities.

Photodynamic therapy with topical photosensitizers in mucosal and semimucosal areas: Review from a dermatologic perspective.

Photodynamic Therapy is a procedure based on the interaction between a Photosensitizer, a light source with a specific wavelength and oxygen. The aim of this review is to provide a brief and updated analysis of scientific reports on the use of PDT with topical PS in the management of oncological, infectious, and inflammatory disorders involving mucosal and semimucosal areas, with a specific focus on diseases of dermatologic interest.

ALA-PDT exerts beneficial effects on chronic venous ulcers by inducing changes in inflammatory microenvironment, especially through increased TGF-beta release: A pilot clinical and translational study.

A cohort of 19 patients affected by chronic venous ulcers was recruited from our centre. A 4-mm punch biopsy from wound bed was taken before application of ALA 20% gel and repeated one hour after the first PDT irradiation. We observed a significant and progressive reduction of wounds mean volumes right after three ALA-PDT sessions (once per week; 4479.9 +/- 345.5 mm3 vs 34599 +/- 190.3 mm3, p < .01). On immunofluorescence staining from biopsy specimens, we observed a change in all tested stains of post treatment specimens compared to pre-treatment ones. An increase of plasmacytoid dendritic cells (from 699 +/- 22 cells/0.018 mm2 to 1369 +/- 27 cells/0.018 mm2, p < .0001); MHC-II expression (260.39 +/- 99.7 Red, Green, Blue [RGB 0-255] to 370.2 +/- 162.6 RGB (0-255), p < .01), TNF-alpha positive mast cells expression (49 +/- 0.3 cells/0.018 mm2 to 69 +/- 0.4 cells/0.018 mm2, p < .001), TGF-beta expression (59.89 +/- 23.2 RGB (0-255)/cell vs 137.39 +/- 56.6 RGB (0-255)/cell, p < .01) and CD4+/CD25+ Treg cells (39 +/- 1 cells/0.018 mm2 vs 209 +/- 10 cells/0.018 mm2, p < .001) was observed. An increase of TGF-beta was correlated in a statistical significant manner with a reduction of wounds' mean volumes.

Safety Profile of Anticancer and Immune-Modulating Biotech Drugs Used in a Real World Setting in Campania Region (Italy): BIO-Cam Observational Study.

Objectives: To investigate the occurrence of adverse events (AEs) in naïve patients receiving biotech drugs. Design: A prospective observational study. Setting: Onco-hematology, Hepato-gastroenterology, Rheumatology, Dermatology, and Neurology Units in Campania Region (Italy). Participants: 775 patients (53.81% female) with mean age 56.0 (SD 15.2). The mean follow-up/patient was 3.48 (95% confidence interval 3.13-3.84). Main outcome measures: We collected all AEs associated to biotech drugs, including serious infections and malignancies. Serious AEs were defined according to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, clinical safety data management: definitions and standards for expedited reporting E2A guideline. Results: The majority of the study population was enrolled in Onco-hematology and Rheumatology Units and the most common diagnosis were hematological malignancies, followed by rheumatoid arthritis, colorectal cancer, breast cancer, and psoriatic arthritis. The most commonly prescribed biotech drugs were rituximab, bevacizumab, infliximab, trastuzumab, adalimumab, and cetuximab. Out of 775 patients, 320 experienced at least one AE. Most of patients experienced AEs to cetuximab therapy, rituximab and trastuzumab. Comparing female and male population, our findings highlighted a statistically significant difference in terms of AEs for adalimumab (35.90% vs. 7.41%, p < 0.001) and etanercept (27.59% vs. 10.00%, p = 0.023). Considering all biotech drugs, we observed a peak for all AEs occurrence at follow-up 91-180 days category. Bevacizumab, brentuximab, rituximab, trastuzumab and cetuximab were more commonly associated to serious adverse events; most of these were possibly related to biotech drugs, according to causality assessment. Three cases of serious infections occurred. Conclusions: The results of our study demonstrated that the majority of AEs were not serious and expected. Few cases of serious infections occurred, while no case of malignancy did. Overall, the safety profile of biotech drugs used in our population was similar to those observed in pivotal trials. Notwithstanding the positive results of our study, some safety concerns still remain unresolved. In order to collect more effectiveness and safety data on biotech drugs, the collection and analysis of real world data should be endorsed as well as the management of post-authorization studies.

