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Aims: Conventional thiopurines (azathioprine and mercaptopurine) remain standard therapy to maintain steroid sparing remission in inflammatory bowel disease (IBD), but are regularly discontinued due to adverse drug reactions (ADRs). Measurement of the metabolites 6‐thioguanine nucleotides (6‐TGN), 6‐methylmercaptopurine ribonucleotides (6‐MMPR) and the 6‐MMPR/6‐TGN ratio, may predict the development of these ADRs. Our aim was to evaluate whether early thiopurine metabolite measurements were associated with clinical outcomes. Methods: A post‐hoc analysis was conducted of a multicentre, prospective, observational study on thiopurine‐induced hepatotoxicity. IBD patients who initiated thiopurine therapy were included and thiopurine metabolite concentrations were assessed after 7 days (±1) (T1). Patients were monitored for 12 weeks to document the occurrence of ADRs, early treatment discontinuation and effectiveness. Results: In total, 181 patients were evaluated. At T1, 6‐MMPR concentrations and 6‐TGN/6‐MMPR ratios were independently related to treatment discontinuation within 12 weeks after correction for sex, age and body mass index (BMI) (P =.034 and.002, respectively). The largest effects were observed for 6‐MMPR ≥3000 pmol/8 × 108 RBC and 6‐TGN/6‐MMPR ratio ≥17. Furthermore, 6‐MMPR concentrations and 6‐TGN/6‐MMPR ratios at T1 were independently related to skewed metabolism at steady state (Week 8, 6‐MMPR/‐6TGN ratio ≥11 and ≥20) (both P <.001). The occurrence of ADRs and effectiveness were not independently related to T1 thiopurine metabolite concentrations. Conclusions: Thiopurine metabolite concentrations at T1 were related to early treatment discontinuation and skewed metabolism at steady state, but not to effectiveness, helping to identify patients with a high risk of thiopurine treatment failure. [ABSTRACT FROM AUTHOR]

Aim: To identify patient‐reported complaints affecting quality of life in Crohn's disease patients with a perianal fistula, and to compare differences between subgroups. Method: A questionnaire was distributed to 1667 patients from the Dutch Crohn's and Colitis Patients' organization, those patients with Crohn's disease and perianal fistula were included. Patients were asked to report (using free text) their most important fistula‐related complaints affecting their quality of life. All responses were structurally analyzed and categorized. Data comparisons were made between subgroups: women versus men, patients with versus without current presence of a seton, and patients aged ≤40 versus >40 years. Results: Of 743 respondents (44.6%), 123 patients with Crohn's disease and perianal fistula were included (92 women, median age 41 years [IQR 34–56] and 36 with seton). A total of 776 complaints were allocated to 36 categories, with 19 reported in >10% of patients. Perianal fistula‐related complaints affected nearly all patients (95.9%). Impact on psychological status (71.7% vs. 29.0%; p < 0.0001) and on sexual activities (37.0% vs. 16.1%; p = 0.003) were more common in women than men. Younger patients more often reported insecurity (38.7% vs. 18.0%; p = 0.026), shame (29.0% vs. 11.5%; p = 0.024), and impact on sexual activities (40.3% vs. 23.0%; p = 0.048) than older patients. Patients with a seton more frequently reported self‐experienced malodour (50.0% vs. 23.0%; p = 0.005), physical activity limitations (41.7% vs. 19.5%; p = 0.014), and work/study impact (22.2% vs. 5.7%; p = 0.019). Conclusion: We identified 19 perianal fistula‐related complaints reported by >10% of patients. These complaints may guide improvement of current outcome measures. [ABSTRACT FROM AUTHOR]

Purpose: Coronectomy is a valuable treatment proven safe for non-pathological mandibular third molars with an increased risk of inferior alveolar nerve injury. Coronectomy may also be useful for mandibular third molars with dentigerous cysts and caries, but this is not commonly performed due to the lack of well-designed, evidence-based studies. Here, we aim to investigate the safety of coronectomy for mandibular third molars with caries and dentigerous cysts. Methods: One hundred fifteen patients with an impacted mandibular third molar with a dentigerous cyst or caries underwent coronectomy or complete removal and received follow-up with clinical and radiographical examinations. We statistically compared the presence of postoperative complications after coronectomy versus complete removal. Results: Data from 121 molars were available for analysis. The results revealed no significant difference in the occurrence of postoperative complications (including persistent pain, inferior alveolar nerve injury, infection, alveolar osteitis, excessive bleeding, and the need for retreatment) between coronectomy and complete removal. Additionally, the incidence of postoperative complications was not related to any analyzed patient- or molar-related factors, including age, gender, health status, smoking, caries, dentigerous cyst extent, and impaction degree. Conclusion: For pathological impacted mandibular third molars with dentigerous cysts and caries, coronectomy exhibited both short-term and long-term safety, showing no significant difference in postoperative complications compared to total removal. Our results suggest that coronectomy can be indicated for pathological mandibular third molars with proximity to the inferior alveolar nerve. Trial registration number: Not applicable. [ABSTRACT FROM AUTHOR]

High-risk human papillomaviruses (HPVs) cause various cancers. While type-specific prophylactic vaccines are available, additional anti-viral strategies are highly desirable. Initial HPV cell entry involves receptor-switching induced by structural capsid modifications. These modifications are initiated by interactions with cellular heparan sulphates (HS), however, their molecular nature and functional consequences remain elusive. Combining virological assays with hydrogen/deuterium exchange mass spectrometry, and atomic force microscopy, we investigate the effect of capsid-HS binding and structural activation. We show how HS-induced structural activation requires a minimal HS-chain length and simultaneous engagement of several binding sites by a single HS molecule. This engagement introduces a pincer-like force that stabilizes the capsid in a conformation with extended capsomer linkers. It results in capsid enlargement and softening, thereby likely facilitating L1 proteolytic cleavage and subsequent L2-externalization, as needed for cell entry. Our data supports the further devising of prophylactic strategies against HPV infections.The study shows that HPV activation requires a minimum glycan length, which enlarges and softens the virus. Using virological assays, AFM, and HDX-MS, the authors propose a model explaining HPV structural activation and its role in infection. [ABSTRACT FROM AUTHOR]

This document is a corrigendum that corrects an error in a previously published paper titled "Monitoring tropical freshwater fish with underwater videography and deep learning." The authors apologize for the mistake, which involves the incorrect color of the bounding box and species name for Ambassis macleayi in Figure 7e. The correct color should have been yellow instead of green. The authors provide a corrected version of the figure and apologize for any confusion caused. [Extracted from the article]

