Denosumab improves trabecular bone score in relationship with decrease in fracture risk of women exposed to aromatase inhibitors.

PURPOSE: Trabecular bone score (TBS) is a gray-level textural metric that has shown to correlate with risk of fractures in several forms of osteoporosis. The value of TBS in predicting fractures and the effects of bone-active drugs on TBS in aromatase inhibitors (AIs)-induced osteoporosis are still largely unknown. The primary objective of this retrospective study was to assess the effects of denosumab and bisphosphonates (BPs) on TBS and vertebral fractures (VFs) in women exposed to AIs. METHODS: 241 consecutive women (median age 58 years) with early breast cancer undergoing treatment with AIs were evaluated for TBS, bone mineral density (BMD) and morphometric VFs at baseline and after 18-24 months of follow-up. During the study period, 139 women (57.7%) received denosumab 60 mg every 6 months, 53 (22.0%) BPs, whereas 49 women (20.3%) were not treated with bone-active drugs. RESULTS: Denosumab significantly increased TBS values (from 1.270 to 1.323; P < 0.001) accompanied by a significant decrease in risk of VFs (odds ratio 0.282; P = 0.021). During treatment with BPs, TBS did not significantly change (P = 0.849) and incidence of VFs was not significantly different from women untreated with bone-active drugs (P = 0.427). In the whole population, women with incident VFs showed higher decrease in TBS vs. non-fractured women (P = 0.003), without significant differences in changes of BMD at any skeletal site. CONCLUSIONS: TBS variation predicts fracture risk in AIs treated women. Denosumab is effective to induce early increase of TBS and reduction in risk of VFs.

Serum testosterone mirrors inflammation parameters in females hospitalized with COVID-19.

BACKGROUND: While low testosterone (T) was described as a predictor of unfavorable coronavirus-disease 19 (COVID-19) outcome in men, data concerning the role of T in women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are scant and limited to small cohorts. This study investigated the relationship between serum T values and outcomes of COVID-19 in a large female hospitalized cohort. METHODS: One-hundred-sixty-eight adult women (median age 77, range 18-100 years; 154 in post-menopause) hospitalized for COVID-19 were assessed for PaO2/Fio2 ratio, serum T and inflammatory parameters. RESULTS: Median duration for hospital stay was 14.2 days (range 1-115) with overall mortality of 26% (n = 44). Subjects who died were significantly older (p < 0.001), had significantly more comorbidities (p = 0.015) and higher serum T (p = 0.040), white blood cells (p = 0.007), c-reactive protein (CRP; p < 0.001), interleukin-6 (IL-6; p < 0.001), procalcitonin (PCT; p < 0.001), lactate dehydrogenase (LDH; p = 0.001), D-dimer (p = 0.035), fibrinogen (p = 0.038) and lower serum free-triiodothyronine (FT3; p < 0.001) and luteinizing hormone (LH; p = 0.024) values. In post-menopausal women, significant associations were observed between T levels and serum CRP (rho: 0.23; p = 0.002), IL-6 (rho: 0.41; p < 0.001), LDH (rho: 0.34; p < 0.001), D-Dimer (rho: 0.21; p = 0.008), PCT (rho: 0.26; p = 0.001) and HDL cholesterol (rho: - 0,22, p = 0.008). In multivariate regression analyses, serum T maintained the significant association with mortality after correction for age, coexistent comorbidities and serum LH and FT3, whereas it was lost after correction for inflammatory parameters. CONCLUSION: In females, high serum T levels might be a mirror of inflammatory phenotype and worse COVID-19 course.

[Dosimetric impact of hydrogel spacer use for stereotactic body radiotherapy of localised prostate cancer]. / Impact dosimétrique de la pose d'un espaceur rectal dans le traitement de cancer de la prostate localisé par irradiation en conditions stéréotaxiques.

