Challenges and advancing strategies of endoscopic submucosal dissection for early gastric cancer: The puzzle of eCura C1.

In this editorial, we explore the challenges of managing noncurative resections in early gastric cancer after endoscopic submucosal dissection (ESD), starting from the consideration recently made by Zhu et al. Specifically, we evaluate the management of eCura C1 lesions, where decisions regarding further interventions are pivotal yet contentious. Collaboration among endoscopists, surgeons, and pathologists is underscored to refine risk assessment and personalize therapeutic management. Recent advancements in ESD techniques and interdisciplinary collaboration offer opportunities for outcome optimization in managing eCura C1 lesions. Moreover, despite needing further clinical validation, molecular biomarkers have emerged as promising tools for enhancing prognostication. This manuscript highlights the ongoing research attempts to define treatment paradigms effectively and evaluates the potential of emerging options, ultimately aiming to improve patient care and outcomes in this complex clinical scenario.

The Derivation and External Validation of a Fibrosis Risk Model for Colorectal Tumours Undergoing Endoscopic Submucosal Dissection.

Background: Endoscopic submucosal dissection (ESD) is an advanced technique that can become more challenging in the presence of submucosal fibrosis. Predicting the grade of fibrosis is important in order to identify technically difficult ESD. Aims and Methods: Our study aimed to derive and validate a prediction model to determine the preoperative degree of submucosal fibrosis in colorectal tumours undergoing ESD. A predictive model was developed to derive the probability of an increasing submucosal fibrosis in the derivation cohort and then externally validated. Results: 309 patients (age: 68 ± 10.9 years) underwent colorectal ESD between January 2016 and June 2020. F0, F1, and F2 fibroses were reported in 196 (63.4%), 70 (22.6%), and 43 (13.9%) cases, respectively. R0 resection was found in 266 (87%) lesions. At multivariable analysis in the derivation cohort, lesion morphology (OR = 0.37 and CI = 0.14-0.97 for LST-NG vs. 0-Is; OR = 0.29 and CI = 0.1-0.87 for the LST mixed type vs. 0-Is; and OR = 0.32 and CI = 0.1-1.03 for LST-G vs. 0-Is) and increasing size (OR = 1.02 and CI = 1.01-1.04 for a 1 mm increase) were significantly associated with an increasing degree of fibrosis. The model had fair discriminating ability in the derivation group (AUROC = 0.61 and CI = 0.52-0.69 for F1-F2 vs. F0 fibroses; AUROC = 0.61 and CI = 0.45-0.77 for F2 vs. F0-F1 fibroses) and in the validation group (AUROC = 0.71 and CI = 0.59-0.83 for F1-F2 vs. F0 fibroses; AUROC = 0.65 and CI = 0.52-0.77 for F2 vs. F0-F1 fibroses). Conclusions: Our findings introduce a new tool for the stratification of ESD technical difficulty based on lesion size and morphological characteristics which could become crucial during the procedure's planning process.

Effectiveness and safety of newly introduced endoscopic submucosal dissection in a Western center: a real-life study.

OBJECTIVES: Endoscopic submucosal dissection (ESD) is a minimally invasive technique for the resection of superficial gastrointestinal lesions, providing high rates of 'en bloc' and R0 resection. East-West differences in ESD quality indicators have been reported. This study aims to assess feasibility, effectiveness, and safety of ESD for the treatment of superficial gastrointestinal (GI) lesions in a Western cohort. METHODS: Consecutive patients undergoing ESD at one Italian endoscopic referral center from September 2018 to March 2020 were included in this prospective study. Primary outcomes were technical success, R0 resection rate, curative resection rate, and adverse events (AEs). RESULTS: In total 111 patients (111 lesions) undergoing ESD were included. Anatomic site of the lesions was rectum in 56.8%, colon in 13.5%, stomach in 24.3%, and esophagus in 5.4% of cases, respectively. For upper GI procedures, technical success was 100%, and R0 and curative resection rates were 84.8% and 78.8%, respectively. For colorectal procedures, technical success was 98.7%, R0 and curative resection rates were 88.5% and 84.6%, respectively. Major AEs were reported in 12 cases (10.8%). CONCLUSION: The introduction of ESD in a Tertiary Center is feasible, effective, and safe, and should be taken into consideration for the treatment of superficial GI lesions requiring 'en bloc' resection.

