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Postoperative ileus results in significant morbidity, prolonged hospitalization, and increased healthcare expenditure. However, the underlying abnormalities in motility remain poorly understood. Recent high-resolution manometry studies demonstrated the distal colon becomes hyperactive with a cyclic motor pattern postoperatively, but did not track this activity beyond 16 hours after surgery.To use high-resolution manometry to evaluate distal colonic motility over the first four days after right-sided colectomy.This was an observational study of patients undergoing perioperative high-resolution colonic manometry using a 36-sensor catheter with 1-cm resolution.A single tertiary hospital.Adult patients undergoing elective laparoscopic or open right-sided colonic resection.Occurrence of distal colonic motor patterns over the perioperative period, defined according to a published classification system. Clinical markers of gut recovery included time to first stool, oral diet, and prolonged postoperative ileus.Seven patients underwent perioperative manometry recordings. Hyperactive cyclic motor patterns emerged intraoperatively and peaked in the first 12 hours postoperatively, occupying 81.8 ± 3.9% of the recording. This gradually returned to normal over the first 4 days, reaching 19.0 ± 4.4% (p = 0.002). No patient had a bowel motion prior to this hyperactivity resolving. High-amplitude propagating sequences were absent in early postoperative recordings, and their return temporally correlated with passage of stool. Abnormal high-amplitude repetitive 0.5-1 cycle/minute activity was observed in the left colon of one patient with prolonged ileus.The invasive nature of recordings limited this study to a small sample size.Cyclic motor patterns are markedly hyperactive in the distal colon following right-sided colectomy, and gradually resolve over the first four postoperative days. High-amplitude propagating sequences are inhibited by surgery and gradually recover. Bowel function may not return until these changes resolve. Other abnormal repetitive hyperactive patterns could contribute to the development of prolonged ileus. See Video Abstract at http://links.lww.com/DCR/B967.

Background Ustekinumab (UST) is an IL-12/23p40 antagonist used to treat pts with moderate-to-severe ulcerative colitis (UC). The ongoing UNIFI long-term extension (LTE) evaluates subcutaneous (SC) 90mg UST maintenance therapy, with efficacy (wk152) and safety (wk156) results reported here. Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (175 SC placebo [PBO]; 172 UST 90mg every 12 weeks [q12w]; 176 UST 90mg q8w). 284 UST pts who completed wk44 entered the LTE. PBO pts were discontinued after wk44 unblinding. Starting at wk56, randomized pts with UC worsening could adjust to q8w. Symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0) was evaluated in randomized pts. Safety was evaluated for all 588 pts treated in the LTE, including the randomized and nonrandomized populations; 188 received PBO and 457 received UST. The nonrandomized population included responders to PBO induction and UST induction nonresponders at wk8 who received SC UST, responded 8 wks later and received UST 90mg q8w. Results Among all pts randomized to UST at maintenance baseline (intent-to-treat population with nonresponder imputation for missing data and treatment failure criteria), 55.2% were in symptomatic remission at wk152 (biologic naïve, 66.1%; biologic failures, 43.5%; Table 1); 96.4% (185/192) of pts in symptomatic remission at wk152 were corticosteroid-free. Overall, 20.1% (39/149 biologic failure, 16/149 biologic naïve) of pts who were randomized to UST and treated in the LTE discontinued treatment between wks44 and 156. Among randomized pts treated with UST in the LTE, 67.6% were in symptomatic remission at wk152; 76.4% of those in clinical remission at wk44 were in symptomatic remission at wk152; and 84.1% of pts with observed data at wk152 were in symptomatic remission. From maintenance wk0-156, combined UST and PBO pts had 1281.6 and 425.0 pt-years of follow-up, respectively; and safety events per 100 pt-years of follow-up for combined UST vs PBO were AEs: 235.81 vs 204.48, SAEs: 7.73 vs 7.53, and serious infections: 2.34 vs 2.35 (Table 2). From wks96-156, there were no reported deaths or major adverse cardiovascular events. One UST-treated pt with fair skin and a prior history of basal cell carcinoma (BCC) reported 2 BCC. One 90 mg q8w UST pt receiving concomitant 6-MP reported SAEs of neutropenic sepsis and oral herpes SAE; the latter events were considered potential opportunistic infections. The dose of 6-MP was reduced, pt recovered and continued UST. Conclusion The efficacy of UST in pts with UC was sustained through 3 years. No new safety signals were observed.

Elevated colonic pressures and increased colonic activity have been thought to contribute to the pathophysiology of diverticulosis. However, evidence for this has been limited to low-resolution manometry, which is of limited accuracy. This study aimed to evaluate the contraction pressures, counts, and distance of propagation recorded by high-resolution colonic manometry in diverticulosis vs control patients. High-resolution colonic manometry was used to record descending and sigmoid colon activity pre- and post-meal in patients with established, asymptomatic diverticulosis and in healthy controls. Antegrade and retrograde propagating contractions, distance of propagation (mm), and mean contraction pressures (mmHg) in the descending and sigmoid colon were compared between patients and controls for all isolated propagating contractions, the cyclic motor pattern, and high-amplitude propagating contractions independently. Mean manometry pressures were not different between controls and diverticulosis patients (p > 0.05 for all comparisons). In the descending colon, diverticulosis patients had lower post-meal mean distance of propagation for all propagating contractions [10.8 (SE1.5) mm vs 20.0 (2.0) mm, p = 0.003] and the cyclic motor pattern [6.0 (2.5) mm vs 17.1 (2.8) mm, p = 0.01]. In the sigmoid colon, diverticulosis patients showed lower post-meal mean distance of propagation for all propagating contractions [10.8 (1.5) mm vs 20.2 (5.9) mm, p = 0.01] and a lower post-meal increase in retrograde propagating contractions (p = 0.04). In this first high-resolution colonic manometry study of patients with diverticular disease, we did not find evidence for increased manometric pressures or increased colonic activity in patients with diverticular disease.