Context: The application of deep learning to monitor tropical freshwater fish assemblages and detect potential anthropogenic impacts is poorly understood. Aims: This study aimed to compare the results between trained human observers and deep learning, using the fish monitoring program for impact detection at Ranger Uranium Mine as a case study. Methods: Fish abundance (MaxN) was measured by trained observers and deep learning. Microsoft's Azure Custom Vision was used to annotate, label and train deep learning models with fish imagery. PERMANOVA was used to compare method, year and billabong. Key results: Deep learning model training on 23 fish taxa resulted in mean average precision, precision and recall of 83.6, 81.3 and 89.1%, respectively. PERMANOVA revealed significant differences between the two methods, but no significant interaction was observed in method, billabong and year. Conclusions: These results suggest that the distribution of fish taxa and their relative abundances determined by deep learning and trained observers reflect similar changes between control and exposed billabongs over a 3-year period. Implications: The implications of these method-related differences should be carefully considered in the context of impact detection, and further research is required to more accurately characterise small-growing schooling fish species, which were found to contribute significantly to the observed differences. Tropical freshwater fish assemblages monitored in Kakadu National Park were measured using underwater videography, and counted by trained human observers and artificial intelligence (AI). Over 3 years of monitoring, both AI and trained human observers detected the same changes in overall fish assemblage composition. However, AI consistenly underestimated the abundance of small-growing schooling fish. Image credit: Andrew Jansen. This article belongs to the collection Ecological Monitoring and Assessment of Freshwater Ecosystems: New Trends and Future Challenges. [ABSTRACT FROM AUTHOR]

Background: In the pragmatic open-label randomised controlled non-inferiority LADI trial we showed that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in patients with Crohn's disease (CD) in clinical and biochemical remission. Aims: To develop a prediction model to identify patients who can successfully increase their ADA dose interval based on secondary analysis of trial data. Methods: Patients in the intervention group of the LADI trial increased ADA intervals to 3 and then to 4 weeks. The dose interval increase was defined as successful when patients had no persistent flare (> 8 weeks), no intervention-related severe adverse events, no rescue medication use during the study, and were on an increased dose interval while in clinical and biochemical remission at week 48. Prediction models were based on logistic regression with relaxed LASSO. Models were internally validated using bootstrap optimism correction. Results: We included 109 patients, of which 60.6% successfully increased their dose interval. Patients that were active smokers (odds ratio [OR] 0.90), had previous CD-related intra-abdominal surgeries (OR 0.85), proximal small bowel disease (OR 0.92), an increased Harvey-Bradshaw Index (OR 0.99) or increased faecal calprotectin (OR 0.997) were less likely to successfully increase their dose interval. The model had fair discriminative ability (AUC = 0.63) and net benefit analysis showed that the model could be used to select patients who could increase their dose interval. Conclusion: The final prediction model seems promising to select patients who could successfully increase their ADA dose interval. The model should be validated externally before it may be applied in clinical practice. Clinical Trial Registration Number: ClinicalTrials.gov, number NCT03172377. [ABSTRACT FROM AUTHOR]

Thiopurine treatment is regularly complicated by drug‐induced liver injury. It has been suggested that oxidative stress may play a synergistic role. To assess whether thiopurine‐induced liver injury coincides with increased oxidative stress and whether co‐administration with N‐acetylcysteine is protective, we performed a randomized open label crossover pilot study in inflammatory bowel disease patients with thiopurine‐induced increased serum liver tests. The study comprised four stages of 4 weeks. Patients received no additional therapy followed by N‐acetylcysteine 1200 mg twice a day, or the other way around, alongside ongoing thiopurine treatment. The third and fourth stages comprised a washout period and thiopurine reintroduction period. Nine patients completed the study, and the addition of N‐acetylcysteine decreased myeloperoxidase concentrations (33.6–24.5 pmol/L, p = 0.038). The other biomarkers remained unchanged, including thiopurine metabolites, xanthine oxidase activity, thiopurine S‐methyltransferase activity and serum liver enzyme activity tests. Reintroduction of thiopurines led to an increase of F2‐isoprostanes (101–157 ng/mmol, p = 0.038), but not of serum liver enzyme activity tests. Results suggests that thiopurines may increase oxidative stress and although the addition of N‐acetylcysteine led to a decrease in plasma myeloperoxidase concentrations, it does not protect from thiopurine‐induced increase of serum liver tests. [ABSTRACT FROM AUTHOR]

Excessive exposure to ultraviolet (UV) light leads to acute and chronic UV damage and is the main risk factor for the development of skin cancer. In most countries with western lifestyle, the topical application of sunscreens on UV‐exposed skin areas is by far the most frequently used preventive measure against sunburn. Further than preventing sunburns, increasing numbers of consumers are appreciating sunscreens with a medium‐ to high‐level sun protective factor (SPF) as basis for sustainable‐skin ageing or skin cancer prevention programs. However, recent investigations indicate that clinically significant DNA damages as well as a lasting impairment of cutaneous immunosurveillance already occur far below the standard of one minimal erythema dose (MED) sunburn level, which contributes to the current discussion of the clinical value of high‐protective SPF values. Ex vivo investigations on human skin showed that the application of SPF30 reduces DNA damage for a day long sun exposure (24 MED) drastically by about 53% but is significantly surpassed by SPF100 reducing DNA damage by approx. 73%. Further analysis on different SPF protection levels in UV‐exposed cell culture assays focusing on IL‐18, cell vitality and cis/trans‐urocanic acid support these findings. Whereas SPF30 and SPF50+ sunscreens already offer a solid UVB cover for most indications, our results indicate that SPF100 provides significant additional protection against mutagenic (non‐apoptotic‐) DNA damage and functional impairment of the cutaneous immunosurveillance and therefore qualifies as an optimized sunscreen for specifically vulnerable patient groups such as immunosuppressed patients, or skin cancer patients. [ABSTRACT FROM AUTHOR]