Underwater Endoscopic Mucosal Resection Vs Conventional Endoscopic Mucosal Resection for Superficial Nonampullary Duodenal Epithelial Tumors in the Western Setting.

BACKGROUND & AIMS: Conventional endoscopic mucosal resection (C-EMR) is established as the primary treatment modality for superficial nonampullary duodenal epithelial tumors (SNADETs), but recently underwater endoscopic mucosal resection (U-EMR) has emerged as a potential alternative. The majority of previous studies focused on Asian populations and small lesions (≤20 mm). We aimed to compare the efficacy and outcomes of U-EMR vs C-EMR for SNADETs in a Western setting. METHODS: This was a retrospective multinational study from 10 European centers that performed both C-EMR and U-EMR between January 2013 and July 2023. The main outcomes were the technical success, procedure-related adverse events (AEs), and the residual/recurrent adenoma (RRA) rate, evaluated on a per-lesion basis. We assessed the association between the type of endoscopic mucosal resection and the occurrence of AEs or RRAs using mixed-effects logistic regression models (propensity scores). Sensitivity analyses were performed for lesions ≤20 mm or >20 mm. RESULTS: A total of 290 SNADETs submitted to endoscopic resection during the study period met the inclusion criteria and were analyzed (C-EMR: n = 201, 69.3%; U-EMR: n = 89, 30.7%). The overall technical success rate was 95.5% and comparable between groups. In logistic regression models, compared with U-EMR, C-EMR was associated with a significantly higher frequency of overall delayed AEs (odds ratio [OR], 4.95; 95% CI, 2.87-8.53), postprocedural bleeding (OR, 7.92; 95% CI, 3.95-15.89), and RRAs (OR, 3.66; 95% CI, 2.49-5.37). Sensitivity analyses confirmed these results when solely considering either small (≤20 mm) or large (>20 mm) lesions. CONCLUSIONS: Compared with C-EMR, U-EMR was associated with a lower rate of overall AEs and RRAs, regardless of lesion size. Our results confirm the possible role of U-EMR as an effective and safe technique in the management of SNADETs.

Technical failure during colorectal endoscopic full-thickness resection: the "through thick and thin" study.

BACKGROUND: Endoscopic full-thickness resection (EFTR) is an effective and safe technique for nonlifting colorectal lesions. Technical issues or failures with the full-thickness resection device (FTRD) system are reported, but there are no detailed data. The aim of our study was to quantify and classify FTRD technical failures. METHODS: We performed a retrospective study involving 17 Italian centers with experience in advanced resection techniques and the required devices. Each center shared and classified all prospectively collected consecutive failures during colorectal EFTR using the FTRD from 2018 to 2022. The primary outcome was the technical failure rate and their classification; secondary outcomes included subsequent management, clinical success, and complications. RESULTS: Included lesions were mainly recurrent (52 %), with a mean (SD) dimension of 18.4 (7.5) mm. Among 750 EFTRs, failures occurred in 77 patients (35 women; mean [SD] age 69.4 [8.9] years). A classification was proposed: type I, snare noncutting (53 %); type II, clip misdeployment (31 %); and type III, cap misplacement (16 %). Among endoscopic treatments completed, rescue endoscopic mucosal resection was performed in 57 patients (74 %), allowing en bloc and R0 resection in 71 % and 64 %, respectively. The overall adverse event rate was 27.3 %. Pooled estimates for the rates of failure, complications, and rescue endoscopic therapy were similar for low and high volume centers (P = 0.08, P = 0.70, and P = 0.71, respectively). CONCLUSIONS: Colorectal EFTR with the FTRD is a challenging technique with a non-negligible rate of technical failure and complications. Experience in rescue resection techniques and multidisciplinary management are mandatory in this setting.

Predicting residual neoplasia after a non-curative gastric ESD: validation and modification of the eCura system in the Western setting: the W-eCura score.