Background Cyclic motor patterns (CMPs) are the most common motor pattern in the distal colon. This study used high‐resolution (HR) colonic manometry to quantify trends in distal colonic motor activity before elective colonic surgery, determine the effect of a preoperative carbohydrate load, and compare this with a meal response in healthy controls. Methods Fiber‐optic HR colonic manometry (36 sensors, 1 cm intervals) was used to investigate distal colonic motor activity in 10 adult patients prior to elective colonic surgery, 6 of whom consumed a preoperative carbohydrate drink (200 kCal). Data were compared with nine healthy volunteers who underwent HR colonic manometry recordings while fasted and following a 700 kCal meal. The primary outcome was the percentage of recording occupied by CMPs, defined as propagating contractions at 2–4 cycles per minute (cpm). Secondary outcomes included amplitude, speed, and distance of propagating motor patterns. Results The occurrence of CMPs progressively increased in time periods closer to surgery (p = 0.001). Consumption of a preoperative drink resulted in significantly increased CMP occurrence (p = 0.04) and propagating distance (p = 0.04). There were no changes in amplitude or speed of propagating motor patterns during the preoperative period. The increase in activity following a preoperative drink was of similar magnitude to the colonic meal response observed in healthy controls, despite the lesser caloric nutrient load. Conclusion Distal colonic CMP increased in occurrence prior to surgery, amplified by ingestion of preoperative carbohydrate drinks. We hypothesize that anxiety, which is also known to rise with proximity to surgery, could play a contributing role., Distal colonic cyclic motor patterns increased in occurrence prior to surgery, amplified by ingestion of preoperative carbohydrate drinks. We hypothesize that anxiety, which is also known to rise with proximity to surgery, could play a contributing role.

Rapid symptomatic relief is an important treatment goal for patients with ulcerative colitis (UC). We aimed to characterize early response with ustekinumab in patients with moderate-to-severe UC during the initial 16 weeks of treatment.We performed a post hoc analysis of data from A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis trial. Patients (N = 961) were randomized (1:1:1) to receive intravenous 130 mg ustekinumab, approximately 6 mg/kg ustekinumab, or placebo at week 0. Symptomatic remission, absolute stool number, Mayo stool frequency and rectal bleeding subscores, partial Mayo score, C-reactive protein, and fecal calprotectin were assessed in the overall population and for patients in the biologic-naïve or prior biologic failure subgroups.A significantly greater percentage of patients in the 130-mg ustekinumab (20.0%; P = .015) or approximately 6-mg/kg ustekinumab (20.2%; P = .012) groups achieved symptomatic remission at week 2 vs placebo (12.9%). Mean [SD] changes from baseline in daily stool number on day 7 were greater in the ustekinumab groups (-1.1 [2.6] in 130 mg [P = .065] and -1.2 [2.5] in ∼6 mg/kg [P = .017]) vs placebo (-0.7 [2.7]). The percentage of patients with Mayo stool frequency subscore of 1 or less and rectal bleeding subscore of 0 increased from baseline through week 16 for both ustekinumab groups. Significant improvements in partial Mayo scores were observed by week 2 in both ustekinumab groups vs placebo (P ≤ .001). Significantly more patients in the ustekinumab groups had normalized C-reactive protein levels from week 2 to week 8 vs placebo (P ≤ .05). Similar results were observed with normalized fecal calprotectin levels between week 2 and week 4 (P ≤ .05).Ustekinumab improved symptoms in patients with UC compared with placebo in as early as 7 days, indicating rapid onset of effect after induction.ClinicalTrials.gov: NCT02407236.

The original version of the article unfortunately contained an error in the unit used for ‘Distance of propagation’. The distance of propagation should be in the unit ‘cm’ rather than ‘mm’ throughout the manuscript.

BACKGROUND Acute cholangitis (AC) complicated by septic shock is associated with 40% mortality. The best screening method for diagnosing sepsis in patients with AC is unknown. In this study, we aimed to compare the discriminative powers of systemic inflammatory response syndrome criteria (SIRS test) and the 2018 Tokyo Guidelines for moderate cholangitis (TG18 test) in screening AC patients for sepsis and to estimate their predictive abilities. METHODS This was a retrospective diagnostic accuracy study in which the TG18 and SIRS tests were applied to two groups of patients; 52 patients with 70 hospital admissions had AC with shock index ≥0.7 and 46 patients with 57 hospital admissions had AC with shock index

Growing mammary epithelial cells as organoids in a three-dimensional (3D) cell culture environment represents a more physiological model system than conventional 2D adherent cell culture systems for studying many different aspects of mammary epithelial cell biology. We have developed MammoCult™ Organoid Growth Medium (Mouse), a serum- and phenol red-free medium for the long-term propagation of organoids from mouse mammary tissue. To initiate the cultures, mouse mammary glands are resected and enzymatically dissociated sequentially in Gentle Collagenase/Hyaluronidase, trypsin, and dispase/DNase I to generate a single-cell suspension, and 4.5 x 103 of the liberated cells are then embedded in Corning® Matrigel® and maintained in MammoCult™ Organoid Growth Medium (Mouse). Alternatively, freshly dissociated mammary cells can be expanded in adherent culture in EpiCult™ Plus Medium prior to seeding into Matrigel®. Approximately 8.4 ± 0.6% (mean ± SEM; n=10) of the freshly dissociated cells seeded in the Corning® Matrigel® will proliferate and generate organoids that are typically > 200 µm in diameter and have a highly branched morphology, although organoids with a cystic morphology are also observed. Immunostaining of these branched organoids reveals that they are composed of a polarized epithelium made up of keratin (K) 8-expressing luminal cells and K5/14-expressing basal cells (n=7). Organoids upregulate transcripts for caseins (Csn1s1, Csn2), whey acidic protein (Wap), and lactoferrin (Ltf) upon stimulation with prolactin, hydrocortisone, and insulin (n=4). These multilineage organoids can be established from multiple inbred mouse strains, including C57Bl6/J, FVB, BALB/c, and CD-1. Organoids can be passaged every 10 - 14 days as small fragments at a 1:3 to 1:4 split ratio, and can be maintained for a minimum of 10 passages while still maintaining multilineage potential and a normal karyotype. These results demonstrate that MammoCult™ Organoid Growth Medium (Mouse) efficiently generates and expands mammary epithelial cell-derived organoids and offers researchers a novel tool for in vitro mammary studies. Citation Format: David Rowbotham, Samantha Rothwell, Allen C. Eaves, Sharon A. Louis, John Stingl. Expansion of mouse mammary epithelial stem cells in serum-free organoid growth medium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6018.