Background: International guidelines on intraductal papillary mucinous neoplasm (IPMN) recommend a formal oncological resection including splenectomy when distal pancreatectomy is indicated. This study aimed to compare oncological and surgical outcomes after distal pancreatectomy with or without splenectomy in patients with presumed IPMN. Methods: An international, retrospective cohort study was undertaken in 14 high-volume centres from 7 countries including consecutive patients after distal pancreatectomy for IPMN (2005–2019). Patients were divided into spleen-preserving distal pancreatectomy (SPDP) and distal pancreatectomy with splenectomy (DPS). The primary outcome was lymph node metastasis (LNM). Secondary outcomes were overall survival, duration of operation, blood loss, and secondary splenectomy. Results: Overall, 700 patients were included after distal pancreatectomy for IPMN; 123 underwent SPDP (17.6%) and 577 DPS (82.4%). The rate of malignancy was 29.6% (137 patients) and the overall rate of LNM 6.7% (47 patients). Patients with preoperative suspicion of malignancy had a LNM rate of 17.2% (23 of 134) versus 4.3% (23 of 539) among patients without suspected malignancy (P < 0.001). Overall, SPDP was associated with a shorter operating time (median 180 versus 226 min; P = 0.001), less blood loss (100 versus 336 ml; P = 0.001), and shorter hospital stay (5 versus 8 days; P < 0.001). No significant difference in overall survival was observed between SPDP and DPS for IPMN after correction for prognostic factors (HR 0.50, 95% c.i. 0.22 to 1.18; P = 0.504). Conclusion: This international cohort study found LNM in 6.7% of patients undergoing distal pancreatectomy for IPMN. In patients without preoperative suspicion of malignancy, SPDP seemed oncologically safe and was associated with improved short-term outcomes compared with DPS. Guidelines recommend splenectomy in patients requiring distal pancreatectomy for intraductal papillary mucinous neoplasm (IPMN) as the safety of spleen-preserving distal pancreatectomy (SPDP) is unknown. Among 700 distal pancreatectomies for IPMN, lymph node metastases were present in 6.7% (47 patients) versus 4.3% of those without suspected malignancy. In patients without preoperative suspicion of malignancy, SPDP seemed oncologically safe and was associated with improved short-term outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Distal pancreatectomy (DP) is associated with a high complication rate of 30–50% with postoperative pancreatic fistula (POPF) as a dominant contributor. Adequate risk estimation for POPF enables surgeons to use a tailor-made approach. Assessment of the risk of POPF prior to DP can lead to the application of preventive strategies. The current study aims to validate the recently published preoperative and intraoperative distal fistula risk score (D-FRS) in a nationwide cohort. Methods: This nationwide retrospective Dutch cohort study included all patients after DP for any indication, all of whom were registered in the Dutch Pancreatic Cancer Audit (DPCA) database between 2013 and 2021. The D-FRS was validated by filling in the probability equations with data from this cohort. The predictive capacity of the models was represented by an area under the receiver operating characteristic (AUROC) curve. Results: A total of 896 patients underwent DP of which 152 (17%) developed POPF of whom 144 grade B (95%) and 8 grade C (5%). The preoperative D-FRS, consisting of the variables pancreatic neck thickness and pancreatic duct diameter, showed an AUROC of 0.73 (95%CI 0.68–0.78). The intraoperative D-FRS, comprising pancreatic neck, duct diameter, BMI, operating time, and soft pancreatic aspect, showed an AUROC of 0.69 (95%CI 0.64–0.74). Conclusion: The current study is the first nationwide validation of the preoperative and intraoperative D-FRS showing acceptable distinguishing capacity for only the preoperative D-FRS for POPF. Therefore, the preoperative score could improve prevention and mitigation strategies such as drain management, which is currently investigated in the multicenter PANDORINA trial. [ABSTRACT FROM AUTHOR]

Summary: Background: Abdominal pain is highly prevalent in patients with inflammatory bowel disease (IBD) in remission, but the aetiology is incompletely understood. Aim: To investigate the association of clinical, lifestyle and psychosocial factors with abdominal pain in patients with IBD in remission. Methods: We performed a prospective multicentre study enrolling consecutive patients with IBD. Data were collected between 1 January 2020 and 1 July 2021, using myIBDcoach, an established remote monitoring platform for IBD. Chronic abdominal pain in IBD in remission (IBDremissionPain+) was defined as abdominal pain score ≥3 (0–10 NRS) on ≥1/3 of all assessments, combined with faecal calprotectin <150 μg/g in 90 days around periodic assessments. Disease activity, lifestyle and psychosocial factors were assessed every 1–3 months during 18 months. Using linear mixed models, the association of these factors with abdominal pain over time was analysed. Results: We included 559 patients, of whom 429 (76.7%) remained in biochemical remission. Of these, 198 (46.2%) fulfilled the criteria for chronic abdominal pain. IBDremissionPain+ patients were characterised by female sex, younger age, higher BMI, and shorter disease duration. They reported more often or higher levels of stress, fatigue, depressive and anxiety symptoms, and life events (all p < 0.001). In the multivariable analysis, sex, disease entity, fatigue, depressive symptoms and life events were associated with abdominal pain over time (all p < 0.05). Conclusion: In this cohort of patients with IBD in remission, abdominal pain was common and associated with psychosocial factors. A more holistic treatment approach for patients with IBD suffering from abdominal pain may improve quality of care and subjective wellbeing. [ABSTRACT FROM AUTHOR]

Tioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients. In this retrospective cohort study, all determined TPMT genotypes (2016–2021) were evaluated for aberrant metabolism (i.e., intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant TPMT genotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness. TPMT genotypes were determined in 485 patients, of whom, 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy. Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late-occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT. [ABSTRACT FROM AUTHOR]

Background: Robot-assisted distal pancreatectomy (RDP) has been suggested to hold some benefits over laparoscopic distal pancreatectomy (LDP) but consensus and data on specific subgroups are lacking. This systematic review and meta-analysis reports the surgical and oncological outcome and costs between RDP and LDP including subgroups with intended spleen preservation and pancreatic ductal adenocarcinoma (PDAC). Methods: Studies comparing RDP and LDP were included from PubMed, Cochrane Central Register, and Embase (inception-July 2022). Primary outcomes were conversion and unplanned splenectomy. Secondary outcomes were R0 resection, lymph node yield, major morbidity, operative time, intraoperative blood loss, in-hospital mortality, operative costs, total costs and hospital stay. Results: Overall, 43 studies with 6757 patients were included, 2514 after RDP and 4243 after LDP. RDP was associated with a longer operative time (MD = 18.21, 95% CI 2.18–34.24), less blood loss (MD = 54.50, 95% CI − 84.49–24.50), and a lower conversion rate (OR = 0.44, 95% CI 0.36–0.55) compared to LDP. In spleen-preserving procedures, RDP was associated with more Kimura procedures (OR = 2.23, 95% CI 1.37–3.64) and a lower rate of unplanned splenectomies (OR = 0.32, 95% CI 0.24–0.42). In patients with PDAC, RDP was associated with a higher lymph node yield (MD = 3.95, 95% CI 1.67–6.23), but showed no difference in the rate of R0 resection (OR = 0.96, 95% CI 0.67–1.37). RDP was associated with higher total (MD = 3009.31, 95% CI 1776.37–4242.24) and operative costs (MD = 3390.40, 95% CI 1981.79–4799.00). Conclusions: RDP was associated with a lower conversion rate, a higher spleen preservation rate and, in patients with PDAC, a higher lymph node yield and similar R0 resection rate, as compared to LDP. The potential benefits of RDP need to be weighed against the higher total and operative costs in future randomized trials. [ABSTRACT FROM AUTHOR]