PURPOSE: Stereotactic body radiotherapy (SBRT) of prostate cancer is associated with rectal toxicities, which can be reduced by using a hydrogel spacer. The object of this retrospective study was to show the feasibility of spacer placement under local anesthesia and utility of hydrogel spacer to reduce the dose to the rectal wall. MATERIAL AND METHODS: We collected data from all patients with localised prostate cancer treated with SBRT (40Gy in 5 fractions) between 2018 and 2020. A hydrogel spacer (SpaceOAR®) was placed depending on the availability of the product. We collected dosimetric data for target volumes and organs at risk. We calculated mean values, which were compared using non-parametric tests. RESULTS: Among 35 patients, mean age was 75 years. Seventeen had a spacer placed, with a mean space created of 10mm. No complication was reported during the intervention. High doses to the rectal wall were significantly lower in spacer group (V38: 0.39 cm3 vs. 0.72 cm3; P=0.02). PTV were better covered in spacer group (P=0.07). Doses to the bladder wall were similar in both groups. CONCLUSION: Spacer procedure under local anesthesia was well tolerated. Hydrogel spacer allowed to reduce doses to the rectum while improving PTV coverage.

Patterns of practice of androgen deprivation therapy combined to radiotherapy in favorable and unfavorable intermediate risk prostate cancer. Results of The PROACT Survey from the French GETUG Radiation Oncology group.

PURPOSE: The intermediate-risk (IR) prostate cancer (PCa) group is heterogeneous in terms of prognosis. For unfavorable or favorable IR PCa treated by radiotherapy, the optimal strategy remains to be defined. In routine practice, the physician's decision to propose hormonal therapy (HT) is controversial. The PROACT survey aimed to evaluate pattern and preferences of daily practice in France in this IR population. MATERIALS AND METHODS: A web questionnaire was distributed to French radiotherapy members of 91 centers of the Groupe d'Etude des Tumeurs Uro-Genitales (GETUG). The questionnaire included four sections concerning: (i) the specialists who prescribe treatments and multidisciplinary decisions (MTD) validation; (ii) the definition of IR subsets of patients; (iii) radiotherapy parameters; (iv) the pattern of practice regarding cardiovascular (CV) and (iv) metabolic evaluation. A descriptive presentation of the results was used. RESULTS: Among the 82 responses (90% of the centers), HT schedules and irradiation techniques were validated by specific board meetings in 54% and 45% of the centers, respectively. Three-fourths (76%) of the centers identified a subset of IR patients for a dedicated strategy. The majority of centers consider PSA>15 (77%) and/or Gleason 7 (4+3) (87%) for an unfavorable IR definition. Overall, 41% of the centers performed systematically a CV evaluation before HT prescription while 61% consider only CV history/status in defining the type of HT. LHRH agonists are more frequently prescribed in both favorable (70%) and unfavorable (98%) IR patients. Finally, weight (80%), metabolic profile (70%) and CV status (77%) of patients are considered for follow-up under HT. CONCLUSION: To the best of our knowledge, this is the first survey on HT practice in IR PCa. The PROACT survey indicates that three-quarters of the respondents identify subsets of IR-patients in tailoring therapy. The CV status of the patient is considered in guiding the HT decision, its duration and type of drug.

[Retrospective study on the intensification of hypofractionated radiotherapy: The organizational change]. / Étude rétrospective sur l'intensification des pratiques de radiothérapie hypofractionnée : le virage organisationnel.

PURPOSE: External radiotherapy process is a chain of steps in which each of them is carried out only if the previous one has been completed. The development of hypofractionation practices in recent years tends to increase the workload of the stages of preparation for irradiation and to decrease the number of fractions per patient. The purpose of this retrospective study is to analyze the evolution of these practices in a single centre and to assess the organizational issues involved. MATERIAL AND METHODS: All radiation therapy records management data were extracted from the Radiation Therapy Information System. Radiotherapy sessions were identified by patient and by ICD (International Classification of Diseases) code. The filling rate of the treatment equipment was calculated using actual data from the radiotherapy department. RESULTS: From 2015 to 2019, there was an increase in the number of scans (+16%), the number of patients treated (+11.6%) and the volume of hours available for treatment (+12%). Also, there was a decrease in the total number of fractions (-5%), in the average number of fractions performed per treatment sequence (-19%), in the occupancy rate of the machines (-7%) and in the average number of fractions performed per patient treated for malignant tumours of the bronchi and lung (-38%), digestive organs (-37%), secondary (-19%) breast (-15%) and prostate (-15%). The number of fractions administered per treatment sequence between 2015 and 2019 decreased significantly for patients in age groups [20-69] (P<0.001) and [>70] (P<0.001). CONCLUSION: A paradox appears between the increase in the total number of patients treated and the decrease in the loading rate of linacs. This shift of workload has an impact on the quality and safety of care and on the organizational and investment strategies. It also has an economic impact where the model of reimbursement is based on per fraction pricing. A reorganization of radiotherapy services is inevitable.