OBJECTIVE: To evaluate the risk factors for lymph node metastasis (LNM) after a non-curative (NC) gastric endoscopic submucosal dissection (ESD) and to validate and eventually refine the eCura scoring system in the Western setting. Also, to assess the rate and risk factors for parietal residual disease. DESIGN: Retrospective multicentre multinational study of prospectively collected registries from 19 Western centres. Patients who had been submitted to surgery or had at least one follow-up endoscopy were included. The eCura system was applied to assess its accuracy in the Western setting, and a modified version was created according to the results (W-eCura score). The discriminative capacities of the eCura and W-eCura scores to predict LNM were assessed and compared. RESULTS: A total of 314 NC gastric ESDs were analysed (72% high-risk resection (HRR); 28% local-risk resection). Among HRR patients submitted to surgery, 25% had parietal disease and 15% had LNM in the surgical specimen. The risk of LNM was significantly different across the eCura groups (areas under the receiver operating characteristic curve (AUC-ROC) of 0.900 (95% CI 0.852 to 0.949)). The AUC-ROC of the W-eCura for LNM (0.916, 95% CI 0.870 to 0.961; p=0.012) was significantly higher compared with the original eCura. Positive vertical margin, lymphatic invasion and younger age were associated with a higher risk of parietal residual lesion in the surgical specimen. CONCLUSION: The eCura scoring system may be applied in Western countries to stratify the risk of LNM after a gastric HRR. A new score is proposed that may further decrease the number of unnecessary surgeries.

Performance of endoscopic submucosal dissection for undifferentiated early gastric cancer: a multicenter retrospective cohort.

Background and study aims Undifferentiated early gastric cancer (UD-EGC) represents an extended indication for endoscopic submucosal dissection (ESD) based on the existing guidelines. This study evaluated the prevalence of UD-EGC recurrence after ESD, and potentially implicated risk factors. Patients and methods Data from 17 centers were collected retrospectively including demographics, endoscopic and pathological findings, and follow-up data from UD-EGC cases treated by ESD. Patients with incomplete resection or advanced disease were excluded. Descriptive statistics quantified variables and calculated the incidence of recurrence. Chi-square test was applied to assess any link between independent variables and relapse; significantly associated variables were inserted to a multivariable regression model. Results Seventy-one patients were eligible, with 2:1 female to male ratio and age of 65.8 ± 11.8 years. Mean lesion size was 33.5 ± 18.8 mm and the most frequent histological subtype was signet ring-cells UGC (2:1). Patients were followed-up every 5.6 ± 3.7 months with a mean surveillance period of 29.3 ± 15.3 months until data collection. Four patients (5.6%) developed local recurrence 8.8 ± 6.5 months post-ESD, with no lymph node or distal metastases been reported. Lesion size was not associated with recurrence ( P = 0.32), in contrast to lymphovascular and perineural invasion which were independently associated with local recurrence ( P = 0.006 and P < 0.001, respectively). Conclusions ESD could be considered as the initial step to manage UD-EGC, providing at least an "entire-lesion" biopsy to guide therapeutic strategy. When histology confirms absence of lymphovascular and perineural invasion, this modality could be therapeutic, providing low recurrence rates.

Risk of Residual Neoplasia after a Local-Risk Resection of Colorectal Lesions by Endoscopic Submucosal Dissection: A Multinational Study.

Endoscopic submucosal dissection (ESD) in colorectal lesions is demanding, and a significant rate of non-curative procedures is expected. We aimed to assess the rate of residual lesion after a piecemeal ESD resection, or after an en bloc resection but with positive horizontal margins (local-risk resection-LocRR), for colorectal benign neoplasia. A retrospective multicenter analysis of consecutive colorectal ESDs was performed. Patients with LocRR ESDs for the treatment of benign colorectal lesions with at least one follow-up endoscopy were included. A cohort of en bloc resected lesions, with negative margins, was used as the control. A total of 2255 colorectal ESDs were reviewed; 352 of the ESDs were "non-curative". Among them, 209 were LocRR: 133 high-grade dysplasia and 76 low-grade dysplasia. Ten cases were excluded due to missing data. A total of 146 consecutive curative resections were retrieved for comparison. Compared to the "curative group", LocRRs were observed in lengthier procedures, with larger lesions, and in non-granular LSTs. Recurrence was higher in the LocRR group (16/199, 8% vs. 1/146, 0.7%; p = 0.002). However, statistical significance was lost when considering only en bloc resections with positive horizontal margins (p = 0.068). In conclusion, a higher rate of residual lesion was found after a piecemeal ESD resection, but not after an en bloc resection with positive horizontal margins.

Factors influencing the presence of potentially explosive gases during colonoscopy: Results of the SATISFACTION study.