There are limited data on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients treated with vedolizumab (VDZ). Although an exposure–response relation has been demonstrated in the post-induction phase, this relationship is more uncertain in the maintenance phase of treatment. The aim of our study was to determine whether there is an association between VDZ trough concentration and clinical and biochemical remission in the maintenance phase. A prospective, observational multicenter study has been performed on patients with IBD on VDZ in the maintenance treatment (≥14 weeks). Patient demographics, biomarkers, and VDZ serum trough concentrations were collected. Clinical disease activity was scored by the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and the Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Clinical remission was determined as HBI < 5 and SCCAI < 3. Biochemical remission was defined as fecal calprotectin <250 mg/kg and serum CRP <5 mg/L. A total of 159 patients (59 CD, 100 UC) were included. In none of the patient groups, a statistically significant correlation between trough VDZ concentration and clinical remission was observed. Patients in biochemical remission had higher VDZ trough concentrations (p = 0.019). In this population, higher trough VDZ concentrations were associated with biochemical remission but not with clinical remission. [ABSTRACT FROM AUTHOR]

The classification of savanna woodland tree species from high-resolution Remotely Piloted Aircraft Systems (RPAS) imagery is a complex and challenging task. Difficulties for both traditional remote sensing algorithms and human observers arise due to low interspecies variability (species difficult to discriminate because they are morphologically similar) and high intraspecies variability (individuals of the same species varying to the extent that they can be misclassified), and the loss of some taxonomic features commonly used for identification when observing trees from above. Deep neural networks are increasingly being used to overcome challenges in image recognition tasks. However, supervised deep learning algorithms require high-quality annotated and labelled training data that must be verified by subject matter experts. While training datasets for trees have been generated and made publicly available, they are mostly acquired in the Northern Hemisphere and lack species-level information. We present a training dataset of tropical Northern Australia savanna woodland tree species that was generated using RPAS and on-ground surveys to confirm species labels. RPAS-derived imagery was annotated, resulting in 2547 polygons representing 36 tree species. A baseline dataset was produced consisting of: (i) seven orthomosaics that were used for in-field labelling; (ii) a tiled dataset at 1024 × 1024 pixel size in Common Objects in Context (COCO) format that can be used for deep learning model training; (iii) and the annotations. Dataset: https://doi.org/10.5281/zenodo.7094916 Dataset License: Creative Commons Attribution 4.0 International (CC BY 4.0) [ABSTRACT FROM AUTHOR]

Summary: Background: Tofacitinib is an oral Janus kinase (JAK) inhibitor and is registered for the treatment of ulcerative colitis (UC). The effectiveness of tofacitinib has been evaluated up to 12 months of treatment. Aim: The aim of this study was to assess the effectiveness and safety of 24 months of tofacitinib use in UC patients in the Netherlands. Methods: Patients initiating tofacitinib treatment were included in the ICC Registry, a nationwide, observational registry. Patients were prospectively evaluated for up to 24 months. The primary outcome was corticosteroid‐free clinical remission (CSFR, Simple Clinical Colitis Activity Index [SCCAI] ≤2) at week 104. Secondary outcomes included biochemical remission (C‐reactive protein (CRP) ≤5 mg/L and faecal calprotectin (FC) ≤250 μg/g), safety, and discontinuation rate. Results: We included 110 patients of whom 104 (94.5%) were anti‐TNF experienced. After 104 weeks of tofacitinib, 31.8% (34/107) were in CSFR, 23.4% (25/107) in biochemical remission and 18.7% (20/107) in combined clinical and biochemical remission. Of the patients in CSFR at week 52, 76.5% (26/34) remained so after 104 weeks of treatment. Sixty‐one patients (55.5%) discontinued tofacitinib after a median duration of 13 weeks (IQR 7–34). The main reasons for discontinuation were non‐response (59%), loss of response (14.8%), and adverse events (18%). There were 33.9 possible tofacitinib‐related adverse events per 100 patient‐years during follow‐up. Adverse events most probably related to tofacitinib were skin reactions and headaches. There were 6.4 herpes zoster infections per 100 patient‐years. Conclusion: Tofacitinib was effective in 31.8% of patients after 24 months of treatment. [ABSTRACT FROM AUTHOR]

Background: Prophylactic abdominal drainage is current standard practice after distal pancreatectomy (DP), with the aim to divert pancreatic fluid in case of a postoperative pancreatic fistula (POPF) aimed to prevent further complications as bleeding. Whereas POPF after pancreatoduodenectomy, by definition, involves infection due to anastomotic dehiscence, a POPF after DP is essentially sterile since the bowel is not opened and no anastomoses are created. Routine drainage after DP could potentially be omitted and this could even be beneficial because of the hypothetical prevention of drain-induced infections (Fisher, 2018). Abdominal drainage, moreover, should only be performed if it provides additional safety or comfort to the patient. In clinical practice, drains cause clear discomfort. One multicenter randomized controlled trial confirmed the safety of omitting abdominal drainage but did not stratify patients according to their risk of POPF and did not describe a standardized strategy for pancreatic transection. Therefore, a large pragmatic multicenter randomized controlled trial is required, with prespecified POPF risk groups and a homogeneous method of stump closure. The objective of the PANDORINA trial is to evaluate the non-inferiority of omitting routine intra-abdominal drainage after DP on postoperative morbidity (Clavien-Dindo score ≥ 3), and, secondarily, POPF grade B/C. Methods/design: Binational multicenter randomized controlled non-inferiority trial, stratifying patients to high and low risk for POPF grade B/C and incorporating a standardized strategy for pancreatic transection. Two groups of 141 patients (282 in total) undergoing elective DP (either open or minimally invasive, with or without splenectomy). Primary outcome is postoperative rate of morbidity (Clavien-Dindo score ≥ 3), and the most relevant secondary outcome is grade B/C POPF. Other secondary outcomes include surgical reintervention, percutaneous catheter drainage, endoscopic catheter drainage, abdominal collections (not requiring drainage), wound infection, delayed gastric emptying, postpancreatectomy hemorrhage as defined by the international study group for pancreatic surgery (ISGPS) (Wente et al., 2007), length of stay (LOS), readmission within 90 days, in-hospital mortality, and 90-day mortality. Discussion: PANDORINA is the first binational, multicenter, randomized controlled non-inferiority trial with the primary objective to evaluate the hypothesis that omitting prophylactic abdominal drainage after DP does not worsen the risk of postoperative severe complications (Wente et al., 2007; Bassi et al., 2017). Most of the published studies on drain placement after pancreatectomy focus on both pancreatoduodenectomy and DP, but these two entities present are associated with different complications and therefore deserve separate evaluation (McMillan et al., 2016; Pratt et al., 2006). The PANDORINA trial is innovative since it takes the preoperative risk on POPF into account based on the D-FRS and it warrants homogenous stump closing by using the same graded compression technique and same stapling device (de Pastena et al., 2022; Asbun and Stauffer, 2011). [ABSTRACT FROM AUTHOR]