Anion intercalated graphite: a combined electrochemical and tribological investigation by in situ AFM.

The intercalation of graphite by electrochemical methods is an efficient strategy to produce massive graphene flakes. In fact, when graphite is biased inside an acidic solution, anions enter inside the stratified structure of the electrode and reduce the layer-to-layer interaction. Consequently, a gentle sonication is sufficient to disperse the graphene flakes inside the electrolyte. In view of an optimisation of the production protocol, a detailed analysis of the intercalation mechanism at the molecular length scale is mandatory. In the last 30 years, electrochemical (EC) scanning probe microscopies (e.g. EC-STM and in situ AFM) have been widely exploited in this research topic. In fact, these techniques have the possibility of combining the EC characterisation (e.g. cyclic-voltammetry, CV) with mechanical characterisation (e.g. adhesion and friction) and topography acquisition with high (molecular) lateral resolution. In this work, we investigate the tribological properties of the basal surface of graphite before and after the anion intercalation. By comparing the results acquired after the extraction of the graphite electrode from the EC cell with those collected inside the EC cell during the CV by an in situ AFM, we show how some features deriving from anisotropic friction can be exploited to unveil the very early stage of graphite exfoliation.

EAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees†.

BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. SETTING: Online Delphi survey and consensus conference. PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach.

[Prostate brachytherapy: New techniques, new indications]. / Curiethérapie de la prostate : évolutions des indications et des techniques.

Prostate brachytherapy has been for a long time one of the standard treatments for low risk prostate cancer, with high rates of biochemical control and low levels of urinary and sexual late toxicity compared to other available techniques, namely external beam radiotherapy and radical prostatectomy. The aim of this article is to review the recent innovations of prostate brachytherapy, which suggest a bright future for the technique. We will discuss the extension of indications of permanent implant brachytherapy to favorable intermediate-risk patients, the use of novel isotopes such as Palladium 103 and Cesium 131, and the benefit of brachytherapy as a boost following external beam radiotherapy for intermediate and high-risk patients. We will also discuss the rise of high dose rate brachytherapy, as a boost or monotherapy, the increasing use of MRI for patient selection and treatment planning, as well as the development of brachytherapy as a means of focal therapy.

Predictors of treatment response to liraglutide in type 2 diabetes in a real-world setting.

AIMS: There is an unmet need among healthcare providers to identify subgroups of patients with type 2 diabetes who are most likely to respond to treatment. METHODS: Data were taken from electronic medical records of participants of an observational, retrospective study in Italy. We used logistic regression models to assess the odds of achieving glycated haemoglobin (HbA1c) reduction ≥ 1.0% point after 12-month treatment with liraglutide (primary endpoint), according to various patient-related factors. RECursive Partitioning and AMalgamation (RECPAM) analysis was used to identify distinct homogeneous patient subgroups with different odds of achieving the primary endpoint. RESULTS: Data from 1325 patients were included, of which 577 (43.5%) achieved HbA1c reduction ≥ 1.0% point (10.9 mmol/mol) after 12 months. Logistic regression showed that for each additional 1% HbA1c at baseline, the odds of reaching this endpoint were increased 3.5 times (95% CI: 2.90-4.32). By use of RECPAM analysis, five distinct responder subgroups were identified, with baseline HbA1c and diabetes duration as the two splitting variables. Patients in the most poorly controlled subgroup (RECPAM Class 1, mean baseline HbA1c > 9.1% [76 mmol/mol]) had a 28-fold higher odds of reaching the endpoint versus patients in the best-controlled group (mean baseline HbA1c ≤ 7.5% [58 mmol/mol]). Mean HbA1c reduction from baseline was as large as - 2.2% (24 mol/mol) in the former versus - 0.1% (1.1 mmol/mol) in the latter. Mean weight reduction ranged from 2.5 to 4.3 kg across RECPAM subgroups. CONCLUSIONS: Glycaemic response to liraglutide is largely driven by baseline HbA1c levels and, to a lesser extent, by diabetes duration.