Langerhans, plasmacytoid dendritic and myeloid-derived suppressor cell levels in mycosis fungoides vary according to the stage of the disease.

Mycosis fungoides (MF) is characterized by a switch from indolent behaviour in the early stages to a worse clinical outcome in the advanced ones. Recently, various studies have investigated the role the microenvironment might play in such a switch. We have analysed the distribution of Langerhans cells, plasmacytoid dendritic cells and myeloid-derived suppressor cells in 46 MF cases in various stages, aiming to assess whether changes occur from early to advanced stage. We have investigated the number of langerin, CD303 and arginase-1 positive cells and their distribution at high power. Data were analysed using t test for continuous variables, χ 2 tests or Fisher's exact test for categorical variables, as well as analysis of covariance. In comparing stages IA/B to IIB, we observed a significant decrease in Langerhans cells (p value 0.03) and a significant increase in CD303 and arginase-1 positive cells (p value <0.01 for both markers). Furthermore, a significant increase in Langerhans cells only was observed in stage IIB in comparison to stage III (p = 0.02), while in stage IV, a significant decrease in Langerhans cells was noted in comparison to stage III (p = 0.02). Our data suggest that changes in the microenvironment might influence disease progression, especially from stages IA/B to IIB, opening new scenarios in MF therapy.

Positive surgical margins and local recurrence after simple enucleation and standard partial nephrectomy for malignant renal tumors: systematic review of the literature and meta-analysis of prevalence.

INTRODUCTION: The definition of the safest width of healthy renal margin to achieve oncological efficacy and therefore of the safest resection technique (RT) during partial nephrectomy (PN) continues to be widely debated. The aim of this study is to evaluate the prevalence of positive surgical margins (PSM), loco-regional recurrence (LRR) and renal recurrence (RER) rates after simple enucleation (SE) and standard partial nephrectomy (SPN) for malignant renal tumors. EVIDENCE ACQUISITION: A systematic review of the English-language literature was performed through August 2016 using the Medline, Web of Science and Embase databases according to the PRISMA criteria. A systematic review and meta-analysis was performed in those studies that defined the exact anatomical location of recurrence after PN. EVIDENCE SYNTHESIS: Overall, 33 studies involving 11,282 patients were selected for quantitative analysis. At a median follow-up of 43 (SE) and 52 (SPN) months, the pooled estimates of the prevalence of PSMs, LRR and RER were 2.7% (95% CI: 1.5-4.6%, P<0.001) and 0.4% (95% CI: 0.1-2.2%, P=0.018), 2.0% (95% CI: 1.4-2.8%, P<0.001) and 0.9% (95% CI: 0.5-1,7%, P=0.04), 1.5% (95% CI: 0.9-2.3%, P=0.001) and 0.9% (95% CI: 0.5-1,7%, P=0.40) in patients undergoing SPN and SE, respectively. CONCLUSIONS: Our systematic analysis and meta-analysis demonstrates that SE is noninferior to SPN regarding PSM, LRR and RER rates in patients undergoing PN for malignant renal tumors. Further studies using standardized reporting tools are needed to evaluate the role of resection techniques for oncologic outcomes after PN.

Anatomical templates of lymph node dissection for upper tract urothelial carcinoma: a systematic review of the literature.

INTRODUCTION: Indications and techniques of lymph node dissection (LND) for upper tract urothelial carcinoma (UTUC) are still controversial. Areas covered: In this study, a systematic review of the English-language literature was performed up to 1 July 2016 using the Medline, Scopus, Cochrane Library and Web of Sciences databases to provide a detailed overview of the most commonly dissected surgical templates of LND for UTUC according to laterality and location of the tumor. Overall, sixteen studies were analyzed. Based on the shared experiences in the scientific literature, the LND template typically included: for right-sided tumors of the renal pelvis, upper third and middle third of the ureter, the renal hilar, paracaval, precaval and retrocaval nodes, while for left-sided tumors the renal hilar, paraaortic and preaortic nodes. For tumors of the lower ureter, an extended pelvic LND was performed in most cases; however, the paracaval, paraaortic or presacral nodes were dissected in selected series. Expert commentary: LND is not routinely performed at the time of surgery for UTUC and both indication and extent of LND vary among surgeons and institutions. Future high-quality studies are needed to define the most accurate LND templates and to assess their oncological efficacy and surgical morbidity.