Background: Iron deficiency (ID) and anemia in patients with Inflammatory Bowel Disease (IBD) are associated with a reduced quality of life. We assessed the prevalence of ID and anemia in Dutch outpatients with IBD and compared routine ID(A) management among medical professionals to the European Crohn's and Colitis Organisation (ECCO) treatment guidelines. Methods: Between January and November 2021, consecutive adult outpatients with IBD were included in this study across 16 Dutch hospitals. Clinical and biochemical data were extracted from medical records. Additionally, medical professionals filled out questionnaires regarding routine ID(A) management. Results: In total, 2197 patients (1271 Crohn's Disease, 849 Ulcerative Colitis, and 77 IBD-unclassified) were included. Iron parameters were available in 59.3% of cases. The overall prevalence of anemia, ID, and IDA was: 18.0%, 43.4%, and 12.2%, respectively. The prevalence of all three conditions did not differ between IBD subtypes. ID(A) was observed more frequently in patients with biochemically active IBD than in quiescent IBD (ID: 70.8% versus 23.9%; p < 0.001). Contrary to the guidelines, most respondents prescribed standard doses of intravenous or oral iron regardless of biochemical parameters or inflammation. Lastly, 25% of respondents reported not treating non-anemic ID. Conclusions: One in five patients with IBD suffers from anemia that—despite inconsistently measured iron parameters—is primarily caused by ID. Most medical professionals treat IDA with oral iron or standard doses of intravenous iron regardless of biochemical inflammation; however, non-anemic ID is often overlooked. Raising awareness about the management of ID(A) is needed to optimize and personalize routine care. [ABSTRACT FROM AUTHOR]

Background: Prophylactic abdominal drainage is current standard practice after distal pancreatectomy (DP), with the aim to divert pancreatic fluid in case of a postoperative pancreatic fistula (POPF) aimed to prevent further complications as bleeding. Whereas POPF after pancreatoduodenectomy, by definition, involves infection due to anastomotic dehiscence, a POPF after DP is essentially sterile since the bowel is not opened and no anastomoses are created. Routine drainage after DP could potentially be omitted and this could even be beneficial because of the hypothetical prevention of drain-induced infections (Fisher, Surgery 52:205-22, 2018). Abdominal drainage, moreover, should only be performed if it provides additional safety or comfort to the patient. In clinical practice, drains cause clear discomfort. One multicenter randomized controlled trial confirmed the safety of omitting abdominal drainage but did not stratify patients according to their risk of POPF and did not describe a standardized strategy for pancreatic transection. Therefore, a large pragmatic multicenter randomized controlled trial is required, with prespecified POPF risk groups and a homogeneous method of stump closure. The objective of the PANDORINA trial is to evaluate the non-inferiority of omitting routine intra-abdominal drainage after DP on postoperative morbidity (Clavien-Dindo score ≥ 3), and, secondarily, POPF grade B/C.Methods/design: Binational multicenter randomized controlled non-inferiority trial, stratifying patients to high and low risk for POPF grade B/C and incorporating a standardized strategy for pancreatic transection. Two groups of 141 patients (282 in total) undergoing elective DP (either open or minimally invasive, with or without splenectomy). Primary outcome is postoperative rate of morbidity (Clavien-Dindo score ≥ 3), and the most relevant secondary outcome is grade B/C POPF. Other secondary outcomes include surgical reintervention, percutaneous catheter drainage, endoscopic catheter drainage, abdominal collections (not requiring drainage), wound infection, delayed gastric emptying, postpancreatectomy hemorrhage as defined by the international study group for pancreatic surgery (ISGPS) (Wente et al., Surgery 142:20-5, 2007), length of stay (LOS), readmission within 90 days, in-hospital mortality, and 90-day mortality.Discussion: PANDORINA is the first binational, multicenter, randomized controlled non-inferiority trial with the primary objective to evaluate the hypothesis that omitting prophylactic abdominal drainage after DP does not worsen the risk of postoperative severe complications (Wente etal., Surgery 142:20-5, 2007; Bassi et al., Surgery 161:584-91, 2017). Most of the published studies on drain placement after pancreatectomy focus on both pancreatoduodenectomy and DP, but these two entities present are associated with different complications and therefore deserve separate evaluation (McMillan et al., Surgery 159:1013-22, 2016; Pratt et al., J Gastrointest Surg 10:1264-78, 2006). The PANDORINA trial is innovative since it takes the preoperative risk on POPF into account based on the D-FRS and it warrants homogenous stump closing by using the same graded compression technique and same stapling device (de Pastena et al., Ann Surg 2022; Asbun and Stauffer, Surg Endosc 25:2643-9, 2011). [ABSTRACT FROM AUTHOR]