Combined interventional sialendoscopy and intraductal steroid therapy for recurrent sialadenitis in Sjögren's syndrome: Results of a pilot monocentric trial.

OBJECTIVES: To evaluate the effectiveness of interventional sialendoscopy alone or combined with outpatient intraductal steroid irrigations in patients with sialadenitis due to Sjögren's syndrome (SS). DESIGN: A pilot therapeutic study. SETTING: ENT Clinics, Universities of Milan and Pavia. STUDY POPULATION: We included 22 patients with SS of whom 12 underwent interventional sialendoscopy followed by intraductal steroid irrigations (group A), and 10 interventional sialendoscopy alone (group B). OUTCOMES MEASURES: The following outcome measures were considered and recorded before and after the therapeutic intervention: (i) number of episodes of glandular swelling, (ii) cumulative prevalence of patients with glandular swelling assessed by the specific domain, the EULAR SS Disease Activity Index (ESSDAI), (iii) severity of pain by means of a 0-10 pain visual analogue scale (VAS), (iv) severity of xerostomia and other disease symptoms assessed by the EULAR SS Patient Reported Index (ESSPRI) and the Xerostomia Inventory questionnaire. RESULTS: The postoperative reduction in the mean number of episodes of glandular swelling was 87% (95% CI: 77-93) and 75% (95% CI: 47%-88%) in the groups A and B, respectively. The percentage of patients with glandular swelling decreased from 41.7% to 0.0% in the group A and from 30.0% to 0.0% in the group B, respectively. Most of the patients experienced a subjective clinical improvement documented by the statistically significant reductions in the postoperative mean pain VAS (group A P<.001; group B P=.004), Xerostomia Inventory (P<.001 and P=.003) and ESSPRI scores (P<.001 and P=.008). Interventional sialendoscopy followed by outpatient intraductal steroid irrigations was more effective than interventional sialendoscopy alone, when pain VAS, Xerostomia Inventory and ESSPRI scores before and after treatment were analysed together using the multivariate Hotelling T2 test (P=.0173). CONCLUSIONS: This pilot study confirms that interventional sialendoscopy with steroid duct irrigation significantly reduces the number of painful episodes of sialadenitis and improves the subjective sensation of oral dryness and other disease symptoms in patients with SS. The study results also suggest that the improvement is greater when interventional sialendoscopy is combined with a cycle of outpatient steroid ductal irrigations. Larger controlled randomised studies are certainly needed to confirm these preliminary data.

[Combination external beam radiation and brachytherapy boost for prostate cancer]. / Association de radiothérapie externe et de curiethérapie pour les cancers de la prostate.

Brachytherapy as sole treatment is standard of care for D'Amico classification low-risk prostate cancer. For intermediate and high-risk patients, brachytherapy can be associated to external beam radiation therapy to better take into account the risk of extracapsular effraction and/or seminal vesicle involvement. Three randomized studies have shown that this association increases freedom from relapse survival compared to exclusive external beam radiation therapy. This benefit is not shown for overall survival. The addition of a hormonal therapy to this association is most likely mandatory for high-risk patients, and needs to be confirmed for intermediate risk patients. Both high-dose rate and low-dose rate brachytherapy are suitable with similar biochemical disease free survival rates. High-dose rate brachytherapy seems to have a better genitourinary tolerance profile, while low-dose rate brachytherapy is an easier process and has a more widespread expertise.

Cyclometalated Pt(ii) complexes with a bidentate Schiff-base ligand displaying unexpected cis/trans isomerism: synthesis, structures and electronic properties.