Background and study aims Refractory variceal bleeding is associated with high mortality in patients with chronic liver disease. A fully-covered self-expanding metal stent (SEMS) has been reported to have excellent rates of technical success and initial bleeding control; however, studies to date are small and limited to Europe and Asia. Our aim was to evaluate the efficacy and safety of this SEMS for control of refractory variceal bleeding (VB). Patients and methods A retrospective analysis was undertaken of all patients who received the SX-ELLA Danis SEMS for management of VB at 9 tertiary centers across Australia and New Zealand. A total of 32 SEMS had been deployed in 30 patients (median age 53.3). Results Technical success of SEMS placement was achieved in 100 % of cases, resulting in immediate control of bleeding across 31 of 32 cases (96.9 %). Re-bleeding with SEMS in situ occurred in three of 32 cases (9.4 %). Mean SEMS in-dwelling time was 6.4 days. Delayed SEMS migration occurred in 6.3 % of cases. Interventional radiological therapy for management of varices within 6 weeks was performed in 12 of 30 patients (40 %). Death with SEMS in situ occurred in seven of 30 patients (23.3 %). Seven-day bleeding-related mortality was 16.7 %, 14-day mortality 23.3 %, and 6-week mortality 33.3 %. Three of 30 patients (10 %) received orthotopic liver transplantation following SEMS insertion, including two patients within 6 weeks. Conclusions SX-Danis Ella SEMS is highly effective for immediate control of refractory VB and bridging to definitive therapy because it has excellent technical success rates, appears to be relatively easy to use, and has low rates of serious adverse events.

Background Ustekinumab (UST) is an IL12/23 blocker approved for use in Crohn’s disease and ulcerative colitis (UC). In the UNIFI maintenance study of patients (pts) with moderate-severe UC, >90% of the pts who achieved clinical response or remission at week (wk) 44 were able to eliminate corticosteroids, an important goal of therapy. In this analysis, we describe the corticosteroid-sparing effects of UST treatment through 3 years among pts who were treated in the UNIFI long-term extension (LTE). Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (SC placebo [PBO], n=175; UST 90mg every 12 wks [q12w], n=172; or UST 90mg q8w, n=176). 284 UST pts who completed wk44 entered the LTE. PBO pts were discontinued after wk44 unblinding. Based on the investigator’s clinical judgement of their UC disease activity, pts in the LTE were eligible to receive dose adjustment starting at wk56: PBO to q8w, q12w to q8w, and q8w to q8w (sham adjustment). Pts in PBO or q8w groups were only eligible for dose adjustment or sham dose adjustment before unblinding. Efficacy was evaluated in randomized pts using symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0). During the maintenance study, all pts receiving corticosteroids at maintenance baseline were required to initiate tapering. Through wk152 of the LTE, symptomatic remission endpoints were calculated with treatment failure and missing data nonresponder imputation, and dose adjustment was not considered to be a treatment failure. Missing corticosteroid dose data was managed using last observation carried forward. Results Of the 284 pts in the randomized population who were treated with UST in the LTE, 139 were receiving corticosteroids at maintenance baseline. Of these, 91.4% (n=127) were no longer receiving corticosteroids at wk152. The average prednisone-equivalent corticosteroid dose among pts receiving corticosteroids at maintenance baseline in the q8w group was 15.4 mg/day at maintenance baseline and 1.7 mg/day at wks44 & 152. In the q12w group, average prednisone-equivalent doses were 15.4, 1.0, and 4.6 mg/day, respectively (Table 1). Corticosteroid-free symptomatic remission rates through wk152 are summarized in Table 2. Results were similar for the q8w and q12w maintenance doses. Of the UST-treated pts who were in symptomatic remission at wk152, 94.6% (88/93) in the q12w group and 98.0% (97/99) in the q8w group were corticosteroid-free. Conclusion UST maintenance therapy, with both q8w and q12w dosing regimens, was effective in reducing and eliminating the use of corticosteroids in pts with UC through 3 years. Through 3 years of treatment with UST, the majority of pts in symptomatic remission were corticosteroid free.