This study tested the hypothesis that bowel preparation with mannitol should not affect the colonic concentration of H2 and CH4 . Therefore, the SATISFACTION study, an international, multicenter, randomized, parallel-group phase II-III study investigated this issue. The phase II dose-finding part of the study evaluated H2 , CH4 , and O2 concentrations in 179 patients randomized to treatment with 50 g, 100 g, or 150 g mannitol. Phase III of the study compared the presence of intestinal gases in 680 patients randomized (1:1) to receive mannitol 100 g in single dose or a standard split-dose 2 L polyethylene glycol (PEG)-Asc preparation (2 L PEG-Asc). Phase II results showed that mannitol did not influence the concentration of intestinal gases. During phase III, no patient in either group had H2 or CH4 concentrations above the critical thresholds. In patients with H2 and/or CH4 levels above detectable concentrations, the mean values were below the risk thresholds by at least one order of magnitude. The results also highlighted the effectiveness of standard washing and insufflation maneuvers in removing residual intestinal gases. In conclusion, bowel cleansing with mannitol was safe as the concentrations of H2 and CH4 were the same as those found in patients prepared with 2 L PEG-Asc. In both groups, the concentrations of gases were influenced more by the degree of cleansing achieved and the insufflation and washing maneuvers performed than by the preparation used for bowel cleansing. The trial protocol was registered with ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT04759885) and with EudraCT (eudract_number: 2019-002856-18).

Risk of residual neoplasia after a noncurative colorectal endoscopic submucosal dissection for malignant lesions: a multinational study.

BACKGROUND : Endoscopic submucosal dissection (ESD) in colorectal lesions is technically demanding and a significant rate of noncurative procedures is expected. We aimed to assess the rate of residual lesions after a noncurative ESD for colorectal cancer (CRC) and to establish predictive scores to be applied in the clinical setting. METHODS : Retrospective multicenter analysis of consecutive colorectal ESDs. Patients with noncurative ESDs performed for the treatment of CRC lesions submitted to complementary surgery or with at least one follow-up endoscopy were included. RESULTS : From 2255 colorectal ESDs, 381 (17 %) were noncurative, and 135 of these were performed in CRC lesions. A residual lesion was observed in 24 patients (18 %). Surgery was performed in 96 patients and 76 (79 %) had no residual lesion in the colorectal wall or in the lymph nodes. The residual lesion rate for sm1 cancers was 0 %, and for > sm1 cancers was also 0 % if no other risk factors were present. Independent risk factors for lymph node metastasis were poor differentiation and lymphatic permeation (NC-Lymph score). Risk factors for the presence of a residual lesion in the wall were piecemeal resection, poor differentiation, and positive/indeterminate vertical margin (NC-Wall score). CONCLUSIONS : Lymphatic permeation or poor differentiation warrant surgery owing to their high risk of lymph node metastasis, mainly in > sm1 cancers. In the remaining cases, en bloc and R0 resections resulted in a low risk of residual lesions in the wall. Our scores can be a useful tool for the management of patients who undergo noncurative colorectal ESDs.

Predictive Factors of Adequate Bowel Cleansing for Colonoscopy in the Elderly: A Retrospective Analysis of a Prospective Cohort.

Factors affecting the quality of bowel preparation for colonoscopy in the elderly are not fully known, and current guidelines provide no specific recommendations. This study aimed to assess the difference in bowel cleansing in young and elderly patients and evaluate predictors of bowel cleansing in the elderly. We retrospectively reviewed a prospective cohort of 1289 patients performing colonoscopy after a 1-, 2-, or 4-L PEG-based preparation. All 1289 were included in the analysis. Overall, 44.6% of patients were aged ≥65 years. Cleansing success (CS) was achieved in 77.3% and 70.3% of patients aged <65 years and ≥65 years, respectively. At multivariable analysis, split regimen (OR = 2.43, 95% CI = 1.34−4.38; p = 0.003), adequate cleansing at previous colonoscopy (OR = 2.29, 95% CI = 1.14−4.73; p = 0.02), tolerability score (OR = 1.29, 95% CI = 1.16−1.44; p < 0.001), a low-fiber diet for at least 3 days (OR = 2.45, 95% CI = 1.42−4.24; p = 0.001), and colonoscopy within 5 h after the end of preparation (OR = 2.67, 95% CI = 1.28−5.56; p = 0.008) were independently associated with CS in the elderly. Combining a low-fiber diet for at least 3 days, split preparation, and colonoscopy within 5 h allowed a CS rate above 90% and should always be encouraged. A 1-L PEG-ASC preparation was also associated with greater high-quality cleansing of the right colon and may be preferred.