Square planar platinum complexes are an important class of compounds used in (nano)technology, optoelectronics, medicinal chemistry and catalysis. The major research interests in cyclometalated Pt(ii) complexes focus on the selective modulation of their electronic properties and the control of the (cis/trans) geometry. For the first time, we unveil and demonstrate that cis-trans isomers of Pt(ii) complexes can be obtained in a derivative carrying the 1-phenyl-pirazolate (Hppz) and 2-hydroxy-1-naphtyl-(N-phenyl)imine ligands. The two isomers display significant differences in both optical and electronic properties. While luminescence is quenched in solution, they are brightly emissive in the PMMA matrix at room temperature and in the 2MeTHF rigid matrix at 77 K. The phosphorescent emission of the cis isomer, blue-shifted compared to that of the trans one, results from the significantly different trans influence of the ppz ligand. Theoretical investigation highlights the almost isoenergetic potential energy of the two isomers therefore explaining their formation and evidences a large geometry distortion of their triplet state, which should be responsible for the observed luminescence efficiency.

The survival impact of neoadjuvant hormonal therapy before radical prostatectomy for treatment of high-risk prostate cancer.

BACKGROUND: Several randomized controlled trials assessed the outcomes of patients treated with neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP). The majority of them included mainly low and intermediate risk prostate cancer (PCa) without specifically assessing PCa-related death (PCRD). Thus, there is a lack of knowledge regarding a possible effect of NHT on PCRD in the high-risk PCa population. We aimed to analyze the effect of NHT on PCRD in a multicenter high-risk PCa population treated with RP, using a propensity-score adjustment. METHODS: This is a retrospective multi-institutional study including patients with high-risk PCa defined as: clinical stage T3-4, PSA >20 ng ml-1 or biopsy Gleason score 8-10. We compared PCRD between RP and NHT+RP using competing risks analysis. Correction for group differences was performed by propensity-score adjustment. RESULTS: After application of the inclusion/exclusion criteria, 1573 patients remained for analysis; 1170 patients received RP and 403 NHT+RP. Median follow-up was 56 months (interquartile range 29-88). Eighty-six patients died of PCa and 106 of other causes. NHT decreased the risk of PCRD (hazard ratio (HR) 0.5; 95% confidence interval (CI) 0.32-0.80; P=0.0014). An interaction effect between NHT and radiotherapy (RT) was observed (HR 0.3; 95% CI 0.21-0.43; P<0.0008). More specifically, of patients who received adjuvant RT, those who underwent NHT+RP had decreased PCRD rates (2.3% at 5 year) compared to RP (7.5% at 5 year). The retrospective design and lack of specific information about NHT are possible limitations. CONCLUSIONS: In this propensity-score adjusted analysis from a large high-risk PCa population, NHT before surgery significantly decreased PCRD. This effect appeared to be mainly driven by the early addition of RT post-surgery. The specific sequence of NHT+RP and adjuvant RT merits further study in the high-risk PCa population.

Estimating the real incidence of invasive listeriosis through an integrated surveillance model in use in Lombardy (Italy, 2006-2014).

The annual incidence of listeriosis in Italy is lower (0·19-0·27 per 100 000 inhabitants per year) than in Europe (0·34-0·52 per 100 000 inhabitants per year). Since the observed incidence of listeriosis may be biased downward for underdiagnosis or under-reporting, this work aims to estimate the real incidence of listeriosis during a 9-year period in the Lombardy region, Italy. Data on listeriosis cases were collected from national mandatory notification system (MAINF) and Laboratory-based Surveillance System (LabSS). The two sources were cross-matched and capture-recapture method was applied to estimate the number of undetected cases and the real incidence of invasive listeriosis. Five hundred and eighty invasive listeriosis cases were detected by the two sources between 2006 and 2014: 50·2% were identified only via MAINF, 16·7% were recorded only via LabSS, overlaps occurred in 192 cases (33·1%). The mean annual incidence detected only by MAINF was 0·56 per 100 000 inhabitants, which rose to 0·67 per 100 000 considering also the cases detected by LabSS. The capture-recapture method allowed to estimate an incidence of 0·84 per 100 000. The high incidence of listeriosis may be due to improved sensitivity of the surveillance system, but also reflect a real increase, associated with an increased population at risk.

Guided folding takes a start from the molecular imprinting of structured epitopes.