Aim Patients frequently suffer from low anterior resection syndrome (LARS) after distal colorectal resection. The pathophysiology of LARS has not been clearly elucidated. We hypothesized that rectosigmoid resection could impair motility patterns in the distal colon, such as the rectosigmoid brake, which contribute to control of stool form and frequency. Method High-resolution colonic manometry was performed in patients who had previously undergone distal colorectal resection (mean 6.8 years after resection) and non-operative controls before and after a standardized meal. Symptoms were assessed using the LARS score. Propagating contractions were compared between patients with and without LARS, and controls. Results Data were analysed from 23 patients (11 no-LARS; 12 LARS) and nine controls. All groups demonstrated a significant meal response. LARS patients had fewer post-prandial antegrade propagating contractions than controls (P = 0.028), and fewer retrograde propagating contractions both pre- (P = 0.005) and post-prandially (P = 0.004). Post-prandially, the LARS group had a significantly lower percentage of propagating contractions that met the criteria for the cyclic motor pattern compared to the control group (26% vs. 58%; P = 0.009). There were significant differences in antegrade and retrograde amplitude (P = 0.049; P = 0.018) and distance of propagation (P = 0.003; P = 0.002) post-prandially between LARS patients and controls. Conclusion Rectosigmoid resection alters the meal response following anterior resection, including impairment of the rectosigmoid brake cyclic motor pattern. These findings help to quantify the impaired functional motility after rectosigmoid resection and offer new insights into the mechanisms of LARS.

Elevated colonic pressures and increased colonic activity have been thought to contribute to the pathophysiology of diverticulosis. However, evidence for this has been limited to low-resolution manometry, which is of limited accuracy.This study aimed to evaluate the contraction pressures, counts, and distance of propagation recorded by high-resolution colonic manometry in diverticulosis vs control patients.High-resolution colonic manometry was used to record descending and sigmoid colon activity pre- and post-meal in patients with established, asymptomatic diverticulosis and in healthy controls. Antegrade and retrograde propagating contractions, distance of propagation (mm), and mean contraction pressures (mmHg) in the descending and sigmoid colon were compared between patients and controls for all isolated propagating contractions, the cyclic motor pattern, and high-amplitude propagating contractions independently.Mean manometry pressures were not different between controls and diverticulosis patients (p 0.05 for all comparisons). In the descending colon, diverticulosis patients had lower post-meal mean distance of propagation for all propagating contractions [10.8 (SE1.5) mm vs 20.0 (2.0) mm, p = 0.003] and the cyclic motor pattern [6.0 (2.5) mm vs 17.1 (2.8) mm, p = 0.01]. In the sigmoid colon, diverticulosis patients showed lower post-meal mean distance of propagation for all propagating contractions [10.8 (1.5) mm vs 20.2 (5.9) mm, p = 0.01] and a lower post-meal increase in retrograde propagating contractions (p = 0.04).In this first high-resolution colonic manometry study of patients with diverticular disease, we did not find evidence for increased manometric pressures or increased colonic activity in patients with diverticular disease.

Background & Aims Antibiotic treatment is the standard care for patients with uncomplicated acute diverticulitis. However, this practice is based on low-level evidence and has been challenged by findings from 2 randomized trials, which did not include a placebo group. We investigated the non-inferiority of placebo vs antibiotic treatment for the management of uncomplicated acute diverticulitis. Methods In the selective treatment with antibiotics for non-complicated diverticulitis study, 180 patients hospitalized for uncomplicated acute diverticulitis (determined by computed tomography, Hinchey 1a grade) from New Zealand and Australia were randomly assigned to groups given antibiotics (n = 85) or placebo (n = 95) for 7 days. We collected demographic, clinical, and laboratory data and answers to questionnaires completed every 12 hrs for the first 48 hrs and then daily until hospital discharge. The primary endpoint was length of hospital stay; secondary endpoints included occurrence of adverse events, readmission to the hospital, procedural intervention, change in serum markers of inflammation, and patient-reported pain scores at 12 and 24 hrs. Results There was no significant difference in median time of hospital stay between the antibiotic group (40.0 hrs; 95% CI, 24.4–57.6 hrs) and the placebo group (45.8 hrs; 95% CI, 26.5–60.2 hrs) (P = .2). There were no significant differences between groups in adverse events (12% for both groups; P = 1.0), readmission to the hospital within 1 week (1% for the placebo group vs 6% for the antibiotic group; P = .1), and readmission to the hospital within 30 days (11% for the placebo group vs 6% for the antibiotic group; P = .3). Conclusions Foregoing antibiotic treatment did not prolong length of hospital admission. This result provides strong evidence for omission of antibiotics for selected patients with uncomplicated acute diverticulitis. ACTRN: 12615000249550.

The management of uncomplicated (Modified Hinchey Classification Ia) acute diverticulitis (AD) has become increasingly conservative, with a focus on symptomatic relief and supportive management. Clear criteria for patient selection are required to implement this safely. This retrospective study aimed to identify risk factors for severe clinical course in patients with uncomplicated AD. Patients admitted to General Surgery at two New Zealand tertiary centres over a period of 18 months were included. Univariate and multivariate analyses were carried out in order to identify factors associated with a more severe clinical course. This was defined by three endpoints: need for procedural intervention, admission >7 days and 30-day readmission; these were analysed separately and as a combined outcome. Uncomplicated AD was identified in 319 patients. Fifteen patients (5%) required procedural intervention; this was associated with SIRS (OR 3.92). Twenty-two (6.9%) patients were admitted for >7 days; this was associated with patient-reported pain score >8/10 (OR 5.67). Thirty-one patients (9.8%) required readmission within 30 days; this was associated with pain score >8/10 (OR 6.08) and first episode of AD (OR 2.47). Overall, 49 patients had a severe clinical course, and associated factors were regular steroid/immunomodulator use (OR 4.34), pain score >8/10 (OR 5.9) and higher temperature (OR 1.51) and CRP ≥200 (OR 4.1). SIRS, high pain score and CRP, first episode and regular steroid/immunomodulator use were identified as predictors of worse outcome in uncomplicated AD. These findings have the potential to inform prospective treatment decisions in this patient group.