From advanced diagnosis to advanced resection in early neoplastic colorectal lesions: Never-ending and trending topics in the 2020s.

Colonoscopy represents the most widespread and effective tool for the prevention and treatment of early stage preneoplastic and neoplastic lesions in the panorama of cancer screening. In the world there are different approaches to the topic of colorectal cancer prevention and screening: different starting ages (45-50 years); different initial screening tools such as fecal occult blood with immunohistochemical or immune-enzymatic tests; recto-sigmoidoscopy; and colonoscopy. The key aspects of this scenario are composed of a proper bowel preparation that ensures a valid diagnostic examination, experienced endoscopist in detection of preneoplastic and early neoplastic lesions and open-minded to upcoming artificial intelligence-aided examination, knowledge in the field of resection of these lesions (from cold-snaring, through endoscopic mucosal resection and endoscopic submucosal dissection, up to advanced tools), and management of complications.

Quality performance measures in upper gastrointestinal endoscopy for lesion detection: Italian AIGO-SIED-SIGE joint position statement.

Esophagogastroduodenoscopy (EGD) plays a crucial role in the management of gastroduodenal diseases by allowing a direct and accurate evaluation of the mucosa and the execution of several operative maneuvers. Despite a constant development of new imaging tools and operative devices, the widespread use of EGD has not resulted in a significant reduction of mortality for patients affected by esophageal/gastric cancer during the last three decades in Western countries. Evidence indicates that this disheartening scenario derives from a high variability of execution of EGD which determines its quality and diagnostic yield, delaying the diagnosis of neoplastic diseases. Based on this evidence, in recent years many scientific societies have produced different position papers aimed at defining quality performance measures in EGD. Thus, the Italian Association of Gastroenterologists and Endoscopists, the Italian Society of Digestive Endoscopy and the Italian Society of Gastroenterology have produced this joint document based on the review of ASGE, ACG, BSG, ESGE and Asian Consensus EGD position papers with the aim of indicating the quality standards of EGD (pre-, intra- and post-procedure) focused on lesion detection to be adopted in the Italian context.

Digital single-operator cholangioscopy in diagnostic and therapeutic bilio-pancreatic diseases: A prospective, multicenter study.

BACKGROUND AND AIM: Digital single-operator cholangioscopy (D-SOC) is an endoscopic procedure that is increasingly used for the management of bilio-pancreatic diseases. We aimed to investigate the efficacy and safety of D-SOC for diagnostic and therapeutic indications. METHODS: This is a multicenter, prospective study(January 2016-June 2019) across eighteen tertiary centers. The primary outcome was procedural success of D-SOC. Secondary outcomes were: D-SOC visual assessment and diagnostic yield of SpyBite biopsy in cases of biliary strictures, stone clearance rate in cases of difficult biliary stones, rate of adverse events(AEs) for all indications. RESULTS: D-SOC was performed in 369 patients (201(54,5%) diagnostic and 168(45,5%)therapeutic). Overall, procedural success rate was achieved in 360(97,6%) patients. The sensitivity, specificity, PPV, NPV and accuracy in biliary strictures were: 88,5%, 77,3%, 83,3%, 84,1% and 83,6% for D-SOC visual impression; 80,2%, 92,6%, 95,1%, 72,5% and 84,7% for the SpyBite biopsy, respectively. For difficult biliary stones, complete duct clearance was obtained in 92,1% patients (82,1% in a single session). Overall, AEs occurred in 37(10%) cases.The grade of AEs was mild or moderate for all cases, except one which was fatal. CONCLUSION: D-SOC is effective for diagnostic and therapeutic indications.Most of the AEs were minor and managed conservatively, even though a fatal event has happened that is not negligible and should be considered before using D-SOC.

Therapeutic strategies for gastroenteropancreatic neuroendocrine neoplasms: State-of-the-art and future perspectives.

Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have always been considered rare tumors, their incidence has risen over the past few decades. They represent a highly heterogeneous group of neoplasms with several prognostic factors, including disease stage, proliferative index (Ki67), and tumor differentiation. Most of these neoplasms express somatostatin receptors on the cell surface, a feature that has important implications in terms of prognosis, diagnosis, and therapy. Although International Guidelines propose algorithms aimed at guiding therapeutic strategies, GEP-NEN patients are still very different from one another, and the need for personalized treatment continues to increase. Radical surgery is always the best option when feasible; however, up to 80% of cases are metastatic upon diagnosis. Regarding medical treatments, as GEP-NENs are characterized by relatively long overall survival, multiple therapy lines are adopted during the lifetime of these patients, but the optimum sequence to be followed has never been clearly defined. Furthermore, although new molecular markers aimed at predicting the response to therapy, as well as prognostic scores, are currently being studied, their application is still far from being part of daily clinical practice. As they represent a complex disease, with therapeutic protocols that are not completely standardized, GEP-NENs require a multidisciplinary approach. This review will provide an overview of the available therapeutic options for GEP-NENs and attempts to clarify the possible approaches for the management of these patients and to discuss future perspectives in this field.

Clinical outcome of non-curative endoscopic submucosal dissection for early colorectal cancer.

OBJECTIVE: Endoscopic submucosal dissection (ESD) in a curative intent for submucosa-invasive early (T1) colorectal cancers (T1-CRCs) often leads to subsequent surgical resection in case of histologic parameters indicating higher risk of nodal involvement. In some cases, however, the expected benefit may be offset by the surgical risks, suggesting a more conservative approach. DESIGN: Retrospective analysis of consecutive patients with T1-CRC who underwent ESD at 13 centres ending inclusion in 2019 (n=3373). Cases with high risk of nodal involvement (non-curative ESD: G3, submucosal invasion>1000 µm, lymphovascular involvement, budding or incomplete resection/R1) were analysed if follow-up data (endoscopy/imaging) were available, regardless of the postendoscopic management (follow-up vs surgery) selected by the multidisciplinary teams in these institutions. Comorbidities were classified according to Charlson Comorbidity Index (CCI). Outcomes were disease recurrence, death and disease-related death rates in the two groups. Rate of residual disease (RD) at both the previous resection site and regional lymph nodes was assessed in the surgical cases as well as from follow-up in the follow-up group. RESULTS: Of 604 patients treated by colorectal ESD for submucosally invasive cancer, 207 non-curative resections (34.3%) were included (138 male; mean age 67.6±10.9 years); in 65.2% of cases, no complete resection was achieved (R1). Of the 207 cases, 60.9% (n=126; median CCI: 3; IQR: 2-4) underwent surgical treatment with RD in 19.8% (25/126), while 39.1% (n=81, median CCI: 5; IQR: 4-6) were followed up by endoscopy in all cases. Patients in the follow-up group had a higher overall mortality (HR=3.95) due to non-CRC causes (n=9, mean survival after ESD 23.7±13.7 months). During this follow-up time, tumour recurrence and disease-specific survival rates were not different between the groups (median follow-up 30 months; range: 6-105). CONCLUSION: Following ESD for a lesion at high risk of RD, follow-up only may be a reasonable choice in patients at high risk for surgery. Also, endoscopic resection quality should be improved. TRIAL REGISTRATION NUMBER: NCT03987828.

The unmet needs for identifying the ideal bowel preparation.

Colonoscopy, since it was first employed over 60 years ago, is now the gold standard method for visualizing the mucosa of the colon, but should be of good quality. Many factors affect quality, including the type of health service organization, type of facility, staff, equipment, patient characteristics, and bowel preparation (BP). The adequacy of bowel cleansing is critical, but, unfortunately, may be inadequate in up to one-third of procedures. The current article will present and discuss the main BPs and their drawbacks, which include patient-dependent and procedure-dependent factors. Cleansing quality depends on the ease/complexity of solution preparation, volume, taste, and timing of consumption. Consequently, important positive factors include simple instructions, easy preparation of the solution, low volume, pleasant taste, short drinking time (e.g. <30 min), and splitting the dose between the evening before and the morning of the colonoscopy (or even better, only one dose in the early morning to avoid night-time problems), and short onset of action. The BP solution must also be safe with negligible side effects. Furthermore, a positive experience supports patient willingness to repeat the procedure.