A biomimetic route towards assisted folding was explored. Molecularly imprinted polymeric nanoparticles (MIP NPs), i.e. biomimetics with entailed molecular recognition properties made by a template assisted synthesis, were prepared to target a structured epitope: the cystine containing peptide CC9ox, which corresponds to the apical portion of the ß-hairpin hormone Hepcidin-25. The structural selection was achieved by the MIP NPs; moreover, the MIP NPs demonstrated favouring the folding of the linear random peptide (CC9red) into the structured one (CC9ox), anticipating the future role of the MIP NPs as in situ nanomachines to counteract folding defects.

Standardization of definitions in focal therapy of prostate cancer: report from a Delphi consensus project.

PURPOSE: To reach standardized terminology in focal therapy (FT) for prostate cancer (PCa). METHODS: A four-stage modified Delphi consensus project was undertaken among a panel of international experts in the field of FT for PCa. Data on terminology in FT was collected from the panel by three rounds of online questionnaires. During a face-to-face meeting on June 21, 2015, attended by 38 experts, all data from the online rounds were reviewed and recommendations for definitions were formulated. RESULTS: Consensus was attained on 23 of 27 topics; Targeted FT was defined as a lesion-based treatment strategy, treating all identified significant cancer foci; FT was generically defined as an anatomy-based (zonal) treatment strategy. Treatment failure due to the ablative energy inadequately destroying treated tissue is defined as ablation failure. In targeting failure the energy is not adequately applied to the tumor spatially and selection failure occurs when a patient was wrongfully selected for FT. No definition of biochemical recurrence can be recommended based on the current data. Important definitions for outcome measures are potency (minimum IIEF-5 score of 21), incontinence (new need for pads or leakage) and deterioration in urinary function (increase in IPSS >5 points). No agreement on the best quality of life tool was established, but UCLA-EPIC and EORTC-QLQ-30 were most commonly supported by the experts. A complete overview of statements is presented in the text. CONCLUSION: Focal therapy is an emerging field of PCa therapeutics. Standardization of definitions helps to create comparable research results and facilitate clear communication in clinical practice.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

Efficacy, safety and acceptability of the new pen needle 33G × 4 mm. AGO 01 study.

OBJECTIVES: Adherence to insulin therapy can be threatened by pain and needle fear. This cross-over randomized non-inferiority trial evaluated a new Pic Insupen 33G × 4 mm needle vs. a 32G × 4 mm needle in terms of metabolic control, safety and acceptability in patients with diabetes treated with insulin. RESEARCH DESIGN AND METHODS: We used a centralized, permuted block randomization, stratified by center and maximum insulin dose per single injection. Subjects used the two needles in two 3 week treatment periods. The primary endpoint was the absolute percentage variation of the blood fructosamine between the two treatments (% |ΔFru|). Additional endpoints were: glycemic variability, total insulin doses, body weight, severe hypoglycemic episodes, leakage at injection sites and pain measured by visual analogue scale. Equivalent glycemic control was defined a priori as % |ΔFru| (including 95% CI) within 20%. RESULTS: Of 87 subjects randomized, 77 completed the study (median age 53.1 [IR 42.3-61.2], median BMI 24.3 Kg/m(2) [IR 21.3-28.5], median duration of insulin therapy [in months] 141.4 (IR 56.3-256.9), median baseline HbA1c 7.9% [IR 7.2-8.8]). The % |ΔFru| was 7.93% (95% CI 6.23-9.63), meeting the non-inferiority criterion. The fasting blood glucose standard deviation was 46.2 (mean 154.6) with the 33G needle and 42.8 (mean 157.3) with the 32G needle (p=0.42). Insulin daily dose and patients' weight did not show any statistically significant variation. We observed 95 episodes of symptomatic hypoglycemia with the 33G needle and 96 with the 32G needle. One episode of severe hypoglycemia was documented in the latter group. As for insulin leakage we observed 37.55 episodes per 100 patient-days with the 33G needle and 32.21 episodes per 100 patient-days with the 32G needle (p=0.31). Patients reported less pain with the 33G × 4 mm needle (p=0.05). STUDY LIMITATIONS: Study sample was mainly composed of adults with type 1 diabetes and study was not blinded. CONCLUSIONS: The 33G needle is not inferior to the 32G needle in terms of efficacy and safety, with reduced pain and no difference in insulin leakage. CLINICAL TRIAL REGISTRATION: NCT01745549.