Background The UNIFI maintenance study evaluated the safety and efficacy of subcutaneous (SC) ustekinumab (UST) in patients with moderately–severely active UC who had responded to IV UST induction. Previously, we reported that health-related quality of life (HRQoL) improvements achieved after UST induction were maintained through Week 44 with UST maintenance. Here, we evaluated HRQoL through Week 92 in patients who continued UST maintenance in the long-term extension (LTE). Methods Patients who completed the maintenance study were eligible to continue their maintenance treatment regimen (placebo [PBO], UST90mg q12w, or UST90mg q8w) in the LTE if the investigator thought they could benefit from continued treatment. PBO patients discontinued from the LTE after the maintenance study was unblinded. Per investigator discretion, patients could receive a single dose adjustment (UST q12w to q8w or UST q8w to q8w [sham dose adjustment]) starting at Week 56. The Inflammatory Bowel Disease Questionnaire (IBDQ) is a 32-item questionnaire with a total score ranging from 32 to 224. Higher scores indicate better HRQoL, a score ≥170 indicates remission, and a change ≥16 was defined as clinically meaningful. General health was assessed using SF-36. A change ≥5 points in physical and mental component scores was defined as clinically meaningful. In this analysis, patients who dose adjusted were considered treatment failures. Results Most patients who received UST in the LTE maintained the improvements in IBDQ and SF-36 that were achieved after induction (Tables 1 and 2) through Week 92. Overall, 158 of 284 patients (55.6%) who received UST were in IBDQ remission at Week 92, and 114 of 169 patients (67.5%) who were in IBDQ remission at maintenance baseline were in IBDQ remission at Week 92. Of the 284 patients, 179 (63.0%) achieved a ≥16-point improvement in IBDQ score from induction baseline to Week 92. Of 250 patients who achieved a ≥16-point improvement from induction baseline to maintenance baseline, 154(61.6%) maintained a ≥16-point improvement at both Weeks 44 and 92. For SF-36, 142 of 284 patients (50.0%) had a ≥5-point improvement from induction baseline to Week 92 in the physical component score, while 128 of 284 (45.1%) had a ≥5-point improvement in the mental component score. Conclusion The majority of patients who were treated with UST in the LTE generally maintained improvements in IBDQ and SF-36 scores that were achieved after IV induction.

Background Ustekinumab (UST) has been shown to induce and maintain clinical response and remission in moderate–severe UC patients in the UNIFI study. In the UNIFI maintenance study, the primary randomised population consisted of patients who were in clinical response 8weeks after UST induction treatment. Patients who had a delayed response to induction were also eligible for the maintenance study but were not included in the randomised analysis set. Here, we present the efficacy and safety of UST maintenance among delayed responders who were treated in the UNIFI long-term extension(LTE). Methods UNIFI was a single protocol of induction and randomised withdrawal maintenance studies in patients with moderate–severe UC who failed conventional or biologic therapy(including TNF antagonists and/or vedolizumab). Delayed responders were patients who were not in clinical response to UST IV induction at Week8 but achieved response at Week16 following a single UST90mg SC dose at Week8. These patients entered the maintenance study and continued to receive UST90mg SC q8w. Patients who completed Week44 evaluations were eligible to enter LTE continuing to receive UST90mg SC q8w. Efficacy in delayed responders to UST(who were treated in LTE) was evaluated over time through Week92 and safety through Week96. Results 116 delayed responders to UST induction were treated in the LTE, including 58 who had previously failed biologic therapy and 58 who had not failed biologic therapy, 54 of whom were bio-naïve. Symptomatic remission(defined as stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0) rates in delayed responders to UST induction increased from maintenance baseline to Weeks 44 and 92 (Table 1). Similar trends were seen within the biologic failure subgroups; although, rates among patients who had not failed biologics (primarily bio-naïve) were greater than those of patients who had failed biologics. Among the 79.3% (n = 92/116) of delayed responders to UST in symptomatic remission at Week 92, 94.6% (n = 87/92) were corticosteroid free. Safety data for randomised and non-randomised patients treated in UNIFI LTE is in Table2. The safety profile for UST in delayed responders was generally similar to that observed among patients randomised to UST; no new safety signals were observed. Conclusion Delayed responders to UST treatment maintained symptomatic remission through Week 92 with UST90mg SC q8w and the majority did so in the absence of corticosteroids.

Background Ustekinumab (UST) is an IL12/23 blocker approved for Crohn’s disease and ulcerative colitis (UC). In the UNIFI maintenance study of patients with moderate–severe UC, >90% of the patients who achieved clinical response or remission at week 44 were able to eliminate corticosteroids, an important goal of therapy. In this analysis, we describe the corticosteroid (CS) sparing effects of UST treatment through week 92 among patients who were treated in the UNIFI long-term extension (LTE). Methods Responders to UST 8 weeks after IV induction entered the maintenance study and were randomised to UST 90mg SC (q12wks or q8wks) or PBO. Patients who did not respond to UST IV induction received a dose of UST 90mg SC at week 8 and were evaluated at week 16. Those in clinical response at week 16 (delayed responders), were not randomised on entry into the maintenance study and received UST 90mg q8wk. All patients who completed week 44 of the maintenance study were eligible to enter the LTE and continue to receive the same dose. Patients could receive UST dose adjustment during the LTE (q12wk to q8wk or q8wk to q8wk [sham dose adjustment]) from week 56 onward. Patients who remained on PBO were discontinued from the LTE after maintenance study unblinding. During the maintenance study, CS tapering was recommended for all patients receiving CS at maintenance baseline. At week 92 of the LTE, CS-free symptomatic remission rates and CS use were calculated using intention-to-treat analyses with a dose adjustment considered to be a treatment failure and with a dose adjustment not considered to be a treatment failure. Results Of the 284 patients in the randomised population who were treated with UST in the LTE, 139 were receiving CS at maintenance baseline. Of these, 92.8% (n = 129) were CS-free at week 92. CS-free symptomatic remission rates at week 92 are summarised in Table 1. Results were similar for the q8wk and q12wk maintenance doses. Of the UST-treated patients who were in symptomatic remission at week 92, 98.4% (182/185) were CS-free; similar results were seen when dose adjustment was not considered to be a treatment failure. Of the 116 delayed responders (non-randomised population) who continued to receive UST in the LTE, 92 patients were in symptomatic remission at week 92; of whom, 94.6% (87/92) were CS-free. Conclusion UST maintenance therapy, with both q8wk and q12wk dosing regimens, was effective in reducing and eliminating the use of CS in patients with UC. Nearly all patients in the LTE who were in symptomatic remission at week 92, were not taking steroids.