The thiopurine derivatives azathioprine (AZA), mercaptopurine (MP) and tioguanine (TG) remain standard treatment of inflammatory bowel disease (IBD). The immune suppressive effect of thiopurines is primarily based on blocking the Ras-related C3 botulinum toxin substrate 1 (Rac1) causing apoptosis of T lymphocytes by inhibition of the phosphorylated downstream transcription factor Signal Transducer and Activator of Transcription 3 (pSTAT3). A functional pharmacodynamic marker in T lymphocytes may be useful to predict therapeutic outcome of thiopurine therapy. The aim of this study was to explore whether protein levels of Rac1 and pSTAT3 in T lymphocytes may be applied as a specific pharmacodynamic marker for thiopurine therapy in IBD patients. Rac1 and pSTAT3 protein levels in T lymphocytes were explored in 57 IBD patients (median age 51 years, 56% female), subdivided into six groups based on IBD activity and its treatment: patients with active disease without IBD maintenance medication (1) or patients in remission on AZA/MP (2), TG (3), infliximab (IFX) (4), thiopurine and IFX combination-treatment (5) or without IBD medication (6). Reference values were obtained from healthy subjects. Rac1 and pSTAT3 protein levels in T lymphocytes from patients on thiopurine monotherapy (group 2 and 3) were compared to the other groups, and to healthy subjects. Absolute Rac1 and pSTAT3 protein levels showed no differences between the thiopurine monotherapy groups when compared to patients with active disease. However, the ratio of Rac1 and pSTAT3 protein levels was lower in thiopurine patients groups compared to patients with active disease. Rac1-corrected pSTAT3 protein levels may serve as a pharmacodynamic marker of thiopurine monotherapy and may be a potential tool to predict therapeutic effectiveness in IBD patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Thiopurines remain recommended as maintenance therapy in patients with inflammatory bowel disease (IBD). Despite their widespread use, long‐term effectiveness data are sparse and safety is an increasingly debated topic which thwarts proper delineation in the current IBD treatment algorithm. Aims: To document effectiveness and safety of thiopurine monotherapy in patients with IBD, using the population‐based IBD South‐Limburg (IBDSL) cohort Methods: All patients starting thiopurine monotherapy as maintenance between 1991 and 2014 were included. Therapy was defined as effective if there was no escalation to biologicals, no course of corticosteroids, no surgery and no hospitalisation for active disease during treatment. Long‐term effectiveness was assessed by adjusting for differences in follow‐up using Kaplan–Meier analyses. Mid‐ to long‐term safety regarding cancer incidence and clinically relevant liver disease was documented. Results: In total, 1016 patients (643 Crohn's disease [CD]; 373 ulcerative colitis [UC]) received thiopurine monotherapy at a median of 15.2 (Q1‐Q3 4.2–48.5) months after diagnosis. During follow‐up, effectiveness rates at 1, 5 and 10 years were 64%, 45%, 32%, respectively, in CD and and 66%, 41%, 36%, respectively in UC. No statistically significant differences in effectiveness were observed after stratification for era of initiation (pre‐biological vs biological, CD: p = 0.56; UC: p = 0.43). Sixteen non‐melanoma skin cancers (incidence rate [IR] 3.33/1000 PY), five lymphomas (IR 1.04/1000 PY) and one urinary tract cancer (IR 0.21/1000 PY) were recorded. Two cases of portal hypertension were identified. Conclusion: In real‐world practice, thiopurine monotherapy remains effective, safe and durable for patients with CD or UC, including in the era of biologics. [ABSTRACT FROM AUTHOR]

/Objectives Postoperative pancreatic fistula (POPF) remains the most common complication after distal pancreatectomy (DP). Traditionally, surgical drains are placed routinely after DP, but some question its efficacy and postulate that the use of drains may convert a self-limiting postoperative collection into a POPF. This study aimed to compare outcomes between three institutions with varying drainage strategies. The study is a retrospective propensity score-matched analysis of intraoperative prophylactic drain placement during DP (2010–2019). The primary outcome is major morbidity. Propensity score matching was used to obtain comparable groups. Overall, 963 patients after DP were included. One center did not place a surgical drain routinely, but decided to place a drain when unsatisfactory pancreatic closure occurred. Prophylactic abdominal drains were placed in 805 patients (84%) of which 74 could be matched to 74 patients without a drain. The rate of major morbidity (8% vs 19%, p = 0.054) and radiological interventions (5% vs 12%, p = 0.147) were non-significantly lower in the no-drain group as compared to the prophylactic drain group, respectively. The rates of POPF (4% vs 16%, p = 0.014) were lower in the no-drain group. In this international retrospective multicenter study, a selective no-drain strategy after DP was not associated with higher rates major morbidity or radiological interventions as compared to routine prophylactic abdominal drainage. Although the rate of POPF was lower in the no-drain group, randomized trials should confirm the safety and outcome of a no-drain strategy after DP. [ABSTRACT FROM AUTHOR]

Summary: From the first report in 1969 to the present day, diagnosis of eccrine porocarcinoma, also known simply as porocarcinoma (PC), remains a challenge. This review presents a concise update of the history, pathogenesis, epidemiology, diagnosis, management and prognosis of this rare sweat gland neoplasm. PC differentiates towards the intraepidermal spiral ducts in the eccrine gland, is more common in people aged > 60 years and often affects the head, neck and legs. PC presents as a dome‐shaped papule, plaque or nodule growing over weeks to months. The exact incidence of PC is unknown but appears to be rising. Diagnosis is difficult because of variable presentations and similar clinical and histological features to cutaneous squamous cell carcinoma. Management involves removal of the tumour, usually using wide local excision or Mohs micrographic surgery. Prognosis is poor, with PC recurring after surgery in 35% of cases. Given the lack of standardized protocols and risk profiles, further studies would help improve the understanding of PC. [ABSTRACT FROM AUTHOR]

Thiopurine derivatives, such as azathioprine and mercaptopurine, are standard conventional treatment options in inflammatory bowel disease (IBD). Unfortunately, approximately half of patients discontinue thiopurine therapy within 2 years. To improve the prediction of clinical effectiveness, thiopurine therapy is currently optimized using therapeutic drug monitoring. Ras‐related C3 botulinum toxin substrate 1 (Rac1) has been suggested as a potential pharmacodynamic marker of the thiopurine effect in lymphocytes. The active thiopurine metabolite 6‐thioguanine triphosphate (6‐Thio‐GTP) causes T cell apoptosis via Rac1 and the downstream transcription factor signal transducer and activator of transcription 3 (STAT3). The aim of this study was to develop and validate a functional pharmacodynamic multiparameter flow cytometric assay to determine Rac1/pSTAT3 expression in the various leukocyte subpopulations in peripheral blood in order to predict therapeutic response in IBD patients in the future. Peripheral blood samples of healthy subjects (no fever or clinical complaints of active disease, C‐reactive protein < 10 mg/L) were used for immunocytochemical labeling, applying an optimized fixation and permeabilization strategy. A gating procedure was performed to separate all leukocyte subpopulations. Quantitative data were obtained by measuring presence and median fluorescent intensity. In vitro, Rac1 presence and expression were detectable in all leukocyte subpopulations. After IL‐6 stimulation, used as proxy for inflammation, a distinct pSTAT3 signal could be detected in T lymphocytes of healthy subjects. In vivo, an upregulated pSTAT3 signal was detected in nearly all IBD patients with active disease and differed substantially from the signal found in IBD patients in remission on thiopurines and healthy subjects. We developed and validated a functional flow cytometric assay to assess Rac1 and pSTAT3 presence and expression. This opens a venue for a pharmacodynamic assay to predict thiopurine effectiveness in IBD patients. [ABSTRACT FROM AUTHOR]

