Sacral nerve stimulation for faecal incontinence: response rate,satisfaction and the value of preoperative investigation in patient selection

Objective Before undergoing sacral nerve stimulation (SNS) for faecal incontinence (FI), patients are investigated with morphologic, dynamic and electrophysiologic tests. The purpose of our study was to evaluate their value in the selection of patients who may benefit most from neuromodulation. Method If temporary stimulation resulted in a good objective response, a permanent neuromodulator was implanted. Patients were reviewed at 3 months and then at 6 monthly intervals. Asked by telephone, patient’s satisfaction was described as good, satisfactory or poor. Results Forty‐five consecutive patients (41 females, median age 59 years) with FI (Wexner 16.1 ± 2.9) underwent SNS. Temporary stimulation was successful in 32 (71)% patients. At a median follow‐up of 33 months, the neuromodulator remained in place in 25 (55%) patients, two do whom switched it off, leaving 23 (51%) with a functioning neuromodulator. There was no statistically significant difference between the characteristics (including manometry, ultrasound and electrophysiology) of patients undergoing implantation (n = 32) or not (n = 13) and those with or without a functioning stimulator (n = 23: n = 13). In the 23 patients with a functioning stimulator the result was good in 12, satisfactory in five and poor in six. There was no statistically significant difference in the patient characteristics between those with a good result (n = 12) and the remainder (n = 32). Conclusion The findings suggest that investigation for FI does not facilitate patient selection for SNS and cannot be used to predict outcome.     

Clinical outcomes of patients with anterior segment neovascularization treated with or without intraocular bevacizumab

Introduction  The purpose of this study was to evaluate the clinical outcomes of patients with anterior segment neovascularization treated with or without intravitreal bevacizumab. Methods  This was a retrospective, comparative case series of 60 patients with anterior segment neovascularization: 30 consecutive patients treated with intravitreal bevacizumab and 30 age-, gender-, and race-matched controls treated without bevacizumab. Results  The mean follow-up time was 9.1±6.3 months in the bevacizumab group and 8.6±6.2 months in the control group (P=0.769). At baseline, no significant difference was observed in initial visual acuity, intraocular pressure, gonioscopy, and iris or angle neovascularization (P=0.179, 0.432, 0.065, and 0.966, respectively). At the final examination, no significant difference was observed in mean intraocular pressure (P=0.464), mean number of glaucoma medications (P=1.00), or presence of anterior segment neovascularization (P=0.699). Final visual acuity better than 20/60 was achieved in six patients in the bevacizumab group and none in the control group (P=0.013). Comparison of linear regressions of baseline and final visual acuity (LogMAR) showed a significant difference between the two groups (P=0.040). In the bevacizumab group, 18 patients required glaucoma surgery, whereas 30 patients in the control group required surgery (P<0.001), usually with a glaucoma drainage implant. Both bevacizumab and control patients who presented with closed angles required glaucoma surgery (P=1.000). Conclusions  Treatment of anterior segment neovascularization with intravitreal bevacizumab significantly improves visual outcomes and significantly decreases the need for glaucoma surgery. In patients with closed anterior chamber angle, addition of bevacizumab treatment does not reduce the need for glaucoma surgery.     

Designs for testing lack of fit for a nonlinear dose-response curve model

We would like to estimate the parameters of a dose-response function with the greatest precision as possible. For a two-parameter model, this is equivalent to minimizing the area of the confidence ellipsoid, i.e., a D-optimal design. Previous work on this particular model has included minimal designs. These designs are unable to determine lack of fit. We introduce a distinct dose level to the design to be able to estimate the lack of fit. The minimal and new designs will be compared, and the sample size needed to achieve adequate power for the lack-of-fit test will be derived.     

Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers

To prevent chemotherapy-induced nausea and vomiting, aprepitant is given with a corticosteroid and a 5-hydroxytryptamine type 3 antagonist, such as dolasetron. Dolasetron is converted to the active metabolite hydrodolasetron, which is cleared largely via CYP2D6. The authors determined whether aprepitant, a moderate CYP3A4 inhibitor, alters hydrodolasetron pharmacokinetics in CYP2D6 poor and extensive metabolizers. Six CYP2D6 poor and 6 extensive metabolizers were randomized in an open-label, crossover fashion to treatment A (dolasetron 100 mg on day 1) and treatment B (dolasetron 100 mg plus aprepitant 125 mg on day 1, aprepitant 80 mg on days 2-3). For hydrodolasetron area under the concentration-versus-time curve (AUC0-infinity) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (2.0) for clinical significance (AUC0-infinity, 1.09 [90% CI, 1.01-1.18], Cmax, 1.08 [90% CI, 0.94-1.24]). Aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.     

Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18

Human papillomavirus (HPV) infection causes cervical cancer and genital warts. Young women (1106) were randomized to receive one of three formulations of a quadrivalent HPV (Types 6/11/16/18) L1 virus-like particle (VLP) vaccine or one of two placebo formulations. The goal was to assess vaccine safety and immunogenicity in baseline HPV 6/11/16 or 18-naïve and previously infected subjects. All three formulations were highly immunogenic. At Month 2 (postdose 1), among women with vaccine-type antibodies at baseline, vaccine-induced anti-HPV responses were ∼12- to 26-fold higher than those observed in baseline-naïve women, suggesting an anamnestic response. Following an initial, similar sized decline, anti-HPV responses plateaued and remained stable through end-of-study (3.0 years). No vaccine-related serious adverse experiences were reported.     

Efficacy and safety of caspofungin therapy in elderly patients with proven or suspected invasive fungal infections

Invasive fungal infections (IFIs) are serious complications in elderly adults. Caspofungin may provide a useful therapeutic option for elderly patients with or at high risk for IFIs. We retrospectively compared efficacy and safety outcomes in elderly (>/=65 years of age) and non-elderly patients in three clinical trials of caspofungin: a double-blind, randomized trial versus amphotericin B for documented invasive candidiasis (IC); an open-label, non-comparative study of definite or probable invasive aspergillosis (IA); and a double-blind, randomized trial versus liposomal amphotericin B as empirical therapy (ET) in febrile neutropenic patients. A total of 159 elderly patients with a median age of 71 years (range, 65-84) received caspofungin in these studies. The median duration of caspofungin therapy was 12 days for IC and ET, and 28 days for IA. Point estimates for the favorable response rates to caspofungin were numerically higher in elderly versus non-elderly patients with IC (83% vs. 68%) or IA (64% vs. 44%) and were similar in patients receiving ET (36% vs. 34%). Adverse events related to caspofungin occurred in generally similar proportions of elderly versus non-elderly patients with IC (clinical, 33% vs. 27%; laboratory, 17% vs. 29%), with IA (clinical, 7% vs. 13%; laboratory, 13% vs. 14%), or receiving ET (clinical, 47% vs. 47%; laboratory, 24% vs. 22%). Nephrotoxicity and infusion-related toxicity developed in comparable proportions of elderly and non-elderly caspofungin recipients in all three studies. In this post-hoc analysis, caspofungin appeared to be as efficacious and well tolerated in elderly patients as in non-elderly patients.     

Safety and clinical efficacy of the double switch from originator infliximab to biosimilars CT‐P13 and SB2 in patients with inflammatory bowel diseases (SCESICS): A multicenter cohort study

Data regarding double switching from originator infliximab (IFX) to IFX biosimilars in inflammatory bowel diseases (IBDs) are lacking. The purpose of this study was to evaluate the safety and efficacy of switching from originator IFX to CT‐P13 and subsequently to SB2 (double switch) in patients with IBD. Patients undergoing IFX‐double switch in eight Centers in Lombardy (Italy) from November 2018 to May 2019 were retrospectively analyzed. The IFX discontinuation rate, incidence and type of adverse events (AEs), and clinical remission rate were recorded. A comparison with a control group of patients with IBD single‐switched from originator IFX to CT‐P13 was performed, before and after an inverse probability of treatment weighting (IPTW)‐based propensity score analysis. Fifty‐two double‐switched patients with IBD were enrolled. The 24‐ and 52‐week proportions of patients continuing on IFX therapy following the second switch (CTP13 → SB2) were 98% (95% confidence interval [CI] 94%–100%) and 90% (95% CI 81%–99%), respectively. Four patients experienced a total of five AEs, all graded 1–3 according to Common Terminology Criteria for Adverse Events (CTCAE). No infusion reactions were observed. The 24‐week and follow‐up end clinical remission rates following the second switch were 94% and 88%, respectively. No differences were observed in the safety and efficacy outcomes by comparing the double‐switch group with a single‐switch group of 66 patients with IBD; all these results were confirmed by IPTW‐adjusted analysis. The study suggests both the safety and efficacy of the double switch from originator IFX to CT‐P13 and SB2 in patients with IBD is maintained. This strategy may be associated with potential cost implications.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Biosimilars reduce the direct costs of therapy and facilitate access to high‐cost therapies to patients. Data show that switching from originator infliximab to infliximab biosimilars (CT‐P13 or SB2) is safe and effective. Few data are available on the outcomes of double switch (from biological originator to a first biosimilar and then to a second biosimilar), and caution has been expressed by the European Crohn’s and Colitis Organization (ECCO) and the Italian Group for the study of inflammatory bowel disease (IBD; IG‐IBD).

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study was aimed to compare the effectiveness and safety of single and double switch of infliximab (IFX) in patients with IBDs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

No differences were found in clinical response and remission as well as adverse events between either single or double IFX switch. Data were consistent with the safety profile of IFX.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Double switch strategy is safe and effective in IBD. These data assume high relevance in terms of cost‐savings strategies.