Outpatient endoscopy non-attendance leads to diagnostic delay and increasing wait times. We aimed to analyse endoscopy non-attendance rates and factors associated with it at the Canterbury and Auckland District Health Boards during a five-year period.Consecutive appointments between April 2012 and March 2017 were assessed. The following procedures were included: gastroscopy, colonoscopy and endoscopic retrograde cholangiopancreatography. Predictors of non-attendance were assessed using univariate and multivariate binary logistic regression.A total of 58,434 appointments were offered (Canterbury-33,697, Auckland-24,737), of which 2,694 (4.6%) were not attended. Māori (OR 3.0, 95%CI 2.63-3.42) and Pacific Peoples (OR 3.1, 95%CI 2.7-3.55) were significantly more likely to miss appointments compared with Europeans. Patients from socioeconomically most deprived areas (NZDep10) had higher rates of non-attendance (OR 2.13, 95%CI 1.72-2.63) compared with NZDep1. Males (OR 1.43, 95%CI 1.32-1.56) and the Auckland District Health Board patients (OR 2.28, 95%CI 2.08-2.50) had higher non-attendance rates.Overall, 4.6% patients did not attend endoscopy appointments. Māori, Pacific Peoples and patients from socioeconomically deprived areas had higher non-attendance rates. Targeted interventions for at-risk groups would potentially lessen health inequalities and optimise utilisation of endoscopy resources.

Background & Aims Most patients with Crohn's disease (CD) eventually require an intestinal resection. However, CD frequently recurs after resection. We performed a randomized trial to compare the ability of infliximab vs placebo to prevent CD recurrence. Methods We evaluated the efficacy of infliximab in preventing postoperative recurrence of CD in 297 patients at 104 sites worldwide from November 2010 through May 2012. All study patients had undergone ileocolonic resection within 45 days before randomization. Patients were randomly assigned (1:1) to groups given infliximab (5 mg/kg) or placebo every 8 weeks for 200 weeks. The primary end point was clinical recurrence, defined as a composite outcome consisting of a CD Activity Index score >200 and a ≥70-point increase from baseline, and endoscopic recurrence (Rutgeerts score ≥i2, determined by a central reader) or development of a new or re-draining fistula or abscess, before or at week 76. Endoscopic recurrence was a major secondary end point. Results A smaller proportion of patients in the infliximab group had a clinical recurrence before or at week 76 compared with the placebo group, but this difference was not statistically significant (12.9% vs 20.0%; absolute risk reduction [ARR] with infliximab, 7.1%; 95% confidence interval: -1.3% to 15.5%; P =.097). A significantly smaller proportion of patients in the infliximab group had endoscopic recurrence compared with the placebo group (30.6% vs 60.0%; ARR with infliximab, 29.4%; 95% confidence interval: 18.6% to 40.2%; P

Background The UNIFI randomised-withdrawal maintenance study evaluated the safety and efficacy of subcutaneous (SC) ustekinumab (UST) in patients (patients) with moderately to severely active ulcerative colitis (UC) who had responded to intravenous (IV) UST during induction. We evaluated the efficacy of UST dose adjustment during the long-term extension (LTE). Methods At Week (Week) 0 of the 44 weeks maintenance study, 523 patients who had responded to IV UST induction were randomly assigned in a 1:1:1 ratio to placebo (PBO) SC, UST SC 90 mg q12w, or 90 mg q8w. Patients who completed the maintenance study were eligible to enter the LTE if the investigator thought they would benefit from continued treatment. PBO patients were discontinued from the LTE after the maintenance study was unblinded and the analysis was complete. Based on investigator’s clinical judgement of UC disease activity, patients in the LTE were eligible to receive dose adjustment starting at Week 56: PBO to q8w, q12w to q8w, and q8w to q8w (sham adjustment). PBO patients were only eligible for dose adjustment before unblinding. Patients were assessed for symptomatic remission (SR), partial Mayo scores, and inflammatory markers ≥16 weeks after dose adjustment. Results Symptomatic remission was maintained through Week 92 among patients treated with UST regardless of dose adjustment in the LTE (Figure). Overall, 40 (28.4%) and 37 (25.9%) patients in the q12w and q8w groups, respectively, underwent dose adjustment (or sham dose adjustment) prior to Week 92 of the LTE. Among patients who received dose adjustment at Week 76 or before and had data ≥16 weeks after dose adjustment, symptomatic remission was observed in 70.0% in the q12w-to-q8w group and 71.4% in the q8w-to-q8w group, the majority of whom were in symptomatic remission at the time of the dose adjustment (Table). The safety profile of UST in patients who received dose adjustment was generally consistent with the overall safety profile of UST. Conclusion Patients may benefit from UST dose adjustment to q8w. However, the majority of UST-treated patients were in SR at the time of dose adjustment in this study. No new safety signals were observed among patients who dose adjusted.