Glioma is the most common form of malignant primary brain tumours in adults. Their highly invasive nature makes the disease incurable to date, emphasizing the importance of better understanding the mechanisms driving glioma invasion. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is characteristic for astrocyte- and neural stem cell-derived gliomas. Glioma malignancy is associated with changes in GFAP alternative splicing, as the canonical isoform GFAPα is downregulated in higher-grade tumours, leading to increased dominance of the GFAPδ isoform in the network. In this study, we used intravital imaging and an ex vivo brain slice invasion model. We show that the GFAPδ and GFAPα isoforms differentially regulate the tumour dynamics of glioma cells. Depletion of either isoform increases the migratory capacity of glioma cells. Remarkably, GFAPδ-depleted cells migrate randomly through the brain tissue, whereas GFAPα-depleted cells show a directionally persistent invasion into the brain parenchyma. This study shows that distinct compositions of the GFAPnetwork lead to specific migratory dynamics and behaviours of gliomas. [ABSTRACT FROM AUTHOR]

Objective: Data on the course of severe COVID-19 in inflammatory bowel disease (IBD) patients remains limited. We aimed to determine the incidence rate and clinical course of severe COVID-19 in the heavily affected South-Limburg region in the Netherlands. Methods: All COVID-19 patients admitted to the only two hospitals covering the whole South-Limburg region between February 27, 2020 and January 4, 2021 were included. Incidence rates for hospitalization due to COVID-19 were determined for the IBD (n = 4980) and general population (n = 597,184) in South-Limburg. Results: During a follow-up of 4254 and 510,120 person-years, 20 IBD patients (0.40%; 11 ulcerative colitis (UC), 9 Crohn's disease (CD)) and 1425 (0.24%) patients from the general population were hospitalized due to proven COVID-19 corresponding to an incidence rate of 4.7 (95% Confidence interval (CI) 3.0–7.1) and 2.8 (95% CI 2.6–2.9) per 1000 patient years, respectively (Incidence rate ratio: 1.68, 95% CI 1.08–2.62, p = 0.019). Median age (IBD: 63.0 (IQR 58.0–75.8) years vs. general population: 72.0 (IQR 62.0–80.0) years, p = 0.10) and mean BMI (IBD: 24.4 (SD 3.3) kg/m2 vs. general population 24.1 (SD 4.9) kg/m2, p = 0.79) at admission were comparable in both populations. As for course of severe COVID-19, similar rates of ICU admission (IBD: 12.5% vs. general population: 15.7%, p = 1.00), mechanical ventilation (6.3% vs. 11.2%, p = 1.00) and death were observed (6.3% vs. 21.8%, p = 0.22). Conclusion: We found a statistically significant higher rate of hospitalization due to COVID-19 in IBD patients in a population-based setting in a heavily impacted Dutch region. This finding reflects previous research that showed IBD patients using systemic medication were at an increased risk of serious infection. However, although at an increased risk of hospitalization, clinical course of severe COVID-19 was comparable to hospitalized patients without IBD. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this systematic review was to compare knee pain and function after tibial nail insertion through an infrapatellar, semi-extended and suprapatellar technique. Methods: A search was carried out to identify articles with an exact description of the method used for insertion of the tibial nail and description of the outcome parameters (knee pain or function). Data on study design, population, rate and severity of anterior knee pain and function scores were extracted. Pooled rates and scores were calculated. Results: 67 studies with 3,499 patients were included. The pooled rate of patients with anterior knee pain was 38% (95% CI 32–44) after nail insertion through an infrapatellar approach and 10% (95% CI 1–26) after insertion through a suprapatellar approach. Pooled analysis was not possible for the semi-extended technique. Knee pain scores as measured by visual analogue score (0–10) ranged from 0.2 (95% CI − 0.1–0.5) for general knee pain to 3.7 (95% CI 1.3–6.1) for pain during kneeling. Pooled estimates for the Lysholm score were 87 points (range 77–97) for the infrapatellar technique and 85 points (range 82–85) for the suprapatellar technique. Iowa Knee scores were 94 (range 86–96) and Anterior Knee Pain Scale scores were 76 (range 75–80) after infrapatellar nail insertion. Discussion: Depending on the technique used, the proportion of patients with knee pain after tibial nailing varied between 10 and 38%. The actual measured knee pain scores were, however, surprisingly low. Knee function was good for both the infra- and suprapatellar technique. [ABSTRACT FROM AUTHOR]

Background: During the COVID-19 pandemic, a decrease in the number of patients presenting with acute appendicitis was observed. It is unclear whether this caused a shift towards more complicated cases of acute appendicitis. We compared a cohort of patients diagnosed with acute appendicitis during the 2020 COVID-19 pandemic with a 2019 control cohort.Methods: We retrospectively included consecutive adult patients in 21 hospitals presenting with acute appendicitis in a COVID-19 pandemic cohort (March 15 - April 30, 2020) and a control cohort (March 15 - April 30, 2019). Primary outcome was the proportion of complicated appendicitis. Secondary outcomes included prehospital delay, appendicitis severity, and postoperative complication rates.Results: The COVID-19 pandemic cohort comprised 607 patients vs. 642 patients in the control cohort. During the COVID-19 pandemic, a higher proportion of complicated appendicitis was seen (46.9% vs. 38.5%; p = 0.003). More patients had symptoms exceeding 24 h (61.1% vs. 56.2%, respectively, p = 0.048). After correction for prehospital delay, presentation during the first wave of the COVID-19 pandemic was still associated with a higher rate of complicated appendicitis. Patients presenting > 24 h after onset of symptoms during the COVID-19 pandemic were older (median 45 vs. 37 years; p = 0.001) and had more postoperative complications (15.3% vs. 6.7%; p = 0.002).Conclusions: Although the incidence of acute appendicitis was slightly lower during the first wave of the 2020 COVID-19 pandemic, more patients presented with a delay and with complicated appendicitis than in a corresponding period in 2019. Spontaneous resolution of mild appendicitis may have contributed to the increased proportion of patients with complicated appendicitis. Late presenting patients were older and experienced more postoperative complications compared to the control cohort. [ABSTRACT FROM AUTHOR]

The article presents the discussion on surgical construction of a vagina indicated in transgender women and cisgender women with congenital or acquired vaginal absence. Topics include affirming surgery, penile inversion, or penoscrotal vaginoplasty being the most commonly performed procedure for genital (re)construction; and Intestinal vaginoplasty mentioned as surgical alternative for patients with shortage of penile skin undergoing revision vaginoplasty.