Background Recovery after colonic surgery is invariably delayed by disturbed gut motility. It is commonly assumed that colonic motility becomes quiescent after surgery, but this hypothesis has not been evaluated rigorously. This study quantified colonic motility through the early postoperative period using high-resolution colonic manometry. Methods Fibre-optic colonic manometry was performed continuously before, during and after surgery in the left colon and rectum of patients undergoing right hemicolectomy, and in healthy controls. Motor events were characterized by pattern, frequency, direction, velocity, amplitude and distance propagated. Results Eight patients undergoing hemicolectomy and nine healthy controls were included in the study. Colonic motility became markedly hyperactive in all operated patients, consistently dominated by cyclic motor patterns. Onset of cyclic motor patterns began to a minor extent before operation, occurring with increasing intensity nearer the time of surgery; the mean(s.d.) active duration was 12(7) per cent over 3 h before operation and 43(17) per cent within 1 h before surgery (P = 0.024); in fasted controls it was 2(4) per cent (P < 0·001). After surgery, cyclic motor patterns increased markedly in extent and intensity, becoming nearly continuous (active duration 94(13) per cent; P < 0·001), with peak frequency 2–4 cycles per min in the sigmoid colon. This postoperative cyclic pattern was substantially more prominent than in non-operative controls, including in the fed state (active duration 27(20) per cent; P < 0·001), and also showed higher antegrade velocity (P < 0·001). Conclusion Distal gut motility becomes markedly hyperactive with colonic surgery, dominated by cyclic motor patterns. This hyperactivity likely represents a novel pathophysiological aspect of the surgical stress response. Hyperactive motility may contribute to gut dysfunction after surgery, potentially offering a new therapeutic target to enhance recovery.

Acute diverticulitis (AD) is one of the most common acute admission diagnoses for general surgery, and its prevalence is increasing, in part due to the ageing population. Currently, most patients who present to a tertiary hospital are admitted for a period of treatment and observation. Simple, safe and cost-effective strategies for improving our current treatment of this condition will be invaluable in providing the most appropriate management for individual patients and for reducing the health resources expended on hospital admissions and parenteral antibiotics. AD can be categorized as uncomplicated or complicated, these two subtypes have a very different clinical course. The management of uncomplicated AD has become increasingly conservative, with a focus on symptomatic relief and supportive management. Recent research has brought into question the need for extended hospital admission and questioned the current use of antibiotics. Anti-inflammatory agents that reduce local inflammation in uncomplicated AD may be a useful means of reducing damage caused by inflammation and aiding earlier resolution of the inflammatory response and associated symptoms. Mesalazine is an anti-inflammatory agent that has been trialled in uncomplicated AD. Mesalazine has been shown to improve time to resolution of endoscopic and histological evidence of inflammation following an episode of AD and also reduce the rate of recurrence. In this literature review, we provide an overview of recent advances in AD classification, pathophysiology and management, and examine the possibility of introducing the use of anti-inflammatory agents in the management of uncomplicated AD.

Background The 2018 Tokyo guidelines for acute cholangitis (AC) use white cell count (WCC) as one of the diagnostic criteria. However, the 2018 Tokyo guidelines grading does not provide guidance for AC patients with normal WCC. In this situation, other inflammatory biomarkers also can be used to diagnose AC and grade severity, but their diagnostic values are yet undetermined. The aims of this study were to evaluate the discriminative powers of common inflammatory markers compared with WCC for diagnosing AC and to determine their diagnostic cutoff levels. Methods This was a retrospective cohort study. Over 2 y, 96 patients who underwent endoscopic biliary decompression were identified from the Auckland City Hospital Radiology Department database. Only patients with a confirmed diagnosis of AC were included in the study. Thirty-four patients with AC and 18 controls met eligibility criteria. Results Comparing areas under the receiver operating characteristic curves, it was the lymphocyte count, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP) that had the highest discriminative powers in diagnosing AC. Values of WCC for diagnosing AC were equal to or above 9.6 × 109/L, neutrophil count equal to or exceeding 4.9 × 109/L, lymphocyte count equal to or below 1.3 × 109/L, NLR 5.3 and above, albumin equal to or below 30.5 g/L, and CRP concentration 23.5 mg/L or above. Conclusions Lymphocyte count, NLR, and CRP have superior discriminative powers to WCC, albumin, and neutrophil count and can be useful in the diagnosis of AC.

Aim Abnormal colonic pressure profiles and high intraluminal pressures are postulated to contribute to the formation of sigmoid colon diverticulosis and the pathophysiology of diverticular disease. This study aimed to review evidence for abnormal colonic pressure profiles in diverticulosis. Method All published studies investigating colonic pressure in patients with diverticulosis were searched in three databases (Medline, Embase, Scopus). No language restrictions were applied. Any manometry studies in which patients with diverticulosis were compared with controls were included. The Newcastle-Ottawa Quality Assessment Scale (NOS) for case-control studies was used as a measure of risk of bias. A cut-off of five or more points on the NOS (fair quality in terms of risk of bias) was chosen for inclusion in the meta-analysis. Results Ten studies (published 1962-2005) met the inclusion criteria. The studies followed a wide variety of protocols and all used low-resolution manometry (sensor spacing range 7.5-15 cm). Six studies compared intra-sigmoid pressure, with five of six showing higher pressure in diverticulosis vs controls, but only two reached statistical significance. A meta-analysis was not performed as only two studies were above the cut-off and these did not have comparable outcomes. Conclusion This systematic review of manometry data shows that evidence for abnormal pressure in the sigmoid colon in patients with diverticulosis is weak. Existing studies utilized inconsistent methodology, showed heterogeneous results and are of limited quality. Higher quality studies using modern manometric techniques and standardized reporting methods are needed to clarify the role of colonic pressure in diverticulosis.