Osteopenia and osteoporosis are common features in inflammatory bowel disease (IBD), comprising both Crohn's disease and ulcerative colitis. Moreover, Crohn's disease is associated with increased fracture risk. The etiology of bone loss in IBD is multifactorial. It includes insufficient intake or absorption of calcium, vitamin D, and potassium; smoking; a low peak bone mass; a low body mass index; and decreased physical activity. In several studies, it has been shown that elevated concentrations of systemic and local pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interferon-γ (IFNγ), interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-13, and IL-17, present in IBD patients are potentially detrimental for bone metabolism and may be responsible for bone loss and increased fracture risk. This perspective aims to review the current literature on the role of inflammatory factors in the pathophysiology of skeletal problems in IBD and to suggest potential treatment to improve bone health, based on a combination of evidence and clinical and pathophysiological reasoning. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Everhov et al paper. To view this article, visit https://doi.org/10.1111/apt.17675 [ABSTRACT FROM AUTHOR]

The subventricular zone (SVZ) in the brain is associated with gliomagenesis and resistance to treatment in glioblastoma. In this study, we investigate the prognostic role and biological characteristics of subventricular zone (SVZ) involvement in glioblastoma. We analyzed T1-weighted, gadolinium-enhanced MR images of a retrospective cohort of 647 primary glioblastoma patients diagnosed between 2005–2013, and performed a multivariable Cox regression analysis to adjust the prognostic effect of SVZ involvement for clinical patient- and tumor-related factors. Protein expression patterns of a.o. markers of neural stem cellness (CD133 and GFAP-δ) and (epithelial-) mesenchymal transition (NF-κB, C/EBP-β and STAT3) were determined with immunohistochemistry on tissue microarrays containing 220 of the tumors. Molecular classification and mRNA expression-based gene set enrichment analyses, miRNA expression and SNP copy number analyses were performed on fresh frozen tissue obtained from 76 tumors. Confirmatory analyses were performed on glioblastoma TCGA/TCIA data. Involvement of the SVZ was a significant adverse prognostic factor in glioblastoma, independent of age, KPS, surgery type and postoperative treatment. Tumor volume and postoperative complications did not explain this prognostic effect. SVZ contact was associated with increased nuclear expression of the (epithelial-) mesenchymal transition markers C/EBP-β and phospho-STAT3. SVZ contact was not associated with molecular subtype, distinct gene expression patterns, or markers of stem cellness. Our main findings were confirmed in a cohort of 229 TCGA/TCIA glioblastomas. In conclusion, involvement of the SVZ is an independent prognostic factor in glioblastoma, and associates with increased expression of key markers of (epithelial-) mesenchymal transformation, but does not correlate with stem cellness, molecular subtype, or specific (mi)RNA expression patterns. [ABSTRACT FROM AUTHOR]

>bold<>italic/italic<>/bold< The authors aimed to conduct an extensive literature review and consensus meeting to identify unmet needs in ulcerative colitis (UC) and ways to overcome them. UC is a relapsing and remitting inflammatory bowel disease with varied, and changing, incidence rates worldwide. UC has an unpredictable disease course and is associated with a high health economic burden. During 2016 and 2017, a panel of experts was convened to identify, discuss and address areas of unmet need in UC. >bold<>italic/italic<>/bold< PubMed and Cochrane Library databases were searched for relevant articles describing studies performed in patients with UC. These findings were used to generate a set of statements relating to unmet needs in UC. Consensus on these statements was then sought from a panel of 9 expert gastroenterologists using a modified Delphi review process that consisted of anonymous surveys followed by live meetings. >bold<>italic/italic<>/bold< In 2 literature reviews, over 5,000 unique records were identified and a total of 138 articles were fully reviewed. These were used to consider 26 areas of unmet need, which were explored in 2 face-to-face meetings, in which the statements were debated and amended, resulting in consensus on 30 final statements. The unmet needs identified were categorised into 7 areas: impact of UC on patients' daily life; importance of early diagnosis and treatment; drawbacks of existing treatments; urgent need for new treatments; and disease-, practice- or patient-focused unmet needs. >bold<>italic/italic<>/bold< These expert group meetings found a number of areas of unmet needs in UC, which is an important first step in tackling them in the future. Future research and development should be focused in these areas for the management of patients with UC. [ABSTRACT FROM AUTHOR]

Summary: Background: Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy. Aim: To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy. Methods: In this nationwide, multicentre study, medical records of tioguanine‐ using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow‐up were listed and graded according to the common terminology criteria (CTC). Results: Two hundred and seventy‐four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient‐years of follow‐up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty‐one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with tioguanine (0.4%). Clinical effectiveness was correlated with 6‐thioguanine nucleotide threshold concentrations >682 pmol/8×108 RBC (P < 0.05). Conclusions: Long‐term tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6‐Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108 RBC is proposed as target level with higher odds for clinical effectiveness. [ABSTRACT FROM AUTHOR]

Background: Thioguanine is associated with liver toxicity, especially nodular regenerative hyperplasia (NRH). We assessed if liver histology alters during long-term maintenance treatment with thioguanine in patients with inflammatory bowel disease (IBD). Methods: Liver specimens of thioguanine treated IBD patients with at least two liver biopsies were revised by two independent liver pathologists, blinded to clinical characteristics. Alterations in histopathological findings between first and sequential liver specimen were evaluated and associated clinical data, including laboratory parameters and abdominal imaging reports, were collected. Results: Twenty-five IBD patients underwent sequential liver biopsies prior to, at time of, or after cessation of thioguanine treatment. The median time between the first and second biopsy was 25 months (range: 14–54). Except for one normal liver specimen, any degree of irregularities including inflammation, steatosis, fibrosis and some vascular disturbances were observed in the biopsies. The rates of perisinusoidal fibrosis (91%), sinusoidal dilatation (68%) and nodularity (18%) were the same in the first and second liver biopsies. A trend towards statistical significance was observed for phlebosclerosis (36% of the first vs. 68% of the second biopsies, p =.092). Presence of histopathological liver abnormalities was not associated with clinical outcomes. Furthermore, two patients in this cohort had portal hypertension in presence of phlebosclerosis. In another two patients, nodularity of the liver resolved upon thioguanine withdrawal. Conclusion: Vascular abnormalities of the liver were commonly observed in thioguanine treated IBD patients, although these were not progressive and remained of limited clinical relevance over time. [ABSTRACT FROM AUTHOR]