To evaluate the current practice and degree of consensus amongst Australasian surgeons regarding non-surgical management of acute diverticulitis (AD) and to determine whether newer approaches to management are being translated into practice.An online survey was distributed to all Australasian colorectal surgeons and all general surgeons in the Auckland region. Responses were collected over two months and analysed to identify points of consensus and areas of significant difference in opinion between these groups.Responses were received from a total of 99 of 200 (49.5%) colorectal surgeons, and 19 of 36 (52.7%) general surgeons. The Hinchey Classification was the most commonly used measure of disease severity, used by 67 (95.7%) colorectal surgeons and 12 (92.3%) general surgeons. There was lack of consensus around important aspects of AD management, including antibiotic therapy, and use and modality of follow-up imaging. Selective antibiotic therapy and use of anti-inflammatory medication as adjuncts to treatment were practised by a minority of those surveyed.Newer approaches to management were being utilised by some respondents. The lack of consensus regarding management of AD may be a consequence of a paucity of high-level evidence to support specific management approaches, particularly in patients with uncomplicated AD.

Growing prostate epithelial cells as organoids in a three-dimensional (3D) cell culture environment represents a more physiological model system than conventional 2D adherent cell culture systems for studying many different aspects of prostate epithelial cell biology. Two types of prostate epithelial organoids have been previously described: large hollow cystic organoids, and smaller solid organoids (Karthaus et al, Cell 2014). Both types of organoids are composed of androgen receptor (AR)-expressing luminal cells and keratin (K) 5-expressing basal cells, but only vary in the proportion of each cell type, with the cystic organoids enriched for luminal cells and solid organoids enriched for basal cells. We are currently developing ProstaCult™ Organoid Growth Medium, a serum-free medium for the long-term propagation of both types of organoids from mouse prostate tissue. To initiate the cultures, mouse prostates are enzymatically dissociated sequentially in collagenase type II, trypsin and dispase to generate a single cell suspension, and 5x103 the liberated cells are then embedded in Corning® Matrigel® and cultured in ProstaCult™ Organoid Growth Medium. Approximately 10±2% (mean±sem; n=6) of the seeded cells will proliferate and generate approximately equivalent numbers of cystic and solid organoids, which can be dissociated and passaged every 7 days as a single cell suspension. Typical total epithelial cell expansion observed during media development ranges from 21-240-fold per passage for a minimum of 4 passages. Experiments are ongoing to determine the long-term passageability of organoids maintained in ProstaCult™ Organoid Growth Medium. Organoids that are generated at multiple passages are composed of a polarized epithelium with AR+K18+ luminal cells and K5+ basal cells. These results demonstrate that ProstaCult™ Organoid Growth Medium efficiently generates and expands prostate epithelial organoids. Citation Format: John Stingl, David Rowbotham, Terry E. Thomas, Allen C. Eaves, Sharon A. Louis. Expansion of mouse prostate epithelial stem cells in serum-free ProstaCult Organoid Growth Medium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3111.

Background Colorectal resections alter colonic motility, including disruption of control by neural or bioelectrical cell networks. The long-term impact of surgical resections and anastomoses on colonic motor patterns has, however, never been assessed accurately. Fibreoptic high-resolution colonic manometry was employed to define motility in patients who had undergone distal colorectal resection. Methods Recruited patients had undergone distal colorectal resections more than 12 months previously, and had normal bowel function. Manometry was performed in the distal colon (36 sensors; 1-cm intervals), with 2-h recordings taken before and after a meal, with comparison to controls. Analysis quantified all propagating events and frequencies (cyclical, short single, and long single motor patterns), including across anastomoses. Results Fifteen patients and 12 controls were recruited into the study. Coordinated propagating events directly traversed the healed anastomoses in nine of 12 patients with available data, including antegrade and retrograde cyclical, short single and long single patterns. Dominant frequencies in the distal colon were similar in patients and controls (2–3 cycles/min) (antegrade P = 0·482; retrograde P = 0·178). Compared with values before the meal, the mean(s.d.) number of dominant cyclical retrograde motor patterns increased in patients after the meal (2·1(2·7) versus 32·6(31·8) in 2 h respectively; P < 0·001), similar to controls (P = 0·178), although the extent of propagation was 41 per cent shorter in patients, by a mean of 3·4 cm (P = 0·003). Short and long single propagating motor patterns were comparable between groups in terms of frequency, velocity, extent and amplitude. Conclusion Motility patterns and meal responses are restored after distal colorectal resection in patients with normal bowel function. Coordinated propagation across healed anastomoses may indicate regeneration of underlying cellular networks.

Acute diverticulitis (AD) is one of the most common acute admission diagnoses for general surgery, and its prevalence is increasing, in part due to the ageing population. Currently, most patients who present to a tertiary hospital are admitted for a period of treatment and observation. Simple, safe and cost-effective strategies for improving our current treatment of this condition will be invaluable in providing the most appropriate management for individual patients and for reducing the health resources expended on hospital admissions and parenteral antibiotics. AD can be categorized as uncomplicated or complicated, these two subtypes have a very different clinical course. The management of uncomplicated AD has become increasingly conservative, with a focus on symptomatic relief and supportive management. Recent research has brought into question the need for extended hospital admission and questioned the current use of antibiotics. Anti-inflammatory agents that reduce local inflammation in uncomplicated AD may be a useful means of reducing damage caused by inflammation and aiding earlier resolution of the inflammatory response and associated symptoms. Mesalazine is an anti-inflammatory agent that has been trialled in uncomplicated AD. Mesalazine has been shown to improve time to resolution of endoscopic and histological evidence of inflammation following an episode of AD and also reduce the rate of recurrence. In this literature review, we provide an overview of recent advances in AD classification, pathophysiology and management, and examine the possibility of introducing the use of anti-inflammatory agents in the management of uncomplicated AD.